TW202228686A - Treatments of angioedema - Google Patents

Abstract

The present invention relates to treatments of bradykinin mediated angioedema with a plasma kallikrein inhibitor, oral modified release pharmaceutical dosage forms comprising a plasma kallikrein inhibitor, and the uses of such dosage forms.

Description

Treatment of angioedema

The present invention relates to the treatment of bradykinin-mediated angioedema with plasma kallikrein inhibitors, oral modified release pharmaceutical dosage forms comprising plasma kallikrein inhibitors and the use of such dosage forms.

Plasma kallikrein inhibitors have various therapeutic applications, especially in the treatment of bradykinin-mediated angioedema, such as hereditary angioedema and bradykinin-mediated nonhereditary angioedema (BK-AEnH ).

Plasma kallikrein is a trypsin-like serine protease that releases kinin from kininogen (see KD Bhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine , pp. 483-493; JW Bryant et al, "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry , 7, pp. 234-250, 2009; KD Bhoola et al, Pharmacological Rev. , 1992, 44 , 1; and DJ Campbell, "Towards understanding the kallikrein-kinin system: insights from the measurement of kinin peptides", Brazilian Journal of Medical and Biological Research 2000, 33 , 665-677). Although its role in the in vivo coagulation cascade is not related to bradykinin release or enzymatic cleavage, it is an essential member of this cascade. Plasma prokallikrein is encoded by a single gene and can be synthesized in the liver as well as in other tissues. It is secreted by hepatocytes as inactive plasma prokallikrein, which circulates in the plasma as a heterodimeric complex bound to high molecular weight kininogen (HK) and is activated to produce active plasma kallikrein. This contact activation system (or contact system) can be activated by activating Factor XII (FXII) to a negatively charged surface of Factor XIIa (FXIIa), specific proteases (eg, plasmin) that may not require a negatively charged surface (Hofman et al , Clin Rev Allergy Immunol 2016), or malfolded proteins (Maas et al , J Clinical Invest 2008). FXIIa mediates the conversion of plasma prokallikrein to plasma kallikrein and the subsequent cleavage of high molecular weight kininogen (HK) to produce bradykinin, a potent inflammatory hormone. Kinin is a potent inflammatory mediator that acts via G protein-coupled receptors, and antagonists of kinin, such as bradykinin receptor antagonists, have previously been investigated as potential therapeutic agents for the treatment of a variety of disorders (F. Marceau and D. Regoli, Nature Rev. , Drug Discovery , 2004, 3 , 845-852).

Plasma kallikrein is thought to play a role in a variety of inflammatory disorders. For example, in patients with advanced diabetic macular edema, the plasma kallikrein-kinin system is elevated. Plasma kallikrein has been reported to contribute to retinal vascular dysfunction in diabetic rats (A. Clermont et al., "Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats" Diabetes , 2011, 60 , 1590-98) . In addition, administration of the plasma kallikrein inhibitor ASP-440 improved retinal vascular permeability and retinal blood flow abnormalities in diabetic rats. Therefore, plasma kallikrein inhibitors should have utility as a therapy to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Other complications of diabetes, such as cerebral hemorrhage, nephropathy, cardiomyopathy, and neuropathy, all of which are associated with plasma kallikrein, can also be considered targets for plasma kallikrein inhibitors.

The major inhibitor of plasma kallikrein is the serine protease inhibitor (serpin) C1 esterase inhibitor. Patients presenting a genetic defect with a C1 esterase inhibitor suffer from hereditary angioedema (HAE), which causes intermittent swelling of the face, hands, throat, gastrointestinal tract, and genitals. The blisters that form during acute attacks contain large amounts of plasma kallikrein, which cleaves high molecular weight kininogen (HK), thereby releasing bradykinin, causing increased vascular permeability. Thus, "hereditary angioedema" can be defined as any condition characterized by repeated bouts of bradykinin-mediated angioedema (eg, severe swelling) caused by an inherited dysfunction/deficiency/mutation . There are currently three known classes of HAEs: (i) type 1 HAEs, (ii) type 2 HAEs, and (iii) normal C1 inhibitor HAEs (normal C1-Inh HAEs). However, the field of HAE is developing rapidly and other types of HAE may be defined in the future.

Without wishing to be bound by theory, it is believed that HAE type 1 is caused by mutations in the SERPING1 gene that cause reduced levels of C1 inhibitors in the blood. Without wishing to be bound by theory, it is believed that HAE type 2 is caused by mutations in the SERPING1 gene that cause C1 inhibitors in the blood to function abnormally. Without wishing to be bound by theory, the etiology of normal C1-Inh HAE has not been clearly defined and the underlying gene dysfunction/deficiency/mutation may still sometimes remain unknown. It is known that the etiology of normal C1-Inh HAEs is not related to reduced levels or dysfunction of C1 inhibitors (unlike Type 1 and Type 2 HAEs). Normal C1-Inh HAE can be diagnosed by reviewing the family history and finding that the angioedema is inherited from the previous generation (and thus, it is hereditary angioedema). Normal C1-Inh HAE can also be diagnosed by determining the presence of functional abnormalities/deficiencies/mutations in genes other than those associated with C1 inhibitors. For example, dysfunction/defect/mutation of plasminogen has been reported to cause normal C1-Inh HAE (see eg Veronez et al, Front Med (Lausanne). 2019 Feb 21;6:28. doi : 10.3389/fmed.2019.00028; or Recke et al, Clin Transl Allergy. 2019 Feb 14;9:9. doi: 10.1186/s13601-019-0247-x.). Dysfunction/deficiency/mutation of Factor XII has also been reported to cause normal C1-Inh HAE (see e.g. Mansi et al., The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine, 2015, 277; 585-593; or Maat et al, J Thromb Haemost . 2019 Jan;17(1):183-194. doi: 10.1111/jth.14325).

Acute HAE episodes typically progress through three key clinically distinct phases: an initial prodromal phase (which typically lasts up to 12 hours), followed by a swelling phase, and then a resorption phase. Most HAE episodes are manifested by prodromal symptoms. Two-thirds of the prodromal signs appeared less than 6 hours before the onset of HAE, and none occurred more than 24 hours before the onset of HAE (Magerl et al., Clinical and Experimental Dermatology 2014, 39 , 298-303). For example, the following prodromal symptoms may begin to be observed: mild swelling (especially affecting the face and neck), typical type of abdominal pain, typical reddening of the skin (called "erythema annulare"). Attacks are fully developed when they have reached their maximum degree of swelling and pain (eg, abdominal attacks), discomfort (eg, peripheral attacks), or life-threatening (eg, throat attacks). After the attack has reached its maximum, the time required for subsequent recovery to normal is determined by the time required for the swelling to subside and the fluid infiltrating the tissue to be reabsorbed.

However, angioedema is not necessarily hereditary. Indeed, another type of angioedema is bradykinin-mediated nonhereditary angioedema (BK-AEnH), which is not caused by an inherited genetic abnormality/deficiency/mutation. The underlying etiology of BK-AEnH is often unknown and/or undefined. However, the signs and symptoms of BK-AEnH are similar to those of HAE and, without being bound by theory, it is believed that this is due to the fact that HAE and BK-AEnH share a bradykinin-mediated pathway. In particular, BK-AEnH is characterized by recurrent exacerbations in which fluid accumulates outside the blood vessels, obstructs the normal flow of blood or lymph, and causes (such as the hands, feet, extremities, face, intestines, respiratory tract or Rapid swelling of tissue in the genitals.

Specific BK-AEnH types include: non-hereditary angioedema with normal C1 inhibitor (AE-nC1 Inh), which can be environmental, hormonal, or drug-induced; acquired angioedema; allergy-related vascular edema; angiotensin-converting enzyme (ACE) inhibitor-induced angioedema; dipeptidyl peptidase-4 inhibitor-induced angioedema; and tPA-induced angioedema (tissue plasminogen activating factor induced angioedema). However, it is not known why these factors and conditions cause angioedema in only a relatively small proportion of individuals.

Environmental factors that can induce AE-nC1 Inh include air pollution (Kedarisetty et al , Otolaryngol Head Neck Surg . 2019 Apr 30:194599819846446. doi: 10.1177/0194599819846446) and silver nanoparticles, such as for use in healthcare, biomedicine and silver nanoparticles as antimicrobial components in consumer products (Long et al ., Nanotoxicology. 2016; 10(4): 501-11. doi: 10.3109/17435390.2015.1088589).

Numerous publications propose the link between bradykinin and contact system pathways and BK-AEnH and the potential efficacy of treatment, see e.g.: Bas et al, ( N Engl J Med 2015); Leibfried and Kovary. ( J Pharm Pract 2017 ); van den Elzen et al., ( Clinic Rev Allerg Immunol 2018); Han et al., ( JCI 2002).

tPA-induced angioedema has been discussed in various publications as a potentially life-threatening complication following thrombolytic therapy in acute stroke victims (see eg, Simão et al , Blood . 2017 Apr 20;129(16 ): 2280-2290. doi: 10.1182/blood-2016-09-740670; Fröhlich et al ., Stroke . Jun 11, 2019: STROKEAHA119025260. doi: 10.1161/STROKEAHA.119.025260; Rathbun, Oxf Med Case Reports . 2019 Jan 24;2019(1):omy112.doi: 10.1093/omcr/omy112;Lekoubou et al ., Neurol Res.2014 Jul;36(7):687-94.doi: 10.1179/1743132813Y.0000000302;Hill et al , Neurology . 2003 May 13;60(9):1525-7)).

Stone et al. ( Immunol Allergy Clin North Am . 2017 Aug;37(3):483-495.) report that certain drugs can cause angioedema.

Scott et al. ( Curr Diabetes Rev. 2018;14(4):327-333. doi: 10.2174/1573399813666170214113856) report that dipeptidyl peptidase-4 inhibitors induce angioedema.

Hermanrud et al. ( BMJ Case Rep . Jan 10, 2017; 2017. pii: bcr2016217802) report recurrent angioedema associated with pharmacological inhibition of dipeptidyl peptidase IV and also discuss angiotensin-converting enzyme Inhibitor (ACEI-AAE)-associated acquired angioedema. Kim et al. ( Basic Clin Pharmacol Toxicol . 2019 Jan;124(1):115-122. doi: 10.1111/bcpt.13097) report angiotensin II receptor blocker (ARB)-related angioedema. Reichman et al. ( Pharmacoepidemiol Drug Saf . 2017 Oct;26(10):1190-1196. doi: 10.1002/pds.4260) also reported vascularity in patients using ACE inhibitors, ARB inhibitors and beta blockers Risk of edema. Diestro et al. ( J Stroke Cerebrovasc Dis . 2019 May;28(5):e44-e45. doi: 10.1016/j.jstrokecerebrovasdis.2019.01.030) also reported a possible association between certain angioedema and ARBs sex.

Giard et al. ( Dermatology . 2012;225(1):62-9. doi: 10.1159/000340029) reported that estrogenic contraceptives can contribute to bradykinin-mediated angioedema.

Cinryze® and Haegarda® contain C1 esterase inhibitors and are approved for the prevention of acute HAE episodes (ie, prophylactic therapy). Treatment with Cinryze® requires preparation of a solution from powder, followed by injections every 3 or 4 days. Similarly, treatment with Haegarda® requires preparation of a solution from a powder, followed by two injections a week. The patient may not always be able to self-administer these treatments, and if not, the patient will need to go to a clinic for treatment. Therefore, these preventive treatments result in a heavy patient burden. In addition, the FDA package insert for Haegarda ^® states that it "should not be used to treat acute HAE episodes," and therefore if an HAE episode occurs, the patient may require additional therapy.

Berinert ^® and Ruconest ^® contain C1 esterase inhibitors and are approved for the treatment of acute HAE attacks. Both treatments also involve the preparation of injectable solutions and subsequent injections. This procedure can be burdensome for the patient, especially when the patient experiences an acute HAE attack. Self-administration of doses may not always be possible, and if not, the administration of the drug can be significantly delayed, thereby increasing the severity of acute HAE episodes in the patient.

There are no approved treatments for plasma kallikrein-related disorders such as HAE and BK-AEnH. In particular, there is no approved oral therapy for plasma kallikrein-related disorders such as for HAE, BK-AEnH. Prophylactic treatment of these conditions requires maintaining strong inhibition of plasma kallikrein over the period of administration to avoid so-called "flare attacks". Prevention of flare-ups of HAE or BK-AEnH is considered more desirable than acute treatment after onset of flare-ups. The level of inhibition is determined at least by the potency and concentration of the drug in plasma. Antibody drugs have inherently long half-lives, but must be administered in injection form, which can be a burden and affect patient compliance and patient satisfaction. Patients require effective oral therapy.

Berotralstat (BCX7353) has been approved as a once-daily oral treatment for the prevention of HAE flare-ups. Hwang et al. (Immunotherapy (2019) 11(17), 1439-1444) indicated that higher doses of beloxostat were associated with more gastrointestinal adverse effects, indicating that toxicity increased with increasing levels. The EMA label for an approved product containing belostatin (Orladeyo ^® ) reported that the most common adverse reactions observed in clinical studies of belostatin were headache, abdominal pain and diarrhea.

Synthesis and small molecule plasma kallikrein inhibitors have been previously described, for example, by Garrett et al., ("Peptide aldehyde...." J. Peptide Res . 52 , 62-71 (1998)); T. Griesbacher et al., (“Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats” British Journal of Pharmacology 137 , 692-700 (2002)); Evans (“Selective dipeptide inhibitors of kallikrein” WO03/ 076458); Szelke et al., ("Kininogenase inhibitors"WO92/04371); DM Evans et al., ( Immunolpharmacology , 32, pp. 115-116, (1996)); Szelke et al., ("Kininogenase inhibitors" WO95/07921 ); Antonsson et al., (“New peptides derivatives” WO94/29335); J. Corte et al., (“Six membered heterocycles useful as serine protease inhibitors” WO2005/123680); J. Stürzbecher et al., (Brazilian J. Med . Biol. Res 27, pp. 1929-34, (1994)); Kettner et al., (US 5,187,157); N. Teno et al., (Chem. Pharm. Bull. 41, pp. 1079-1090, (1993) ); WB Young et al., (“Small molecule inhibitors of plasma kallikrein” Bioorg. Med. Chem. Letts. 16, pp. 2034-2036, (2006)); Okada et al., (“Development of potent and selective plasmin and plasma kallikrein inhibitors and studies on the structure-activity relationship” Chem. Pharm. Bull. 48, pp. 1964-72, (2000)); Steinmetzer et al, (“Trypsin-like serine protease inhibitors and their preparation and use WO08/049595); Zhang et al, (“Discovery of highly potent small molecule kallikrein inhibitors” Medicinal Chemistry 2, pp. 545-553, (2006)); Sinha et al, (“Inhibitors of plasma kallikrein” WO08/016883 ); Shigenaga et al, (“Plasma Kallikrein Inhibitors” WO2011/118672); and Kolte et al, (“Biochemical characterization of a novel high-affinity and specific kallikrein inhibitor”, British Journal of Pharmacology (2011), 162 (7) , 1639-1649). In addition, Steinmetzer et al. ("Serine protease inhibitors" WO2012/004678) describe cyclized peptide analogs that are inhibitors of human plasmin and plasma kallikrein.

There remains a need to develop small molecule synthetic plasma kallikrein inhibitors for medical use. The molecules described in the known art suffer from limitations such as poor selectivity for related enzymes such as KLK1, thrombin and other serine proteases and poor oral availability. Treatment with large protein plasma kallikrein inhibitors has been shown to be effective in the treatment of HAE by preventing the release of bradykinin which increases vascular permeability (A. Lehmann "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery” Expert Opin. Biol. Ther. 8, pp. 1187-99). However, ecallantide is administered by subcutaneous injection, and ecallantide has been reported to carry a risk of allergic reactions. Treatment with a plasma kallikrein monoclonal antibody (lanadelumab) has been shown to reduce the rate of exacerbations in HAE patients (Banerji A. et al, Effect of lanadelumab Compared with Placebo on Prevention of Hereditary Angioedema Attacks: a Randomized Clinical Trial. JAMA. 2018 Nov 27;320(20):2108-2121). However, administration of lanalizumab is also by subcutaneous injection, and allergy, dizziness, rash, myalgia, and injection site reactions are reported on the EMA label of the lanalizumab product (Takhzyro ^® ) as Common or very common side effects.

Furthermore, many molecules in the known art are characterized by highly polar and ionizable guanidine or amidine functional groups. It is well known that such functional groups have limitations in intestinal permeability and thus in oral availability. For example, Tamie J. Chilcote and Sukanto Sinha ("ASP-634: An Oral Drug Candidate for Diabetic MacularEdema", ARVO May 6-May 9, 2012, Fort Lauderdale, Florida, Presentation 2240) have Poor oral availability of ASP-440, a benzamidine, was reported. It has also been reported that absorption can be improved by making prodrugs such as ASP-634. However, well-known prodrugs may suffer from several disadvantages, such as poor chemical stability and potential toxicity caused by inert carriers or unanticipated metabolites. Indoleamides have been proposed as compounds that may overcome the problems associated with drug processing, poor or inappropriate ADME-tox and physicochemical properties, but no inhibition against plasma kallikrein has been shown or suggested (Griffioen et al., "Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases”, WO2010142801).

Other plasma kallikrein inhibitors known in the art are generally small molecules, some of which include highly polar and ionizable functional groups, such as guanidines or amidines. More recently, plasma kallikrein inhibitors that do not feature guanidine or amidine functional groups have been reported. For example, Brandl et al., (“N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein” WO2012/017020); Evans et al., (“Benzylamine derivatives as inhibitors of plasma kallikrein” kallikrein" WO2013/005045); Allan et al., ("Benzylamine derivatives" WO2014/108679); Davie et al., ("Heterocyclic derivates" WO2014/188211); Davie et al., ("N-((het)arylmethyl)- heteroaryl-carboxamides compounds as plasma kallikrein inhibitors” WO2016/083820); and Davie et al., (“Pyrazole derivatives as plasma kallikrein inhibitors” WO2017/207983).

Davie et al. ("Pyrazole derivatives as plasma kallikrein inhibitors" WO2017/207983) disclose the following plasma kallikrein inhibitors: 1-({4-[(5-fluoro-2-oxypyridin-1-yl)methyl yl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide. Name 1-({4-[(5-Fluoro-2-oxypyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridine-2 -yl)methyl]-3-(methoxymethyl)pyrazol-4-carboxamide indicates the structure depicted in formula A.

Crowe et al. ("Solid forms of a plasma kallikrein inhibitor and salts thereof" WO 2019/106377) describe various solid forms of compounds of formula A (referred to herein as "compounds").

Therefore, there is a need for an effective oral prophylactic treatment for plasma kallikrein-related diseases, especially bradykinin-mediated angioedema HAE and BK-AEnH. In particular, there is a need for plasma kallikrein-related diseases (especially bradykinin-mediated angioedema HAE and BK-AEnH) with minimal side effects (such as gastrointestinal adverse effects), especially in view of the intended long-term use of the treatment ) is an effective oral prophylactic treatment.

The inventors faced many challenges in planning the development of oral prophylactic treatments for bradykinin-mediated angioedema disorders such as HAE and BK-AEnH.

First, because bradykinin-mediated angioedema disorders such as HAE and BK-AEnH can be characterized by an unpredictable rapid onset of potentially life-threatening symptoms such as swelling, it is important that any preventive measures Sexual therapy is capable of maintaining therapeutically effective concentrations of the active ingredient in the patient to avoid flare-ups or reduce their severity. Therefore, any prophylactic treatment must be adapted to maintain the minimum concentration (Cmin) of the active ingredient above the minimum therapeutically effective concentration.

It is also important, however, that any oral prophylactic treatment does not cause a deleterious buildup of compound concentrations over time that could result in serious adverse events. Since prophylactic treatment is usually performed on a long-term basis (ie, over a longer period of time, possibly lifelong), it is desirable that the treatment does not cause any adverse events (eg, causing intolerance to the liver or gastrointestinal tract) that might lead to discontinuation of treatment damage or irritation).

Second, it is important that any oral prophylactic treatment provides good patient compliance. In particular, the heavy burden caused by too many dosage forms (eg, lozenges) can lead to patient dissatisfaction, especially if the treatment is long-term. Therefore, any effective oral preventive therapy must minimize pill burden and administration frequency.

For the purposes of the present invention, the inventors have carefully and technically analyzed the unique pharmacokinetic (PK) and pharmacodynamic (PD) properties of the compound of formula A, and have designed and developed Dosage forms and dosing regimens for oral prophylactic treatment of bradykinin-mediated angioedema (HAE or BK-AEnH, preferably HAE).

Definitions As used herein and unless expressly specified otherwise, the term "compound" or "compound of formula A" is shorthand for "compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof)" . The compound of formula A is shown below and named: 1-({4-[(5-Fluoro-2-oxypyridin-1-yl)methyl]phenyl}methyl)-N-[(3 -Fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide.

It should be understood that "a pharmaceutically acceptable salt and/or solvate thereof" means "a pharmaceutically acceptable salt thereof", "a pharmaceutically acceptable solvate thereof" and "a pharmaceutically acceptable salt thereof" Scientifically acceptable solvates".

The term "pharmaceutically acceptable salt" means a physiologically or toxicologically acceptable salt, which may be, for example, a pharmaceutically acceptable acid addition salt. For example, since compounds of formula A contain basic groups, such as basic nitrogens, pharmaceutically acceptable acid addition salts that can be formed include hydrochloride, hydrobromide, sulfate, phosphate , acetate, citrate, lactate, tartrate, mesylate, succinate, oxalate, phosphate, ethanesulfonate, tosylate, benzenesulfonate, naphthalenedisulfonic acid Salt, maleate, adipate, fumarate, hippurate, camphorate, xinafoates, p-aminobenzoate, dihydroxybenzoate, hydroxynaphthoate acid salts, succinates, ascorbates, oleates, bisulfates and similar salts. The pharmaceutically acceptable salt of the preferred compound is the hydrochloride salt.

Hemi-salts of acids, such as hemi-sulfates, can also be formed.

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The term "solvate" is used herein to describe a molecular complex comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules such as ethanol or water. The term "hydrate" is used where the solvent is water and for the avoidance of any doubt, the term "solvate" encompasses the term "hydrate".

Compounds of formula A may include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which a hydrogen is replaced by deuterium or tritium or in which a carbon is replaced ^{by13C or14C} are within the scope of this invention.

"Cmin" is used herein to mean the lowest plasma concentration achieved by a compound (in its free base form) prior to administration of a subsequent dose. All concentrations of compounds reported herein are concentrations of the free base, regardless of whether the compounds are administered as salts and/or solvates. "Plasma" is plasma prepared from blood.

Term "acute episode of bradykinin-mediated angioedema", "acute bradykinin-mediated episode of angioedema", "attack of bradykinin-mediated angioedema" or "bradykinin-mediated episode of angioedema" Onset of angioedema" is used interchangeably herein. "Bradykinin-mediated angioedema" may be HAE or BK-AEnH. Preferably, the bradykinin-mediated angioedema is HAE, and in this case, "acute attack of bradykinin-mediated angioedema" will be "acute attack of HAE", which can be compared with "acute attack of bradykinin-mediated angioedema". HAE attack," "HAE attack," or "HAE attack" are used interchangeably.

The term "hereditary angioedema" (abbreviated as HAE) means any bradykinin-mediated angioedema caused by an inherited genetic abnormality, defect or mutation. Thus, the term "HAE" includes at least type 1 HAE, type 2 HAE, and normal C1 inhibitor type HAE (normal C1-Inh HAE).

The term "bradykinin-mediated non-hereditary angioedema" or "BK-AEnH" refers to bradykinin-mediated angioedema that is not caused by an inherited genetic abnormality/deficiency/mutation, i.e., it does not Hereditary angioedema (HAE). The underlying etiology of BK-AEnH may be unknown and/or undefined, but the signs and symptoms of BK-AEnH are similar to those of HAE, and without being bound by theory, it is believed that this is due to HAE and BK- AEnH shares the bradykinin-mediated pathway. Particular BK-AEnHs that can be treated according to the present invention are selected from: non-hereditary angioedema with normal C1 inhibitors (AE-nC1 Inh), which can be environmental, hormonal or drug-induced; acquired angioedema; Allergy-associated angioedema; angiotensin-converting enzyme (ACE or ace) inhibitor-induced angioedema; dipeptidyl peptidase-4 inhibitor-induced angioedema; and tPA-induced angioedema (tissue plasminogen activator-induced angioedema).

"Prophylactic treatment" of bradykinin-mediated angioedema (eg, HAE and BK-AEnH) as described herein means administering to the patient a compound that reduces the onset of bradykinin-mediated angioedema ( such as HAE episodes or BK-AEnH episodes) number (or even prevent episodes) and/or alleviate the symptoms of such episodes. In the prophylactic treatment of the present invention, the Cmin of the compound is maintained above the minimum effective therapeutic concentration for prophylactic treatment of bradykinin-mediated episodes of angioedema (eg, HAE episodes or BK-AEnH episodes). The prophylactic treatment of the present invention can reduce the number of bradykinin-mediated angioedema episodes (eg, HAE episodes or BK-AEnH episodes) that require acute treatment. For example, the prophylactic treatment of the present invention can reduce the number of moderate or severe bradykinin-mediated angioedema episodes (eg, HAE episodes or BK-AEnH episodes) that require acute treatment.

Prophylactic Treatment of the Invention The inventors have determined that the compounds of formula A are suitable for prophylactic treatment. Without wishing to be bound by theory, the inventors have determined that it is important to achieve a Cmin of at least about 30 ng per milliliter of patient plasma. To obtain this cut-off value, the inventors assessed the presence of normal levels of C1 inhibitors in healthy patients (as described in Tarzi et al., Clinical and Experimental Immunology, 2007; 149 : 513-516), from existing commercially available treatments (Haegarda ^® ) achieved Cmin, and the PK and PD properties of the compounds of formula A were carefully studied. This is further described in Example 1.

To further investigate the efficacy and safety of the compound of formula A in the prophylactic treatment of HAE, the inventors designed a Phase 2 clinical trial to further study three dose levels of the compound of formula A in individuals with HAE. This is further described in Example 4. The Phase 2 clinical trial protocol has been ethically approved by the Canadian Institutional Review Board (IRB) and approved by Canada's Office of Clinical Trials. The Phase 2 program has also obtained Clinical Trial Authorisation (CTA) from the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK.

Accordingly, the present invention provides a method for the prophylactic treatment of bradykinin-mediated angioedema, comprising orally administering a compound of formula A (or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable salt thereof to a patient in need thereof) or solvate).

The present invention also provides the use of a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for the manufacture of a medicament for the prophylactic treatment of bradykinin-mediated angioedema, the Treatment comprises oral administration of a compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof.

The present invention also provides a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use in a method for the prophylactic treatment of bradykinin-mediated angioedema, the method comprising A compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is orally administered to a patient in need.

The bradykinin-mediated angioedema can be selected from HAE and BK-AEnH. The bradykinin-mediated angioedema can be BK-AEnH. Preferably, the bradykinin-mediated angioedema is HAE.

The prophylactic treatment of the present invention is a treatment for bradykinin-mediated angioedema. When the bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention is related to the onset of HAE. When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention relates to BK-AEnH flare.

In the treatment of the invention described herein, the patient is preferably a human. For example, HAE is an inherited disease and patients of all ages can experience episodes of HAE. Thus, a human patient can be a child (age 0 to 18 years) or an adult (18 years or older). In particular, the patient can be 12 years old and older. The patient age may also be 2 years and older.

As noted above, the prophylactic treatment of the present invention may comprise providing (per milliliter of patient plasma) at least about 30 ng Cmin of a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof), wherein Cmin is Cmin in free base form. This is the preferred treatment of the present invention. The prophylactic treatment of the present invention may also comprise providing (per milliliter of patient plasma) at least about 40 ng of Cmin. The prophylactic treatment of the present invention may comprise providing (per milliliter of patient plasma) at least 50 ng of Cmin. The prophylactic treatment of the present invention may comprise providing (per milliliter of patient plasma) at least 60 ng of Cmin. The prophylactic treatment of the present invention may comprise providing (per milliliter of patient plasma) at least 80 ng of Cmin. The prophylactic treatment of the present invention may comprise providing (per milliliter of patient plasma) at least 100 ng of Cmin. Prophylactic treatment of the present invention may comprise providing (per milliliter of patient plasma) at least 120 ng of Cmin. The prophylactic treatment of the present invention may comprise providing (per milliliter of patient plasma) at least 140 ng of Cmin. The prophylactic treatment of the present invention may comprise providing (per milliliter of patient plasma) at least 150 ng of Cmin.

More specifically, the prophylactic treatment of the present invention can provide a Cmin of between about 30 ng/mL and about 1000 ng/mL. The prophylactic treatment of the present invention may provide a Cmin of between about 30 ng/mL and about 750 ng/mL. The prophylactic treatment of the present invention can provide a Cmin of between about 30 ng/mL and about 500 ng/mL. The prophylactic treatment of the present invention may provide a Cmin of between about 30 ng/mL and about 250 ng/mL. The prophylactic treatment of the present invention can provide a Cmin of between about 30 ng/mL and about 150 ng/mL. The prophylactic treatment of the present invention can provide a Cmin of between about 30 ng/mL and about 100 ng/mL. The prophylactic treatment of the present invention may provide a Cmin of between about 30 ng/mL and about 75 ng/mL.

As described in Example 1, the "normal" range for C1-INH in healthy patients is between 0.15 and 0.35 g/L, and the inventors determined that the lower limit of "normal" corresponds to a C of the compound of formula A of about 18ng/mL. Thus, the prophylactic treatment of the present invention can provide a Cmin of at least about 18 ng/mL (eg, between about 18 ng/mL and about 1000 ng/mL).

The prophylactic treatment of the present invention reduces the number of episodes of bradykinin-mediated angioedema compared to untreated patients, where "untreated patients" means those who have not received any other treatments for bradykinin Patients with prophylactic drugs for peptide-mediated episodes of angioedema. The prophylactic treatment of the present invention can prevent the onset of bradykinin-mediated angioedema. When bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention can reduce the number of (or prevent) episodes of acute HAE. For example, the prophylactic treatments of the present invention can be administered for routine prevention of recurrent episodes of HAE (especially in patients 12 years of age and older). When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention can reduce the number of (or prevent) acute BK-AEnH episodes. The prophylactic treatment of the present invention can reduce the average number of episodes to less than 2 episodes per month, less than 1.5 episodes per month, less than 1 episode per month, and less than 0.5 episodes per month.

Although the primary goal of prophylactic therapy is to reduce the number (or prevent) of bradykinin-mediated episodes of angioedema (BK-AEnH episodes, or preferably HAE episodes), flare-ups can still occur. A "sudden attack" is an attack that occurs despite preventive treatment. Sudden attacks may require treatment with acute (or as needed) therapy. The prophylactic treatment of the present invention reduces the number of bradykinin-mediated angioedema episodes that require acute treatment compared to untreated patients. When bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention can reduce the number of acute HAE episodes that require acute treatment. When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention can reduce the number of acute BK-AEnH episodes that require acute treatment. The prophylactic treatment of the present invention can reduce the average number of episodes requiring acute treatment to less than 2 episodes per month, less than 1.5 episodes per month, less than 1 episode per month, and less than 0.5 episodes per month.

If acute therapy is required to treat a flare-up, the therapy may be selected from the group consisting of C1 esterase inhibitors, pdC1INH, rhC1INH, icatibant, and KVD900 (N-[(3-fluoro- 4-Methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxypyridin-1-yl)methyl]phenyl} Methyl)pyrazole-4-carboxamide or its salts and solvates). Acute treatment can be KVD900. Contains N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxypyridine-1 On-demand (acute) treatment of -yl)methyl]phenyl}methyl)pyrazol-4-carboxamide is described in: PCT/GB2020/051439 and PCT/GB2020/051441, and Maetzel. A et al. , "PD0493 | Rapid and nearly complete suppression of plasma kallikrein activity with the oral inhibitor KVD900: Results of a phase 1 study evaluating KVD900's potential as a treatment for acute attacks of HAE (2019)", Abstracts PDS. Allergy, 74: 130- 331, and Hampton et al ., “KVD900 as a Single Dose, Rapid, Oral Plasma Kallikrein Inhibitor for the On-Demand Treatment of Hereditary Angioedema Attacks: Pharmacokinetic and Pharmacodynamic results from a Phase 1 Single Ascending Dose Study”, JACI, 143, 2 , Supplement, AB39. Acute treatment can be a C1 esterase inhibitor. On-demand therapy can be pdC1INH. Acute treatment can be rhC1INH. On-demand treatment can be icatibant.

Accordingly, the treatment of the present invention also provides a method of treating bradykinin-mediated angioedema comprising: administering to a patient a C1 esterase inhibitor for the treatment of bradykinin-mediated angioedema (sudden onset of bradykinin-mediated angioedema) ) episodes, wherein the compound of Formula A is administered to the patient as prophylactic treatment also in accordance with any of the prophylactic treatments described herein. In other words, the treatment of the present invention also provides a C1 esterase inhibitor for use in a method of treating a (sudden) attack of bradykinin-mediated angioedema, wherein also according to any of the prophylactic treatments described herein, Compounds of formula A are administered to patients as prophylactic treatment.

The treatment of the present invention also provides a method of treating bradykinin-mediated angioedema comprising: administering to a patient icatibant to treat a (sudden) attack of bradykinin-mediated angioedema, Where also in accordance with any of the prophylactic treatments described herein, a compound of formula A is administered to the patient as prophylactic treatment. In other words, the treatment of the present invention also provides icatibant for use in a method of treating a (sudden) attack of bradykinin-mediated angioedema, wherein the patient is also provided to the patient according to any of the prophylactic treatments described herein. Compounds of formula A are administered as prophylactic treatment.

The treatment of the present invention also provides a method of treating bradykinin-mediated angioedema, comprising: administering to a patient pdC1INH to treat a (sudden) attack of bradykinin-mediated angioedema, also according to For any prophylactic treatment described herein, a compound of formula A is administered to the patient as prophylactic treatment. In other words, the treatments of the present invention also provide pdC1INH for use in a method of treating a (sudden) attack of bradykinin-mediated angioedema, wherein the patient is also administered according to any of the prophylactic treatments described herein Compounds of formula A are used as prophylactic treatment.

The treatment of the present invention also provides a method of treating bradykinin-mediated angioedema, comprising: administering to a patient rhC1INH to treat a (sudden) attack of bradykinin-mediated angioedema, also according to For any prophylactic treatment described herein, a compound of formula A is administered to the patient as prophylactic treatment. In other words, the treatments of the present invention also provide rhC1INH for use in a method of treating a (sudden) attack of bradykinin-mediated angioedema, wherein the patient is also administered to a patient according to any of the prophylactic treatments described herein Compounds of formula A are used as prophylactic treatment.

The treatment of the present invention also provides a method of treating bradykinin-mediated angioedema, comprising: administering to a patient KVD900 to treat a (sudden) attack of bradykinin-mediated angioedema, also according to For any prophylactic treatment described herein, a compound of formula A is administered to the patient as prophylactic treatment. In other words, the treatment of the present invention also provides KVD900 for use in a method of treating a (sudden) attack of bradykinin-mediated angioedema, wherein the patient is also administered to a patient according to any of the prophylactic treatments described herein. Compounds of formula A are used as prophylactic treatment.

The prophylactic treatment of the present invention reduces the number of moderate or severe bradykinin-mediated episodes of angioedema compared to untreated patients. "Moderate" or "severe" seizures are measured according to a 5-point Likert scale (5LS) (see e.g. Allergy Asthma Proc. 2018 Jan 1;39(1):74 -80. doi: 10.2500/aap.2018.39.4095), the 5-point Likert scale can be used to report the severity of HAE episodes and, for example, can be used to report episodes as "none", "mild", "moderate" Severe, Severe, or Extremely Severe. When bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention can reduce the number of episodes of moderate or severe HAE. When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention can reduce the number of moderate or severe BK-AEnH episodes. The prophylactic treatment of the present invention can reduce the number of moderate or severe episodes to less than 2 episodes per month, less than 1.5 episodes per month, less than 1 episode per month, and less than 0.5 episodes per month.

Compared to untreated patients, the prophylactic treatment of the present invention reduces the number of episodes of bradykinin-mediated angioedema that do not require acute treatment. When bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention can reduce the number of acute HAE episodes that do not require acute treatment. When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention can reduce the number of acute BK-AEnH episodes that require no acute treatment. The prophylactic treatment of the present invention can reduce the number of episodes that do not require acute treatment to less than 2 episodes per month, less than 1.5 episodes per month, less than 1 episode per month, and less than 0.5 episodes per month.

The prophylactic treatment of the present invention results in an increase in the number of seizure-free days for a set duration compared to untreated patients. When bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention increases the number of days without HAE episodes for a set duration compared to untreated patients. When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention increases the number of days without BK-AEnH episodes for a set duration compared to untreated patients.

The prophylactic treatment of the present invention increases the time between episodes compared to untreated patients. When bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention increases the time between episodes of HAE compared to untreated patients. When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention increases the time between episodes of BK-AEnH compared to untreated patients.

Each episode of bradykinin-mediated angioedema (eg, a BK-AEnH episode, preferably a HAE episode) can vary in severity and in the area affected. Patients with bradykinin-mediated angioedema (eg, BK-AEnH, preferably HAE), medical professionals who understand bradykinin-mediated angioedema (eg, BK-AEnH, preferably HAE) and caregivers of patients with bradykinin-mediated angioedema (eg, BK-AEnH patients, preferably HAE patients) can well identify episodes of bradykinin-mediated angioedema (eg, BK-AEnH episodes, preferably symptoms of HAE attacks).

In the prodromal phase of acute bradykinin-mediated angioedema episodes (eg, BK-AEnH episodes, preferably HAE episodes), mild swelling, especially affecting the face and neck, is recognized as the symptom. In addition, or in other cases, symptoms may also include abdominal pain. In addition, or in other instances, the symptoms may be reddening of the skin, such as erythema annulare.

The prophylactic treatment of the present invention reduces the number of bradykinin-mediated angioedema episodes that progress to the prodromal stage compared to untreated patients. When bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention can reduce the number of bradykinin-mediated angioedema episodes that progress to the prodromal phase of HAE episodes. When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention can reduce the number of bradykinin-mediated angioedema episodes progressing to the prodromal stage of BK-AEnH episodes.

The prophylactic treatment of the present invention reduces the severity of any symptoms in the prodromal phase of bradykinin-mediated angioedema episodes compared to untreated patients. When bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention can reduce the severity of any symptoms in the prodromal phase of the HAE episode. When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention can reduce the severity of any symptoms in the prodromal phase of a BK-AEnH attack.

Bradykinin-mediated episodes of angioedema (eg, BK-AEnH episodes, preferably HAE episodes) can progress through the prodromal phase to the swollen phase of the episode. The tumescent phase of an attack is characterized by more severe swelling, pain (eg, abdominal attack), discomfort (eg, peripheral attack), and/or life-threatening (eg, throat attack) than any swelling in the prodromal phase. Swelling can affect hands, feet, extremities, face, bowel and/or respiratory tract; cause fatigue, headache, muscle pain, skin tingling, abdominal pain, nausea, vomiting, diarrhea, difficulty swallowing, hoarseness, shortness of breath and/or mood changes.

The prophylactic treatment of the present invention reduces bradykinin-mediated episodes of angioedema (eg, BK-AEnH episodes, preferably HAE episodes) compared to untreated patients, including those in the swollen phase of the attack the severity of any symptoms. In particular, the prophylactic treatment of the present invention can reduce the rate of decrease as measured according to the 5-point Likert scale (5LS) (see, eg, Allergy Asthma Proc. 2018 Jan 1;39(1):74-80. doi: 10.2500/aap.2018.39.4095) the severity of any symptoms of bradykinin-mediated angioedema episodes (eg BK-AEnH episodes, preferably HAE episodes). More specifically, the prophylactic treatment of the present invention can reduce the severity of any symptoms of bradykinin-mediated angioedema episodes (eg, BK-AEnH episodes, preferably HAE episodes) such that symptoms do not develop beyond " mild" stage.

The prophylactic treatment of the present invention reduces the rate of progression of bradykinin-mediated episodes of angioedema (eg, BK-AEnH episodes, preferably HAE episodes) compared to untreated patients. Specifically, the prophylactic treatment of the present invention reduces bradykinin-mediated angioedema that progresses to a score of "worse" or "significantly worse" according to the 7-point transition question (7TQ) The number of episodes (eg BK-AEnH episodes, preferably HAE episodes). More specifically, the prophylactic treatment of the present invention reduces bradykinin-mediated episodes of angioedema (eg, BK-AEnH episodes, preferably BK-AEnH episodes) that progress to a score of "significantly worse" according to the 7-point metastasis question (7TQ). is the number of HAE episodes). The 7TQ index is an index known in the art that can be used to score the development of HAE episodes and to report episodes as "significantly better", "better", "slightly better", "no change", " slightly worse", "worse" or "significantly worse".

The prophylactic treatment of the present invention reduces the duration of episodes of bradykinin-mediated angioedema compared to untreated patients. When bradykinin-mediated angioedema is HAE, the prophylactic treatment of the present invention can shorten the duration of HAE episodes. When the bradykinin-mediated angioedema is BK-AEnH, the prophylactic treatment of the present invention can shorten the duration of BK-AEnH episodes.

The inventors have unexpectedly discovered that the treatment of the present invention can provide patients with enhanced protection against bradykinin-mediated angioedema episodes (eg BK-AEnH episodes, preferably HAE episodes) during the night, which is especially important , because bradykinin-mediated angioedema episodes (eg, BK-AEnH episodes, preferably HAE episodes) that start at night run the risk of going undetected by the patient, making them more severe than earlier episodes to stop . This unexpected finding was found when a compound of formula A was administered to a patient twice daily, with one dose administered in the morning (after the patient woke up) and one dose administered in the evening (before the patient went to bed) effect. As shown in Example 3, the Cmin before the patient took their morning dose was higher than the Cmin before the patient took their evening dose.

Thus, the prophylactic treatment of the present invention may provide enhanced efficacy during the night compared to the day. Specifically, when a compound of formula A is administered twice daily, one dose in the morning (after the patient wakes up) and one dose in the evening (before the patient goes to bed), the prevention of the present invention Sexual therapy may provide enhanced efficacy during the night (after the patient's evening dose and before the patient's morning dose). The prophylactic treatment of the present invention may provide more prophylactic treatment throughout the night (following the patient's evening dose and prior to the patient's morning dose) compared to the day (following the patient's morning dose and prior to the patient's evening dose). High Cmin. The morning dose can be administered within 1 hour of waking up (eg, within 45 minutes, 30 minutes, 15 minutes, or 5 minutes) of the patient. And the evening dose can be administered within 1 hour before the patient goes to bed (eg, within 45 minutes, 30 minutes, 15 minutes, or 5 minutes). Alternatively or additionally, depending on the patient's lifestyle, the two daily doses may be separated by about 12 hours, which may coincide with wake and bedtime.

Oral Modified Release Pharmaceutical Dosage Forms for Use in the Treatments of the Invention In order to provide effective prophylactic treatment, the dosage form needs to be capable of maintaining a therapeutically effective amount of the compound in the patient's plasma during the treatment period, but avoiding potentially deleterious accumulation of the compound. The dosage form also needs to minimize patient burden by minimizing pill burden and dosing frequency. To this end, the inventors have ingeniously designed and developed oral modified release pharmaceutical dosage forms for the treatments described herein.

The term "modified release" is known in the art to mean manipulating or modifying the release of a drug from a dosage form with the aim of delivering the drug substance: i) at a desired rate, ii) at a predetermined point in time, or iii) at specific sites in the gastrointestinal tract. The design of the oral modified release pharmaceutical dosage forms described herein requires the inventors to consider the physiology of the gastrointestinal tract, the physiochemical properties of the drug, the design of the dosage form, the mechanism of drug release, specific disease factors, and the biological properties of the drug. This careful balance requires the collection of data from human clinical studies to investigate, inter alia, whether these dosage forms have PK profiles suitable for use in the prophylactic treatment of the present invention. The Phase 1 study described in Example 3 demonstrated that the oral modified release pharmaceutical dosage form described herein has a PK profile suitable for use in the prophylactic treatment of the present invention. No serious adverse events were found in the study.

Accordingly, the present invention provides an oral modified release pharmaceutical dosage form comprising a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof). The dosage form of the present invention may comprise between about 20% and about 70% by weight of the compound of formula A. The dosage form of the present invention may comprise between about 20% and about 60% by weight of the compound of formula A. The dosage form of the present invention may comprise between about 30% and about 60% by weight of the compound of formula A. The dosage form of the present invention may comprise between about 30% and about 50% by weight of the compound of formula A. The dosage form of the present invention may comprise between about 35% and about 45% by weight of the compound of formula A. The dosage form of the present invention may comprise between about 40% and about 45% by weight of the compound of formula A. The dosage form of the present invention may comprise between about 42% and about 43% by weight of the compound of formula A.

Preferably, the oral modified release pharmaceutical dosage form is a lozenge. Tablets may be coated with a film. The film coating may comprise one or more of the following: hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidine, polyvinyl alcohol, aminoalkyl methacrylate copolymer , cellulose derivatives (such as ethyl cellulose or cellulose acetate), polyglucosamine, methyl methacrylate copolymers, methacrylic acid copolymers, phthalates (such as hydroxypropyl methyl cellulose) phthalates, cellulose acetate phthalates and polyvinyl acetate phthalates), plasticizers (eg polyols such as polyethylene glycol and propylene glycol; organic esters such as phthalates) Diethyl dicarboxylate, glyceryl monocaprylate, and triethyl citrate; or oils/glycerides such as fractionated coconut oil), colorants (eg, iron oxide pigments, titanium dioxide, and aluminum lakes), lactose monohydrate, and triacetic acid Glycerides. The film coating may contain polyvinyl alcohol. The film coating may comprise polyethylene glycol (PEG). The film coating may contain titanium dioxide. Preferably, the film coating comprises polyvinyl alcohol, polyethylene glycol (PEG) and titanium dioxide.

Oral modified release pharmaceutical dosage forms may contain release modifying agents. Oral modified release pharmaceutical dosage forms may contain one or more release modifying agents. The release-modifying agent may be present in an amount sufficient to provide a PK profile suitable for use in the prophylactic treatment of the present invention, e.g., in an amount sufficient to provide a Cmin of at least about 30 ng/mL when administered as part of a prophylactic treatment as described herein amount exists.

Oral modified release pharmaceutical dosage forms can contain between about 1% and about 80% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 2% and about 60% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 2% and about 50% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 2% and about 40% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 3% and about 30% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 3% and about 20% by weight of the release modifier. Oral modified release pharmaceutical dosage forms can comprise between about 3% and about 15% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 5% and about 15% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 10% and about 15% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 10% and about 14% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 11% and about 13% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise between about 11.5% and about 13% by weight of the release modifier. More specifically, the oral modified release pharmaceutical dosage form can comprise about 12.5% by weight of the release modifier.

Preferably, the oral modified release pharmaceutical dosage form may comprise between about 11.5% and about 13% by weight, specifically, between about 12% and about 13% by weight, specifically, about 12.5% by weight Release modifier.

The release modifier can be a pH sensitive polymer. pH sensitive polymers include polymers based on methacrylic acid copolymers, such as Eudragit polymers, eg Eudragit L, which can be used alone or with plasticizers; having on contact with water or aqueous media such as gastric contents High swelling release modifiers; polymeric materials that form gels upon contact with water or aqueous media; and polymeric materials that exhibit swelling and gelling characteristics upon contact with water or aqueous media.

Release modifiers with high swelling include, for example, croscarmellose sodium, croscarmellose, high molecular weight hydroxypropyl methylcellulose, carboxymethylamide, potassium divinyl methacrylate Benzene copolymer, polymethyl methacrylate and high molecular weight polyvinyl alcohol.

Release modifiers that are gelatable polymers include, for example, methyl cellulose, carboxymethyl cellulose, low molecular weight hydroxypropyl methyl cellulose, low molecular weight polyvinyl alcohol, polyoxyethylene glycol, and xanthan gum gum).

Release modifiers that have both swelling and gelling properties include, for example, medium viscosity hydroxypropyl methylcellulose and medium viscosity polyvinyl alcohol.

Examples of other release modifiers that can be used include Methocel K4M, Methocel E5, Methocel E50, Methocel E4M, Methocel K15M, and Methocel K100M.

Examples of other release modifiers that can be used include Methocel K4M, Methocel E5, Methocel E50, Methocel E4M, Methocel K15M, Methocel K100M, and Methocel K100LV.

Other known release modifiers that can be used include hydrocolloids such as natural or synthetic gums, cellulose derivatives other than those listed above, carbohydrate based substances such as acacia ), gum tragacanth, locust bean gum, guar gum, agar, pectin, carrageenan, soluble and insoluble alginates), carboxypolymethylene, Casein, zein and their analogs, and proteinaceous substances such as gelatin.

Preferred release modifiers are selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR), hydroxypropyl methylcellulose, hydroxypropyl Cellulose, polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303) and carboxymethylcellulose and salts thereof. Particularly preferred release modifiers are selected from the group consisting of polyoxyethylenes such as Polyox WSR N750 or Polyox WSR 303 and hydroxypropyl methylcelluloses such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR), and most preferably hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR, especially Methocel DC2 K4M.

Preferred release modifiers are selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV), hydroxypropyl methylcellulose, Hydroxypropylcellulose, polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303) and carboxymethylcellulose and its salts. Particularly preferred release modifiers are selected from the group consisting of polyoxyethylene (such as Polyox WSR N750 or Polyox WSR 303) and hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV), and most preferably hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV, especially Methocel K100LV.

The modified release oral pharmaceutical dosage form may comprise between about 3% and 30% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR , Methocel E10MCR or Methocel K100LV. The modified release oral pharmaceutical dosage form may comprise between about 3% and 30% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR.

The modified release oral pharmaceutical dosage form may comprise between about 3% and 20% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR , Methocel E10MCR or Methocel K100LV. The modified release oral pharmaceutical dosage form may comprise between about 3% and 20% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR.

The modified release oral pharmaceutical dosage form may comprise between about 3% and 15% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR , Methocel E10MCR or Methocel K100LV. The modified release oral pharmaceutical dosage form may comprise between about 3% and 15% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR.

The modified release oral pharmaceutical dosage form may comprise between about 3% and 30% by weight of a release modifier selected from polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303). The modified release oral pharmaceutical dosage form may comprise between about 3% and 20% by weight of a release modifier selected from polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303). The modified release oral pharmaceutical dosage form may comprise between about 8% and 20% by weight (eg, about 15% by weight) of a release modifier selected from polyoxyethylene (eg, Polyox WSR N750 or Polyox WSR 303) . The modified release oral pharmaceutical dosage form may comprise about 15% by weight of a release modifier (eg, about 15% by weight), wherein the release modifier is selected from polyoxyethylene (eg, Polyox WSR N750 or Polyox WSR 303).

The modified release oral pharmaceutical dosage form may comprise between about 3% and 15% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR) and polyoxyethylenes (eg Polyox WSR N750 or Polyox WSR 303), especially hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR. More specifically, the dosage form may comprise between about 3% and 15% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR, especially hydroxypropyl methylcellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage form may comprise between about 5% and about 15% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR), polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303), especially hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR. More specifically, the dosage form may comprise between about 5% and 15% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR, especially hydroxypropyl methylcellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage form may comprise between about 10% and about 15% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR), polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303), especially hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR. More specifically, the dosage form may comprise between about 10% and about 15% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR, especially hydroxypropyl methylcellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage form may comprise between about 10% and about 14% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR), polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303), especially hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR. More specifically, the dosage form may comprise between about 10% and about 14% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR, especially hydroxypropyl methylcellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage form may comprise between about 11% and about 13% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR), polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303), especially hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR. More specifically, the dosage form may comprise between about 11% and about 13% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR, especially hydroxypropyl methylcellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage form may comprise about 12.5% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR), polyoxyl Ethylene (eg Polyox WSR N750 or Polyox WSR 303), especially hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR. More specifically, the dosage form may comprise about 12.5% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR, especially such as Hydroxypropyl methylcellulose of Methocel DC2 K4M.

The modified release oral pharmaceutical dosage form may comprise between about 10% and about 30% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV), polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303). More specifically, the dosage form may comprise between about 10% and about 30% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV, especially hydroxypropyl methylcellulose such as Methocel K100LV.

The modified release oral pharmaceutical dosage form may comprise between about 15% and about 30% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV), polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303). More specifically, the dosage form may comprise between about 15% and about 30% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV, especially hydroxypropyl methylcellulose such as Methocel K100LV.

The modified release oral pharmaceutical dosage form may comprise between about 20% and about 30% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV), polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303). More specifically, the dosage form may comprise between about 20% and about 30% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV, especially hydroxypropyl methylcellulose such as Methocel K100LV.

The modified release oral pharmaceutical dosage form may comprise between about 15% and about 25% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV), polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303). More specifically, the dosage form may comprise between about 15% and about 25% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV, especially hydroxypropyl methylcellulose such as Methocel K100LV.

The modified release oral pharmaceutical dosage form may comprise between about 15% and about 20% by weight of a release modifier selected from the group consisting of hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV), polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303). More specifically, the dosage form may comprise between about 15% and about 20% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV, especially hydroxypropyl methylcellulose such as Methocel K100LV.

The modified release oral pharmaceutical dosage form may comprise about 15% by weight of a release modifier selected from hydroxypropyl methylcellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV) , Polyoxyethylene (eg Polyox WSR N750 or Polyox WSR 303). More specifically, the dosage form may comprise about 15% by weight of a release modifier, wherein the release modifier is selected from hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV , especially hydroxypropyl methylcellulose such as Methocel K100LV.

The modified release oral pharmaceutical dosage forms of the present invention may also contain diluents. The modified release oral pharmaceutical dosage forms of the present invention may also contain one or more diluents. The diluent may be selected from lactose (eg lactose monohydrate, spray dried lactose, anhydrous lactose), sorbitol, mannitol, sucrose, starch and pregelatinized starch, cellulose (eg powdered cellulose, microcrystalline cellulose) , such as Avicel PH101, Avicel PH102), calcium phosphates (eg, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, tricalcium phosphate), tricalcium citrate, and mixtures thereof. Preferably, the diluent is selected from microcrystalline cellulose (such as Avicel PH101, Avicel PH102) and/or mannitol.

Diluents can comprise from about 15% to about 60% by weight of the dosage form. Diluents can comprise from about 20% to about 60% by weight of the dosage form. The diluent may comprise from about 20% to about 50% by weight of the dosage form. The diluent may comprise from about 30% to about 50% by weight of the dosage form. Diluents can comprise from about 30% to about 40% by weight of the dosage form. The diluent may comprise from about 35% to about 40% by weight of the dosage form. The diluent may comprise from about 37% to about 38% by weight of the dosage form.

The diluent can be selected from microcrystalline cellulose (such as Avicel PH101, Avicel PH102) and/or mannitol (preferably microcrystalline cellulose and mannitol, such as Pearlitol 200SD), and the diluent can comprise about 30% of the dosage form % to about 50% by weight, preferably from about 30% to about 40% by weight, and most preferably from about 35% to about 40% by weight of the dosage form.

The modified release oral pharmaceutical dosage forms of the present invention may also contain binders. The modified release oral pharmaceutical dosage forms of the present invention may also contain one or more binders. The binder may be selected from the group consisting of sugars (such as glucose, sucrose, fructose, dextrose, lactose), sugar alcohols (such as xylitol, maltitol, erythritol, sorbitol), polysaccharides (such as crystalline cellulose, powdered cellulose, methylcellulose), corn starch, starch 1500, acacia, other natural polymers (such as gelatin), synthetic polymers (such as polyvinylpyrrolidone (eg copovidone) (copovidone), polyvinylpolypyrrolidone (crospovidone), polyethylene glycol, cross-linked acrylic acid and acrylic acid copolymers (eg Carbopol ^® ), inorganic compounds (such as calcium carbonate) and their Mixtures (more specifically, glucose, lactose, cornstarch, starch 1500, gelatin, acacia, methylcellulose, polyvinylpyrrolidone, and mixtures thereof). Preferably, the binder is a synthetic polymer such as polyvinylpyrrolidone (e.g. copovidone), polyvinylpolypyrrolidone (cross-linked povidone), especially polyvinylpyrrolidone (e.g. copovidone) ketone). Optimally, the binder is polyvinylpyrrolidone (eg copovidone).

Binders can comprise from about 1% to about 20% by weight of the dosage form. The binder may comprise from about 1% to about 15% by weight of the dosage form. The binder may comprise from about 1% to about 10% by weight of the dosage form. The binder can comprise from about 1% to about 7% by weight of the dosage form. Binders can comprise from about 1% to about 5% by weight of the dosage form. The binder may comprise from about 2% to about 5% by weight of the dosage form. The binder may comprise from about 2% to about 4% by weight of the dosage form. The binder can comprise about 3% by weight of the dosage form.

The binder can be polyvinylpyrrolidone (eg, copovidone), and can comprise from about 1% to about 10% by weight of the dosage form, more preferably from about 1% to about 5% by weight of the dosage form, and most preferably from about 1% to about 5% by weight of the dosage form. From about 2% to about 5% by weight of the dosage form.

The modified release oral pharmaceutical dosage forms of the present invention may also contain lubricants. The modified release oral pharmaceutical dosage forms of the present invention may also contain one or more lubricants. The lubricant may be selected from magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, glyceryl behenate, glyceryl palmitostearate, polyethylene glycol, polyoxyethylene hard Fatty acid esters, lauryl sulfate, talc, paraffin and mixtures thereof. Preferably, the lubricant is selected from magnesium stearate and/or talc.

Lubricants can comprise from about 0.25% to about 6% by weight of the dosage form. Lubricants may comprise from about 0.25% to about 5% by weight of the dosage form. Lubricants may comprise from about 0.25% to about 4% by weight of the dosage form. Lubricants can comprise from about 0.5% to about 4% by weight of the dosage form. Lubricants can comprise from about 1% to about 4% by weight of the dosage form. Lubricants can comprise from about 2% to about 4% by weight of the dosage form. Lubricants can comprise from about 3% to about 4% by weight of the dosage form. Lubricants can comprise about 3.5% by weight of the dosage form.

The lubricant can be magnesium stearate and/or talc (preferably magnesium stearate and talc), and can comprise from about 2% to about 4% by weight of the dosage form, preferably from about 3% to about 3% by weight of the dosage form 4% by weight, optimally about 3.5% by weight of the dosage form.

The modified release oral pharmaceutical dosage forms of the present invention can be prepared by forming granules, followed by the addition of extragranular excipients. In such cases, the release modifiers, diluents, binders and/or lubricants described above may form the intragranular composition (weight % still based on the total dosage form). Extragranular excipients may include, for example, one or more of the following lubricants, slip agents and diluents.

The extragranular lubricant may comprise one or more extragranular lubricants selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, glyceryl behenate, palm stearin Glycerides, polyethylene glycols, polyoxyethylene stearate, lauryl sulfate, talc, paraffin, and mixtures thereof. Preferably, the extragranular lubricant is magnesium stearate.

Extragranular lubricants can comprise from about 0.1% to about 3% by weight of the dosage form. Extragranular lubricants can comprise from about 0.1% to about 2% by weight of the dosage form. Lubricants can comprise from about 0.1% to about 1.5% by weight of the dosage form. Extragranular lubricants can comprise from about 0.1% to about 1% by weight of the dosage form. Extragranular lubricants can comprise from about 0.2% to about 1% by weight of the dosage form. Extragranular lubricants may comprise from about 0.2% to about 0.7% by weight of the dosage form. Extragranular lubricants can comprise from about 0.3% to about 0.7% by weight of the dosage form. Extragranular lubricants can comprise from about 0.4% to about 0.6% by weight of the dosage form. Extragranular lubricants may comprise about 0.5% by weight of the dosage form.

The extragranular lubricant can be magnesium stearate and can comprise from about 0.2% to about 0.7% by weight of the dosage form, preferably from about 0.4% to about 0.6% by weight of the dosage form, and most preferably from about 0.5% by weight of the dosage form .

The extragranular slip agent may comprise one or more extragranular slip agents selected from the group consisting of talc, colloidal silica, magnesium trisilicate, powdered cellulose, starch, tricalcium phosphate, and mixtures thereof. Preferably, the extragranular slip agent is colloidal silica.

Extragranular slip agents can comprise from about 0.1% to about 2% by weight of the dosage form. Extragranular slip agents may comprise from about 0.1% to about 1.5% by weight of the dosage form. Extragranular slip agents may comprise from about 0.1% to about 1.0% by weight of the dosage form. Extragranular slip agents may comprise from about 0.5% to about 1.5% by weight of the dosage form. Extragranular slip agents may comprise from about 0.7% to about 1.5% by weight of the dosage form. Extragranular slip agents may comprise from about 0.7% to about 1.2% by weight of the dosage form. Extragranular slip agents may comprise from about 0.9% to about 1.1% by weight of the dosage form. Extragranular slip agents can comprise about 1% by weight of the dosage form.

The extragranular slip agent can be colloidal silica and can comprise from about 0.1% to about 2% by weight of the dosage form, preferably from about 0.7% to about 1.5% by weight of the dosage form, and most preferably comprises about 1% by weight of the dosage form weight%.

Extragranular diluents may comprise one or more extragranular diluents selected from the group consisting of lactose (eg, lactose monohydrate, spray-dried lactose, lactose anhydrous), sorbitol, mannitol, sucrose, starch, and pregelatinized starch , cellulose (eg powdered cellulose, microcrystalline cellulose, eg Avicel PH101, Avicel PH102), calcium phosphate (eg anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, tricalcium phosphate), tricalcium citrate and mixtures thereof. Preferably, the extragranular diluent is microcrystalline cellulose, such as Avicel PH101, Avicel PH102.

Extragranular diluents can comprise from about 1% to about 20% by weight of the dosage form. The diluent may comprise from about 3% to about 15% by weight of the dosage form. Extragranular diluents can comprise from about 6% to about 15% by weight of the dosage form. Extragranular diluents can comprise from about 6% to about 12% by weight of the dosage form. Extragranular diluents can comprise from about 7% to about 11% by weight of the dosage form. Extragranular diluents may comprise from about 8% to about 10% by weight of the dosage form. Extragranular diluents can comprise about 9% by weight of the dosage form.

The extragranular diluent can be microcrystalline cellulose, such as Avicel PH101, Avicel PH102, and can comprise from about 1% to about 20% by weight of the dosage form, preferably from about 6% to about 15% by weight of the dosage form, most preferably About 9% by weight of the dosage form.

The modified release oral pharmaceutical dosage form of the present invention may comprise: (i) between about 3% and 15% by weight of a release modifier, wherein the release modifier is hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR; (ii) between about 30 wt% and about 40 wt% diluent, wherein the diluent is microcrystalline cellulose (such as Avicel PH101, Avicel PH102) and/or mannitol (preferably microcrystalline cellulose and mannitol); (iii) between about 1 wt% and about 5 wt% binder, wherein the binder is polyvinylpyrrolidone (eg povidone) ); (iv) between about 3% and about 4% by weight of a lubricant, wherein the lubricant is magnesium stearate and/or talc (preferably magnesium stearate and talc); (v) at about between 0.4 wt% and about 0.6 wt% extragranular lubricant, wherein the extragranular lubricant is magnesium stearate; (vi) between about 0.7 wt% and about 1.5 wt% extragranular lubricant, wherein The extragranular slip agent is colloidal silica; (vii) between about 6 wt% and 15 wt% extragranular diluent, wherein the extragranular diluent is microcrystalline cellulose, eg Avicel PH101, Avicel PH102.

The modified release oral pharmaceutical dosage form of the present invention may comprise: (i) between about 15% and 30% by weight of a release modifier, wherein the release modifier is hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV; (ii) between about 30 wt% and about 40 wt% diluent, wherein the diluent is microcrystalline cellulose (such as Avicel PH101, Avicel PH102) and/or Mannitol (preferably microcrystalline cellulose and mannitol); (iii) between about 1 wt% and about 5 wt% binder, wherein the binder is polyvinylpyrrolidone (e.g. povidone) ); (iv) between about 3% and about 4% by weight of a lubricant, wherein the lubricant is magnesium stearate and/or talc (preferably magnesium stearate and talc); (v) at about between 0.4 wt% and about 0.6 wt% extragranular lubricant, wherein the extragranular lubricant is magnesium stearate; (vi) between about 0.7 wt% and about 1.5 wt% extragranular lubricant, wherein The extragranular slip agent is colloidal silica; (vii) between about 6 wt% and about 15 wt% extragranular diluent, wherein the extragranular diluent is microcrystalline cellulose, such as Avicel PH101, Avicel PH102 .

The modified release oral pharmaceutical dosage forms of the present invention may be characterized by their dissolution profile. When the modified release oral pharmaceutical dosage forms of the present invention were tested in the dissolution method described in Table 1, the percent release values described below were achieved. Compound analysis was performed on samples from the dissolution vessel under the conditions detailed in Table 2 below using the reverse isocratic HPLC method. In particular, dissolution was performed according to the harmonised mongraph (Ph. Eur. 2.9.3). Table 1 Element condition equipment USP Apparatus II (Agitator) medium Phase 1 (0-60 minutes): 500 mL of 0.1 M hydrochloric acid Stage 2 (60 minutes-19 hours): 400 mL of 0.05 M sodium phosphate buffer with 4.5% SDS (added to the medium of stage 1) medium volume Phase 1: 500 mL Phase 2: 900 mL spinning speed 75 rpm (150 rpm infinite rotation) sampling time point Phase 1: 30 and 60 minutes Stage 2: 90 minutes, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18 and 19 hours (infinite spins between 18-19 hours) Table 2 Element condition String: Waters Cortecs C18 Column (3.0 mm x 100 mm) 2.7 μm or appropriately validated alternative Mobile phase: 70:30 0.05 M sodium phosphate buffer (pH 6.8):acetonitrile Detect: UV detection at 315 nm

At about 2 hours, the dosage form can release less than about 40% of the compound. At about 3 hours, the dosage form can release less than about 40% of the compound. At about 4 hours, the dosage form can release less than about 40% of the compound. At about 5 hours, the dosage form can release less than about 40% of the compound.

At about 3 hours, the dosage form can release less than about 60% (or about 40% to about 60%) of its compound. At about 4 hours, the dosage forms of the present invention can release less than about 60% (or from about 40% to about 60%) of their compounds. At about 5 hours, the dosage forms of the present invention can release less than about 60% (or from about 40% to about 60%) of their compounds. At about 6 hours, the dosage form of the present invention can release less than about 60% (or from about 40% to about 60%) of its compound. At about 7 hours, the dosage form of the present invention can release less than about 60% (or about 40% to about 60%) of its compound. At about 8 hours, the dosage form of the present invention can release less than about 60% (or from about 40% to about 60%) of its compound.

At about 5 hours, the dosage form can release less than about 80% (or from about 60% to about 80%) of its compound. At about 6 hours, the dosage form of the present invention can release less than about 80% (or from about 60% to about 80%) of its compound. At about 7 hours, the dosage form of the present invention can release less than about 80% (or from about 60% to about 80%) of its compound. At about 8 hours, the dosage form of the present invention can release less than about 80% (or from about 60% to about 80%) of its compound. At about 9 hours, the dosage form of the present invention can release less than about 80% (or about 60% to about 80%) of its compound. At about 10 hours, the dosage form of the present invention can release less than about 80% (or from about 60% to about 80%) of its compound. At about 11 hours, the dosage form of the present invention can release less than about 80% (or from about 60% to about 80%) of its compound. At about 12 hours, the dosage forms of the present invention can release less than about 80% (or from about 60% to about 80%) of their compounds.

At about 6 hours, the dosage form can release less than about 90% (or about 80% to about 90%) of its compound. At about 7 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 8 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 9 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 10 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 11 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 12 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 13 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 14 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 15 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 16 hours, the dosage form of the present invention can release less than about 90% (or from about 80% to about 90%) of its compound. At about 17 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound. At about 18 hours, the dosage form of the present invention can release less than about 90% (or about 80% to about 90%) of its compound.

More specifically, the dosage form can release less than about 40% of its compound at about 2 hours; and/or about 40% to about 60% of its compound at about 3 hours; and/or at about 5 hours About 60% to about 80% of its compound; and/or about 80% to about 90% of its compound is released at about 7 hours.

More specifically, the dosage form can release less than about 40% of its compound at about 3 hours; and/or about 40% to about 60% of its compound at about 6 hours; and/or at about 9 hours about 60% to about 80% of its compound; and/or about 80% to about 90% of its compound is released at about 11 hours.

More specifically, the dosage form can release less than about 40% of its compound at about 2 hours; and/or about 30% to about 70% of its compound at about 6 hours; and/or at about 9 hours about 50% to about 90% of its compound; and/or more than about 80% of its compound is released at about 16 hours.

More specifically, the dosage form can release about 40% to about 70% of its compound at about 6 hours; and/or about 55% to about 85% of its compound at about 9 hours; and/or at about 11 About 65% to about 95% of its compounds are released at hours.

As used herein, the term "bioequivalent" describes that when used under the same conditions in a pharmacokinetic assessment, the equivalent dosage form. For example, such dosage forms may comply with FDA guidelines for bioequivalence testing; regardless of biopharmaceutical class (see http://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-BioAvail-BioEquiv .pdf, see also https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4241B1-02-23-FDA-Bioequiv%20OGD%20Oct%206%202006%20Background.pdf), Or in accordance with EMA's Guideline EMA/CHMP/EWP/280/96 Rev. 1 of 20 November 2014. As used herein, a value of "bioequivalent" means a pharmacokinetic value (such as the Cmax or AUC of the formulations described herein) that exhibits a substantially similar pharmacokinetic profile or therapeutic effect. Bioequivalence can be demonstrated by in vivo and in vitro methods. Such methods may include, for example, pharmacokinetic, pharmacodynamic, clinical and in vitro studies. Bioequivalence can be demonstrated using any suitable pharmacokinetic measure or combination of pharmacokinetic measures known in the art, including loading dose, steady state dose, initial or steady state concentration of drug, biological half-life, elimination rate , area under the curve (AUC), clearance, peak blood or plasma concentration (Cmax), time to peak concentration (Tmax), bioavailability and potency. When AUC(0-t) (area under the plasma concentration curve from administration to the last observed concentration at time t), AUC(0-∞) (area under the plasma concentration curve extrapolated to infinite time), Cmax (maximum When the geometric mean of plasma concentrations) is between 80% and 125% of the reference pharmacokinetic value (eg, at a 90% confidence interval), the value may be bioequivalent to the reference pharmacokinetic value. For modified release oral pharmaceutical dosage forms, bioequivalence can also be considered for Cmax,ss (Cmax at steady state), Cτ,ss (concentration at the end of the dosing interval at steady state) and AUC(0-τ)ss ( AUC during the dosing interval at steady state).

Accordingly, the present invention provides an oral modified release pharmaceutical dosage form that is bioequivalent to any of the dosage forms described herein. Accordingly, the present invention provides an oral modified release pharmaceutical dosage form that is bioequivalent to any of the dosage forms described herein, wherein "bioequivalent" means AUC(0-t), AUC(0-∞), Cmax, Cmax, One or more of ss, Cτ,ss, and AUC(0-τ)ss is between 80% and 125% (eg, under a 90% confidence interval) of any oral modified release pharmaceutical dosage form described herein.

Administration As used herein, dosages are expressed in free base equivalents. Thus, and by way of example only, administration of 107.2 mg of Compound hydrochloride will be described as a 100 mg dose, since 107.2 mg of Compound free base is equivalent to 100 mg of Compound free base.

In the treatments described herein, a therapeutically effective amount of a compound of formula A is administered orally such that plasma concentrations of the compound of formula A are maintained above the minimum therapeutically effective concentration for achieving prophylactic effects. As noted above, compounds of formula A can be administered orally to provide a Cmin of about 30 ng/mL.

The compound of formula A may be administered in a daily dose of about 300 mg to about 2400 mg. "Daily dose" means the total amount administered during the day. More specifically, the compound of formula A can be administered in a daily dose of about 600 mg to about 2100 mg. The compound of formula A may be administered in a daily dose of about 600 mg to about 1800 mg. The compound of formula A may be administered in a daily dose of about 900 mg to about 1800 mg. The compound of formula A may be administered in a daily dose of about 1200 mg to about 1800 mg. The daily dose may be about 300 mg. The daily dose may be about 600 mg. The daily dose may be about 1200 mg. The daily dose may be about 1800 mg.

Treatments of the present invention can achieve steady-state concentrations of the compound within 2 days of initiation of treatment. Treatments of the present invention can achieve steady-state concentrations of the compound within 3 days of initiation of treatment. Treatments of the present invention can achieve steady-state concentrations of the compound within 4 days of initiation of treatment. Treatments of the present invention can achieve steady-state concentrations of the compound within one week of initiation of treatment. The treatment of the present invention can achieve steady state concentrations of the compound within 1 to 2 days after initiation of treatment. Treatments of the present invention can achieve steady-state concentrations of the compound within 2 to 3 days of initiating treatment. Treatments of the present invention can achieve steady-state concentrations of the compound within 3 to 4 days after initiation of treatment. Preferably, the treatment of the present invention achieves a steady state concentration of the compound within 2 to 3 days after initiation of treatment.

The daily dose can be administered as a twice-daily treatment. The first dose can be administered in the morning (after the patient wakes up) and the second dose can be administered in the evening (before the patient goes to bed). The first dose can be administered within one hour after the patient wakes up. The first dose can be administered within 30 minutes after the patient wakes up. The first dose can be administered within 15 minutes after the patient wakes up. The second dose can be administered within one hour before the patient goes to bed. The second dose can be administered within 30 minutes before the patient goes to bed. The second dose can be administered within 15 minutes before the patient goes to bed. The two doses may also be administered about 12 hours apart. Preferably, the two doses are also administered about 12 hours apart.

The twice-daily treatment of the present invention may comprise administering a compound of formula A with food. More specifically, a twice-daily treatment of the present invention may require administration of the first dose in the morning when the patient consumes his first meal of the day (eg, breakfast), and in the evening when the patient consumes his evening meal (eg, The second dose is administered at dinner). The first dose can be administered less than about 30 minutes, more specifically, less than about 15 minutes, even more specifically, less than about 10 minutes or even less than about 5 minutes from the first meal of the day. The second dose can be administered less than about 30 minutes, more specifically, less than about 15 minutes, even more specifically, less than about 10 minutes or even less than about 5 minutes from the evening meal of the day.

The twice-daily treatment of the present invention may comprise administering a compound of formula A after a meal. More specifically, a twice-daily treatment of the present invention may entail administering the first dose in the morning after the patient has eaten their first meal of the day (eg, breakfast), and in the evening after the patient has eaten their evening meal (eg, with their evening meal). A second dose is administered after dinner). The first dose can be administered within about 30 minutes, more specifically within about 15 minutes, even more specifically within about 10 minutes or even within about 5 minutes of the first meal of the day. The second dose can be administered within about 30 minutes, more specifically within about 15 minutes, even more specifically within about 10 minutes or even within about 5 minutes of the evening meal of the day.

When the treatment of the present invention is a twice-daily treatment, the daily dose may be divided equally between the two doses. For example, when the daily dose is 1800 mg, twice-daily treatment may involve the administration of two 900 mg doses, eg, about 12 hours apart. When the daily dose is 1200 mg, twice-daily treatment may involve the administration of two 600 mg doses, eg, about 12 hours apart. When the daily dose is 600 mg, twice-daily treatment may involve the administration of two 300 mg doses, eg, about 12 hours apart. When the daily dose is 300 mg, twice-daily treatment may involve the administration of two 150 mg doses, eg, about 12 hours apart.

Each dose can be administered in a unit dosage form (eg, a lozenge) or subdivided into multiple unit dosage forms (eg, a plurality of lozenges). For example, each unit dosage form may contain about 100 mg of the compound. Alternatively, each unit dosage form may contain about 150 mg of the compound. Alternatively and preferably, each unit dosage form may contain about 300 mg of the compound.

BK-AEnH As noted above, bradykinin-mediated angioedema can be BK-AEnH.

When BK-AEnH is dipeptidyl peptidase-4 inhibitor-induced angioedema, BK-AEnH can be induced by using dipeptidyl peptidase-4 inhibitor as an antidiabetic drug. BK-AEnH can be composed of sitagliptin, metformin, saxagliptin, linagliptin, empagliflozin, alogliptin Or dipeptidyl peptidase-4 inhibitor-induced by pioglitazone.

In the case where BK-AEnH is inhibitor-induced angioedema, BK-AEnH can be composed of benazepril, captopril, enalapril, fosinopril (fosinopril), lisinopril (lisinopril), moexipril (moexipril), perindopril (perindopril), quinapril (quinapril), ramipril (ramipril) or trandolapril (trandolapril) ) caused by ace inhibitor-inducible.

Where BK-AEnH is tPA-induced angioedema, BK-AEnH can be induced by thrombolytic therapy using tissue plasminogen activator. Patients may receive thrombolytic therapy using tissue plasminogen activator factor, eg, to treat acute stroke, such as ischemic stroke.

In the case where BK-AEnH is non-hereditary angioedema with normal C1 inhibitor (AE-nC1 Inh) and is drug-inducible (ie, drug-induced AE-nC1 Inh), BK-AEnH may be derived from Drug-inducible form caused by at least one of non-steroidal anti-inflammatory agents, beta-lactam antibiotics, and non-beta-lactam antibiotics. The non-steroidal anti-inflammatory agent may be at least one of the following: aspirin, celecoxib, diclofenac, diflunisal, etodolac ibuprofen, Indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxib piroxicam, salsalate, sulindac and tolmetin.

In the case where BK-AEnH is non-hereditary angioedema with normal C1 inhibitor (AE-nC1 Inh) and is drug-inducible (ie, drug-inducible AE-nC1 Inh), BK-AEnH can be vasoconstricted receptor blocker (ARB) induction. For example, BK-AEnH may be azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan (olmesartan), telmisartan (telmisartan) or valsartan (valsartan) induction.

Where BK-AEnH is drug-induced AE-nC1 Inh, BK-AEnH may be drug-inducible by beta blockers.

Where BK-AEnH is a non-hereditary angioedema with normal C1 inhibitor (AE-nC1 Inh) and is hormone-inducible, AE-nC1 Inh may be hormone-inducible by hormonal contraceptives. In some embodiments, AE-nCl Inh may be hormone-inducible by estrogen. For example, the patient can be female and is using estrogen, eg, as a contraceptive.

Compounds of Formula A As noted above, compounds of Formula A may be in the form of the free base or a pharmaceutically acceptable salt and/or solvate thereof.

The compound of formula A is preferably provided in the form of the hydrochloride salt. More specifically, the compound of formula A is preferably provided in the form 5 of the hydrochloride salt.

The present invention provides a solid form (Form 5) of the hydrochloride salt of the compound of formula A having an X-ray powder diffraction pattern comprising characteristic peaks (in °2Θ) at about 10.4, 15.6, 16.7 and 20.8 .

The present invention provides a solid form (Form 5) of the hydrochloride salt of the compound of formula A having an X-ray powder orbit comprising characteristic peaks (in °2Θ) at about 10.4, 13.9, 15.6, 16.7 and 20.8 shot map.

The present invention provides a solid form (Form 5) of the hydrochloride salt of the compound of formula A which exhibits characteristic X-ray powder diffraction peaks (Cu Kα radiation, expressed in °2Θ) at least at about: (1) 10.4, 15.6, 16.7, 17.3 and 20.8; or (2) 10.4, 12.0, 15.6, 16.7, 17.3, 19.7 and 20.8; or (3) 10.4, 12.0, 13.5, 13.9, 15.6, 16.7, 17.3, 19.7 and 20.8.

The present invention also provides a solid form of the hydrochloride salt of the compound of formula A (Form 5) having characteristic peaks comprising at about 10.4, 12.0, 13.5, 13.9, 15.6, 16.1, 16.7, 17.3, 19.7, 20.8 and 25.3 X-ray powder diffraction pattern (expressed in °2Θ).

The present invention provides Form 5 of the hydrochloride salt of the compound of Formula A having an X-ray powder diffraction pattern substantially identical to the X-ray powder diffraction pattern shown in FIG. 5 .

As used herein, the term "about" means that the measurement of °2θ has an uncertainty of ±0.3 (expressed in °2θ), preferably ±0.2 (expressed in °2θ).

The present invention provides Form 5 of the hydrochloride salt of the compound of Formula A, which exhibits an endothermic peak at 161±3°C, preferably 161±2°C, more preferably 161±1°C in its STA thermogram.

The present invention provides Form 5 of the hydrochloride salt of the compound of Formula A having a STA thermogram substantially identical to the STA thermogram shown in FIG. 6 . The present invention also provides a method for the manufacture of any of the oral modified release dosage forms described herein, wherein Form 5 is used in the method.

EXAMPLES General Experimental Details In the following examples, the following abbreviations and definitions are used: Aq aqueous solution DCM Dichloromethane DMF N,N-Dimethylformamide DMSO dimethyl sulfite EtOAc Ethyl acetate HPMC Hydroxypropyl methylcellulose methyl cellulose Hrs Hour IPA 2-Propanol/Propan-2-ol/Isopropanol LCMS liquid chromatography mass spectrometry MCC Microcrystalline Cellulose PH 102 Me methyl MeCN Acetonitrile MeOH methanol Min minute MS mass spectrometry NMR Nuclear Magnetic Resonance Spectroscopy - NMR spectra were recorded at 400 MHz unless otherwise indicated PD pharmacodynamics Pet. Ether Petroleum ether fraction boiling at 60-80°C Ph phenyl PK pharmacokinetics PKa plasma kallikrein PPK Plasma prokallikrein rt room temperature STA Simultaneous Thermal Analysis THF tetrahydrofuran XRPD X-ray powder diffraction All reactions were carried out under nitrogen atmosphere unless otherwise indicated. ^1H NMR spectra were recorded with a Bruker (400 MHz) or JEOL (400 MHz) spectrometer with reference to deuterium solvent and at room temperature.

Molecular ions were obtained using LCMS under the following conditions: Chromolith Speedrod RP-18e column, 50 x 4.6 mm, linear gradient from 10% to 90% 0.1% _HCO2H /MeCN to 0.1% in 13 minutes _HCO2H / _H2O at a flow rate of 1.5 mL/min; or using Agilent, X-Select, acidic, 5%-95% MeCN/water in 4 minutes. Data were collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electrospray ionizer and a Thermofinnigan Surveyor LC system.

Alternatively, molecular ions were obtained using LCMS performed on an Agilent Poroshell 120 EC-C18 (2.7 μm, 3.0 × 50 mm) column, 0.1% v/v formic acid in water [eluent A], MeCN [ Eluent B], the flow rate was 0.8 mL/min and the equilibration time between samples was 1.5 minutes, the gradient is shown below. Mass detection was performed with an API 2000 mass spectrometer (electrospray). gradient: time ( minutes ) Solvent A (%) Solvent B (%) 0.00 95 5 0.20 95 5 2.00 5 95 3.00 5 95 3.25 95 5 3.50 95 5

In the case of purification of the product by flash chromatography, "silica" refers to 0.035 to 0.070 mm (220 to 440 mesh) silica gel (eg Merck Silica 60) used for chromatography, and the applied Nitrogen pressures up to 10 p.s.i facilitate column elution. Reverse-phase preparative HPLC purification was performed using a Waters 2525 binary gradient pumping system at a flow rate typically 20 mL/min using a Waters 2996 photodiode array detector.

All solvents and commercially available reagents were used as received.

Chemical names are generated using automated software such as Autonom software provided as part of the ISIS Draw suite of software from MDL Information Systems or Chemaxon software provided as a component of MarvinSketch or a component of IDBS E-WorkBook.

Example 1 - Determination of Cmin for Prophylactic Treatment ( From an Efficacy Perspective ) Figure 1 shows activation of the contact system. The contact system can be activated by a negatively charged surface that activates FXII to FXIIa. FXIIa mediates the conversion of PPK to PKa and the subsequent cleavage of high molecular weight kininogen (HK) to produce bradykinin, a potent inflammatory hormone.

C1 inhibitors (C1-INH) are major physiological inhibitors of PKa activity. Haegarda® is a medicinal product containing a plasma derived concentrate of C1-INH for the treatment of HAE.

The inventors have developed a novel method for determining a target Cmin suitable for achieving prophylaxis. The goal is to restore the patient to "normal" PKa control. In order to determine what constitutes "normal" Pka control, the inventors have conducted a study of the minimum therapeutic concentration (Ctrough) of Haegarda® given during treatment and its correspondence with "normal" levels of C1-INH in healthy patients. a careful and technical analysis. Knowing that Haegarda® is approved by regulatory agencies (eg FDA) for the prophylactic treatment of HAE, the inventors were able to determine the IC50 multiple of Haegarda® required to provide prophylactic treatment. Because Haegarda® inhibits PKa, which in turn inhibits the contact system, the inventors considered from an efficacy standpoint (ie, regardless of issues such as oral bioavailability and potential adverse events), if a PKa inhibitor could achieve the same The Cmin corresponding to the multiple level of IC50 achieved under Ctrough is suitable for prophylactic treatment.

Without wishing to be bound by theory, the inventors have determined that this assay is the most accurate for a particular assay. Specifically, dextran sulfate-activated (DXS, Sigma; 6.25 μg/ml) plasma (undiluted VisuCon-F control plasma, Affinity Biologicals Inc) was determined by time-dependent hydrolysis of the fluorescent substrate. Catalytic activity of PKa. For IC50 and efficacy determinations, the compound of formula A or C1-INH (Sigma cat# E0518) was added prior to addition of DXS to plasma (Figure 2).

Following this analysis, the inventors have determined the IC50 of Haegarda® to be about 2500 nM. The "normal" range of C1-INH in healthy patients is between 0.15 g/L and 0.35 g/L, with a mean of 0.302 g/L (Tarzi et al., Clinical and Experimental Immunology, 2007; 149: 513-516) . The molecular weight of C1-INH is 105 kDa, so the "normal" range for C1-INH is 1428 nM to 3333 nM.

The mean Ctrough of Haegarda® was 48%, which was 2400 nM ([IC50 Haegarda®/50]×48).

The compound of formula A has an IC50 of 62 nM. The molecular weight of the compound is 509.5 Da.

Using this information, the inventors were able to determine the minimum concentration (Cmin) of the compound considered suitable for prophylactic treatment, as shown in Table 3 below. Table 3 nM (C1-INH) IC50 multiple (IC50 of Haegarda® is 2500 nM) nM ( compound of formula A ) Compound concentration of formula A (ng/mL) 1428 ("normal" lower limit) 0.57 35.4 18.0 2400 Haegarda® Ctrough 0.96 59.5 30.3 3333 ("normal" upper limit) 1.33 82.7 42.1

Compounds of formula A considered suitable for prophylactic therapy due to their similarity to Haegarda's Ctrough have a minimum Cmin of about 30 ng/mL. Example 2 describes a method for preparing a dosage form suitable for achieving this Cmin.

In addition, the compound of formula A was tested and found to be more selective for plasma kallikrein than a series of other serine proteases, as shown in Table 4. Table 4 Target selectivity multiple tissue kallikrein >1000 plasmin >1000 Thrombin >1000 interstitial protease >1000 trypsin >1000 Factor Vila, X, XIa, XIIa >1000

Human serine proteases, namely tissue kallikrein, plasmin, thrombin, interstitial proteases, trypsin and factors VIIx, X, XIa, XIIa, were assayed for enzymatic activity using appropriate fluorescent substrates. Protease activity is measured by monitoring the accumulation of fluorescence released from the substrate. The linear rate of fluorescence increase per minute is expressed as percent activity (%). The Km of each substrate cleavage was determined by standard transformation of the Michaelis-Menten equation. Compound inhibitor assays were performed at substrate Km concentrations and enzymatic activity was calculated as the concentration of inhibitor ( _IC50 ) that produced 50% inhibition of uninhibited enzymatic activity (100%).

example 2 - Formulation manufacturing method i. Synthesis example preparation 1 -({ 4 -[( 5 - fluorine - 2 - side oxypyridine - 1 - base ) methyl ] phenyl } methyl )- N -[( 3 - fluorine - 4 - Methoxypyridine - 2 - base ) methyl ]- 3 -( Methoxymethyl ) Pyrazole - 4 - carboxamide ( Mode A ) the form of 1

向含4-(氯甲基)苯甲醇(4.50 g，28.7 mmol)之丙酮(150 mL)中添加5-氟-2-羥基吡啶(3.57 g，31.6 mmol)及K ₂CO ₃(11.9 g，24.2 mmol)，且在50℃下攪拌反應混合物36小時。冷卻反應混合物，且在真空中移除溶劑。將殘餘物溶解於CHCl ₃(150 mL)中，且用水(30 mL)洗滌，乾燥(Na ₂SO ₄)，過濾且蒸發。用20% IPA-氯仿(3×50 mL)萃取水層。合併所有有機層。使殘餘物吸附至二氧化矽上，且用MeOH-DCM溶離藉由自動急驟層析法純化，得到被鑑別為標題化合物的白色固體(5.65 g，24.2 mmol，84%)。 [M+H] ⁺= 234.2 5 - Fluoro - 1- ( 4 - hydroxymethyl - benzyl ) -1H - pyridin - 2 - one _

To 4-(chloromethyl)benzyl alcohol (4.50 g, 28.7 mmol) in acetone (150 mL) was added 5-fluoro- ₂ -hydroxypyridine (3.57 g, 31.6 mmol) and K2CO3 ₍ 11.9 g, 24.2 mmol), and the reaction mixture was stirred at 50 °C for 36 h. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was dissolved in _CHCl3 (150 mL) and washed with water (30 mL), dried ( _{Na2SO4 )} , filtered and evaporated. The aqueous layer was extracted with 20% IPA-chloroform (3 x 50 mL). All organic layers were combined. The residue was adsorbed onto silica and purified by automated flash chromatography eluting with MeOH-DCM to give a white solid (5.65 g, 24.2 mmol, 84%) identified as the title compound. [M+H] ⁺ = 234.2

向含5-氟-1-(4-羥基甲基-苯甲基)-1H-吡啶-2-酮(1.65g，7.1 mmol)之DCM (100 mL)中添加三溴化磷(665 mL，7.1 mmol)，且在室溫下攪拌反應物2小時。反應混合物用CHCl ₃(100 mL)稀釋，且用飽和NaHCO ₃(aq) (50 mL)、水(10 mL)及鹽水(10 mL)洗滌。將有機層乾燥(Na ₂SO ₄)，過濾且蒸發，得到被鑑別為標題化合物的無色膠狀物(1.85 g，6.3 mmol，88%)，其不經進一步純化即使用。 [M+Na] ⁺= 318.2 1- ( 4 - Bromomethyl - benzyl ) -5 - fluoro - 1H - pyridin - 2 - one

To 5-fluoro-1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one (1.65 g, 7.1 mmol) in DCM (100 mL) was added phosphorus tribromide (665 mL, 7.1 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with _CHCl3 (100 mL) and washed with saturated _NaHCO3 (aq) (50 mL), water (10 mL) and brine (10 mL). The organic layer was dried ( _{Na2SO4 )} , filtered and evaporated to give a colorless gum (1.85 g, 6.3 mmol, 88%) identified as the title compound which was used without further purification. [M+Na] ⁺ = 318.2

向含3-甲氧基甲基-1H-吡唑-4-甲酸甲酯(259 mg，1.5 mmol)之DMF(2 mL)中添加1-(4-溴甲基-苯甲基)-5-氟-1H-吡啶-2-酮(450 mg，1.5 mmol)及K ₂CO ₃(420 mg，3.04 mmol)。在室溫下攪拌反應混合物18小時。濃縮反應混合物，且隨後將其分配於EtOAc (60 mL)與水(20 mL)之間，且依序用水(3×10 mL)及鹽水(10 mL)洗滌。將有機層乾燥(Na ₂SO ₄)，過濾且蒸發。用EtOAc/乙腈-甲醇溶離藉由自動急驟層析法純化粗殘餘物，得到兩種區位異構物。藉由 ¹H NOESY鑑別區位異構物，且分離出呈灰白色固體狀之標題化合物(327 mg，0.85 mmol，55%)。 [M+H] ⁺= 385.8 ¹H NMR (CDCl ₃) 3.49 (3H, s), 3.81 (3H, s), 4.74 (2H, s), 5.10 (2H, s), 5.30 (2H, s), 6.61 (1H, dd, J = 10.4, 5.4 Hz), 7.16 (1H, t, J = 3.5 Hz), 7.25-7.26 (2H, m), 7.29-7.33 (3H, m), 7.81 (1H, s) 1- [ 4- ( 5 - Fluoro - 2 - oxy - 2H - pyridin - 1 - ylmethyl ) -benzyl ] -3 - methoxymethyl- 1H - pyrazole - 4 - carboxylic acid methyl ester

To methyl 3-methoxymethyl-1H-pyrazole-4-carboxylate (259 mg, 1.5 mmol) in DMF (2 mL) was added 1-(4-bromomethyl-benzyl)-5 -Fluoro-lH-pyridin- ₂ -one (450 mg, 1.5 mmol) and K2CO3 ₍ 420 mg, 3.04 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated and then partitioned between EtOAc (60 mL) and water (20 mL) and washed sequentially with water (3 x 10 mL) and brine (10 mL). The organic layer was dried ( _{Na2SO4 )} , filtered and evaporated. The crude residue was purified by automated flash chromatography using EtOAc/acetonitrile-methanol elution to give two regioisomers. The regioisomers were identified ^by1H NOESY and the title compound was isolated as an off-white solid (327 mg, 0.85 mmol, 55%). [M+H] ⁺ = 385.8 ¹ H NMR (CDCl ₃ ) 3.49 (3H, s), 3.81 (3H, s), 4.74 (2H, s), 5.10 (2H, s), 5.30 (2H, s), 6.61 (1H, dd, J = 10.4, 5.4 Hz), 7.16 (1H, t, J = 3.5 Hz), 7.25-7.26 (2H, m), 7.29-7.33 (3H, m), 7.81 (1H, s)

向含1-[4-(5-氟-2-側氧基-2H-吡啶-1-基甲基)-苯甲基]-3-甲氧基甲基-1H-吡唑-4-甲酸甲酯(327mg，0.85 mmol)之乙醇(50 mL)中添加NaOH (339 mg，8.5 mmol)，且在劇烈回流下加熱24小時。冷卻且濃縮反應混合物。粗殘餘物用水(5 mL)稀釋且用DCM (7 mL)洗滌。獲取水相，且用2 M HCl調節至pH 2，且接著用90% CH ₃Cl/10% IPA (6×15 mL)萃取。將有機層乾燥(Na ₂SO ₄)，過濾且濃縮，得到淡黃色固體，其不經進一步純化即使用。 1- [ 4- ( 5 - Fluoro - 2 - oxy - 2H - pyridin - 1 - ylmethyl ) -benzyl ] -3 - methoxymethyl- 1H - pyrazole - 4 - carboxylic acid

to 1-[4-(5-fluoro-2-oxy-2H-pyridin-1-ylmethyl)-benzyl]-3-methoxymethyl-1H-pyrazole-4-carboxylic acid To methyl ester (327 mg, 0.85 mmol) in ethanol (50 mL) was added NaOH (339 mg, 8.5 mmol) and heated at vigorous reflux for 24 hours. The reaction mixture was cooled and concentrated. The crude residue was diluted with water (5 mL) and washed with DCM (7 mL). The aqueous phase was taken and adjusted to pH 2 with 2M HCl, and then extracted with 90% _CH3Cl /10% IPA (6 x 15 mL). The organic layer was dried ( _{Na2SO4 )} , filtered and concentrated to give a pale yellow solid which was used without further purification.

3 - Fluoro - 4 - methoxy- pyridine - 2 - carbonitrile In a large microwave vial, copper cyano (1.304 g, 14.6 mmol) was added to 2-bromo-3-fluoro-4-methoxypyridine ( 1 g, 4.9 mmol) in DMF (5 mL). The reaction vial was sealed and heated to 100°C for 16 hours. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The thick suspension was sonicated and additional water (40 mL) and EtOAc (2 x 50 mL) and sonication were required to decompose the precipitated solid. The combined layers were filtered through a plug of celite and the organic layer was separated, washed with brine (50 mL), dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure to give what was identified as 3-fluoro-4-methoxy yl-pyridine-2-carbonitrile as a pale green solid (100 mg, 0.58 mmol, 12% yield).

( 3 - Fluoro - 4 - methoxy- pyridin - 2 - ylmethyl ) -carbamic acid tert-butyl ester 3-Fluoro-4-methoxy-pyridine-2-carbonitrile (100 mg, 0.58 mmol ) was dissolved in anhydrous MeOH (10 mL, 247 mmol) and nickel chloride hexahydrate (14 mg, 0.058 mmol) was added followed by di-tertiary-butyl dicarbonate (255 mg, 1.16 mmol). The resulting pale green solution was cooled to -5°C in an ice-salt bath, and then sodium borohydride (153 mg, 4.1 mmol) was added in portions while maintaining the reaction temperature at about 0°C. The dark brown solution was stirred at 0°C and slowly warmed to room temperature, and then stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness at 40°C to give a black residue, which was diluted with DCM (10 mL) and washed with sodium bicarbonate (aq) (10 mL). An emulsion formed, so the organics were separated via a phase separation cartridge and concentrated. The crude liquid was purified by chromatography eluting with EtOAc/isohexane to give (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid as a clear yellow oil ( 108 mg, 62% yield). [MH] ⁺ = 257

( 3 - Fluoro - 4 - methoxy- pyridin - 2 - yl ) -methylamine dihydrochloride (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tris Butyl ester (108 mg, 0.36 mmol) was dissolved in isopropanol (1 mL), and then HCl (6 N in isopropanol) (1 mL, 0.58 mmol) was added at room temperature, and at 40 Stir at °C for 2 hours. The reaction mixture was concentrated under reduced pressure and then triturated with diethyl ether and sonicated to give (3-fluoro-4-methoxy-pyridin-2-yl)-methylamine dihydrochloride identified as (3-fluoro-4-methoxy-pyridin-2-yl)-methylamine dihydrochloride of milky white solid (75 mg, 55% yield). [MH] ⁺ = 157

向1-(4-((5-氟-2-側氧基吡啶-1(2 H)-基)甲基)苯甲基)-3-(甲氧基甲基)-1 H-吡唑-4-甲酸(19.4 g，52.1 mmol)於DMF (112 mL)中之溶液中添加1,1'-羰基二咪唑(8.45 g，52.1 mmol)，且將反應混合物加熱至50℃持續2小時。此後，向反應混合物中添加(3-氟-4-甲氧基-吡啶-2-基)-甲胺二氫氯酸鹽(12.0 g，52.1 mmol)，且繼續在50℃下加熱隔夜。將反應混合物冷卻至室溫，隨後在劇烈攪拌下逐滴添加至水(1 L)中。在添加完成後，繼續攪拌1小時。藉由過濾收集產物，且用水(250 mL)洗滌。將濕物質溶解於DCM中且分離水。有機層經Na ₂SO ₄乾燥且經由矽藻土過濾。在真空中移除溶劑，得到21.9 g。 1 -({ 4 -[( 5 - Fluoro - 2 - oxypyridin - 1 - yl ) methyl ] phenyl } methyl ) -N - [( 3 - fluoro - 4 - methoxypyridine - 2- yl ) methyl ] -3- ( methoxymethyl ) pyrazole - 4 - carboxamide Form 1

To 1-(4-((5-fluoro-2-oxypyridin-1( 2H )-yl)methyl)benzyl)-3-(methoxymethyl ) -1H-pyrazole To a solution of -4-carboxylic acid (19.4 g, 52.1 mmol) in DMF (112 mL) was added 1,1'-carbonyldiimidazole (8.45 g, 52.1 mmol) and the reaction mixture was heated to 50 °C for 2 hours. After this time, (3-fluoro-4-methoxy-pyridin-2-yl)-methylamine dihydrochloride (12.0 g, 52.1 mmol) was added to the reaction mixture and heating at 50 °C continued overnight. The reaction mixture was cooled to room temperature and then added dropwise to water (1 L) with vigorous stirring. After the addition was complete, stirring was continued for 1 hour. The product was collected by filtration and washed with water (250 mL). The wet material was dissolved in DCM and the water was separated. The organic layer was dried _{over Na2SO4} and filtered through celite. The solvent was removed in vacuo to give 21.9 g.

The residue was recrystallized from IPA (170 mL) at reflux, cooled to room temperature, then filtered, then dissolved in DCM twice, washed with sodium bicarbonate (aq), dried over Na ₂ SO ₄ , filtered and Concentrate under reduced pressure. The residue was recrystallized from IPA (160 mL) at reflux, cooled to room temperature, and filtered. Trituration with cold tertiary butyl methyl ether and drying gave 1-({4-[(5-fluoro-2-oxypyridin-1-yl)methyl]phenyl}methyl)-N-[( 3-Fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide Form 1 (17 g). ¹ H NMR (400Mhz, d6-DMSO) δ 3.17 (3H, s), 3.83 (3H, s), 4.42 (2H s), 4.44 (2H, d, J = 3.2Hz), 4.92 (2H, s), 5.19 (2H, s), 6.35 (1H, dd, J = 10.0, 5.5Hz), 7.09 (1H, t, J = 6.0Hz), 7.14 (2H, d, J = 8.2Hz), 7.20 (2H, d , J = 8.2Hz), 7.46-7.51 (1H, m), 7.92 (1H, t, J = 0.9Hz), 8.14 (1H, d, J = 5.5Hz), 8.17 (1H, s), 8.34 (1H , t, J = 5.3Hz) ppm.

X-ray powder diffraction patterns were collected with a Philips X-Pert MPD diffractometer and analyzed using the following experimental conditions: Scan parameters: Scan axis: Gonio Start position [°2θ]: 4.0084 Final position [°2θ]: 39.9804 Step size [°2θ]: 0.0170 Scan step time [s]: 10.1600 Scan Type: continuous PSD mode: scanning PSD length [°2θ]: 2.12 Offset [°2θ]: 0.0000 Divergent slit type: automatic Radiation length [mm] 10.00 Sample length [mm]: 10.00 Measuring temperature [℃]: 25.00 Anode material: Cu K-α1 [Å]: 1.54060 K-α2 [Å]: 1.54443 K-A2/K-A1 ratio: 0.50000 Generator settings: 40mA, 40kV Diffraction Type: 0000000011038600 Diffraction number: 0 Goniometer radius [mm]: 240.00 Focal point - divergence slit distance [mm]: 100.00 Incident Beam Monochromator: none Spin: Have

Gently compress approximately 5 mg of the analytical sample on an XRPD zero back ground single beveled silica sample holder. The sample is then loaded into the diffractometer for analysis.

Simultaneous thermal analysis (STA) data was collected using the following method: approximately 5 mg of sample was accurately weighed into a ceramic crucible and placed in the chamber of a Perkin-Elmer STA 600 TGA/DTA analyzer at ambient temperature. The sample is then heated at a rate of 10°C/min (typically from 25°C to 300°C), during which time the weight change as well as the DTA signal are monitored. The purge gas used was nitrogen with a flow rate of 20 cm ³ /min.

The XRPD diffraction pattern of Form 1 is shown in FIG. 3 .

Peak position table: Numbering position [°2θ ] height [cts ] Relative strength [%] 1 7.7 290.2 12.1 2 8.3 91.1 3.8 3 10.7 34.0 1.4 4 11.6 385.3 16.1 5 12.6 247.8 10.3 6 12.8 139.4 5.8 7 13.7 39.4 1.6 8 14.1 48.2 2.0 9 14.7 1090.1 45.4 10 15.2 200.8 8.4 11 15.5 112.2 4.7 12 16.4 54.7 2.3 13 17.1 193.3 8.1 14 17.6 409.3 17.1 15 17.9 1246.2 52.0 16 18.1 1785.6 74.4 17 19.4 1386.7 57.8 18 20.1 2398.9 100.0 19 20.8 583.3 24.3 20 21.4 1207.4 50.3 twenty one 22.1 567.3 23.7 twenty two 22.5 1106.6 46.1 twenty three 23.4 925.6 38.6 twenty four 23.9 567.5 23.7 25 24.2 362.1 15.1 26 24.5 375.2 15.6 27 25.3 563.5 23.5 28 26.0 404.1 16.9 29 26.8 448.1 18.7 30 27.2 229.3 9.6 31 28.3 183.9 7.7 32 29.2 413.8 17.3 33 29.6 441.4 18.4 34 30.2 159.3 6.6 35 31.3 250.7 10.5 36 32.2 198.3 8.3 37 33.6 175.8 7.3 38 34.7 169.1 7.1 39 37.0 83.7 3.5 40 38.1 77.8 3.2 41 38.6 48.5 2.0

Simultaneous Thermal Analysis (STA) The STA data of Form 1 is shown in FIG. 4 .

Preparation of 1 -({ 4 -[( 5 - Fluoro - 2 - oxypyridin - 1 - yl ) methyl ] phenyl } methyl ) -N -[( 3 - fluoro - 4 - methoxypyridine - 2 -yl ) methyl ] -3- ( methoxymethyl ) pyrazole- 4 - carboxamide ( Formula A ) , Form 5 to contain 1-({ 4 -[(5-fluoro-2-pendant oxy Pyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole -4-Carboxamide (15 mg) in THF (150 μL) was added 1.1 equiv of 5 M hydrochloric acid. The mixture was shaken well by hand and the mixture was temperature cycled between ambient temperature and 40°C for 18-24 hours. The supernatant was decanted and the solid was dried by evaporation under nitrogen to give 1-({4-[(5-fluoro-2-oxypyridin-1-yl)methyl]phenyl}methyl) - Form 5 of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide hydrochloride.

1-({4-[(5-Fluoro-2-oxypyridin-1-yl)methyl]phenyl}methyl)-N-[ was also formed by substituting acetone or acetonitrile for THF in the above procedure Form 5 of (3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide hydrochloride.

Alternatively, make 1-({4-[(5-fluoro-2-oxypyridin-1-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridine -2-yl)methyl]-3-(methoxymethyl)pyrazol-4-carboxamide (200 mg) in acetonitrile (1.5 mL) was warmed until the solid dissolved. To the warm solution was added 5.825 M hydrochloric acid prepared by diluting the concentrated acid two-fold (75 μL) and mixed well. The solution remained clear on cooling and was shaken and temperature cycled between 40°C and ambient temperature overnight (18-24 hours). During this time, solids precipitated. This product was filtered, washed with acetonitrile (2 x 1 mL) and dried in a vacuum oven at 45°C to constant weight.

The XRPD diffraction pattern of Form 5 is shown in FIG. 5 .

X -ray powder diffraction ( XRPD ) gently compresses approximately 5 mg of sample on an XRPD zero background single beveled silica sample holder. The samples were then loaded into a Philips X-Pert MPD diffractometer and analyzed using the following experimental conditions. Tube Anode: Cu Generator Voltage: 40 kV Tube Current: 40 mA Wavelength α1: 1.5406 Å Wavelength α2: 1.5444 Å Starting Angle [2θ]: 5 Final Angle [2θ]: 50 Continuous Scan

Slower scan speeds were also used in the range of 4-40° 2Θ.

Peak position table: Peak number Position [ ° 2θ ] height [ cts ] Relative strength [%] 1 10.4042 157.76 30.67 2 12.0072 153.29 29.80 3 13.4813 33.23 6.46 4 13.8923 95.13 18.49 5 14.7637 45.59 8.86 6 15.5554 444.35 86.39 7 16.1659 69.96 13.60 8 16.7151 158.17 30.75 9 17.3384 175.96 34.21 10 17.9408 53.35 10.37 11 18.4108 66.93 13.01 12 19.6706 107.44 20.89 13 20.8041 514.37 100.00 14 21.7757 94.72 18.42 15 22.1694 93.49 18.18 16 22.9322 123.42 23.99 17 23.3265 294.63 57.28 18 23.8368 250.66 48.73 19 24.3231 204.21 39.70 20 24.7721 150.64 29.29 twenty one 25.3337 421.72 81.99 twenty two 26.6168 255.80 49.73 twenty three 26.9841 263.00 51.13 twenty four 27.7541 347.79 67.61 25 28.9760 140.09 27.23 26 30.0910 115.90 22.53 27 31.2447 87.27 16.97 28 32.4371 70.66 13.74 29 32.8761 71.70 13.94 30 33.7488 136.86 26.61 31 34.2919 74.48 14.48 32 34.9433 95.02 18.47 33 35.6342 113.65 22.09 34 36.9027 48.73 9.47 35 39.2527 81.64 15.87

Simultaneous Thermal Analysis ( STA ) Figure 6 shows the STA data for Form 5.

II. Modified Release Lozenge Formulations of Form 5 of the Compound of Formula A Granule Formulations Three blends were prepared according to the blend compositions in Table 5. table 5 Element Blend 1 (% w / w ) Blend 2 (% w / w ) Blend 3 (% w / w ) Intragranular ingredients Compound HCl salt ¹ 42.88% 42.88% 42.88% HPMC (DC2 K4M) 3.00% 5.00% 12.50% Mannitol (Pearlitol 200SD) 17.12% 15.12% 7.62% MCC 20.00% 20.00% 20.00% Povidone Copolyvidone (Kollidon VA 64 Fine) 3.00% 3.00% 3.00% Magnesium stearate 0.50% 0.50% 0.50% talc 3.00% 3.00% 3.00% extragranular components Magnesium stearate 0.50% 0.50% 0.50% MCC 9.00% 9.00% 9.00% Colloidal silica (Cab-o-Sil) 1.00% 1.00% 1.00% total 100.00% 100.00% 100.00% The ¹ salt conversion factor is 1.072, that is, 107.2 mg of HCl salt is equivalent to 100 mg of compound free base.

By sieving each excipient in a 10% excess through an 850 μm screen, the desired amount of each intragranular excipient (except magnesium stearate) was then weighed out and added to the blending vessel to prepare blend formulations. The intragranular excipients (excluding magnesium stearate) were then blended for 18 minutes (until homogenous) using a Turbula® 3D shaking mixer at 23 rpm. The magnesium stearate fraction within the granules was then sieved through a 600 μm screen and added to the blending vessel. The final intragranular blend was then blended for 3 minutes (until homogenous) using a Turbula® 3D shaking mixer at 23 rpm.

The two blends were then dry granulated by rolling the two blends using a Vector TFC experimental micro-roller (Roller Compactor; RC). The RC parameters used were 1000 psi pressure, 1.0 rpm roll speed and 17.0 rpm screw speed.

The collected ribbons were then ground using a mortar and pestle to collect particles with a particle size of less than 800 μm. The granular blend was then sieved through a 250 μm screen and the amount of fines (below 250 μm) was weighed to determine the percentage of fines. The target amount of fines is less than 20%. When the fines content was greater than 20%, the fines were passed through a roller press again and ground again using a mortar and pestle to collect particles smaller than 800 μm. The resulting granules were combined with the granules from the first pass to obtain the final fines content.

The granules are then mixed with extragranular excipients to produce a tableting blend. First, the required amounts of MCC and colloidal silica were weighed out in a 10% excess and sieved through an 850 μm screen. The desired amounts of sieved MCC and colloidal silica are then weighed out and added to the container containing the granules. The resulting blend was then mixed for 12 minutes using a Turbula® 3D shaking mixer at 23 rpm. The required amount plus a 10% excess of magnesium stearate was sieved through a 600 μm sieve. Finally, the required amount of sieved magnesium stearate was added to the vessel containing MCC and colloidal silica and mixed for 3 minutes using a Turbula® 3D shaker mixer at 23 rpm. The final lozenge blend is thus obtained.

Tablet Formulations Each tableting blend was then compressed into 300 mg dose lozenges using a Natoli® Compressor RD10A according to Table 6, resulting in the lozenges of Table 7. Table 6 Lozenge number Lozenge 1 ( from Blend 1 ) Lozenge 2 ( from Blend 2 ) Lozenge 3 ( from Blend 3 ) Dosage (mg) 300 ¹ 300 ¹ 300 ¹ Lozenge weight (mg) 750 750 750 Machining diameter (mm) 12.70 12.70 12.70 Machining convex radius (mm) 18.43 18.43 18.43 Pressure (N) 14000 14000 14000 Table 7 Lozenge number Lozenge 1 ( from Blend 1 ) ( mg ) Lozenge 2 ( from Blend 2 ) ( mg ) Lozenge 3 ( from Blend 3 ) ( mg ) Intragranular ingredients HPMC (DC2 K4M) 22.50 37.50 93.75 Mannitol (Pearlitol 200SD) 128.40 113.40 57.15 MCC 150.00 150.00 150.00 Povidone Copolyvidone (Kollidon VA 64 Fine) 22.50 22.50 22.50 Magnesium stearate 3.75 3.75 3.75 talc 22.50 22.50 22.50 extragranular components Magnesium stearate 3.75 3.75 3.75 MCC 67.50 67.50 67.50 Colloidal silica (Cab-o-Sil) 7.50 7.50 7.50 total 750.00 750.00 750.00 ¹ Dosage strengths are expressed in free base equivalents of the compound.

The 300 mg lozenge was found to be stable during the test period stored at 15-25°C for 70 days (protected from light).

A batch of Tablets 3 was prepared using a pressure of 17,000 N, and then film coated, resulting in Tablets 4. Tablet 4 is film-coated with 30 mg of Opadry® II 85F280012 (white). Opadry® II 85F280012 (white) is a combination of polyvinyl alcohol, polyethylene glycol (PEG) 3350 and titanium dioxide. The total weight of the film-coated tablet 4 was 780 mg.

Placebo for Modified Release Lozenge Formulations A placebo lozenge was prepared for the Phase 1 study. Prosolv® Easytab SP (a mixture of 95.0-98.0% microcrystalline cellulose, 1.5-2.5% colloidal silica, 0.5-2.0% sodium starch glycolate and 0.3-1.0% stearyl rich sodium malate as a commercially available excipient) to prepare lozenges that match the weight and thickness of the 750 mg (300 mg dose) modified release lozenge formulation.

A placebo lozenge was prepared for the Phase 2 study. The composition of the placebo lozenge is the same as that of lozenge 4, except that the compound of formula A is replaced with microcrystalline cellulose PH-200. Placebos were prepared by direct compression. The appearance, thickness and weight of the placebo lozenge and the lozenge 4 were matched.

III. Immediate Release Capsule Formulations of Form 5 of the Compound of Formula A Immediate release (IR) lozenge formulations were prepared according to Table 8.

Hard gelatin Swedish orange capsules of size 00EL are filled with the HCl salt of the compound. The HCl salt of the compound was sieved through an 850 μm screen before filling. Use a spatula to prepare capsules manually. A 300 mg dose is required to be filled to achieve the desired fill weight.

The only excipients included in the immediate release capsule formulation were Swedish orange hard gelatin capsules, a mixture of red iron oxide (colorant; about 1.18 wt%), titanium dioxide (opalescent; about 0.49 wt%) and hard gelatin (framework ; about 98.33% by weight) made of non-prescription excipients. Table 8 Element Quantity per 300 mg capsule ( mg ) ¹ HCl salt of compound 321.60 No. 00, Swedish Orange Hydroxypropyl Methylcellulose Capsules 1 capsule Total amount per capsule ( mg ) 300.00 ¹ Dosage strengths are expressed in free base equivalents of the compound.

Both immediate release capsule formulations were found to be stable during the test period stored at 15-25°C for 35 days (protected from light).

Example 3 - Phase 1 Study A multi-part, Phase 1 crossover study was conducted in healthy individuals to evaluate novel modified release (MR) formulations administered at single and multiple doses compared to a reference immediate release (IR) formulation Pharmacokinetic (PK) profiles of subsequent compounds.

PART 1 - OBJECTIVES AND METHODS The main objectives are as follows: • To evaluate the pharmacokinetics of the compound of formula A following a single oral administration of a modified release (MR) lozenge formulation containing the compound to healthy individuals in the fasted state ( PK) curve. • Relative oral bioavailability of compounds was determined following administration of a single oral dose of the MR prototype lozenge formulation compared to a reference immediate release (IR) capsule formulation in healthy individuals in the fasted state.

A secondary objective was to provide additional information on the safety and tolerability of a single oral dose of the MR prototype tablet formulation and the reference IR capsule formulation in healthy individuals.

Methods Part 1 is a single-center, open-label, non-randomized, 6-period, crossover study designed to study the compound containing formula in healthy male and female subjects compared to a reference immediate release capsule formulation containing the compound. PK and Safety of Modified Release Formulations of Compound A.

Up to 16 subjects are recruited to receive a single oral dosage form comprising a compound of formula A over 6 treatment periods, wherein in cycles 1-5, administration is performed sequentially in the fasted state. In Cycle 6, the effect of food on PK was assessed by administering the dosage form 30 minutes after a standard high-fat breakfast. There was an interval of at least 7 days between administrations of the product. The interval between dosing in Cycles 1 and 3, Cycles 3 and 4, Cycles 4 and 5, and Cycles 5 and 6 was about 14 days.

The 6 cycles are outlined below: cycle dose number of individuals 1 2 x Lozenges 3 16 2 2 x IR capsules 16 3 2 x lozenges 2 16 4 3 x Lozenges 3 15 5 2 x lozenge 3 + 1 x lozenge 1 13 6 3 x lozenges 3 (eaten) 16

Subjects were subjected to a preliminary screening procedure for the study at the screening visit (Day -28 to Day -2). Subjects arrived at the clinical department in the morning prior to product administration (Day -1) in Cycle 1 and in the evening prior to product administration (Day -1) in Cycles 2-6. Subjects remained in the department until 48 hours after dosing (until day 3). Subjects received the formulation in the morning on Day 1 in a non-random fashion after an overnight fast (or high fat breakfast, as appropriate only in Cycle 5 or Cycle 6). Dosing is performed on day 1, with appropriate intervals (eg, about 10 minutes) between individuals based on logistical needs. Start time based on logistics. There is an interval of at least 7 days between each product administration. Meal choices were standardized across treatment periods.

Venous blood samples are collected at the following times: • Collect pre-dose samples ≤ 1 hour before dosing. • Collect samples from 0 to 1 hour post-dose within ±2 minutes of the nominal post-dose sampling time. • Collect samples >1 to 12 hours post-dose within ±10 minutes of the nominal post-dose sampling time. • Collect samples >12 hours post-dose within ±30 minutes of the nominal post-dose sampling time.

Samples were collected into appropriate tubes as instructed by the bioanalytical laboratory.

The samples were analyzed for the free base of the compound of formula A.

Results The mean plasma concentration profile of 6 cycles is shown in FIG. 7, which shows the modified release profile of the tablet of the invention described in Example 2.

No individuals have withdrawn from the study to date. Any adverse events reported were mild and resolved without treatment or intervention.

Part 2 - Objectives and Methods The primary objectives are as follows: • To provide information on the safety and tolerability of multiple oral doses of MR lozenge formulations comprising a compound of Formula A in healthy individuals. • Evaluation of the PK profile of the compound of formula A following multiple oral administrations of selected MR lozenge formulations comprising the compound of formula A at various dose levels in healthy individuals.

The exploratory objective was to collect blood samples for exploratory pharmacodynamic (PD) analysis of plasma kallikrein (PKa) enzymatic activity.

Methods Part 2 was a single-center, randomized, double-blind, placebo-controlled, multiple dose cohort study to investigate the PK and safety of MR lozenge formulations containing compounds in healthy male and female subjects.

18 individuals were recruited and divided into 2 groups (9 individuals in each group). Subjects in each group were randomized in a 7:2 ratio to receive the MR lozenge formulation or placebo for up to 14 days. Meal choices and timing were standardized for each treatment period. Doses for the first cohort were selected after review of the safety and PK data from Part 1, and doses for the second cohort were selected after an interim review of the safety and PK data from Part 2, Cohort 1. During this study period, dose escalation between cycles did not exceed 2-fold.

The 2 groups are outlined below: Group dose number of individuals 1 2 x Lozenges 3 9 (2 received placebo) 2 3 x Lozenges 3 9 (2 received placebo)

Subjects were subjected to a preliminary screening procedure for the study at the screening visit (Day -28 to Day -2). Subjects arrive in the clinical department in the morning prior to product administration (Day -1). Subjects remained in the department until 48 hours after the last dose. Dosing is performed twice daily (every 12 hours) on Days 1 to 13, with the last dose in the morning on Day 14, with an appropriate interval (eg, about 10 minutes) between individuals based on logistical needs ). On the last dosing day, only the morning dose was administered. Start time based on logistics. Standardize meal choices and timings. A follow-up visit is planned 5 to 7 days after the last dose to ensure the individual remains healthy.

A third group (9 individuals) was recruited. Subjects were randomized 7:2 to receive the MR lozenge formulation or placebo for up to 14 days. Meal choices and timing were standardized for each treatment period, and group 3 was tested under "fasting" conditions. Group dose number of individuals 3 ( fasting ) 3 x Lozenges 3 9 (2 received placebo)

Subjects in Cohort 3 were subjected to a preliminary screening procedure for the study at the screening visit (Day -28 to Day -2). Subjects arrive in the clinical department in the morning prior to product administration (Day -1). Subjects remained in the department until 48 hours after the last dose. Dosing is performed twice daily (every 12 hours) on days 1 to 13, with the last dose in the morning on day 14, with appropriate intervals between individuals based on logistical needs (eg, about 10 minutes) ). On the last dosing day, only the morning dose was administered. Start time based on logistics. Subjects are provided a light breakfast about 2 hours after the morning dose, lunch about 4 hours after the morning dose, dinner about 10 hours after the morning dose, and a late night snack about 14 hours after the morning dose. A follow-up visit is planned 5 to 7 days after the last dose to ensure the individual remains healthy.

Venous blood samples are collected at the following times: ● On Day 1 only: Collect pre-dose samples ≤ 1 hour prior to dosing. • On Days 1 to 14: Samples were collected within ≤ 10 minutes of the nominal time point where the 12-hour dosing was consistent with the pre-dose sample. • Collect samples from 0 to 1 hour post-dose within ±2 minutes of the nominal post-dose sampling time. • Collect samples >1 to 12 hours post-dose within ±10 minutes of the nominal post-dose sampling time. • Collect samples >12 hours post-dose within ±30 minutes of the nominal post-dose sampling time.

Samples were collected into appropriate tubes as instructed by the bioanalytical laboratory.

Samples were analyzed for compounds of formula A.

Pharmacodynamic activity was analyzed according to the following procedure. Three aliquots of pre-dose plasma from each individual were provided. These aliquots were activated individually to yield 3 predose activity values. The 3 values were averaged to obtain 100% activity of each individual. The remaining pre-dose plasma was then pooled and used for QC purposes. Tests were performed unactivated and activated, n=4 times. This data was used to confirm whether there was any pre-activation in the pre-dose plasma samples caused by DXS stimulation, and secondly to identify whether there were changes in the activation of individual plasmas.

Plasma samples for PK assessment were analyzed using a validated liquid chromatography coupled with mass spectrometry (LC MS/MS) method.

PD measurements were determined in dextran sulfate (DXS) stimulated undiluted plasma using a luciferase assay and a capillary-based HK lysis immunoassay.

The catalytic activity of PKa in DXS stimulated (Sigma; 6.25 μg/ml) plasma samples was determined by time-dependent hydrolysis of the fluorescent substrate in all samples from all parts of the study.

The time to onset of detectable amidohydrolase activity in DXS-stimulated plasma (lag time) was calculated from the catalytic activity assay. Using a Spark (Tecan) fluorometer, the rate of catalytic activity in plasma was detected with a sensitivity of fluorescence increments up to 1 ΔF units/sec.

Results The mean plasma concentration profiles for subjects in Group 1 who did not receive placebo are shown in FIG. 8 . This graph shows that steady state was reached on day 2/3. This graph also shows that the Cmin before the morning dose (ie, during the night) is higher compared to the Cmin before the evening dose (ie, during the day).

Figure 9 overlays the PK curves of Day 1, Day 14 with the PK curves of Cycle 1 (from Part 1) for subjects not receiving placebo. This shows that the MR formulations of the present invention have consistent PK profiles during repeated doses, indicating that multiple dosing has little effect on absorption and/or clearance rates. This reduces the likelihood of drug-drug interactions.

Figure 10 shows mean plasma kallikrein activity levels for subjects in Group 1 who did not receive placebo compared to pre-dose levels. Figure 11 shows mean plasma kallikrein activity levels on Days 1 and 14 for subjects in Group 1 who did not receive placebo, compared to pre-dose levels. The curve shows a decrease in PKa activity in the individual, which is indicative of plasma kallikrein inhibition by the compound of formula A.

Figure 12 shows other reported PK parameters for Group 1 in Part 2 and Cycles 1, 4 and 6 in Part 1.

No individuals in group 1 dropped out. Any adverse events reported were mild and resolved without treatment or intervention.

Figure 13a shows the complete mean plasma concentration profile of subjects in Group 2 in Part 2 who did not receive placebo. This graph shows that steady state was reached on day 2/3. This graph also shows that the Cmin before the morning dose (ie, during the night) is higher compared to the Cmin before the evening dose (ie, during the day).

Figure 13b shows the overlap of the mean plasma concentration profile on Day 1 for subjects in Group 2 who did not receive placebo and the PK profile for Group 1 on Day 1. Figure 13c shows the mean plasma kallikrein activity levels for subjects in Group 2 who did not receive placebo compared to pre-dose levels.

Figure 14a shows the overlap of the mean plasma concentration profiles from Day 1 to Day 7 for subjects in Cohort 2 who did not receive placebo and the PK profile for Day 1 to Day 14 in Cohort 1. Figure 14b shows the overlap of the complete mean plasma concentration profile from Day 1 to Day 14 for subjects in Group 2 who did not receive placebo and the PK profile for Group 1 from Day 1 to Day 14. Figures 14a and 14b show that group 2 reached steady state on day 2/3. This graph also shows that the Cmin before the morning dose (ie, during the night) is higher compared to the Cmin before the evening dose (ie, during the day).

No individuals have withdrawn from the study to date. Any adverse events reported were mild and resolved without treatment or intervention.

As shown in Figure 15a, where Cmin is expressed as an IC50-fold value, as tested in the undiluted plasma assay described in Example 1, the Cmin reported for both groups in excess of that can be considered suitable for prophylactic treatment the minimum Cmin (about 30 ng/mL). Indeed, Cmin exceeded IC50 throughout the study. Thus, the concentration of the compound is maintained at least at levels comparable to normal C1inh levels, and many times higher than this level for most of the day. Indeed, Figure 15a shows that the steady state Cmin is at least about 2-fold higher than the approved Ctrough of the approved treatment Haegarda® (by comparing their respective IC50 folds). Figure 15b shows the complete 14-day data for groups 1 and 2.

Figure 16a shows the mean plasma concentration profile of subjects in Group 3 who did not receive placebo. Figure 16b shows the PK curves of group 3 at day 1, day 10 and day 14. The PK curves on Days 1 and 14 were recorded after the morning dose, while the PK curve on Day 10 was recorded after the evening dose.

Figure 17a shows the overlap of the mean plasma concentration curves from Day 1 to Day 14 for subjects in groups 1 to 3 who did not receive placebo. Figure 17b shows the overlap of the mean plasma concentration curves on Day 1 and Day 14 for subjects in groups 1 to 3 who did not receive placebo. Figure 17c shows the complete PK information for Cycles 1, 4 and 6 in Part 1 and Groups 1, 2 and 3 in Part 2.

These data indicate that the oral modified release pharmaceutical dosage form of the present invention provides a PK profile of a compound of formula A suitable for the prophylactic treatment of bradykinin-mediated angioedema (eg, BK-AEnH, more preferably HAE).

Example 4 - Example Phase 2 Study of Compound of Formula A is based on a Phase 2 clinical trial protocol, which has received ethical approval from the Canadian Institutional Review Board (IRB) and has been approved by the Canadian Division of Clinical Trials. The Phase 2 program has also received a Clinical Trial Authorization (CTA) from the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom.

OBJECTIVE : To evaluate the efficacy and safety of compounds of formula A in the prophylactic treatment of angioedema episodes in adult individuals with type I or type II hereditary angioedema.

Methods : The study was a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2 clinical trial investigating three doses of a compound (oral plasma kallikrein inhibitor) in patients with type I or type II hereditary Efficacy and safety in long-term prophylactic treatment of individuals with angioedema (EudraCT number: 2021-000136-59).

Objectives : Primary Objectives : • To demonstrate the clinical efficacy of prophylactic treatment with compound in preventing the onset of Hereditary Angioedema (HAE) compared to placebo.

Secondary objectives: • To further characterize the clinical efficacy of the compound. ● To study the safety and tolerability of the compounds.

Benefit / Risk The compound has been evaluated in two Phase 1 studies in adult healthy volunteers, one of which is described above. Pharmacodynamic evaluation of the compound has shown that the compound inhibits plasma kallikrein activity ex vivo at levels greater than the equivalent concentration of beloxostat, the currently approved indication for the prevention of HAE episodes. Oral plasma kallikrein inhibitor once daily. The compound achieves sufficient plasma concentrations and continues to inhibit plasma kallikrein over an interval of 12 to 14 hours. These data support further investigation of the compound as an orally administered treatment with sufficient plasma kallikrein inhibition to potentially prevent or reduce the occurrence of HAE episodes.

Administration of this compound to humans is supported by preclinical studies (including in vitro and in vivo safety pharmacology studies) and animal studies in mice, rats and non-human primates. The doses given in this trial were well tolerated in a previous clinical trial involving 16 subjects who received a single dose of the compound up to 900 mg, and 21 subjects who received at least 600 mg twice daily for 14 days the individual. All adverse events observed in these studies were mild and of short duration. No grade 3 (severe) or serious adverse events (SAEs) were reported.

Setting : This is a multicenter, randomized, double-blind, placebo-controlled Phase 2 clinical trial. Individuals with HAE will be recruited through global HAE treatment centers.

This trial will be conducted on an outpatient basis and will include clinical visits or home health visits when clinical visits are not possible (eg, in the event of a pandemic or other reasons that prevent individuals from attending clinical visits).

Screening interview The screening period includes the screening interview and the enrollment period. All subjects will sign informed consent prior to any trial-related procedures. Consent may be collected via a remote electronic consent scheme if permitted by national and regional regulations. Individuals will be 18 years of age or older at the time of screening and diagnosed with HAE Type I or Type II.

During the interview, a physical examination, 12-lead electrocardiogram (ECG), laboratory tests, and other evaluations will also be performed.

Subjects will be trained by field staff on the requirements for reporting episodes and the information expected to be provided by the subject in an electronic diary (eDiary) provided by the study sponsor. Subjects will confirm understanding of the requirements for reporting episodes.

Enrollment Period Screened individuals will enter an enrollment period lasting up to 8 weeks. The start of the enrolment period is determined by the type of HAE therapy an individual is using at the time of screening, as follows: On-demand therapy only for HAE episodes : On-demand therapy only individuals will be assessed at the completion of the screening visit electronic diary into the inclusion period. • Use of prophylactic therapy to treat HAE episodes : After discontinuation of all prophylactic therapy, subjects using any prophylactic therapy will enter the enrollment period following the first investigator-confirmed episode of HAE. This episode did not count towards the total number of episodes required to meet the eligibility criteria. Individuals must enter the Enrollment Period within 8 weeks of completing the Electronic Diary Assessment of the Screening Interview.

During the inclusion period, all individuals must meet one of the following eligibility criteria: • Two investigator-confirmed episodes within the first 4 weeks. ● Three investigator-confirmed episodes within ≤8 weeks.

Once the above inclusion period criteria are met, individuals can proceed to random access. Individuals who do not meet the inclusion criteria will not be eligible for randomization and will not be allowed to rescreen.

Randomized individuals will complete the randomization visit within 10 days of completing the enrollment period. Subjects will be randomized 1:1:1:1 to receive one of the following treatments twice daily: ● 300 mg (1 x 300 mg lozenges) of compound ● 600 mg (2 x 300 mg lozenges) of compound ● 900 mg (3 x 300 mg lozenges) compound Match placebo

The remaining number of subjects assigned to placebo will receive 1, 2 or 3 lozenges.

Randomization will be graded by the number of investigator-confirmed episodes of HAE during the inclusion period (ie, < 3 episodes/4 weeks or >3 episodes/4 weeks).

Treatment Period The treatment period will last 12 weeks and will begin with the first dose of the investigational medicinal product (IMP). Subjects will take their first dose at breakfast the day following receipt of the IMP. During the treatment period, subjects will self-administer IMP (300, 600 or 900 mg of compound or matching placebo) twice daily at breakfast and dinner, approximately 12 hours apart.

The following treatments were not permitted during the trial: ● Long-term or short-term prevention of HAE, including: o C1-esterase inhibitors (C1-INH) for prophylaxis (eg Haegarda, Cinryze, Berinert, Ruconest). o Lanalizumab o Anti-androgens (eg, stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) o Antifibrinolytics (eg, tranexamic acid) o Belostat o Other investigational therapies for HAE prophylaxis (eg, garadacimab, PKK-LRx, PHVS416) ● Angiotensin-converting enzyme (ACE) inhibitors ● Estrogen-containing drugs that are systemically absorbed, including: o Oral contraceptives or hormone replacement therapy including ethinyl estradiol ● Potent CYP3A4 inhibitor and inducer. • Narrow therapeutic index drugs metabolized by CYP3A4 or CYP2C9 or transported by OAT1, OCT2 and OATP1B1 were also inhibited throughout the experiment, as determined by the investigator.

During the trial period, including the enrollment period, treatment of HAE episodes should be managed according to the individual's known care, including the use of on-demand therapy as deemed medically appropriate. C1-INH is licensed as on-demand therapy, but not as long-term or short-term prophylaxis. Even if an individual requires on-demand treatment due to an episode of HAE during the trial, the administration of the investigational product and the trial procedure will continue without changing the schedule specified by the protocol.

During the trial, subjects will be instructed to record details of each episode of HAE in an electronic diary. The investigator (or a qualified designee) will assess whether the reported episodes are caused by HAE, as described below.

During treatment, subjects will complete clinical or home health visits at Weeks 2, 6 and 12/Early Termination (ET). A 12-lead ECG, laboratory tests, and other evaluations will be performed during the clinical or home health visit. Interviews should take place within 3 days of the Week 2 and Week 6 interviews. The Week 12/ET visit should be within 7 days of the last dose of IMP.

Subjects will also complete a quality of life assessment at the screening visit, at weeks 4 and 8 after starting dosing, and at the last dose. The Medication Satisfaction Questionnaire (TSQM) will be completed at the time of the last dose.

Investigational medicinal product : Compound of Formula A, 300 mg modified release lozenge 4, as described in Example 2, Part II.

Placebo for Compound 300 mg modified release lozenge, as described in Example 2, Part II, above.

The lozenge must be swallowed whole; the lozenge must not be crushed or modified in any way.

Number of individuals : Approximately 48 individuals were randomly assigned to the trial.

Population : The trial population will include male and female individuals 18 years of age or older with HAE type I or II.

Inclusion criteria : 1) Male or female individuals 18 years of age and older. 2) Diagnosis of HAE type I or II at any time in the medical history: a) A clinical history record consistent with HAE (subcutaneous or mucosal, non-pruritic swelling episodes, but not accompanied by urticaria), and either of the following Those who: b) Diagnostic test results obtained during screening confirm type I or II HAE: C1-INH functional level <40% of normal level. Individuals were eligible if their functional C1-INH level was 40% to 50% of the normal level, and their C4 level was also below the normal range. If the results are inconsistent with clinical history, or the investigator believes confounding due to recent use of prophylactic or therapeutic C1-INH, the individual may be retested during screening, or c) confirm known HAE type I or II The documented genetic findings of the mutation. 3) The individual has access and ability to use known treatments for HAE episodes. 4) The subject is willing to discontinue any medications currently used for HAE prevention, and the investigator determines that this does not expose the subject to any undue safety risks. 5) The subject's last use of a sterile androgen line was at least 28 days prior to randomization. 6) During the inclusion period, the subject met one of the following criteria: a) Had two investigator-confirmed episodes within the first 4-week period. b) Three investigator-confirmed episodes within ≤8 weeks. 7) Throughout the trial, fertile and heterosexual individuals must adhere to the following contraceptive requirements: a) Female individuals must agree to use at least one highly effective method of contraception from the screening visit until the end of the trial. Highly effective methods of contraception include: i) Progestin-only hormonal contraceptives associated with ovulation inhibition: oral/injectable/implantable (hormonal contraceptives containing estrogens including ethinyl estradiol are excluded according to exclusion criterion 4). ii) Intrauterine Device (IUD). iii) Intrauterine hormone releasing system (IUS). iv) Bilateral tubal closure. v) The vasectomy partner (with the restriction that the partner is the only sexual partner of a fertile female individual, and the vasectomy partner has been medically assessed as a successful operation). b) Male subjects with female partners (who are fertile) must agree to use condoms throughout the treatment period and within 90 days of the last dose of the investigational medicinal product (IMP). Female partners were encouraged to use contraception as outlined in inclusion criteria 7a) from the screening visit until the end of the trial. Hormonal contraceptives containing estrogen including ethinyl estradiol are acceptable for female partners. 8) As defined below, infertile or sexually inactive individuals do not require contraception. a) Individuals who did not engage in sexual intercourse with the opposite sex during the trial (if the reliability of heterosexual abstinence has been assessed for the duration of the clinical trial and this is the individual's preferred and common lifestyle). b) Male individuals who have been surgically sterilized (eg, vasectomy that has been medically evaluated as successful surgery). c) Female individuals who have been surgically sterilized (eg, have undergone hysterectomy, bilateral oophorectomy or bilateral tubal ligation) or who have been postmenopausal for at least 12 months. 9) The subject must be able to swallow the test lozenge whole. 10) The individual assessed by the investigator must be able to receive and store the IMP appropriately and be able to read, understand and complete the electronic diary. 11) The investigator believes that the individual is willing and able to comply with all protocol requirements. 12) The individual provides signed informed consent and is willing and able to comply with the trial requirements and procedures.

Exclusion Criteria : 1) Any concomitant diagnosis of another form of chronic angioedema such as acquired C1 inhibitor deficiency, HAE with normal C1-INH (previously known as HAE type III), idiopathic angioedema or concomitant Angioedema with urticaria. 2) History of clinically significant adverse reactions to C1-INH therapy or plasma kallikrein inhibitor therapy used to manage HAE in the opinion of the investigator. 3) Use of an angiotensin-converting enzyme (ACE) inhibitor after the screening visit or within 7 days prior to randomization. 4) Use of any systemically absorbable estrogen-containing medication (such as oral contraceptives including ethinyl estradiol or hormone replacement therapy) after the screening visit or within 7 days prior to randomization. 5) Use of narrow therapeutic index drugs metabolized by CYP3A4 or CYP2C9 or transported by OAT1, OCT2, and OATP1B1 at initiation of screening, as determined by the investigator. 6) Use of potent CYP3A4 inhibitors and inducers during participation in the trial since the screening visit. Note: These drugs include (but are not limited to) the following: Inhibitors : boceprevir, clarithromycin, cobicistat, denoprevir, eltig elvitegravir, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone ), nelfinavir, ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, Telaprevir, telithromycin, tipranavir, troleandomycin and voriconazole. Inducers : apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort . John's Wort). 7) Organ insufficiency, including (but not limited to): a) Alanine aminotransferase (ALT) > 2×ULN b) Aspartate aminotransferase (AST) > 2×ULN c) Direct bilirubin > 1.25×ULN d) International Normalized Ratio (INR) > 1.2 e) Clinically significant hepatic impairment, defined as Child-Pugh B or C f) eGFR < 60 mL/min 8) In the opinion of the investigator, after participating in the trial Any clinically significant comorbidity or systemic dysfunction that would compromise the safety of the individual. 9) History of substance abuse or dependence that would interfere with completion of the trial, as determined by the investigator. 10) Known hypersensitivity to compound or placebo or any excipient. 11) Any previous gene therapy treatment with HAE. 12) Participate in any interventional investigational clinical trial, including an investigational COVID-19 vaccine trial, within 4 weeks of the last dose of the investigational drug prior to screening. 13) Anyone who is pregnant or breastfeeding.

Assessment : Individual Demographics and Medical History Demographic and baseline data will include year of birth, height (meters [m]; no shoes), weight (kg), race and ethnicity (if allowed), and sex.

The medical history will document any relevant pre-existing and concurrent diseases, history of HAE disease; therapies and complementary treatments used within the past 4 weeks; and participation in interventional clinical studies within the past 4 weeks.

Efficacy Assessment When an HAE episode occurs, the individual will provide a description of the HAE episode in the individual electronic diary. If the individual is incapacitated during the episode and details cannot be recorded, this information can be recorded after the incapacitation has resolved. This description will include: ● Start and stop dates/times of each episode ● Site of each episode ● Symptoms including prodromal symptoms ● Effects on activity ● Conventional treatments used for each episode ● Individual assessment of episode severity

Field staff and subjects are to be contacted as soon as possible and within 5 working days after each episode has ended to confirm, clarify and correct any recorded electronic diary information. Field staff collecting information on HAE episodes from individuals must be assigned and qualified to perform this task. Additionally, assigned field staff will ask questions about each episode to assist the investigator (or qualified designee) in confirming each episode.

The investigator (or a qualified designee) will assess whether the reported episodes are caused by HAE. To be classified as an investigator-confirmed HAE episode, an event must have symptoms or conditions consistent with an episode in at least one of the following: ● Peripheral angioedema: swelling of the skin involving the extremities, face, neck, trunk, and/or urogenital tract area. ● Abdominal angioedema: abdominal pain with or without bloating, nausea, vomiting, or diarrhea. ● Angioedema of the throat: hoarseness, difficulty breathing, difficulty speaking, swallowing, throat tightness, or swelling of the tongue, palate, uvula, or larynx.

The investigator (or a qualified designee) will rate the severity of each episode on the following scale: ● mild ● Moderate ● Severe

Despite the presence of these symptoms, the investigator can clinically determine that the event is not indicative of an HAE episode if there are features that strongly contradict such a diagnosis. For example, the reported event was accompanied by symptoms inconsistent with an HAE episode (eg, urticaria), the reported event duration was well beyond the typical time course of an HAE episode, or the event had a possible other etiology (eg, the individual's Abdominal symptoms may be caused by viral gastroenteritis).

Description of HAE episodes: ● A new symptom must occur at least 24 hours after the resolution of the previous episode to be considered a separate episode and distinct from the previous episode. ● The prodrome itself is not considered an episode. • The use of drugs known to treat acute HAE episodes by themselves does not confirm the occurrence of an episode. • Onset time was defined as the time when the first symptom appeared or when the individual experienced symptoms (eg, upon awakening). ● Seizure resolution is defined as the absence of seizure symptoms.

Angioedema Control Test ( AECT ) AECT is a validated, self-administered, retrospective, 4-item patient-reported outcome measure for patients with recurrent angioedema, which is used for quantitative disease control and adjuvant therapy decision making (Weller K et al, Development of the Angioedema Control Test-A patient-reported outcome measure that assesses disease control in patients with recurrent angioedema. Allergy. 2020 May;75(5):1165-1177. doi: 10.1111/all .14144; Weller K et al, Validation of the Angioedema Control Test (AECT)-A Patient-Reported Outcome Instrument for Assessing Angioedema Control. J Allergy Clin Immunol Pract. 2020 Jun;8(6):2050-2057.e4 . doi: 10.1016/j.jaip.2020.02.038). The questionnaire addressed the incidence of angioedema, angioedema-related impairment of quality of life (QoL), the unpredictability of angioedema onset, and the control of angioedema by current treatments. Each of the 4 AECT items is scored on a scale of 0 to 4, with higher scores indicating higher levels of angioedema control. The AECT score was calculated by adding the scores for all 4 items, with the minimum and maximum possible scores being 0 and 16 points. 1. How often have you experienced angioedema in the past 4 weeks? 2. How much has your quality of life been affected by angioedema in the past 4 weeks? 3. How much has the unpredictability of angioedema bothered you in the past 4 weeks? 4. How well has your angioedema been controlled with treatment in the past 4 weeks?

Angioedema Quality of Life Questionnaire ( AE - QoL ) The AE-QoL is a symptom-specific health-related QoL tool for patients with recurrent angioedema. It consists of 17 items that can be grouped into a total score or 4 distinct domain scores ("Function", "Fatigue/Mood", "Worry/Shame" and "Eating"), which are collectively assessed within the past 4 weeks Degree of QoL impairment associated with angioedema. Each AE-QoL question has 5 answer options (scores 1-5), with lower and higher scores indicating less and greater adverse effects, respectively. The total score was calculated and subsequently converted to a linear scale ranging from 0 to 100, with a score of 100 indicating the most severe damage possible. A minimal clinically important difference of 6 has been described (Weller K et al, Development and construct validation of the angioedema quality of life questionnaire. Allergy. 2012 Oct;67(10):1289-98. doi: 10.1111/all.12007 ; Weller K et al, The Angioedema Quality of Life Questionnaire (AE-QoL) - assessment of sensitivity to change and minimal clinically important difference. Allergy. 2016 Aug;71(8):1203-9. doi: 10.1111/all .12900).

Medication Treatment Satisfaction Questionnaire ( TSQM ) TSQM is a psychometrically reasonable and valid measure of patient satisfaction with medication (Atkinson et al., Validation of a general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004 Feb 26;2:12. doi: 10.1186/1477-7525-2-12). The questionnaire contains 14 questions, which are rated on a 7-point bipolar scale ranging from "extremely satisfied" to "extremely dissatisfied." ● How satisfied or dissatisfied are you with the drug's ability to prevent or treat the condition? ● How satisfied or dissatisfied are you with the way your medication relieves your symptoms? ● How satisfied or dissatisfied are you with the time it takes for the drug to start working? ● Are you currently experiencing any side effects from taking this drug? ● How much trouble do you have with the side effects of the medicines you use to treat your condition? ● How much does the side effect interfere with your physical health and function (ie strength, energy levels, etc.)? ● How much does the side effect interfere with your mental functioning (ie, the ability to think clearly, stay awake, etc.)? ● To what extent do medication side effects affect your overall satisfaction with your medication? ● How easy is it to use the drug in its current form? ● How easy is it to plan the timing of each use of the medication? ● How convenient or inconvenient is it to take the medication as directed? ● Overall, how confident are you that taking this drug will benefit you? ● How certain are you that the benefits of the drug outweigh the harms? ● All things considered, how satisfied or dissatisfied are you with this drug?

Safety variables : ● Physical examination results. ● Vital signs, including the subject's pulse rate, respiratory rate, and systolic and diastolic blood pressure after at least 5 minutes of rest. ● 12-lead electrocardiogram (ECG) results. ● Laboratory test results (clinical chemistry, hematology, coagulation, liver enzymes, electrolytes and urinalysis). ● Pregnancy testing (for female individuals of childbearing potential). ● Adverse events (AEs), including serious adverse events (SAEs).

Efficacy Assessment Criteria Primary Endpoint • Investigator-confirmed HAE episode rate during treatment.

Secondary endpoints • Proportion of individuals who did not experience an investigator-confirmed episode of HAE during the treatment period. ● Investigator-confirmed HAE episode rate requiring conventional therapy during treatment. ● AE-QoL total and domain scores during the treatment period. ● AECT scores and domain scores during the treatment period. • Proportion of subjects with AECT score ≥12 at the end of the treatment period. Exploratory Endpoints • Investigator-confirmed incidence of HAE episodes during treatment, by severity. ● Utilization of known treatments during treatment. • Total TSQM score at the end of the treatment period.

GENERAL STATISTICAL METHODS AND TYPES OF ANALYSIS POPULATIONS USED FOR ANALYSIS ● The screening group included all individuals who had signed informed consent. ● The inclusion group included all individuals who had signed informed consent and started the inclusion period. • The randomization group includes all subjects randomized. • The safety arm (SAF) includes all subjects randomized and receiving at least one dose of IMP. • The Full Analysis Set (FAS) included all subjects who were randomized, received at least 1 dose of IMP, and recorded post-baseline HAE diaries. Individuals will be analyzed according to randomized treatment. The FAS population will be the population for the efficacy analysis. • The per-protocol group (PPS) included all subjects from FAS who completed the 12-week trial and had no pre-defined major protocol deviation that could affect the primary efficacy endpoint.

Sample size : Using a two-sided 5% test adjusted with Bonferroni correction, approximately 48 subjects (each efficacious dose and placebo) detected a 70% reduction in monthly attack rates. A dose level of approximately 12 randomly assigned) of total sample volume will provide at least 90% accuracy (power). This assumes that subjects on placebo had an average of at least 2 seizures every 4 weeks and that approximately 90% of these subjects completed the Poisson distribution of the 12-week trial. This sample volume will also provide over 80% accuracy in detecting the minor effect of a 50% reduction in seizure rate. In addition, this sample size also ensured approximately 90% accuracy in detecting a 70% reduction if the attack rate in the placebo group was lower than the expected attack every 4 weeks. The onset rate of HAE was assumed to follow a Poisson distribution, therefore, a test of the ratio of two Poisson rates was used to calculate sample size, but negative binomial regression was used as the primary analysis to correct for potential overdispersion in the model. Sample volume calculations were performed using PASS v20.0.3.

General considerations will be to analyze quantitative data by the number of observations and the number and percentage of individuals in each category.

Quantitative data will be analyzed by number of observations, mean and standard deviation (SD), median, first and third quartiles, minimum and maximum.

All statistical tests will be 2-sided, with an alpha of 0.05. The primary efficacy endpoint analysis will be adjusted for Bonfronib multiplicity for multiple dose levels, so the pairwise comparison test will be 2-sided with an alpha of 0.0167. No multiplicity adjustment was made for analyses of secondary or exploratory endpoints.

The primary end point will be analyzed by negative binomial regression with the randomization stratification factor of baseline attack rate every 4 weeks during the inclusion period as a fixed covariate and treatment as a fixed factor, and each individual has a "during treatment period" The logarithm of the observation time was used as the offset variable in the model. This model will be used to estimate the rate of HAE episodes and the rate of HAE episodes (compound versus placebo for each dose group) during the treatment period, with 95% confidence intervals and 2-sided p-values.

。 The present invention also provides the following numbered embodiments: 1. A method for the prophylactic treatment of bradykinin-mediated angioedema, comprising: orally administering a compound of formula A (or a medicament thereof to a patient in need thereof) Chemically acceptable salts and/or solvates), wherein the compound of formula A is

.

。 2. A compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use in a method for the prophylactic treatment of bradykinin-mediated angioedema, the method comprising: Oral administration of a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need, wherein the compound of formula A is

.

。 3. Use of a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for the manufacture of a medicament for the prophylactic treatment of bradykinin-mediated angioedema, the prophylactic Sexual therapy comprises orally administering to a patient in need a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof), wherein the compound of formula A is

.

4. The method of embodiment 1; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 2; or the use of embodiment 3; wherein the prevention Sexual therapy is prophylactic treatment against bradykinin-mediated episodes of angioedema.

5. The method of any one of embodiments 1 or 4; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any one of embodiments 2 or 4 ; or the use of any one of embodiments 3 to 4; wherein the bradykinin-mediated angioedema is hereditary angioedema (HAE); or wherein the bradykinin-mediated angioedema is bradykinin-mediated angioedema Kinin-mediated nonhereditary angioedema (BK-AEnH).

6. The method of embodiment 5; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 5; or the use of embodiment 5; Kinin-mediated angioedema is hereditary angioedema (HAE).

7. The method of embodiment 5; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 5; or the use of embodiment 5; Kinin-mediated angioedema is bradykinin-mediated nonhereditary angioedema (BK-AEnH).

8. The method of any one of embodiment 1 or embodiment 4 to 7; the compound of formula A (or a pharmaceutically acceptable form thereof) for use according to any one of embodiment 2 or embodiment 4 to 7. salt and/or solvate); or the use of any one of embodiments 3 to 7; wherein the prophylactic treatment reduces the mean number of bradykinin-mediated episodes of angioedema.

9. The method of any one of embodiment 1 or embodiment 4 to 8; the compound of formula A (or a pharmaceutically acceptable form thereof) for use in any one of embodiment 2 and embodiment 4 to 8 salt and/or solvate); or the use of any one of embodiments 3 to 8; wherein the prophylactic treatment reduces the average number of bradykinin-mediated angioedema episodes requiring acute treatment.

10. The method of embodiment 9; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 9; or the use of embodiment 9; wherein it may be desired The acute treatment is rescue medication selected from the group consisting of pdC1INH, rhC1INH, icatibant and KVD900 (N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3- (Methoxymethyl)-1-({4-[(2-Oxypyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide).

11. The method of any one of embodiment 1 or embodiment 4 to 10; the compound of formula A (or a pharmaceutically acceptable form thereof) for use according to any one of embodiment 2 or embodiment 4 to 10 salt and/or solvate); or the use of any one of embodiments 3 to 10; wherein the prophylactic treatment reduces the mean number of moderate or severe bradykinin-mediated episodes of angioedema.

12. The method of any one of embodiment 1 or embodiment 4 to 11; the compound of formula A (or a pharmaceutically acceptable form thereof) for use according to any one of embodiment 2 or embodiment 4 to 11 salt and/or solvate); or the use of any one of embodiments 3 to 11; wherein the prophylactic treatment reduces the average number of bradykinin-mediated angioedema episodes progressing to the prodromal stage.

13. The method of any one of embodiment 1 or 4 to embodiment 12; the compound of formula A (or a pharmaceutically acceptable form thereof) for use as of any one of embodiment 2 or embodiment 4 to 12 salt and/or solvate); or the use of any one of embodiments 3 to 12; wherein the prophylactic treatment prevents any bradykinin-mediated episode of angioedema from progressing to the swollen stage of the episode.

14. The method of any one of embodiment 1 or embodiment 4 to 13; the compound of formula A (or a pharmaceutically acceptable form thereof) for use according to any one of embodiment 2 or embodiment 4 to 13 salt and/or solvate); or the use of any one of embodiments 3 to 13; wherein the treatment prevents the onset of bradykinin-mediated angioedema.

15. The method of any one of embodiment 1 or embodiment 4 to 14; the compound of formula A (or a pharmaceutically acceptable form thereof) for use according to any one of embodiment 2 or embodiment 4 to 14 salt and/or solvate); or the use as in any one of embodiments 3 to 14; wherein the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is prepared with hydrochloric acid Supplied in salt form.

16. The method of embodiment 15; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 15; or the use of embodiment 15; wherein hydrogen chloride The acid salts are in solid form exhibiting characteristic X-ray powder diffraction peaks (Cu Kα radiation in °2Θ) at least at about 10.4, 15.6, 16.7 and 20.8 below.

17. The method of embodiment 15; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 15; or the use of embodiment 15; wherein hydrogen chloride The acid salts are in solid form exhibiting characteristic X-ray powder diffraction peaks (Cu Ka radiation in °2Θ) at least at about 10.4, 15.6, 16.7, 17.3 and 20.8 below.

18. The method of any one of embodiments 16 or 17; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any one of embodiments 16 or 17 ; or the use of any of embodiments 16 or 17; wherein the solid form has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 5 .

19. The method of any one of embodiments 15 to 18; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any one of embodiments 15 to 18 ; or the use of any one of embodiments 15 to 18; wherein the solid form has substantially the same STA thermogram as the STA thermogram shown in FIG. 6 .

20. The method of any one of embodiment 1 or embodiment 4 to 19; the compound of formula A (or a pharmaceutically acceptable form thereof) for use according to any one of embodiment 2 and embodiment 4 to 19 salt and/or solvate); or the use of any one of embodiments 3 to 19; wherein the treatment provides a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) of Cmin is at least about 30 ng (per milliliter of patient plasma), where Cmin is Cmin in free base form.

21. The method of any one of embodiment 1 or embodiment 4 to 20; the compound of formula A (or a pharmaceutically acceptable form thereof) for use according to any one of embodiment 2 or embodiment 4 to 20 salt and/or solvate); or the use of any one of embodiments 3 to 20; wherein the treatment provides a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) of Cmin is between about 30 ng/mL and about 1000 ng/mL, wherein Cmin is Cmin in the free base form.

22. The method of any one of embodiment 1 or embodiment 4 to 21; the compound of formula A (or a pharmaceutically acceptable form thereof) for use according to any one of embodiment 2 or embodiment 4 to 21 salt and/or solvate); or the use as in any one of embodiments 3 to 21; wherein the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is administered daily twice.

23. The method of embodiment 22; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 22; or the use of embodiment 22; Two daily doses are administered over 12 hours.

24. The method of embodiment 23; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as in embodiment 23; or the use of embodiment 23; wherein formula A The compound (or a pharmaceutically acceptable salt and/or solvate thereof) is administered with food.

25. The method of any one of embodiments 22 or 24; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any one of embodiments 22 or 24 ; or the use of any one of embodiments 22 or 24; wherein one dose is administered in the morning (after the patient wakes up) and one dose is administered in the evening (before the patient goes to bed), and wherein the The patient had a higher Cmin before taking his morning dose than before taking his evening dose, where Cmin is the Cmin in the free base form.

26. The method of any one of embodiment 22 or 25; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use of any one of embodiment 22 or 25 ; or the use of any of embodiments 22 or 25; wherein one dose is administered in the morning (after the patient wakes up) and one dose is administered in the evening (before the patient goes to bed).

27. The method of any one of embodiment 1 or embodiment 4 to 26; the compound of formula A (or a pharmaceutically acceptable form thereof) for use according to any one of embodiment 2 or embodiment 4 to 26 salt and/or solvate); or the use of any one of Embodiments 3 to 26; wherein the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is administered daily. The total amount is between about 300 mg and about 2400 mg expressed as free base equivalents.

28. The method of embodiment 27; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 27; or the use of embodiment 27; wherein daily The total amount of compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) administered is about 1,200 mg expressed as free base equivalents.

29. The method of embodiment 28; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 28; or the use of embodiment 28; wherein each The twice-daily treatment form administers a daily total of about 1,200 mg by two doses of about 600 mg, expressed as free base equivalents.

30. The method of embodiment 27; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 27; or the use of embodiment 27; wherein daily The total amount of compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) administered is about 1,800 mg expressed as free base equivalents.

31. The method of embodiment 30; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 30; or the use of embodiment 30; wherein by Two doses of about 900 mg administered a total daily amount of about 1,800 mg expressed as free base equivalents.

32. The method of any one of embodiments 22 to 31; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any one of embodiments 22 to 31 ; or the use of any one of embodiments 22 to 31; wherein each dose comprises administering more than one unit dosage form.

33. The method of embodiment 32; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as of embodiment 32; or the use of embodiment 32; wherein each A dosage contains a unit dosage form containing 300 mg of a compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) expressed as free base equivalents.

。 34. An oral modified release pharmaceutical dosage form comprising a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof), wherein the compound of formula A is

.

35. The oral modified release pharmaceutical dosage form of embodiment 34, wherein the oral modified release pharmaceutical dosage form comprises a release modifier.

36. The oral modified release pharmaceutical dosage form of embodiment 35, comprising between about 1% and about 80% by weight of the release modifier.

37. The oral modified release pharmaceutical dosage form of embodiment 36, comprising between about 3% and about 30% by weight of the release modifier.

38. The oral modified release pharmaceutical dosage form of embodiment 37, comprising between about 3% and about 15% by weight of the release modifier.

39. The oral modified release pharmaceutical dosage form of embodiment 38, wherein the oral modified release pharmaceutical dosage form comprises between about 11 wt% and about 13 wt% release modifier.

40. The oral modified release pharmaceutical dosage form of any one of embodiments 34 to 39, wherein the release modifier is selected from one or more of the group consisting of: polyoxyethylene, such as Polyox WSR N750 or Polyox WSR 303 and hydroxypropyl methylcellulose, such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR or Methocel E10MCR.

41. The oral modified release pharmaceutical dosage form of embodiment 40, wherein the release modifier is hydroxypropyl methylcellulose, such as Methocel DC2 K4M.

42. The oral modified release pharmaceutical dosage form of embodiment 41, wherein the release modifier is Methocel K100LV.

43. The oral modified release pharmaceutical dosage form of any one of embodiments 34 to 42, wherein the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is provided as a hydrochloride salt.

44. The oral modified release pharmaceutical dosage form of embodiment 43, wherein the hydrochloride salt is in solid form, which exhibits characteristic X-ray powder diffraction peaks (Cu Kα radiation, at least at about 10.4, 15.6, 16.7 and 20.8 below) °2θ is expressed in units).

45. The oral modified release pharmaceutical dosage form of embodiment 43, wherein the hydrochloride salt is in solid form exhibiting characteristic X-ray powder diffraction peaks (Cu Kα radiation at least at about 10.4, 15.6, 16.7, 17.3 and 20.8 below) , expressed in °2θ).

46. The oral modified release pharmaceutical dosage form of embodiment 44 or 45, wherein the solid form has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in FIG. 5 .

47. The oral modified release pharmaceutical dosage form of any one of embodiments 42 to 46, wherein the solid form has substantially the same STA thermogram as the STA thermogram shown in FIG. 6 .

48. The oral modified release pharmaceutical dosage form of any one of embodiments 34 to 47, wherein the dosage form is formulated such that the C of the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is (per milliliter of patient plasma) at least about 30 ng, where Cmin is Cmin in free base form.

49. The oral modified release pharmaceutical dosage form of any one of embodiments 34 to 48, which is a lozenge.

50. An oral modified release pharmaceutical dosage form that is bioequivalent to any one of the modified dosage forms as defined in any one of embodiments 34-49.

51. The method for the prophylactic treatment of bradykinin-mediated angioedema of any one of embodiments 1 to 33, wherein the oral modified release pharmaceutical dosage form of any one of embodiments 34 to 50 comprises a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof).

52. The oral modified release pharmaceutical dosage form of any one of embodiments 34 to 50, for use in the prophylactic treatment of bradykinin-mediated vascular disease according to any one of embodiments 2 or 4 to 33 In the method for edema, wherein the oral modified release pharmaceutical dosage form of any one of embodiments 34 to 50 comprises a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof).

53. Use of the oral modified release pharmaceutical dosage form of any one of embodiments 34 to 50 for the manufacture of a medicament for the prophylactic treatment of bradykinin-mediated angioedema, the prophylactic treatment comprising according to an embodiment Any one of 3 to 33 is orally administered with an oral modified release pharmaceutical dosage form, wherein the oral modified release pharmaceutical dosage form of any one of embodiments 34 to 50 comprises a compound of formula A (or a pharmaceutically acceptable salt thereof) and/or solvates).

54. A method for making the oral modified release pharmaceutical dosage form of any one of embodiments 34 to 50.

The invention will now be illustrated by the following non-limiting examples. In these instances, the following schemas are presented: Figure 1: Schematic diagram of the contact activation system. Figure 2: In vitro plasma kallikrein activity of compounds of formula A (solid line) and Haegarda® (dotted line). Figure 3: X-ray powder diffraction pattern of the free base form 1 of the compound of formula A. Figure 4: STA thermogram of the free base Form 1 of the compound of formula A. Figure 5: X-ray powder diffraction pattern of the hydrochloride salt form 5 of the compound of formula A. Figure 6: STA thermogram of the hydrochloride salt form 5 of the compound of formula A. Figure 7: PK curves for 6 cycles in part 1 of a phase 1 study. Figure 8: Mean PK curves from Day 1 to Day 14 for Cohort 1 in Part 2 of the Phase 1 study. Figure 9: Overlap of PK curves for Day 1 and Day 14 of Cohort 1 in Part 2 of the Phase 1 study and Cycle 1 in Part 1 of the Phase 1 study. Figure 10: Mean PD curves from Day 1 to Day 14 for Cohort 1 in Part 2 of a Phase 1 study showing mean plasma kallikrein activity as a percentage of pre-dose levels. Figure 11: Overlap of PD curves for Day 1 and Day 14 for Cohort 1 in Part 2 of the Phase 1 study showing mean plasma kallikrein activity as a percentage of pre-dose levels. Figure 12: Different PK parameters reported by Group 1 and Cycles 1, 4 and 6. Figure 13a: Mean PK curves from Day 1 to Day 14 for Cohort 2 in Part 2 of the Phase 1 study. Figure 13b: Overlap of the PK curves for Day 1 of Cohort 2 of the Phase 1 study and the PK curves of Day 1 of Cohort 1 in Part 2 of the Phase 1 study. Figure 13c: Mean PK curves from Day 1 to Day 14 for Cohort 2 in Part 2 of Phase 1 study. Figure 14a: PK profile of Cohort 2 from Day 1 to Day 7 in Part 2 of Phase 1 study and PK profile of Cohort 1 from Day 1 to Day 14 of Part 2 of Phase 1 study of overlapping. Figure 14b: Complete PK profiles from Day 1 to Day 14 for Cohort 2 in Part 2 of the Phase 1 study and PK from Day 1 to Day 14 for Cohort 1 in Part 2 of the Phase 1 study The overlapping of the curves. Figure 15a: PK profiles from Day 1 to Day 7 of Cohorts 1 and 2 in Part 2 of a Phase 1 study showing treatment of the invention compared to an approved HAE treatment (Haegarda®) Cmin is higher. Figure 15b: Complete PK profiles from Day 1 to Day 14 for Cohorts 1 and 2 in Part 2 of a Phase 1 study, showing the efficacy of the invention compared to the approved HAE treatment (Haegarda®). The treated Cmin was higher. Figure 16a: Mean PK curves from Day 1 to Day 14 for Cohort 3 in Part 2 of Phase 1 study. Figure 16b: Overlap of PK curves for Day 1, Day 10 and Day 14 of Cohort 3 in Part 2 of Phase 1 study. Figure 17a: Overlap of PK curves from Day 1 to Day 14 for Cohorts 1 to 3 in Part 2 of the Phase 1 study. Figure 17b: Overlap of Day 1 and Day 14 PK curves for Cohorts 1 to 3 in Part 2 of the Phase 1 study. Figure 17c: Various PK parameters reported from Cohorts 1 to 3 of the complete Part 2 study and Cycles 1, 4 and 6 of the Part 1 study.

Claims (33)

A method for the prophylactic treatment of bradykinin-mediated angioedema, comprising: orally administering a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof to a patient in need thereof) ), wherein the compound of formula A is

. A compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use in a method for the prophylactic treatment of bradykinin-mediated angioedema, the method comprising: applying A patient in need is orally administered the compound of the formula A (or its pharmaceutically acceptable salt and/or solvate), wherein the compound of the formula A is

. Use of a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for the manufacture of a medicament for the prophylactic treatment of bradykinin-mediated angioedema, the prophylactic treatment Including oral administration of the compound of the formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need, wherein the compound of the formula A is

. The method of claim 1; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as claimed in claim 2; or the use of claim 3; wherein the prophylactic treatment For the preventive treatment of bradykinin-mediated episodes of angioedema. The method of any one of claims 1 or 4; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any one of claims 2 or 4; or The use of any one of claims 3 to 4; wherein the bradykinin-mediated angioedema is hereditary angioedema (HAE); or wherein the bradykinin-mediated angioedema is bradykinin Mediated non-hereditary angioedema (BK-AEnH). The method of claim 5; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as claimed in claim 5; or the use of claim 5; wherein the bradykinin The mediated angioedema is hereditary angioedema (HAE). The method of any one of claims 1 or 4 to 6; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any one of claims 2 or 4 to 6 drug); or the use of any one of claims 3 to 6; wherein the prophylactic treatment reduces the mean number of bradykinin-mediated episodes of angioedema. The method according to any one of claim 1 or 4 to 7; the compound of formula A (or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable salt thereof) for use according to any one of claim 2 and claim 4 to 7 solvate); or the use of any one of claims 3 to 7; wherein the prophylactic treatment reduces the average number of bradykinin-mediated angioedema episodes requiring acute treatment. Such as claim 1 or the method of any one of claims 4 to 8; such as claim 2 or any one of claims 4 to 8 for use The compound of formula A (or a pharmaceutically acceptable salt thereof and or solvate); or the use of any one of claims 3 to 8; wherein the prophylactic treatment reduces the average number of episodes of moderate or severe bradykinin-mediated angioedema. Such as claim 1 or the method of any one of claims 4 to 9; such as claim 2 or any one of claims 4 to 9 for use The compound of formula A (or a pharmaceutically acceptable salt thereof and or solvate); or the use of any one of claims 3 to 9; wherein the treatment prevents the onset of bradykinin-mediated angioedema. Such as claim 1 or the method of any one of claims 4 to 10; such as claim 2 or any one of claims 4 to 10 for use The compound of formula A (or a pharmaceutically acceptable salt thereof and or solvate); or use as in any one of claims 3 to 10; wherein the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is a hydrochloride salt form provided. The method of claim 11; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as claimed in claim 11; or the use of claim 11; wherein the hydrochloric acid The salt is in solid form which exhibits characteristic X-ray powder diffraction peaks (Cu Kα radiation in °2Θ) at least at about 10.4, 15.6, 16.7 and 20.8 below. The method of claim 12; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as claimed in claim 12; or the use of claim 12; wherein the solid form has An X-ray powder diffraction pattern that is substantially the same as the X-ray powder diffraction pattern shown in FIG. 5 . Such as claim 1 or the method of any one of claims 4 to 13; such as claim 2 and any one of claims 4 to 13 for use The compound of formula A (or a pharmaceutically acceptable salt thereof and or solvate); or the use of any one of claims 3 to 13; wherein the treatment provides a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) with a Cmin of (per milliliter of patient plasma) at least about 30 ng, wherein the Cmin is the Cmin in the free base form. As claimed in claim 1 or the method of any one of claims 4 to 14; as claimed in claim 2 or any one of claims 4 to 14 for use of a compound of formula A (or a pharmaceutically acceptable salt thereof and or solvate); or the use of any one of claims 3 to 14; wherein the treatment provides a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) with a Cmin of Between about 30 ng/mL and about 1000 ng/mL, wherein the Cmin is the Cmin in the free base form. The method of claim 1 or any one of claims 4 to 15; the compound of formula A (or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable salt thereof) for use according to claim 2 or any one of claims 4 to 15 solvate); or the use of any one of claims 3 to 15; wherein the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is administered twice daily. The method of claim 16; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as claimed in claim 16; or the use of claim 16; wherein the separation is about 12 hours Two daily doses are administered. The method of claim 16; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use as claimed in claim 16; or the use of claim 16; wherein one dose is in the morning is administered between (after the patient wakes up) and one dose is administered in the evening (before the patient goes to bed), and wherein the patient takes his morning dose before taking his Cmin before his evening dose. The Cmin is higher, where the Cmin is the Cmin in the free base form. The method of any one of claims 16 to 18; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any one of claims 16 to 18; or The use of any one of claims 16 to 18; wherein one dose is administered in the morning (after the patient wakes up) and one dose is administered in the evening (before the patient goes to bed). Such as claim 1 or the method of any one of claims 4 to 19; such as claim 2 or any one of claims 4 to 19 for use The compound of formula A (or a pharmaceutically acceptable salt thereof and or solvate); or the use of any one of claims 3 to 19; wherein the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is administered daily. The total amount is about 1,200 mg, expressed as free base equivalents; and wherein a daily total of about 1,200 mg, expressed as free base equivalents, is administered in two doses of about 600 mg twice daily. The method of any one of claims 16 to 20; the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any one of claims 16 to 20; or The use according to any one of claims 16 to 20; wherein each dose comprises a unit dosage form comprising 300 mg of the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) in free form Base equivalent representation. An oral modified release pharmaceutical dosage form comprising a compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof), wherein the compound of formula A is

. The oral modified release pharmaceutical dosage form of claim 22, wherein the oral modified release pharmaceutical dosage form comprises a release modifier. The oral modified release pharmaceutical dosage form of claim 23, wherein the release modifier is one or more selected from the group consisting of: polyoxyethylene, such as Polyox WSR N750 or Polyox WSR 303; and hydroxypropyl methylcellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, Methocel E10MCR or Methocel K100LV. The oral modified release pharmaceutical dosage form of any one of claims 22 to 24, wherein the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is provided in the form of a hydrochloride salt. The oral modified release pharmaceutical dosage form of claim 25, wherein the hydrochloride salt is in solid form exhibiting characteristic X-ray powder diffraction peaks (Cu Kα radiation, in °) at least at about 10.4, 15.6, 16.7 and 20.8 below 2θ is expressed in units). The oral modified release pharmaceutical dosage form of claim 26, wherein the solid form has substantially the same X-ray powder diffraction pattern as shown in FIG. 5 . The oral modified release pharmaceutical dosage form of any one of claims 22 to 27, wherein the dosage form is formulated such that the C of the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is (per milliliters of patient plasma) at least about 30 ng, wherein the Cmin is the Cmin in the free base form. An oral modified release pharmaceutical dosage form that is bioequivalent to any one of the modified dosage forms of any one of claims 22 to 28. The method for the prophylactic treatment of bradykinin-mediated angioedema according to any one of claims 1 to 21, wherein the oral modified release pharmaceutical dosage form according to any one of claims 22 to 29 comprises the formula A A compound (or a pharmaceutically acceptable salt and/or solvate thereof). The oral modified release pharmaceutical dosage form according to any one of claims 22 to 29 for use in the method for the prophylactic treatment of bradykinin-mediated angioedema according to claim 2 or any one of claims 4 to 21 , wherein the oral modified release pharmaceutical dosage form of any one of claims 22 to 29 comprises the compound of formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Use of an oral modified release pharmaceutical dosage form according to any one of claims 22 to 29 for the manufacture of a medicament for the prophylactic treatment of bradykinin-mediated angioedema, the prophylactic treatment comprising according to claim Any one of 3 to 21 for oral administration of an oral modified release pharmaceutical dosage form, wherein the oral modified release pharmaceutical dosage form of any one of claims 22 to 29 comprises the compound of formula A (or a pharmaceutically acceptable compound thereof). salts and/or solvates). A method for the manufacture of an oral modified release pharmaceutical dosage form as claimed in any one of claims 22 to 29.

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