WO2023002219A1

WO2023002219A1 - Treatments of hereditary angioedema

Info

Publication number: WO2023002219A1
Application number: PCT/GB2022/051934
Authority: WO
Inventors: Matthew Scott IVERSON; Michael David Smith; Christopher Martyn Yea
Original assignee: Kalvista Pharmaceuticals Limited
Priority date: 2021-07-23
Filing date: 2022-07-22
Publication date: 2023-01-26

Abstract

The present invention relates to treatments of hereditary angioedema (HAE) with a plasma kallikrein inhibitor and oral modified release pharmaceutical dosage forms comprising a plasma kallikrein inhibitor for use in these treatments.

Description

TREATMENTS OF HEREDITARY ANGIOEDEMA

BACKGROUND OF THE INVENTION

Inhibitors of plasma kallikrein have a number of therapeutic applications, particularly in the treatment of hereditary angioedema (HAE).

Plasma kallikrein is a trypsin-like serine protease that can liberate kinins from kininogens (see K. D. Bhoola et al., "Kallikrein-Kinin Cascade", Encyclopedia of Respiratory Medicine, p483-493; J. W. Bryant et al., "Human plasma kallikrein-kinin system: physiological and biochemical parameters" Cardiovascular and haematological agents in medicinal chemistry, 7, p234-250, 2009; K. D. Bhoola et al., Pharmacological Rev., 1992, 44, 1; and D. J. 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). It is an essential member of the intrinsic blood coagulation cascade, although its role in this cascade does not involve the release of bradykinin or enzymatic cleavage. Plasma prekallikrein is encoded by a single gene and can be synthesized in the liver, as well as other tissues. It is secreted by hepatocytes as an inactive plasma prekallikrein that circulates in plasma as a heterodimer complex bound to high molecular weight kininogen (HK) which is activated to give the active plasma kallikrein. This contact activation system (or contact system) can be activated by negatively charged surfaces that activate Factor XII (FXII) to Factor XI la (FXIIa), by certain proteases e.g. plasmin (Hofman et al., Clin Rev Allergy Immunol 2016), which may not require negative surfaces, or by misfolded proteins (Maas et al., J Clinical Invest 2008). FXIIa mediates conversion of plasma prekallikrein to plasma kallikrein and the subsequent cleavage of high molecular weight kininogen (HK) to generate bradykinin, a potent inflammatory hormone. Kinins are potent mediators of inflammation that act through G protein-coupled receptors and antagonists of kinins (such as bradykinin receptor antagonists) have previously been investigated as potential therapeutic agents for the treatment of a number 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 number of inflammatory disorders. For example, the plasma kallikrein-kinin system is abnormally abundant in patients with advanced diabetic macular edema. It has been reported that plasma kallikrein contributes to retinal vascular dysfunctions 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). Furthermore, administration of the plasma kallikrein inhibitor ASP-440 ameliorated both retinal vascular permeability and retinal blood flow abnormalities in diabetic rats. Therefore a plasma kallikrein inhibitor should have utility as a treatment to reduce retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema.

Other complications of diabetes such as cerebral haemorrhage, nephropathy, cardiomyopathy and neuropathy, all of which have associations with plasma kallikrein may also be considered as targets for a plasma kallikrein inhibitor.

The major inhibitor of plasma kallikrein is the serpin Cl esterase inhibitor. Patients who present with a genetic deficiency in Cl esterase inhibitor suffer from hereditary angioedema (FIAE) which results in intermittent swelling of face, hands, throat, gastro-intestinal tract and genitals. Blisters formed during acute episodes contain high levels of plasma kallikrein which cleaves high molecular weight kininogen (HK) liberating bradykinin leading to increased vascular permeability. "Flereditary angioedema" can thus be defined as any disorder characterised by recurrent episodes of bradykinin-mediated angioedema (e.g. severe swelling) caused by an inherited dysfunction/fault/mutation. There are currently three known categories of FIAE: (i) FIAE type 1, (ii) FIAE type 2, and (iii) normal Cl inhibitor FIAE (normal Cl-lnh FIAE). Flowever, the FIAE field is developing quickly and further types of FIAE might be defined in the future.

Without wishing to be bound by theory, it is thought that FIAE type 1 is caused by mutations in the SERPING1 gene that lead to reduced levels of Cl inhibitor in the blood. Without wishing to be bound by theory, it is thought that FIAE type 2 is caused by mutations in the SERPING1 gene that lead to dysfunction of the Cl inhibitor in the blood. Without wishing to be bound by theory, the cause of normal Cl-lnh FIAE is less well defined and the underlying genetic dysfunction/fault/mutation can sometimes remain unknown. What is known is that the cause of normal Cl-lnh FIAE is not related to reduced levels or dysfunction of the Cl inhibitor (in contrast to FIAE types 1 and 2). Normal Cl-lnh FIAE can be diagnosed by reviewing the family history and noting that angioedema has been inherited from a previous generation (and thus it is hereditary angioedema). Normal Cl-lnh FIAE can also be diagnosed by determining that there is a dysfunction/fault/mutation in a gene other than those related to Cl inhibitor. For example, it has been reported that dysfunction/fault/mutation with plasminogen can cause normal Cl-lnh HAE (see e.g. 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/sl3601-019-0247-x.). It has also been reported that dysfunction/fault/mutation with Factor XII can cause normal Cl-lnh FIAE (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(l):183-194. doi: 10.1111/jth.14325).

Acute FIAE attacks normally progress through three key clinically distinct stages: an initial prodromal stage (that can typically last for up to 12 hours), followed by a swelling stage, and then an absorption stage. A majority of FIAE attacks announce themselves with prodromal symptoms. Two thirds of prodromes appeared less than 6 hours before a FIAE attack and no prodromes occur more than 24 hours before a FIAE attack (Magerl et al., Clinical and Experimental Dermatology 2014, 39, 298-303). For example, the following prodromal symptoms may start to be observed: a slight swelling (particularly affecting the face and neck), a typical type of abdominal pain, a typical reddening of the skin called "erythema marginatum". An attack is fully developed when it has reached maximum swelling and maximum expression of pain (e.g. abdominal attack), discomfort (e.g. peripheral attack) or threat to life (e.g. laryngeal attack). Once the attack has reached its peak, the subsequent time period to normalization is determined by the time it takes for the swelling to disappear and the liquid that has penetrated the tissues to be reabsorbed.

Cinryze^® and Flaegarda^® contain a Cl esterase inhibitor and are authorised to prevent acute FIAE attacks (i.e. prophylactic treatment). Treatment with Cinryze^® requires the preparation of a solution from a powder, which is then injected every 3 or 4 days. Similarly, treatment with Flaegarda^® requires the preparation of a solution from a powder, which is then injected twice a week. It is not always possible for a patient to self-administer these treatments, and if this is the case, the patient is required to visit a clinic for treatment. Thus, both of these prophylactic treatments suffer from high patient burden. Additionally, the FDA packet insert for Flaegarda^® states that it "should not be used to treat an acute FIAE attack", and therefore a patient may require additional therapy if a FIAE attack develops.

Berinert^® and Ruconest^® contain a Cl esterase inhibitor and are authorised to treat acute FIAE attacks. Both of these treatments also involve the preparation of an injectable solution followed by injection. This process can be burdensome on the patient, especially when the patient is suffering from an acute HAE attack. Self-administration of the dosage amount is also not always possible, and if it is not, administration of the drug can be substantially delayed thus increasing the severity of the acute HAE attack for the patient.

There is a lack of approved treatments for HAE. In particular, there is a lack of approved oral treatments for plasma kallikrein-related disorders, such as for HAE. Prophylactic treatment of these disorders requires strong inhibition of plasma kallikrein maintained over the dosing period to avoid so-called "breakthrough attacks". Preventing an attack of HAE is considered more desirable than acute treatment once an attack has started. The level of inhibition is determined by at least potency and concentration of the drug in the blood plasma. Antibody drugs have inherent long half-life, but must be given as an injection, which can be burdensome and affect patient compliance and patient satisfaction. There is a desire amongst patients for an effective oral treatment.

Berotralstat (BCX7353) has been approved as a once-daily oral treatment for the prevention of HAE attacks. Hwang et al. (Immunotherapy (2019) 11(17), 1439-1444) states that higher doses of berotralstat were associated with more gastrointestinal adverse effects indicating increased toxicity at higher levels. The EMA label for the approved product containing berotralstat (Orladeyo^®) reports that very common adverse reactions observed in its clinical studies were headache, abdominal pain, and diarrhoea.

Synthetic and small molecule plasma kallikrein inhibitors have been described previously, 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), D. M. Evans et al. (Immunolpharmacology, 32, pll5-116 (1996)), Szelke et al. ("Kininogen inhibitors" WO95/07921), Antonsson et al. ("New peptides derivatives" W094/29335), J. Corte et al. ("Six membered heterocycles useful as serine protease inhibitors" W02005/123680), J. StOrzbecher et al. (Brazilian J. Med. Biol. Res 27, pl929-34 (1994)), Kettner et al. (US 5,187,157), N. Teno et al. (Chem. Pharm. Bull. 41, pl079-1090 (1993)), W. B. Young et al. ("Small molecule inhibitors of plasma kallikrein" Bioorg. Med. Chem. Letts. 16, p2034-2036 (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, pl964-72 (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, p545-553 (2006)), Sinha etal. ("Inhibitors of plasma kallikrein" W008/016883), 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). Also, Steinmetzer et al. ("Serine protease inhibitors" W02012/004678) describes cyclized peptide analogs which 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 over related enzymes such as KLK1, thrombin and other serine proteases, and poor oral availability. Treatment with a large protein plasma kallikrein inhibitor has been shown to effectively treat HAE by preventing the release of bradykinin which causes increased 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, pll87-99). However, ecallantide is administered by subcutaneous injection and there have been reported risks of anaphylactic reactions for ecallantide. Treatment with the plasma kallikrein monoclonal antibody, lanadelumab, has been shown to lower the rate of attacks 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 lanadelumab is similarly by subcutaneous injection and hypersensitivity, dizziness, rashes, myalgia and injection site reactions are reported as common or very common side effects on the EMA label for the lanadelumab product (Takhzyro^®).

Furthermore, many molecules in the known art feature a highly polar and ionisable guanidine or amidine functionality. It is well known that such functionalities may be limiting to gut permeability and therefore to oral availability. For example, it has been reported by Tamie J. Chilcote and Sukanto Sinha ("ASP-634: An Oral Drug Candidate for Diabetic MacularEdema", ARVO 2012 May 6th - May 9th, 2012, Fort Lauderdale, Florida, Presentation 2240) that ASP-440, a benzamidine, suffers from poor oral availability. It is further reported that absorption may be improved by creating a prodrug such as ASP-634. However, it is well known that prodrugs can suffer from several drawbacks, for example, poor chemical stability and potential toxicity from the inert carrier or from unexpected metabolites. In another report, indole amides are claimed as compounds that might overcome problems associated with drugs possessing poor or inadequate ADME-tox and physicochemical properties although no inhibition against plasma kallikrein is presented or claimed (Griffioen etai, "Indole amide derivatives and related compounds for use in the treatment of neurodegenerative diseases", W02010142801).

Other plasma kallikrein inhibitors known in the art are generally small molecules, some of which include highly polar and ionisable functional groups, such as guanidines or amidines. Recently, plasma kallikrein inhibitors that do not feature guanidine or amidine functionalities have been reported. For example Brandi et al. ("N-((6-amino-pyridin-3-yl)methyl)-heteroaryl-carboxamides as inhibitors of plasma kallikrein" W02012/017020), Evans et al. ("Benzylamine derivatives as inhibitors of plasma kallikrein" W02013/005045), 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" W02016/083820) and Davie et al. ("Pyrazole derivatives as plasma kallikrein inhibitors" WO2017/207983).

Davie et al. ("Pyrazole derivatives as plasma kallikrein inhibitors" WO2017/207983) discloses the following plasma kallikrein inhibitor: l-({4-[(5-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3- fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide. The name l-({4- [(5-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide denotes the structure depicted in Formula A.

O Formula A

Crowe et al. ("Solid forms of a plasma kallikrein inhibitor and salts thereof" WO2019/106377) describes various solid forms of the compound of Formula A (herein referred to simply as the "compound").

There is therefore a need for an effective oral prophylactic treatment of HAE. In particular, there is a need for an effective oral prophylactic treatment of HAE that has minimal side effects (e.g. such as gastrointestinal adverse effects), especially in view of expected long-term use of the treatment. DESCRIPTION OF THE INVENTION

The inventors faced many challenges when setting out to develop an oral prophylactic treatment for HAE.

First, because HAE can be characterised by a rapid onset of potentially life-threatening symptoms (e.g. swelling) that can occur unpredictably, it is essential that any prophylactic treatment can maintain a therapeutically effective concentration of active ingredient in the patient to avoid, or reduce the severity of, breakthrough attacks. Any prophylactic treatment must therefore be suitable for maintaining the minimum concentration of active ingredient (Cmin) above the minimum therapeutically effective concentration.

However, it is also important that any oral prophylactic treatment does not lead to a harmful build-up of concentration of the compound over time such that serious adverse events may develop. As prophylactic treatments are typically taken chronically (i.e. over a long period of time, potentially for life), it is desirable that the treatment does not lead to any adverse events that might result in the ceasing of treatment (e.g. causing intolerable damage or irritation to the liver or gastrointestinal tract).

Second, it is important that any oral prophylactic treatment provides good patient compliance. Specifically, it is unsatisfactory for a patient to be overburdened with too many dosage forms (e.g. tablets), particularly in view of the treatment being a chronic treatment. Any effective oral prophylactic treatment must therefore minimise pill burden and dose frequency.

Third, a patient's quality of life is affected not only by the severity of their HAE attacks, but also by the frequency with which they occur. The frequency of HAE attacks can vary between HAE patients and over the lifetime of an individual patient. In general, the greater the frequency of HAE attacks, the greater the effect on a patient's quality of life. The present invention is directed to the prophylactic treatment of a specific subgroup of patients who have a specific frequency of HAE attacks.

In arriving at the present invention, the inventors carefully and skilfully analysed the unique pharmacokinetic (PK) and pharmacodynamic (PD) properties of the compound of Formula A, and have designed and developed a dosage form and dosage regimen that are suitable for oral prophylactic treatment of HAE in a specific subgroup of patients. Definitions

As used herein, and unless explicitly 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 is named: l-({4-[(5-fluoro-2- oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3- (methoxymethyl)pyrazole-4-carboxamide.

O Formula A

It will be understood that "pharmaceutically acceptable salts and/or solvates thereof" means "pharmaceutically acceptable salts thereof", "pharmaceutically acceptable solvates thereof", and "pharmaceutically acceptable solvates of salts thereof".

As used herein, the terms "sebetralstat" and "KVD900" are used to refer to the compound which is N-

[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide.

The term "pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt, which can be, for example, pharmaceutically acceptable acid addition salts. For instance, as the compound of Formula A contains a basic group, e.g. a basic nitrogen, pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, succinates, oxalates, phosphates, esylates, tosylates, benzenesulfonates, naphthalenedisulphonates, maleates, adipates, fumarates, hippurates, camphorates, xinafoates, pacetamidobenzoates, dihydroxybenzoates, hydroxynaphthoates, succinates, ascorbates, oleates, bisulfates and the like. The preferred pharmaceutically acceptable salt of the compound is the hydrochloride salt. Hemisalts of acids can also be formed, for example, hemisulfate salts.

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 the compound of the invention and a one or more pharmaceutically acceptable solvent molecules, for example, ethanol or water. The term "hydrate" is employed when the solvent is water and for the avoidance of any doubt, the term "hydrate" is encompassed by the term "solvate".

The compound of Formula A can include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds wherein hydrogen is replaced by deuterium or tritium, or wherein carbon is replaced by ¹³C or ¹⁴C, are within the scope of the present invention.

"Cmin" is used herein to mean the minimum blood plasma concentration reached by the compound (in its free base form) prior to administration of a subsequent dose. All concentrations of the compound reported herein are concentrations of the free base, regardless of whether the compound was administered as a salt and/or solvate. "Blood plasma" is plasma prepared from blood.

The term "acute attack of HAE" can be used interchangeably with "acute HAE attack", "HAE attack", or "attack of HAE".

The term "hereditary angioedema" (shortened to HAE) means any bradykinin-mediated angioedema caused by an inherited genetic dysfunction, fault, or mutation. As a result, the term "HAE" includes at least HAE type 1, HAE type 2, and normal Cl inhibitor HAE (normal Cl-lnh HAE).

"Prophylactic treatment" of hereditary angioedema (HAE) as described herein means that the compound is administered to a patient in order to reduce the number of (or even prevent) HAE attacks and/or to ameliorate the symptoms of such attacks. In prophylactic treatments according to the present invention, the Cmin of the compound is maintained above the minimum effective therapeutic concentration for preventative treatment of an HAE attack. Prophylactic treatments of the invention can reduce the number of HAE attacks requiring acute treatment. For example, prophylactic treatments of the invention can reduce the number of moderate or severe HAE attacks requiring acute treatment. The "specific subgroup of patients" referred to in the context of the treatments of the invention are patients wherein: in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had: (i) at least two attacks of HAE in the first four weeks of the eight week period; or (ii) at least three attacks of HAE in the eight week period; or in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), and in the absence of another prophylactic treatment of FIAE, the patient would have had: (i) at least two attacks of FIAE in the first four weeks of the eight week period; or (ii) at least three attacks of FIAE in the eight week period.

Prophylactic treatments of the invention

The inventors have determined that the compound of Formula A is 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 mL of the patient's blood plasma. In arriving at this threshold, the inventors have assessed the normal levels of Cl inhibitor present in a healthy patient (as described in Tarzi et al. Clinical and Experimental Immunology, 2007; 149: 513-516), the Cmin achieved by an existing marketed treatment (Flaegarda^®), and carefully studied the PK and PD properties of the compound of Formula A. This is described further in Example 1.

To further investigate the efficacy and safety of the compound of Formula A in the prophylactic treatment of FIAE, the inventors devised a phase 2 clinical trial to investigate three dose levels of the compound of Formula A in subjects with FIAE. The phase 2 clinical trial protocol has received ethical approval from the Canadian Institutional Review Board (IRB), and has been approved by Canada's Office of Clinical Trials. The phase 2 protocol has also been granted a Clinical Trial Authorisation (CTA) by the UK's Medicines and Flealthcare products Regulatory Agency (MFIRA). The patients investigated in the phase 2 clinical trial are the specific subgroup of patients focussed on in the treatments of the present invention.

Accordingly, the invention provides a method for prophylactic treatment of FIAE in the specific subgroup of patients comprising oral administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof. The invention also provides the use of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) in the manufacture of a medicament for prophylactic treatment of HAE in the specific subgroup of patients comprising oral administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof.

The invention also provides the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use in a method for prophylactic treatment of FIAE in the specific subgroup of patients comprising oral administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof.

FIAE patients are typically highly aware of how frequent their attacks occur. FIAE patients often keep diaries noting the timings of FIAE attacks (start and stop times and dates), their frequency, and the severity of each FIAE attack. Indeed, this is encouraged when the patient is seeking a FIAE diagnosis and/or considering treatment options. For example, Takeda, the EMA holder forTakhzyro^®, provide a FIAE diary template (https://www.takeda.com/4ab533/siteassets/downloads/hae-patient-diary.pdf). By following a diary, the patient or a qualified medical professional (e.g. a medical doctor), may be able to better identify triggers of attacks and/or formulate treatment plans for individual patients.

As defined above, the subgroup of patients treated according to the invention can be identified by the frequency of their FIAE attacks. The prophylactic treatments of the invention can comprise administering the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof, wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had (i) at least two attacks of FIAE in the first four weeks of the eight week period or (ii) at least three attacks of FIAE in the eight week period.

The prophylactic treatments of the invention can comprise administering the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof, wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had at least two attacks of FIAE in the first four weeks of the eight week period. The prophylactic treatments of the invention can comprise administering the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof, wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had at least three attacks of FIAE in the eight week period.

During the eight week period the patient could have been an untreated patient (i.e. a patient that is not receiving another prophylactic treatment for FIAE). Alternatively, during the eight week period, the patient could have been receiving a prophylactic treatment for FIAE other than the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). For instance, in spite of taking another prophylactic treatment of FIAE the patient still had (i) at least two attacks of FIAE in the first four weeks of the eight week period or (ii) at least three attacks of FIAE in the eight week period.

During the eight week period, the patient could have received an acute treatment for FIAE attacks. Indeed, it is common for FIAE patients to use acute treatments for FIAE attacks in response to breakthrough FIAE attacks when on prophylactic treatments for FIAE. Alternatively, during the eight week period the patient could not have received any acute treatment for FIAE attacks.

Any FIAE attack counts as an attack for the purposes of meeting the criteria of the specific patient subgroup treated in accordance with the invention, regardless of whether the patient was taking another prophylactic treatment for FIAE (e.g. a breakthrough attack) or whether the patient took an acute treatment of FIAE to treat the attack.

As defined above, the subgroup of patients treated according to the invention also includes patients wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), and in the absence of another prophylactic treatment of FIAE, the patient would have had: (i) at least two attacks of FIAE in the first four weeks of the eight week period; or (ii) at least three attacks of FIAE in the eight week period. These patients were already taking another prophylactic treatment of FIAE (i.e. a prophylactic treatment other than the compound of Formula A). Flowever, had they not been taking another prophylactic treatment (i.e. in the absence of another prophylactic treatment of FIAE), they would have had (i) at least two attacks of FIAE in the first four weeks of the eight week period; or (ii) at least three attacks of FIAE in the eight week period. Patients falling into these criteria are identifiable based on the patient's HAE attack clinical history. For instance, the patient or qualified medical professionals (e.g. medical doctors) are able to identify such patients by reviewing the treatment plan of the HAE patient and considering the number of HAE attacks a patient would have experienced in the absence of another prophylactic treatment. For example, the patient may be close to having (i) at least two attacks of HAE in the first four weeks of the eight week period or (ii) at least three attacks of HAE in the eight week period, even when on another prophylactic HAE treatment such that removing the other treatment would mean that the patient does indeed experience this attack frequency. The patient's underlying HAE symptoms may also have become more severe during the period that they have been on another prophylactic treatment for HAE. For example, the patient or medical professional would know if the frequency of HAE attacks has increased during the period that the another prophylactic treatment has been administered such that removal of the treatment would mean that the patient would have experienced (i) at least two attacks of HAE in the first four weeks of the eight week period or (ii) at least three attacks of HAE in the eight week period in the absence of the other prophylactic treatment.

Accordingly, the prophylactic treatments of the invention can comprise administering the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof wherein, in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) and in the absence of another prophylactic treatment of HAE, the patient would have had: (i) at least two attacks of HAE in the first four weeks of the eight week period; or (ii) at least three attacks of HAE in the eight week period.

The prophylactic treatments of the invention can comprise administering the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof wherein, in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) and in the absence of another prophylactic treatment of HAE, the patient would have had at least two attacks of HAE in the first four weeks of the eight week period.

The prophylactic treatments of the invention can comprise administering the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) to a patient in need thereof wherein, in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) and in the absence of another prophylactic treatment of HAE, the patient would have had at least three attacks of HAE in the eight week period. The "eight week period" referred to in the treatments of the invention can be any eight week period in the patient's lifetime prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be any eight week period in the 20 year period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be any eight week period in the 10 year period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be any eight week period in the 5 year period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be any eight week period in the 4 year period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be any eight week period in the 3 year period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be any eight week period in the 2 year period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be any eight week period in the 1 year period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be any eight week period in the 6 month period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be any eight week period in the 3 month period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the eight week period can be the eight week period immediately prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof).

Alternatively, the eight week period can be any eight week period prior to the first administration of any prophylactic treatment. Alternatively, the eight week period can be the eight week period immediately prior to the first administration of any prophylactic treatment.

The "the other prophylactic treatment of FIAE", "another prophylactic treatment of FIAE" or "another prophylactic treatment" is a prophylactic treatment other than the compound of Formula A. For example, the other prophylactic treatment can be a Cl-esterase inhibitor (e.g. Cinryze^® or Flaegarda^®), an attenuated androgen (e.g. stanozolol, danazol, oxandrolone, methyltestosterone, testosterone), an anti-fibrinolytic (e.g. tranexamic acid), a plasma kallikrein inhibitor (e.g. lanadelumab or berotralstat), a Factor Xlla inhibitor (e.g. garadacimab), a plasma pre-kallikrein inhibitor (e.g. PKK-LRx) or a B2-receptor antagonist (e.g. PHVS416).

The prophylactic treatments of the invention relate to prophylactic treatments of HAE attacks, which are the key symptomatic events that HAE patient suffer from.

In the treatments of the invention described herein, the patient is preferably a human. For instance HAE is a hereditary disease and patients of all ages can suffer from HAE attacks. Accordingly, the human patient can be a child (ages 0 to 18 years) or an adult (18 years old or older). Specifically, the patient can be aged 12 years and above. The patient can also be aged 2 years and above.

As noted above, the prophylactic treatments of the invention can comprise providing a Cmin of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) of at least about 30 ng/(mL of the patient's blood plasma), wherein the Cmin is the Cmin of the free base form. This is a preferred treatment of the invention. The prophylactic treatments of the invention can also comprise providing a Cmin of at least 40 ng/(mL of the patient's blood plasma). The prophylactic treatments of the invention can comprise providing a Cmin of at least 50 ng/(mL of the patient's blood plasma). The prophylactic treatments of the invention can comprise providing a Cmin of at least 60 ng/(mL of the patient's blood plasma). The prophylactic treatments of the invention can comprise providing a Cmin of at least 80 ng/(mL of the patient's blood plasma). The prophylactic treatments of the invention can comprise providing a Cmin of at least 100 ng/(mL of the patient's blood plasma). The prophylactic treatments of the invention can comprise providing a Cmin of at least 120 ng/(mL of the patient's blood plasma). The prophylactic treatments of the invention can comprise providing a Cmin of at least 140 ng/(mL of the patient's blood plasma). The prophylactic treatments of the invention can comprise providing a Cmin of at least 150 ng/(mL of the patient's blood plasma).

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

As described in Example 1, the "normal" range of Cl-INH in healthy patients is between 0.15 and 0.35g/L, with the inventors determining that the low end of "normal" corresponds to a Cmin of the compound of Formula A of about 18 ng/mL. The prophylactic treatments of the invention can therefore provide a Cmin of at least about 18 ng/mL (e.g. between about 18 ng/mL and about 1000 ng/mL).

The prophylactic treatments of the invention can reduce the number of HAE attacks compared to an untreated patient - "untreated patient" herein means a patient that is not receiving any other prophylactic medication for treating HAE attacks. The prophylactic treatments of the invention can prevent HAE attacks. The prophylactic treatments of the invention can reduce the number of (or prevent) acute HAE attacks. For instance, the prophylactic treatments of the invention can be administered for routine prevention of recurrent attacks of HAE (particularly in patients aged 12 years and older). The prophylactic treatments of the invention can reduce the mean number of attacks to below 2 attacks per month, below 1.5 attacks per month, below 1 attack per month, below 0.5 attacks per month.

Although the primary aim for a prophylactic treatment is to reduce the number of (or prevent) HAE attacks, breakthrough attacks can still arise. "Breakthrough attacks" are attacks that occur in spite of prophylactic treatment. Breakthrough attacks can require treatment with acute (or on-demand) treatments. The prophylactic treatments of the invention can reduce the number of HAE attacks requiring acute treatment compared to an untreated patient. The prophylactic treatments of the invention can reduce the number of acute HAE attacks requiring acute treatment. The prophylactic treatments of the invention can reduce the mean number of attacks requiring acute treatment to below 2 attacks per month, below 1.5 attacks per month, below 1 attacks per month, below 0.5 attacks per month.

If an acute treatment is required to treat breakthrough attacks, it can be selected from the group consisting of Cl esterase inhibitor, pdClINH, rhClINH, icatibant, and sebetralstat (KVD900; N-[(3- fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide or salts and solvates thereof). Alternatively, if an acute treatment is required to treat breakthrough attacks, it can be selected from the group consisting of Cl esterase inhibitor, pdClINH, rhClINH, icatibant, ecallantide and sebetralstat (KVD900; (N-[(3- fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide or salts and solvates thereof).

The acute treatment can be sebetralstat. On-demand (acute) treatments comprising N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(2-oxopyridin-l- yl)methyl]phenyl}methyl)pyrazole-4-carboxamide are described in PCT/GB2020/051439 and PCT/GB2020/051441, as well as 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. The acute treatment can be Cl esterase inhibitor. The on-demand treatment can be pdClINH. The acute treatment can be rhClINH. The on-demand treatment can be icatibant.

Thus, treatments of the invention also provide a method for treatment of HAE comprising: administering Cl esterase inhibitor to a patient to treat (breakthrough) attacks of HAE, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein. In other words, treatments of the invention also provide Cl esterase inhibitor for use in a method of treating (breakthrough) attacks of HAE, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein.

Treatments of the invention also provide a method for treatment of a bradykinin-mediated angioedema comprising: administering icatibant to a patient to treat (breakthrough) attacks of HAE, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein. In other words, treatments of the invention also provide icatibant for use in a method of treating (breakthrough) attacks of HAE, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein.

Treatments of the invention also provide a method for treatment of HAE comprising: administering pdClINH to a patient to treat (breakthrough) attacks of bradykinin-mediated angioedema, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein. In other words, treatments of the invention also provide pdClINH for use in a method of treating (breakthrough) attacks of HAE, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein.

Treatments of the invention also provide a method for treatment of HAE comprising: administering rhClINH to a patient to treat (breakthrough) attacks of HAE, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein. In other words, treatments of the invention also provide rhClINH for use in a method of treating (breakthrough) attacks of HAE, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein.

Treatments of the invention also provide a method for treatment of HAE comprising: administering sebetralstat to a patient to treat (breakthrough) attacks of HAE, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein. In other words, treatments of the invention also provide sebetralstat for use in a method of treating (breakthrough) attacks of HAE, wherein the patient is also being administered the compound of Formula A as a prophylactic treatment, in accordance with any of the prophylactic treatments described herein.

The prophylactic treatments of the invention can reduce the number of moderate or severe HAE attacks compared to an untreated patient.

A "moderate" or "severe" attack can be measured by reference to the 5-point Likert scale (5LS) (see e.g. Allergy Asthma Proc. 2018 Jan l;39(l):74-80. Doi: 10.2500/aap.2018.39.4095) that can be used to report the severity of HAE attacks and for example can be used to report attacks as "none", "mild", "moderate", "severe" or "very severe". The prophylactic treatments of the invention can reduce the number of moderate or severe HAE attacks. The prophylactic treatments of the invention can reduce the mean number of moderate or severe attacks to below 2 attacks per month, below 1.5 attacks per month, below 1 attacks per month, below 0.5 attacks per month.

Alternatively, a "moderate" or "severe" attack can be rated on a 3-point scale of "mild", "moderate" and "severe", as used in the phase 2 protocol described in Example 4. Qualified medical professionals working in the field of HAE use this 3-point scale. This scale is used in the field, for example in the phase 3 trial of lanadelumab (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. doi: 10.1001/jama.2018.16773. Erratum in: JAMA. 2019 Apr 23;321(16):1636). The prophylactic treatments of the invention can reduce the number of moderate or severe HAE attacks, as measured on this 3-point scale. The prophylactic treatments of the invention can reduce the mean number of moderate or severe attacks, as measured on this 3-point scale, to below 2 attacks per month, below 1.5 attacks per month, below 1 attack per month, below 0.5 attacks per month.

The prophylactic treatments of the invention can reduce the number of HAE attacks that do not require acute treatment compared to an untreated patient. The prophylactic treatments of the invention can reduce the number of HAE attacks that did not require acute treatment to below 2 attacks per month, below 1.5 attacks per month, below 1 attack per month, below 0.5 attacks per month.

The prophylactic treatments of the invention can increase the number of HAE attack free days over a set duration compared to an untreated patient.

The prophylactic treatments of the invention can increase the length of time between HAE attacks compared to an untreated patient.

Each HAE attack can be different in severity and in terms of the area(s) affected. Patients who suffer from HAE, medical professionals with knowledge of HAE, and carers of HAE patients are astute in identifying symptoms of an HAE attack.

In the prodromal phase of an acute HAE attack, the symptoms recognised can be a slight swelling, in particular, a slight swelling affecting the face and neck. In addition, or in the alternative, the symptoms can also include abdominal pain. In addition, or in the alternative, the symptom can be a reddening of the skin such as erythema marginatum.

The prophylactic treatments of the invention can reduce the number of HAE attacks progressing through the prodromal phase of an attack, compared to an untreated patient. The prophylactic treatments of the invention can reduce the severity of any symptoms in the prodromal phase of an HAE attack, compared to an untreated patient.

HAE attacks can progress through the prodromal phase to the swelling stage of an attack. The swelling stage of an attack is characterised by swelling that is more severe than any in the prodromal phase, pain (e.g. abdominal attack), discomfort (e.g. peripheral attack), and/or a threat to life (e.g. laryngeal attack). The swelling can affect the hands, feet, limbs, face, intestinal tract, and/or airway; cause fatigue, headache, muscle aches, skin tingling, abdominal pain, nausea, vomiting, diarrhoea, difficulty swallowing, hoarseness, shortness of breath, and/or mood changes.

The prophylactic treatments of the invention can reduce the severity of any symptoms of an HAE attack, compared to an untreated patient, including those in the swelling stage of an attack. Specifically, the prophylactic treatments of the invention can reduce the severity of any symptoms of an HAE attack as measured on the 5-point Likert scale (5LS) (see e.g. Allergy Asthma Proc. 2018 Jan l;39(l):74-80. doi: 10.2500/aap.2018.39.4095). More specifically, the prophylactic treatments of the invention can reduce the severity of any symptoms of an HAE attack) such that the symptoms do not progress past the "mild" stage.

The prophylactic treatments of the invention can reduce the severity of an HAE attack as measured on the 3-point scale of "mild", "moderate" or "severe", as determined by a qualified medical professional as described above, e.g. a medical doctor. More specifically, the prophylactic treatments of the invention can reduce the severity of any symptoms of an HAE attack such that the symptoms do not progress past the "mild" stage, as determined by a qualified medical professional, e.g. a medical doctor.

The prophylactic treatments of the invention can reduce the rate of progression of an HAE attack, compared to an untreated patient. Specifically, the prophylactic treatments of the invention can reduce the number of HAE attacks that progress with a score of "worse" or "much worse", on a 7-point transition question (7TQ). More specifically, the prophylactic treatments of the invention can reduce the number of HAE attacks, that progress with a score of "much worse", on a 7-point transition question (7TQ). The 7TQ index is an index known in the art that can be used to score the progression of an HAE attack and to report attacks as "much better", "better", "a little better", "no change", "a little worse", "worse", or "much worse". The prophylactic treatments of the invention can shorten the duration of HAE attacks compared to an untreated patient.

The inventors have unexpectedly found that the treatments of the invention can provide the patient with increased protection from an HAE attack during the night, which is particularly important because HAE attacks that begin overnight risk going unnoticed by the patient such that they develop into serious attacks that are more difficult to halt compared to early-stage attacks. This surprising effect has been identified when the patient is administered the compound of Formula A twice daily, with one dosage amount in the morning (after the patient wakes up) and with one dosage amount at night (before the patient's bedtime). As shown in Example 3, the Cmin is higher before the patient takes their morning dosage amount compared with the Cmin before the patient takes their night-time dosage amount.

The prophylactic treatment of the invention can therefore provide increased efficacy during the night compared with the day. Specifically, the prophylactic treatment of the invention can provide increased efficacy during the night (after the patient's night time dosage amount and before their morning dosage amount) when the compound of Formula A is administered twice daily, with one dosage amount being administered in the morning (after the patient wakes up) and with one dosage amount at night (before the patient's bedtime). The prophylactic treatment of the invention can provide a higher Cmin through the night (after the patient's night time dosage amount and before their morning dosage amount) compared with the day (after the patient's morning dosage amount and before their night time dosage amount before their bedtime). The morning dosage amount can be administered within 1 hour of the patient waking up (e.g. within 45 minutes, 30 minutes, 15 minutes, or 5 minutes). And the night time dosage amount can be administered within 1 hour of the patient going to sleep (e.g. within 45 minutes, 30 minutes, 15 minutes, or 5 minutes). Additionally, or alternatively, these two daily amounts can be about 12 hours apart, which depending on the patient's lifestyle, might coincide with waking up and going to bed.

The Angioedema Control Test (AECT) is a validated, self-administered, retrospective 4-item patient reported outcome measure for patients with recurrent angioedema. The AECT is used to quantify diseases control and to aid treatment decisions (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 addresses the frequency of angioedema, angioedema- related quality-of-life (QoL) impairment, unpredictability of angioedema attacks, and angioedema control by the current treatment approach. Each of the 4 AECT items is scored from 0 to 4 points with higher scores indicating a higher level of angioedema control. The AECT score is calculated by summing up all 4 item scores, with a minimum and maximum possible score of 0 and 16 points.

The treatments of the invention can lead to the patient having a score on the AECT of at least 12.

The Angioedema Quality of Life Questionnaire (AE-QoL) is a symptom-specific health-related QoL instrument for patients with recurrent angioedema. It consists of 17 items that can be grouped together to a total score or to 4 different domain scores ("Functioning", "Fatigue/Mood", "Fears/Shame" and "Food") that collectively evaluate the extent of angioedema-dependent QoL impairment during the previous 4 weeks. Each AE-QoL question has 5 answer options (scored 1-5), with lower and higher scores indicting less and more adverse impact, respectively. The total score is calculated, which is then transformed into a linear scale that ranges from 0 to 100, with a score of 100 indicating the worst possible impairment. A minimal clinically important difference of 6 points 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).

The treatments of the invention can decrease the patient's score on the Angioedema Quality of Life Questionnaire (AE-QoL) by at least 6 points compared with the patient's score on the AE-QoL prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). For example, the patient's score on the AE-QoL prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) can be the patient's score when they were previously being administered a prophylactic treatment for HAE other than the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the patient's score on the AE-QoL prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) can be the patient's score prior to the patient being administered any prophylactic treatment for HAE. Alternatively, the patient's score on the AE-QoL prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) can be the score the patient would have received in the absence of another prophylactic treatment for HAE.

The Treatment Satisfaction Questionnaire for Medication (TSQM) is a psychometrically sound and valid measure of the major dimensions of patients' 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 comprises 14 questions that are scaled on, e.g., a 7-point bipolar scale ranging from "Extremely Satisfied" to "Extremely Dissatisfied."

The treatments of the invention can increase the patient's score on the Treatment Satisfaction Questionnaire for Medication (TSQM) compared with the patient's score on the TSQM prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). For example, the patient's score on the TSQM prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) can be the patient's score when they were previously being administered a prophylactic treatment for HAE other than the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). Alternatively, the patient's score on the TSQM prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) can be the patient's score prior to the patient being administered any prophylactic treatment for HAE. Alternatively, the patient's score on the TSQM prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) can be the score the patient would have received in the absence of another prophylactic treatment for HAE.

Oral modified release pharmaceutical dosage forms for use in the treatments of the invention

To provide an effective prophylactic treatment, a dosage form needs to be capable of maintaining a therapeutically effective amount of the compound in the patient's blood plasma for the duration of treatment, but avoid potentially harmful accumulation of the compound. The dosage forms also need to minimise burden on the patient by minimising pill burden and dosage frequency. To do this, the inventors have skilfully designed and developed an oral modified release pharmaceutical dosage form for use in the treatments described herein. The term "modified release" is known in the art to mean the manipulation or modification of drug release from a dosage form with the aim of delivering drug substance at i) desired rates, ii) pre-defined time points or iii) specific sites in the gastrointestinal tract. Design of the oral modified release pharmaceutical dosage forms described herein required the inventors to take account of the physiology of the gastrointestinal tract, the physiochemical properties of the drug, the design of the dosage form, the drug release mechanism, the particular disease factors, and the biological properties of a drug. This careful balance required gathering data from human clinical studies to, inter alia, investigate whether the dosage forms had a PK profile suitable for the prophylactic treatments of the invention. The phase 1 study described in Example 3 demonstrates that the oral modified release pharmaceutical dosage forms described herein have a PK profile that is suitable for the prophylactic treatments of the invention. No serious adverse events were identified in the study.

The invention therefore provides using the oral modified release pharmaceutical dosage forms described herein in the treatments of the invention.

The invention provides a method for prophylactic treatment of HAE comprising oral administration of the 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 (or a pharmaceutically acceptable salt and/or solvate thereof) is comprised within an oral modified release pharmaceutical dosage form.

The invention provides the use of an oral modified release pharmaceutical dosage form in the manufacture of a medicament for prophylactic treatment of hereditary angioedema (FIAE) of the invention as described above, comprising oral administration of the oral modified release pharmaceutical dosage form, wherein the oral modified release pharmaceutical dosage form comprises the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof).

The invention provides an oral modified release pharmaceutical dosage form for use in a method for prophylactic treatment of hereditary angioedema (FIAE) of the invention as described above, wherein the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is comprised within the oral modified release pharmaceutical dosage form.

The oral modified release pharmaceutical dosage form comprises the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof). The dosage forms can comprise between about 20 and about 70 wt% of the compound of Formula A. The dosage forms can comprise between about 20 and about 60 wt% of the compound of Formula A. The dosage forms can comprise between about 30 and about 60 wt% of the compound of Formula A. The dosage forms can comprise between about 30 and about 50 wt% of the compound of Formula A. The dosage forms can comprise between about 35 and about 45 wt% of the compound of Formula A. The dosage forms can comprise between about 40 and about 45 wt% of the compound of Formula A. The dosage forms can comprise between about 42 and about 43 wt% of the compound of Formula A.

Preferably, the oral modified release pharmaceutical dosage form is a tablet. The tablet can be film coated. The film coating can comprise one or more of hypromellose, methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidine, polyvinyl alcohol, aminoalkyl methacrylate copolymers, cellulose derivatives (e.g. ethyl cellulose or cellulose acetate), chitosan, methylmethacrylate copolymers, methacrylic acid copolymers, phthalate esters (e.g. hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and poly vinyl acetate phthalate), plasticizers (e.g. polyols such as polyethylene glycols and propylene glycols; organic esters such as diethyl phthalate, glyceryl monocaprylate and triethyl citrate; or oils/glycerides such as fractionated coconut oil), colourants (e.g. iron oxide pigments, titanium dioxide, and aluminium lakes) lactose monohydrate, and triacetin. The film coating can comprise polyvinyl alcohol. The film coating can comprise polyethylene glycol (PEG). The film coating can comprise titanium dioxide. Preferably, the film coating comprises polyvinyl alcohol, polyethylene glycol (PEG) and titanium dioxide.

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

The oral modified release pharmaceutical dosage forms can comprise between about 1 and about 80 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 2 and about 60 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 2 and about 50wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 2 and about 40 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 3 and about 30 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 3 and about 20 wt% of the release modifying agent. The oral modified release pharmaceutical dosage forms can comprise between about 3 and about 15 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 5 and about 15 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 10 and about 15 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 10 and about 14 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 11 and about 13 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise between about 11.5 and about 13 wt% of the release modifying agent. More specifically, the oral modified release pharmaceutical dosage forms can comprise about 12.5 wt% of the release modifying agent.

Preferably the oral modified release pharmaceutical dosage forms can comprise between about 11.5 and about 13 wt% of the release modifying agent, particularly between about 12 and about 13 wt%, specifically about 12.5 wt%.

The release modifying agent can be a pH sensitive polymer. pH sensitive polymers include polymers based upon methacrylic acid copolymers such as the Eudragit polymers, for example Eudragit L which can be used either alone or with a plasticiser; release modifying agents which have a high degree of swelling in contact with water or aqueous media such as the stomach contents; polymeric materials which form a gel on contact with water or aqueous media; and polymeric materials which have both swelling and gelling characteristics in contact with water or aqueous media.

Release modifying agents that have a high degree of swelling include, e.g., cross-linked sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, high-molecular weight hydroxypropylmethylcellulose, carboxymethylamide, potassium methacrylatedivinylbenzene co polymer, polymethylmethacrylate, and high-molecular weight polyvinylalcohols.

Release modifying agents that are gellable polymers include, e.g., methylcellulose, carboxymethylcellulose, low-molecular weight hydroxypropylmethylcellulose, low-molecular weight polyvinylalcohols, polyoxyethyleneglycols, and xanthan gum. Release modifying agents simultaneously possessing swelling and gelling properties include, e.g. medium-viscosity hydroxypropylmethylcellulose and medium-viscosity polyvinylalcohols.

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

Other known release modifying agents 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, carageenin, soluble and insoluble alginates, carboxypolymethylene, casein, zein, and the like, and proteinaceous substances such as gelatin.

Preferred release modifying agents are selected from the group consisting of hydroxypropyl methyl cellulose (such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR), hydroxypropyl methyl cellulose, hydroxypropyl celluloses, polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303), and carboxymethylcellulose and salts thereof. Particularly preferred release modifying agents are selected from the group consisting of polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303), and hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, and most preferably hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, especially Methocel DC2 K4M.

The modified release oral pharmaceutical dosage forms can comprise between about 3 and 30 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. The modified release oral pharmaceutical dosage forms can comprise between about 3 and 20 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. The modified release oral pharmaceutical dosage forms can comprise between about 3 and 15 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. The modified release oral pharmaceutical dosage forms can comprise between about 3 and 30 wt% of the release modifying agent, wherein the release modifying agent is selected from polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303). The modified release oral pharmaceutical dosage forms can comprise between about 3 and 20 wt% of the release modifying agent, wherein the release modifying agent is selected from polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303). The modified release oral pharmaceutical dosage forms can comprise between about 8 and 20 wt% of the release modifying agent (e.g. about 15wt%), wherein the release modifying agent is selected from polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303). The modified release oral pharmaceutical dosage forms can comprise about 15 wt% of the release modifying agent (e.g. about 15wt%), wherein the release modifying agent is selected from polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303)

The modified release oral pharmaceutical dosage forms can comprise between about 3 and 15 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, and polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303), particularly, hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. More specifically, the dosage forms can comprise between about 3 and 15 wt% of the release modifying agent, wherein the release modifying agent is hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, particularly hydroxypropyl methyl cellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage forms can comprise between about 5 and about 15 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303), particularly, hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. More specifically, the dosage forms can comprise between 5 and about 15 wt% of the release modifying agent, wherein the release modifying agent is e.g. hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, particularly hydroxypropyl methyl cellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage forms can comprise between about 10 and about 15 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303), particularly, hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. More specifically, the dosage forms can comprise between about 10 and about 15 wt% of the release modifying agent, wherein the release modifying agent is hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, particularly hydroxypropyl methyl cellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage forms can comprise between about 10 and about 14 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303), particularly, hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. More specifically, the dosage forms can comprise between about 10 and about 14 wt% of the release modifying agent, wherein the release modifying agent is hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, particularly hydroxypropyl methyl cellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage forms can comprise between about 11 and about 13 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303), particularly, hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. More specifically, the dosage forms can comprise between about 11 and about 13 wt% of the release modifying agent, wherein the release modifying agent is hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, particularly hydroxypropyl methyl cellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage forms can comprise between about 11 and about 13 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxylpropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303), particularly, hydroxylpropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. More specifically, the dosage forms can comprise between about 11 and about 13 wt% of the release modifying agent, wherein the release modifying agent is hydroxylpropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, particularly hydroxylpropyl methyl cellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage forms can comprise between about 12.5 wt% of the release modifying agent, wherein the release modifying agent is selected from hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, polyethylene oxides (e.g. Polyox WSR N750, or Polyox WSR 303), particularly, hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR. More specifically, the dosage forms can comprise between about 12.5 wt% of the release modifying agent, wherein the release modifying agent is hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR, particularly hydroxypropyl methyl cellulose such as Methocel DC2 K4M.

The modified release oral pharmaceutical dosage forms can also comprise a diluent. The modified release oral pharmaceutical dosage forms can also comprise one or more diluents. The diluent can be selected from lactose (e.g. lactose monohydrate, spray dried lactose, anhydrous lactose), sorbitol, mannitol, sucrose, starch and pregelatinized starch, cellulose (e.g. powdered cellulose, microcrystalline cellulose such as Avicel PH101, Avicel PH102), calcium phosphates (e.g. anhydrous dibasic calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate), tricalcium citrate, and mixtures thereof. Preferably the diluent is selected from microcrystalline cellulose (such as Avicel PH101, Avicel PH102) and/or mannitol.

The diluent can comprise between about 15 wt% and about 60 wt% of the dosage form. The diluent can comprise between about 20 wt% and about 60 wt% of the dosage form. The diluent can comprise between about 20 wt% and about 50 wt% of the dosage form. The diluent can comprise between about 30 wt% and about 50 wt% of the dosage form. The diluent can comprise between about 30 wt% and about 40 wt% of the dosage form. The diluent can comprise between about 35 wt% and about 40 wt% of the dosage form. The diluent can comprise between about 37 wt% and about 38 wt% 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 e.g. Pearlitol 200SD), and the diluent can comprise between about 30 wt% and about 50 wt% of the dosage form, preferably between about 30 wt% and about 40 wt%, most preferably between about 35 wt% and about 40 wt% of the dosage form.

The modified release oral pharmaceutical dosage forms can also comprise a binder. The modified release oral pharmaceutical dosage forms can also one or more binders. The binder can be selected from a binder selected from saccharides (such as glucose, sucrose, fructose, dextrose, lactose), sugar alcohols (such as xylitol, maltitol, erythritol, sorbitol), polysaccharides (such as crystalline cellulose, powdered cellulose, methyl cellulose, ), corn starch, starch 1500, acacia, other natural polymers (such as gelatin), synthetic polymers (such as polyvinyl pyrrolidone (e.g. copovidone), polyvinyl polypyrolidone (crospovidone)), polyethylene gylcol, crosslinked acrylic acid and acrylic acid copolymers (e.g. Carbopol^®), inorganic compounds (such as calcium carbonate), and mixtures thereof (more specifically glucose, lactose, corn starch, starch 1500, gelatin, acacia, methyl cellulose, polyvinyl pyrrolidone, and mixtures thereof). Preferably, the binder is a synthetic polymers such as polyvinyl pyrrolidone (e.g. copovidone), polyvinyl polypyrolidone (crospovidone)), particularly polyvinyl pyrrolidone (e.g. copovidone). Most preferably, the binder is polyvinyl pyrrolidone (e.g. copovidone).

The binder can comprise between about 1 wt% and about 20 wt% of the dosage form. The binder can comprise between about l wt% and about 15 wt% of the dosage form. The binder can comprise between about 1 wt% and about 10 wt% of the dosage form. The binder can comprise between about 1 wt% and about 7 wt% of the dosage form. The binder can comprise between about 1 wt% and about 5 wt% of the dosage form. The binder can comprise between about 2 wt% and about 5 wt% of the dosage form. The binder can comprise between about 2 wt% and about 4 wt% of the dosage form. The binder can comprise about 3 wt% of the dosage form.

The binder can be polyvinyl pyrrolidone (e.g. copovidone) and can comprise between about 1 wt% and about 10 wt% of the dosage form, more preferably between about 1 wt% and about 5 wt% of the dosage form, most preferably between about 2 wt% and about 5 wt% of the dosage form.

The modified release oral pharmaceutical dosage forms can also comprise a lubricant. The modified release oral pharmaceutical dosage forms can also one or more lubricants. The lubricant can be selected from magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, glyceryl behenate, glyceryl palmitostearate, polyethylene glycol, polyoxyethylene stearates, lauryl sulphate, talc, paraffin, and mixtures thereof. Preferably, the lubricant is selected from magnesium stearate and/or talc. The lubricant can comprise between about 0.25 wt% and about 6 wt% of the dosage form. The lubricant can comprise between about 0.25 wt% and about 5 wt% of the dosage form. The lubricant can comprise between about 0.25 wt% and about 4 wt% of the dosage form. The lubricant can comprise between about 0.5 wt% and about 4 wt% of the dosage form. The lubricant can comprise between about 1 wt% and about 4 wt% of the dosage form. The lubricant can comprise between about

2 wt% and about 4 wt% of the dosage form. The lubricant can comprise between about 3 wt% and about 4 wt% of the dosage form. The lubricant can comprise about 3.5 wt% of the dosage form.

The lubricant can be magnesium stearate and/or talc (preferably magnesium stearate and talc), and can comprise between about 2 wt% and about 4 wt% of the dosage form, preferably between about

3 wt% and about 4 wt% of the dosage form, most preferably about 3.5 wt% of the dosage form.

The modified release oral pharmaceutical dosage forms can be made by forming granules, followed by adding extragranular excipients. In these circumstances, the release modifying agent, diluent, binder, and/or lubricant described above can form the intra-granular composition (the wt% provided are still compared to the total dosage form). The extragranular excipients can comprise one or more of a lubricant, a glidant, and a diluent, as follows.

The extragranular lubricant can comprise one or more extragranular lubricants selected from magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, mineral oil, glyceryl behenate, glyceryl palmitostearate, polyethylene glycol, polyoxyethylene stearates, lauryl sulphate, talc, paraffin, and mixtures thereof. Preferably, the extragranular lubricant is magnesium stearate.

The extragranular lubricant can comprise between about 0.1 wt% and about 3wt% of the dosage form. The extragranular lubricant can comprise between about 0.1 wt% and about 2wt% of the dosage form. The lubricant can comprise between about 0.1 wt% and about 1.5 wt% of the dosage form. The extragranular lubricant can comprise between about 0.1 wt% and about 1 wt% of the dosage form. The extragranular lubricant can comprise between about 0.2 wt% and about 1 wt% of the dosage form. The extragranular lubricant can comprise between about 0.2 wt% and about 0.7 wt% of the dosage form. The extragranular lubricant can comprise between about 0.3 wt% and about 0.7 wt % of the dosage form. The extragranular lubricant can comprise between about 0.4 wt% and about 0.6 wt % of the dosage form. The extragranular lubricant can comprise about 0.5 wt% of the dosage form. The extragranular lubricant can be magnesium stearate and can comprise between about 0.2 wt% and about 0.7 wt% of the dosage form, preferably between about 0.4 wt% and about 0.6 wt % of the dosage form, most preferably about 0.5 wt% of the dosage form.

The extragranular glidants can comprise one or more extragranular glidants selected from talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tribasic calcium phosphate, and mixtures thereof. Preferably, the extragranular glidant is colloidal silicon dioxide.

The extragranular glidant can comprise between about 0.1 wt% and about 2 wt% of the dosage form. The extragranular glidant can comprise between about 0.1 wt% and about 1.5 wt% of the dosage form. The extragranular glidant can comprise between about 0.1 wt% and about 1.0 wt% of the dosage form. The extragranular glidant can comprise between about 0.5 wt% and about 1.5 wt% of the dosage form. The extragranular glidant can comprise between about 0.7 wt% and about 1.5 wt% of the dosage form. The extragranular glidant can comprise between about 0.7 wt%and about 1.2 wt%of the dosage form. The extragranular glidant can comprise between about 0.9 wt% and about 1.1 wt % of the dosage form. The extragranular glidant can comprise about 1 wt% of the dosage form.

The extragranular glidant can be colloidal silicon dioxide, and can comprise between about 0.1 wt% and about 2 wt% of the dosage form, preferably between about 0.7 wt% and about 1.5 wt% of the dosage form, most preferably about 1 wt% of the dosage form.

The extragranular diluent can comprise one or more extragranular diluents selected from lactose (e.g. lactose monohydrate, spray dried lactose, anhydrous lactose), sorbitol, mannitol, sucrose, starch and pregelatinized starch, cellulose (e.g. powdered cellulose, microcrystalline cellulose e.g. Avicel PH101, Avicel PH102), calcium phosphates (e.g. anhydrous dibasic calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate), tricalcium citrate, and mixtures thereof. Preferably, the extragranular diluent is microcrystalline cellulose e.g. Avicel PH101, Avicel PH102.

The extragranular diluent can comprise between about 1 wt% and about 20 wt% of the dosage form. The diluent can comprise between about 3 wt% and about 15 wt% of the dosage form. The extragranular diluent can comprise between about 6 wt% and about 15 wt% of the dosage form. The extragranular diluent can comprise between about 6 wt% and about 12 wt% of the dosage form. The extragranular diluent can comprise between about 7 wt% and about 11 wt% of the dosage form. The extragranular diluent can comprise between about 8 wt% and about 10 wt % of the dosage form. The extragranular diluent can comprise about 9 wt% of the dosage form.

The extragranular diluent can be microcrystalline cellulose e.g. Avicel PH101, Avicel PH102, and can comprise between about 1 wt% and about 20 wt% of the dosage form, preferably between about 6 wt% and about 15 wt% of the dosage form, most preferably about 9 wt% of the dosage form.

The modified release oral pharmaceutical dosage form can comprise: (i) between about 3 and 15 wt% of a release modifying agent, wherein the release modifying agent is hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR; (ii) between about 30 wt% and about 40 wt% of a 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% of a binder, wherein the binder is polyvinyl pyrrolidone (e.g. povidone), (iv) between about 3 wt% and about 4 wt% of a lubricant, wherein the lubricant is magnesium stearate and/or talc (preferably magnesium stearate and talc), (v) between about 0.4 wt% and about 0.6 wt % of an extragranular lubricant, wherein the extragranular lubricant is magnesium stearate, (vi) between about 0.7 wt% and about 1.5 wt% of a extragranular glidant, wherein the extragranular glidant is colloidal silicon dioxide, (vii) between about 6 wt% and about 15 wt% of an extragranular diluent, wherein the extragranular diluent is microcrystalline cellulose e.g. Avicel PH101, Avicel PH102.

The modified release oral pharmaceutical dosage forms can be characterised by their dissolution profile. The release % values described below are achieved when the modified release oral pharmaceutical dosage forms are tested in the dissolution method described in Table 1. Samples from the dissolution vessel are analysed for compound using a reversed phase isocratic HPLC method with the conditions detailed in Table 2 below. Specifically, dissolution is performed in accordance with the harmonised monograph (Ph. Eur. 2.9.3).

Table 1

Table 2

The dosage forms can release less than about 40% of the compound at about 2 hours. The dosage forms can release less than about 40% of the compound at about 3 hours. The dosage forms can release less than about 40% of the compound at about 4 hours. The dosage forms can release less than about 40% of the compound at about 5 hours. The dosage forms can release less than about 60% (or between about 40% and about 60%) of their compound at about 3 hours. The dosage forms can release less than about 60% (or between about 40% and about 60%) of their compound at about 4 hours. The dosage forms can release less than about 60% (or between about 40% and about 60%) of their compound at about 5 hours. The dosage forms of can release less than about 60% (or between about 40% and about 60%) of their compound at about 6 hours. The dosage forms can release less than about 60% (or between about 40% and about 60%) of their compound at about 7 hours. The dosage forms can release less than about 60% (or between about 40% and about 60%) of their compound at about 8 hours.

The dosage forms can release less than about 80% (or between about 60% and about 80%) of their compound at about 5 hours. The dosage forms can release less than about 80% (or between about 60% and about 80%) of their compound at about 6 hours. The dosage forms can release less than about 80% (or between about 60% and about 80%) of their compound at about 7 hours. The dosage forms can release less than about 80% (or between about 60% and about 80%) of their compound at about 8 hours. The dosage forms can release less than about 80% (or between about 60% and about 80%) of their compound at about 9 hours. The dosage forms can release less than about 80% (or between about 60% and about 80%) of their compound at about 10 hours. The dosage forms can release less than about 80% (or between about 60% and about 80%) of their compound at about 11 hours. The dosage forms can release less than about 80% (or between about 60% and about 80%) of their compound at about 12 hours.

The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 6 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 7 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 8 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 9 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 10 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 11 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 12 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 13 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 14 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 15 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 16 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 17 hours. The dosage forms can release less than about 90% (or between about 80% and about 90%) of their compound at about 18 hours.

More specifically, the dosage forms can release less than about 40% of their compound at about 2 hours; and/or between about 40% and about 60% of their compound at about 3 hours; and/or between about 60% and 80% of their compound at about 5 hours; and/or between about 80% and about 90% of their compound at about 7 hours. More specifically, the dosage forms can release less than about 40% of their compound at about 3 hours; and/or between about 40% and about 60% at about 6 hours; and/or between about 60% and about 80% at about 9 hours; and/or between about 80% and 90% at about 11 hours.

More specifically, the dosage forms can release less than about 40% of their compound at about 2 hours; and/or between about 30 and about 70% of their compound at about 6 hours; and/or between about 50 and about 90% of their compound at about 9 hours; and/or more than about 80% of their compound at about 16 hours.

More specifically, the dosage forms can release between about 40 and 70% of their compound at about 6 hours; and/or between about 55 and about 85% of their compound at about 9 hours; and/or between about 65 and about 95% of their compound at about 11 hours.

The term "bioequivalent", as used herein, describes a dosage form that is therapeutically equivalent to the innovator's reference product (e.g. any approved dosage form comprising the compound of Formula A) when given under the same conditions in a pharmacokinetic evaluation. For example, these can be conforming to FDA Guidance on Bioequivalence Testing; regardless of biopharmaceutical class (see http://www.fda.gov/ohrms/dockets/ac/03/briefing/3995Bl_07_GFI-BioAvail-BioEquiv.pdf, see also https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4241Bl-Q2-23-FDA- Bioequiv%200GD%200ct%206%202006%20Background.pdf), or the EMA's guidance EMA/CFIMP/EWP/280/96 Revl dated 20th November 2014. A value that is "bioequivalent", as used herein, is meant to refer to a pharmacokinetic value (such as the Cmax or AUC of a formulation described herein) that exhibits substantially similar pharmacokinetic profiles or therapeutic effects. Bioequivalence can be demonstrated through in vivo and in vitro methods. These methods can include, for example, pharmacokinetic, pharmacodynamic, clinical and in vitro studies. Bioequivalence can be demonstrated using any suitable pharmacokinetic measures 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, the peak blood or plasma concentration (Cmax), time to peak concentration (Tmax), bioavailability and potency. A value can be bioequivalent to a reference pharmacokinetic value when the geometric mean of the AUC(O-t) (Area under the plasma concentration curve from administration to last observed concentration at time t), AUC(0- ) (Area under the plasma concentration curve extrapolated to infinite time), Cmax (maximum plasma concentration) is between 80% and 125% (e.g., at 90% confidence interval) of the reference pharmacokinetic value. For modified release oral pharmaceutical dosage forms, bioequivalence can also take into account the Cmax,ss (Cmax at steady state), the Cu,ss (the concentration at the end of the dosing interval at steady state), and AUC(0-T)SS (AUC during a dosage interval at steady state).

An oral modified release pharmaceutical dosage form that is bioequivalent to any of the dosage forms described herein can be used in the treatments of the invention. An oral modified release pharmaceutical dosage form that is bioequivalent to any of the dosage forms described herein, wherein "bioequivalent" means having one or more of AUC(O-t), AUC(0- ), Cmax, Cmax,ss, the Cu,ss , and AUC(0-T)SS between 80% and 125% (e.g., at 90% confidence interval) of any of the oral modified release pharmaceutical dosage forms described herein can be used in the treatments of the invention.

Dosing

As used herein, dosage amounts are expressed as free base equivalent. As such, and purely for example, administering 107.2 mg of the HCI salt of the compound would be described as a 100 mg dose as 107.2mg of the of compound free base is equivalent to 100 mg of the free base of the compound.

In the treatments described herein, the compound of Formula A is orally administered in a therapeutically effective amount such that the compound of Formula A is maintained at a concentration in the blood plasma above the minimum therapeutically effective concentration for achieving prophylaxis. As noted above, the compound of Formula A can be orally administered to provide a Cmin of about 30 ng/mL.

The compound of Formula A can be administered at a daily dosing amount of between about 300 mg and about 2400 mg. "Daily dosage amount" means the total amount administered in one day. More specifically, the compound of Formula A can be administered at a daily dosing amount of between about 600 mg and about 2100 mg. The compound of Formula A can be administered at a daily dosing amount of between about 600 mg and about 1800 mg. The compound of Formula A can be administered at a daily dosing amount of between about 900 mg and about 1800 mg. The compound of Formula A can be administered at a daily dosing amount of between about 1200 mg and about 1800 mg. The daily dosing amount can be about 300 mg. The daily dosing amount can be about 600 mg. The daily dosing amount can be about 1200 mg. The daily dosing amount can be about 1800mg. The treatments of the invention can achieve a steady-state concentration of the compound within 2 days of starting treatment. The treatments of the invention can achieve a steady-state concentration of the compound within 3 days of starting treatment. The treatments of the invention can achieve a steady-state concentration of the compound within 4 days of starting treatment. The treatments of the invention can achieve a steady-state concentration of the compound within a week of starting treatment. The treatments of the invention can achieve a steady-state concentration of the compound within 1 to 2 days of starting treatment. The treatments of the invention can achieve a steady-state concentration of the compound within 2 to 3 days of starting treatment. The treatments of the invention can achieve a steady-state concentration of the compound within 3 to 4 days of starting treatment. Preferably, the treatments of the invention can achieve a steady-state concentration of the compound within 2 to 3 days of starting treatment.

The daily dosage amount can be administered as a twice daily treatment. A first dosage amount can be administered in the morning (after the patient wakes up) and a second dosage amount can be administered at night (before the patient's bedtime). The first dosage amount can be administered within an hour of the patient waking up. The first dosage amount can be administered within 30 minutes of the patient waking up. The first dosage amount can be administered within 15 minutes of the patient waking up. The second dosage amount can be administered within an hour of the patient's bedtime. The second dosage amount can be administered within 30 minutes of the patient's bedtime. The second dosage amount can be administered within 15 minutes of the patient's bedtime. The two dosage amounts can also be administered about 12 hours apart. Preferably, the two dosage amounts can also be administered about 12 hours apart.

The twice daily treatments of the invention can comprise administering the compound of Formula A with food. More specifically, the twice daily treatments of the invention can require administering a first dosage amount in the morning when the patient eats their first meal of the day (e.g. breakfast), and a second dosage amount in the evening when the patient eats their evening meal (e.g. dinner). The first dosage amount can be administered within about 30 minutes of their first meal of the day, more specifically within about 15 minutes, even more specifically within about 10 minutes, or even within about 5 minutes. The second dosage amount can be administered within about 30 minutes of their evening meal of the day, more specifically within about 15 minutes, even more specifically within about 10 minutes, or even within about 5 minutes. The twice daily treatments of the invention can comprise administering the compound of Formula A after food. More specifically, the twice daily treatments of the invention can require administering a first dosage amount in the morning after the patient eats their first meal of the day (e.g. breakfast), and a second dosage amount in the evening after the patient eats their evening meal (e.g. dinner). The first dosage amount can be administered within about 30 minutes after their first meal of the day, more specifically within about 15 minutes, even more specifically within about 10 minutes, or even within about 5 minutes. The second dosage amount can be administered within about 30 minutes after their evening meal of the day, more specifically within about 15 minutes, even more specifically within about 10 minutes, or even within about 5 minutes.

When the treatments of the invention are twice daily treatment, the daily dosage amount can be split evenly between the two dosage amounts. For instance, when the daily dosage amount is 1800mg, the twice daily treatment can involve administering two dosage amounts of 900 mg, e.g. about 12 hours apart. When the daily dosage amount is 1200mg, the twice daily treatment can involve administering two dosage amounts of 600 mg, e.g. about 12 hours apart. When the daily dosage amount is 600mg, the twice daily treatment can involve administering two dosage amounts of 300 mg, e.g. about 12 hours apart. When the daily dosage amount is 300mg, the twice daily treatment can involve administering two dosage amounts of 150 mg, e.g. about 12 hours apart.

Each dosage amount can be administered as one single unit dosage form (e.g. one tablet), or sub-divided into multiple unit dosage form (e.g. multiple tablets). For instance, each unit dosage form can comprise about lOOmg of the compound. Alternatively, each unit dosage form can comprise about 150mg of the compound. Alternatively and preferably, each unit dosage form can comprise about 300mg of the compound.

The treatment of the invention can be a twice daily treatment comprising administering two dosage amounts of 300 mg about 12 hours apart; wherein the first dose is administered with a morning meal and the second dose is administered with an evening meal.

The treatment of the invention can be a twice daily treatment comprising administering two dosage amounts of 600 mg about 12 hours apart; wherein the first dose is administered with a morning meal and the second dose is administered with an evening meal. The treatment of the invention can be a twice daily treatment comprising administering two dosage amounts of 900 mg about 12 hours apart; wherein the first dose is administered with a morning meal and the second dose is administered with an evening meal.

The Compound of Formula A

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

The compound of Formula A is preferably provided as the hydrochloride salt. More specifically, the compound of Formula A can preferably be provided as hydrochloride salt Form 5.

The invention provides Form 5 of the hydrochloride salt of compound of Formula A exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Ka radiation, expressed in degrees 2Q) at approximately:

(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 (Form 5) of the hydrochloride salt of compound of Formula A, having an X ray powder diffraction pattern comprising characteristic peaks (expresses in degrees 2Q) at approximately 10.4, 12.0, 13.5, 13.9, 15.6, 16.1, 16.7, 17.3, 19.7, 20.8, and 25.3.

The invention provides Form 5 of the hydrochloride salt of the compound of Formula A has an X-ray powder diffraction pattern substantially the same as that shown in Figure 5.

The term "approximately" means in this context that there is an uncertainty in the measurements of the degrees 2Q of ± 0.3 (expressed in degrees 2Q), preferably ± 0.2 (expressed in degrees 2Q).

The invention provides Form 5 of the hydrochloride salt of the compound of Formula A, which exhibits an endothermic peak in its STA thermograph at 161 ± 3 °C, preferably 161 ± 2 °C, more preferably 161 ± 1 °C. The invention provides Form 5 of the hydrochloride salt of compound of Formula A, having an STA thermograph substantially the same as that shown in Figure 6.

The invention also provides a method for manufacturing any of the oral modified release dosage forms described herein, wherein Form 5 is used in the method.

EXAMPLES

The invention will now be illustrated by the following non-limiting examples. In the examples the following figures are presented:

Figure 1: Simplified diagram of the contact activation system. Figure 2: In vitro plasma kallikrein activity of the compound of Formula A (filled line) and Haegarda^® (dashed line).

Figure 3: X-ray powder diffraction pattern of Form 1 of the free base of the compound of Formula A.

Figure 4: STA thermograph of Form 1 of the free base of the compound of Formula A. Figure 5: X-ray powder diffraction pattern of Form 5 of the hydrochloride salt of the compound of Formula A.

Figure 6: STA thermograph of Form 5 of the hydrochloride salt of the compound of Formula A. Figure 7: PK profiles for the 6 periods in part 1 of the phase 1 study. Figure 8: Average PK profile for days 1 to 14 for cohort 1 in part 2 of the phase 1 study. Figure 9: Overlay of the PK profiles for days 1 and 14 of cohort 1 in part 2 of the phase 1 study with period 1 in part 1 of the phase 1 study.

Figure 10: Average PD profile for days 1 to 14 of cohort 1 in part 2 of the phase 1 study showing the average plasma kallikrein activity as a % of pre-dose levels.

Figure 11: Overlay of the PD profile for days 1 and 14 of cohort 1 in part 2 of the phase 1 study showing the average plasma kallikrein activity as a % of pre-dose levels.

Figure 12: Various PK parameters reported from cohort 1 and periods 1, 4, and 6. Figure 13a: Average PK profile for days 1 to 14 for cohort 2 in part 2 of the phase 1 study. Figure 13b: PK profile for day 1 of cohort 2 of the phase 1 study overlaid with the PK profile for day 1 of cohort 1 in part 2 of the phase 1 study.

Figure 13c: Average PD profile for days 1 to 14 of cohort 2 in part 2 of the phase 1 study. Figure 14a: PK profile for days 1 to 7 of cohort 2 in part 2 of the phase 1 study overlaid with the PK profile for days 1 to 14 of cohort 1 in part 2 of the phase 1 study.

Figure 14b: Complete PK profile for days 1 to 14 of cohort 2 in part 2 of the phase 1 study, overlaid with the PK profile for days 1 to 14 of cohort 1 in part 2 of the phase 1 study.

Figure 15a: PK profiles for days 1 to 7 of cohorts 1 and 2 in part 2 of the phase 1 study showing a higher Cmin for treatments of the invention compared to an approved FIAE treatment (Flaegarda^®).

Figure 15b: Complete PK profiles for days 1 to 14 of cohorts 1 and 2 in part 2 of the phase 1 study showing a higher Cmin for treatments of the invention compared to an approved FIAE treatment (Flaegarda^®).

Figure 16a: Average PK profile for days 1 to 14 for cohort 3 in part 2 of the phase 1 study. Figure 16b: Overlay of the PK profiles for days 1, 10, and 14 of cohort 3 in part 2 of the phase 1. Figure 17a: Overlay of the PK profiles for days 1 to 14 of cohorts 1 to 3 in part 2 of the phase 1 study.

Figure 17b: Overlay of the PK profiles for days 1 and 14 of 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 completed part 2 study and periods 1, 4, and 6 of the part 1 study.

General Experimental Details

In the following examples, the following abbreviations and definitions are used:

All reactions were carried out under an atmosphere of nitrogen unless specified otherwise.

¹H NMR spectra were recorded on a Bruker (400MHz) or on a JEOL (400MHz) spectrometer with reference to deuterium solvent and at rt.

Molecular ions were obtained using LCMS which was carried out using a Chromolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HCC H/MeCN into 0.1% HCO2H/H2O over 13 min, flow rate 1.5 mL/min, or using Agilent, X-Select, acidic, 5-95% MeCN/water over 4 min. Data was collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electospray ionisation in conjunction with a Thermofinnigan Surveyor LC system.

Alternatively, molecular ions were obtained using LCMS which was carried out using an Agilent Poroshell 120 EC-C18 (2.7pm, 3.0 x 50mm) column with 0.1% v/v Formic acid in water [eluent A]; MeCN [eluent B]; Flow rate 0.8mL/min and 1.5 minutes equilibration time between samples, gradient shown below. Mass detection was afforded with API 2000 mass spectrometer (electrospray).

Gradient:

Where products were purified by flash chromatography, 'silica' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Merck silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution. Reverse phase preparative FIPLC purifications were carried out using a Waters 2525 binary gradient pumping system at flow rates of typically 20 mL/min using a Waters 2996 photodiode array detector.

All solvents and commercial reagents were used as received.

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

Example 1 - Establishing a Cmin suitable for prophylactic treatment (from an efficacy perspective)

Figure 1 shows activation of the contact system. The contact system can be activated by negatively charged surfaces that activate FXII to FXIIa. FXIIa mediates conversion of PPK to PKa and the subsequent cleavage of high molecular weight kininogen (HK) to generate bradykinin, a potent inflammatory hormone.

Cl inhibitor (Cl-INFI) is the primary physiological inhibitor of PKa activity. Flaegarda^® is a medicinal product comprising a plasma-derived concentrate of Cl-INFI that is used to treat FIAE.

The inventors have established a novel method for determining a target Cmin suitable for achieving prophylaxis. The aim is to restore patients to "normal" control of PKa. To determine what "normal" control of PKa is, the inventors have carefully and skilfully analysed the minimum therapeutic concentrations of Flaegarda^® provided during treatment (Ctrough) and how it corresponds to the "normal" levels of Cl-INFI of a healthy patient. Knowing that Flaegarda^® is approved by regulatory authorities (e.g. the FDA) for prophylactic treatment of FIAE, the inventors can determine the fold IC50 of Haegarda^® required to provide prophylactic treatment. Because Haegarda^® inhibits PKa, which in turn inhibits the contact system, the inventors consider from an efficacy perspective (i.e. leaving aside issues such as oral bioavailability and potential adverse events) that a PKa inhibitor can be suitable for prophylactic treatment if it can achieve a Cmin corresponding to fold IC50 levels achieved by Haegarda^® at its Ctrough.

Without wishing to be bound by theory, the inventors have determined that this analysis is most accurate on a specific assay. Specifically, catalytic activity of PKa in dextran sulfate-activated (DXS, Sigma; 6.25 pg/ml) plasma (undiluted VisuCon-F control plasma, Affinity Biologicals Inc) was determined by the time-dependent hydrolysis of fluorogenic substrate. For IC50 and efficacy determination, the compound of Formula A or Cl-INH (Sigma Cat #E0518) were added before (Figure 2) the addition of DXS to the plasma.

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

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

The IC50 of the compound of Formula A is 62nM. The molecular weight of the compound is 509.5Da.

Using this information, the inventors are able to establish a minimum concentration of the compound (Cmin) that considered suitable for prophylactic treatment, as shown below in Table 3.

Table 3

The Cmin of the compound of Formula A, above which, can be considered suitable for prophylactic treatment because it is comparable to the Ctrough of Haegarda is about 30 ng/rnL Example 2 describes the process for making a dosage form suitable for achieving this Cmin.

Additionally, the compound of Formula A was tested and found to be selective for plasma kallikrein over a range of other serine proteases, as shown in Table 4.

Table 4

Fluman serine protease enzymes tissue kallikrein, plasmin, thrombin, matriptase, trypsin, and Factors Vllx, X, Xla, XI la were assayed for enzymatic activity using an appropriate fluorogenic substrate. Protease activity was measured by monitoring the accumulation of liberated fluorescence from the substrate. The linear rate of fluorescence increase per minute was expressed as percentage (%) activity. The Km for the cleavage of each substrate was determined by standard transformation of the Michaelis-Menten equation. The compound inhibitor assays were performed at substrate Km concentration and activities were calculated as the concentration of inhibitor giving 50% inhibition (IC₅₀) of the uninhibited enzyme activity (100%).

Example 2 - Formulation manufacturing process

I. Synthetic Examples

Preparation of Form 1 of the l-({4-[(5-fluoro-2-oxopyridin-l-yl)methyl1phenyl}methyl)-N-[(3-fluoro-

4-methoxypyridin-2-yl)methvn-3-(methoxymethyl)pyrazole-4-carboxamide (Formula A) 5-Fluoro-l-(4-hydroxymethyl-benzyl)-lH-pyridin-2-one

To 4-(chloromethyl)benzylalcohol (4.50 g, 28.7 mmol) in acetone (150 mL) was added 5-fluoro-2- hydroxypyridine (3.57 g, 31.6 mmol) and K₂C0₃ (11.9 g, 24.2 mmol) and the reaction mixture was stirred at 50 °C for 36 hrs. The reaction mixture was cooled and solvent was removed in vacuo. The residue was taken up in CHCI₃ (150 mL) and washed with water (30 mL), dried (Na₂S0₄), 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 identified as the title compound (5.65 g, 24.2 mmol, 84%).

[M+H]⁺ = 234.2 l-(4-Bromomethyl-benzyl)-5-fluoro-lH-pyridin-2-one

To 5-fluoro-l-(4-hydroxymethyl-benzyl)-lH-pyridin-2-one (1.65g, 7.1 mmol) in DCM (100 mL) was added phosphorous tribromide (665 mL, 7.1 mmol) and the reaction stirred at rt for 2 hrs. The reaction mixture was diluted with CHCI₃ (100 mL) and washed with saturated NaHC0₃(aq) (50 mL), water (10 mL) and brine (10 mL). The organic layer was dried (Na₂S0₄), filtered and evaporated to give a colourless gum identified as the title compound which was used without further purification (1.85 g, 6.3 mmol, 88%).

[M+Na]⁺ = 318.2 l-[4-(5-Fluoro-2-oxo-2H-pyridin-l-ylmethyl)-benzyl]-3-methoxymethyl-lH-pyrazole-4-carboxylic acid methyl ester To 3-methoxymethyl-lH-pyrazole-4-carboxylic acid methyl ester (259 mg, 1.5 mmol) in DMF (2 mL) was added l-(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 rt for 18 hrs. The reaction mixture was concentrated and then partitioned between EtOAc (60 mL) and water (20 mL) and washed sequentially with water (3x 10 mL) and brine (10 mL). The organic layer was dried (I ^SC ), filtered and evaporated. The crude residue was purified by automated flash chromatography eluting with EtOAc/acetonitrile-methanol to give two regioisomers. The regioisomers were identified by ¹H NOESY and the title compound isolated as an off-white solid (327 mg, 0.85 mmol, 55%).

[M+H]⁺ = 385.8

^XH NMR (CDCI3) 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) l-[4-(5-Fluoro-2-oxo-2H-pyridin-l-ylmethyl)-benzyl]-3-methoxymethyl-lH-pyrazole-4-carboxylic acid

To l-[4-(5-fluoro-2-oxo-2H-pyridin-l-ylmethyl)-benzyl]-3-methoxymethyl-lH-pyrazole-4-carboxylic acid methyl ester (327mg, 0.85 mmol) in ethanol (50 mL) was added NaOH (339 mg, 8.5 mmol) and heated at vigorous reflux for 24hrs. The reaction mixture was cooled and concentrated. The crude residue was diluted with water (5mL) and washed with DCM (7mL). The aqueous phase was taken and adjusted to pH 2 with 2M HCI and then extracted with 90% CH3CI / 10% IPA (6 x 15mL). The organic layer was dried (I ^SC ), filtered and concentrated to give a pale yellow solid that was used without further purification. 3-Fluoro-4-methoxy-pyridine-2-carbonitrile

To a large microwave vial, cyanocopper (1.304 g, 14.6 mmol) was added to a solution of 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 hrs. The reaction mixture was diluted with water (20 mL) and EtOAc (20 mL). The thick suspension was sonicated and required additional water (40 mL) and EtOAc (2 x 50 mL) with sonication to break-up the solid precipitated. The combined layers were filtered through a plug of Celite and the organic layer isolated, washed with brine (50 mL), dried over MgS04, filtered and the solvent removed under reduced pressure to give a pale green solid identified as 3-fluoro-4-methoxy-pyridine-2- carbonitrile (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- tert-butyl dicarbonate (255 mg, 1.16 mmol). The resulting pale green solution was cooled in an ice- salt bath to -5 °C and then sodium borohydride (153 mg, 4.1 mmol) was added portionwise maintaining the reaction temperature ~0 °C. The deep brown solution was left to stir at 0 °C and slowly allowed to warm to rt and then left to stir at rt for 3 hrs. The reaction mixture was evaporated to dryness at 40 °C to afford a black residue which was diluted with DCM (10 mL) and washed with sodium hydrogen carbonate (aq) (10 mL). An emulsion formed so the organics were separated via a phase separating cartridge and concentrated. The crude liquid was purified by chromatography eluting with EtOAc / iso-hexane to afford (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester as a clear yellow oil (108 mg, 62 % yield)

[MH]⁺= 257

(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine dihydrochloride salt

(3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester (108 mg, 0.36 mmol) was taken up in iso-propyl alcohol (1 mL) and then HCI (6N in iso-propyl alcohol) (1 mL, 0.58 mmol) was added at rt and left to stir at 40 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure and then triturated with diethyl ether and sonicated to give a cream coloured solid (75 mg, 55% yield) identified as (3-fluoro-4-methoxy-pyridin-2-yl)-methylamine dihydrochloride salt.

[MH]⁺= 157 Form 1 of l-({4-[(5-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide

I, -Carbonyldiimidazole (8.45 g, 52.1 mmol) was added to a solution of l-(4-((5-fluoro-2-oxopyridin- l(2/-/)-yl)methyl)benzyl)-3-(methoxymethyl)-l/-/-pyrazole-4-carboxylic acid (19.4 g, 52.1 mmol) in DMF (112 mL) and the reaction mixture was heated to 50°C for 2 hrs. After that time, (3-fluoro-4- methoxypyridin-2-yl)methanamine dihydrochloride (12.0 g, 52.1 mmol) was added to the reaction mixture and heating at 50°C was continued overnight. The reaction mixture was cooled to rt then added dropwise to water (1 L) with vigorous stirring. After addition was completed stirring was continued for 1 hour. The product was collected by filtration and was washed with water (250 mL). The wet material was dissolved in DCM and water was separated. The organic layer was dried over Na2S04 and filtered through Celite. The solvent was removed in vacuo to yield 21.9 g.

The residue was recrystallized from IPA (170 mL) at reflux, cooling to rt before filtering, then twice taken up into DCM, washed with sodium bicarbonate (aq), dried over I ^SC , filtered and concentrated under reduced pressure. The residue was recrystallized from IPA (160 mL) at reflux, cooling to rt before filtering. Trituration with cold tert-butyl methyl ether and drying gave Form 1 of l-({4-[(5-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide (17 g).

NMR (400Mhz, d6-DMSO) d 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 on a Philips X-Pert MPD diffractometer and analysed using the following experimental conditions:

Scan parameters:

Approximately 5 mg of sample under analysis was gently compressed on the XRPD zero background single obliquely cut silica sample holder. The sample was then loaded into the diffractometer for analysis.

Simultaneous Thermal Analysis (STA) data were collected using the following method: Approximately 5 mg of sample was accurately weighed into a ceramic crucible and it was placed into the chamber of Perkin-Elmer STA 600 TGA/DTA analyzer at ambient temperature. The sample was then heated at a rate of 10°C/min, typically from 25°C to 300°C, during which time the change in weight was monitored as well as DTA signal. The purge gas used was nitrogen at a flow rate of 20 cm3/min.

An XRPD diffractogram of Form 1 is shown in Figure 3. Peak position table:

Simultaneous Thermal Analysis (STA)

The STA data for Form 1 are shown in Figure 4.

Preparation of Form 5 of the l-({4-[(5-fluoro-2-oxopyridin-l-yl)methyl1phenyl)methyl)-N-[(3- fluoro-4-methoxypyridin-2-yl)methyl1-3-(methoxymethyl)pyrazole-4-carboxamide (Formula A)

To l-({4-[(5-fluoro-2-oxopyridin-l-yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2- yl)methyl]-3-(methoxymethyl)pyrazole-4-carboxamide (15 mg) in THF (150 pL) was added 1.1 equivalents of 5M hydrochloric acid. The mixture was shaken well by hand, and the mixture temperature cycled between ambient and 40 °C for 18-24 hrs. The supernatant was decanted off, and the solid dried by evaporation under nitrogen to afford Form 5 of l-({4-[(5-fluoro-2-oxopyridin-l- yl)methyl]phenyl}methyl)-N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)pyrazole-4- carboxamide hydrochloride.

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

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

An XRPD diffractogram of Form 5 is shown in Figure 5.

X-ray Powder Diffraction (XRPD)

Approximately 5 mg of sample was gently compressed on the XRPD zero back ground single obliquely cut silica sample holder. The sample was then loaded into a Philips X-Pert MPD diffractometer and analysed using the following experimental conditions.

Tube anode: Cu Generator tension: 40 kV Tube current: 40 mA

Wavelength alphal: 1.5406 A Wavelength alpha2: 1.5444 A Start angle [2 theta]: 5 End angle [2 theta]: 50 Continuous scan

A slower scan speed was also used over a range of 4 - 40°2Q.

Peak position table:

Simultaneous Thermal Analysis (STA)

The STA data for Form 5 are shown in Figure 6.

II. Modified Release Tablet Formulations of Form 5 of the Compound of Formula A

Granule Formulation Three blends were prepared according to the blend compositions in Table 5.

Table 5

¹Salt conversion factor 1.072 i.e. 107.2 mg of HCI salt equivalent to 100 mg of compound free base. Blend preparations were prepared by screening each of the excipients with 10% excess through 850 pm sieves, before the required amount of each intra-granular excipient (except the magnesium stearate) was weighed out and added to the blending vessel. The intra-granular excipients (excluding the magnesium stearate) were then blended using a Turbula^® 3D shaker mixer at 23 rpm for 18 minutes (until homogeneous). Then the intra-granular portion of magnesium stearate was sieved through a 600 pm sieve and added to the blending vessel. The final intra-granular blend was then blended using a Turbula^® 3D shaker mixer at 23 rpm for 3 minutes (until homogeneous).

Dry granulation by roller compaction was then performed using a Vector TFC Lab-micro Roller Compactor (RC) for both blends. The RC parameters used were 1000 psi pressure, 1.0 rpm roll speed and 17.0 rpm screw speed. The collected ribbons were then milled using a mortar and pestle to collect granules of particle size below 800 pm. The granulated blend was then sieved through a 250 pm sieve and the quantity of fine particles (below 250 pm) was weighed in order to determine the percentage of fine particles. The target for fine particles was less than 20%. When the fine particle content was greater than 20%, these fine particles were passed through the roller compactor a second time and again milled using a mortar and pestle to collect granules below 800 pm. The resulting granules were combined with the granules from the first pass to yield a final fine particle content.

The granules were then mixed with the extra-granular excipients to make the tabletting blends. Firstly, the required quantities of MCC and colloidal silicon dioxide were weighed with an additional 10% excess and sieved through 850 pm screens. Then the required amounts of the sieved MCC and colloidal silicon dioxide were weighed out and added to the vessel containing the granules. The resulting blends were then mixed using the Turbula^® 3D shaker mixer at 23 rpm for 12 minutes. The required quantities of magnesium stearate with an additional 10% excess were sieved through 600 pm sieves. Finally the required amounts of sieved magnesium stearate were added to the vessels containing the, MCC and colloidal silicon dioxide and mixed using the Turbula^® 3D shaker mixer at 23 rpm for 3 minutes. This is now the final tablet blend.

Tablet Formulation Each of the tabletting blends were then compressed into 300 mg dose tablets using a Natoli^® Press RD10A according to Table 6 to yield tablets according to Table 7.

Table 6

Table 7

¹ Dose strength expressed as free base equivalent of compound.

The 300 mg tablets were found to be stable over a test period of 70 days stored at 15-25 °C (protected from light).

A batch of Tablet 3 was prepared using a compression force of 17,000 N and then film-coated to yield Tablet 4. Tablet 4 was film coated with 30 mg of Opadry^® II 85F280012 (white). Opadry^® II 85F280012 (white) is a composition of polyvinyl alcohol, polyethylene glycol (PEG) 3350 and titanium dioxide. The total weight of the film coated Tablet 4 was 780 mg.

Placebo to Modified Release Tablet Formulations

Placebo tablets for the phase 1 study were prepared. Prosolv^® Easytab SP, a commercially available excipient composite of 95.0-98.0% microcrystalline cellulose, 1.5-2.5% colloidal silicon dioxide, 0.5- 2.0% sodium starch glycolate and 0.3-1.0% sodium stearyl fumarate, was compressed on a Natoli^®

Press RD10A to prepare tablets matching the weight and thickness of the 750 mg (300 mg dose) modified release tablet formulations.

Placebo tablets for the phase 2 study were prepared. The components of the placebo tablet were the same as for Tablet 4, except the compound of Formula A was replaced by microcrystalline cellulose PH-200. The placebo was prepared by direct compression. The placebo tablet matched the appearance, thickness and weight of Tablet 4.

III. Immediate Release Capsule Formulations of Form 5 of the Compound of Formula A

An immediate release (IR) tablet formulations was prepared according to Table 8.

Size 00EL hard gelatin Swedish orange capsules were filled with the HCI salt of the compound. Prior to filling, The HCI salt of the compound was sieved through an 850 pm screen. The capsules were prepared manually using a spatula. The 300 mg dose required tamping to achieve the required fill weight.

The only excipient included in the immediate release capsule formulations are the Swedish orange hard gelatin capsules, a non-pharmacopoeial excipient made from red iron oxide (colourant; approx. 1.18 wt.%), titanium dioxide (opacifier; approx. 0.49 wt.%) and hard gelatin (structure; approx. 98.33 wt.%).

Table 8

¹ Dose strength expressed as free base equivalent of the compound

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

Example 3 - Phase 1 study

Multiple Part, Phase 1 Crossover Study in Healthy Subjects to Evaluate the Pharmacokinetic (PK) Profile of the Compound Following Single and Multiple Doses of Novel Modified Release (MR) Formulations Compared to a Reference Immediate Release (IR) Formulation. Part 1 - Aims and Methodology

Aim

The primary aims were, as follows:

• To evaluate the pharmacokinetic (PK) profile of the compound of Formula A following single oral dosing of modified release (MR) tablet formulations comprising the compound in healthy subjects in the fasted state.

• To determine the relative oral bioavailability of the compound following administration of single oral doses of the MR prototype tablet formulations, compared to a reference immediate release (IR) capsule formulation in healthy subjects in the fasted state.

The secondary aim was to provide additional information on the safety and tolerability of single oral doses of MR prototype tablet formulations and a reference IR capsule formulation in healthy subjects.

Methodology

Part 1 is a single-centre, open-label, non-randomised, 6-period crossover study designed to investigate the PK and safety of modified release formulations comprising the compound of Formula A compared to a reference an immediate release capsule formulation comprising the compound in healthy male and female subjects.

Up to 16 subjects were enrolled to receive single oral dosage forms comprising the compound of Formula A across 6 treatment periods, in a sequential manner in the fasted state for periods 1 to 5. The effect of food on the PK was assessed by administering the dosage form 30 minutes after a standard high-fat breakfast in period 6. There was a minimum washout of 7 days between each product administration. The interval between dosing in Periods 1 and 3, 3 and 4, 4 and 5, and 5 and 6 was approximately 14 days.

The 6 periods are outlined below:

Subjects underwent preliminary screening procedures for the study at the screening visit (Day -28 to Day -2). Subjects were admitted to the clinical unit on the morning prior to product administration (Day -1) in Period 1, and the evening prior to product administration (Day -1) in Periods 2 to 6. Subjects remained on site until 48 h post-dose (up to Day 3). Subjects received the formulations in the morning of Day 1 in a non-randomised manner following an overnight fast (or a high-fat breakfast, optional in Period 5 or 6 only). Administration was performed on Day 1, with an appropriate interval between subjects based on logistical requirements (e.g. ~10 min). Start time was determined based on logistics. There was a minimum washout of 7 days between each product administration. Meal choices were standardised for each treatment period.

Venous blood samples were taken at the following times:

• The pre-dose samples were taken <1 h before dosing.

• 0 to 1 h post-dose samples were taken within ± 2 min of the nominal post-dose sampling time.

• >1 to 12 h post-dose samples were taken within ± 10 min of the nominal post-dose sampling time.

• >12 h post-dose samples were taken within ± 30 min of the nominal post-dose sampling time.

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

Samples were analysed for the free base of the compound of Formula A.

Results

The mean plasma concentration profile for the 6 periods is shown in Figure 7 showing the modified release profile of the tablets of the invention described in Example 2.

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

Part 2 - Aims and Methodology The primary aims were, as follows:

• To provide information on the safety and tolerability of multiple oral doses of a MR tablet formulation comprising the compound of Formula A in healthy subjects.

• To evaluate the PK profile of the compound of Formula A following multiple oral dosing of a selected MR tablet formulations comprising the compound of Formula A at different dose levels in healthy subjects

An exploratory aim was to collect blood samples for exploratory pharmacodynamics (PD) analysis of plasma kallikrein (PKa) enzyme activity.

Methodology

Part 2 is a single-centre, randomised, double-blind, placebo-controlled, multiple dose group study to investigate the PK and safety of a MR tablet formulation comprising the compound in healthy male and female subjects.

18 subjects were enrolled in 2 cohorts (9 subjects per cohort). Subjects in each cohort were randomised to receive either the MR tablet formulation or placebo in a 7:2 ratio for up to 14 days. Meal choices and times were standardised for each treatment period. The dose for the first cohort was selected following review of safety and PK data from Part 1, the dose for the second cohort was selected following interim review of safety and PK data from Part 2 Cohort 1. Dose escalation did not exceed 2 fold between periods during this study.

The 2 Cohorts are outlined below:

Subjects underwent preliminary screening procedures for the study at the screening visit (Day -28 to Day -2). Subjects were admitted to the clinical unit on the morning prior to product administration (Day -1). Subjects remained on site until 48 h post-final dose. Twice daily (12 hourly) administration was performed on Days 1 up to 13, with the last dose on the morning of Day 14, with an appropriate interval between subjects based on logistical requirements (e.g. ~10 min). On the final dosing day, only the morning dose was administered. Start time was determined based on logistics. Meal choices and times was standardised. A follow-up visit was scheduled to take place 5 to 7 days post-final dosing occasion to ensure the ongoing wellbeing of the subjects.

A third cohort was enrolled (9 subjects). The subjects were randomised to receive either the MR tablet formulation or placebo in a 7:2 ratio for up to 14 days. Meal choices and times were standardised for each treatment period, and cohort 3 was tested under "fasted" conditions.

Subjects in cohort 3 underwent preliminary screening procedures for the study at the screening visit (Day -28 to Day -2). Subjects were admitted to the clinical unit on the morning prior to product administration (Day -1). Subjects remained on site until 48 h post-final dose. Twice daily (12 hourly) administration was performed on Days 1 up to 13, with the last dose on the morning of Day 14, with an appropriate interval between subjects based on logistical requirements (e.g. ~10 min). On the final dosing day, only the morning dose was administered. Start time was determined based on logistics. Subjects were provided with a light breakfast at approximately 2 h post-morning dose, lunch at approximately 4h post-morning dose, dinner at approximately 10 h post-morning dose and an evening snack at approximately 14 h post-morning dose. A follow-up visit was scheduled to take place 5 to 7 days post-final dosing occasion to ensure the ongoing wellbeing of the subjects.

Venous blood samples were taken at the following times:

• Day 1 only: The pre-dose samples were taken <1 h before dosing.

• On Days 1 to 14: Where a 12 h dosing coincides with the pre-dose sample, samples were taken <10 min of the nominal time point.

Samples were analysed for the compound of Formula A. Pharmacodynamic activity was according to the following procedure. 3 aliquots of predose plasma are supplied for each subject. These are activated individually to generate 3 predose activity values. These 3 values are averaged to give the 100% activity for each subject. The remaining predose is then pooled and used for QC purposes. It is tested unactivated and activated n=4 times. This data is used to show if there is any pre-activation in the predose plasma samples with DXS stimulation and secondly to identify if there is variability in the activation of a subjects plasma.

Plasma samples used for PK assessment were analysed using a validated liquid chromatography tandem mass spectrometry (LC MS/MS) method.

PD measurements were determined in dextran sulfate (DXS) stimulated undiluted plasma using a fluorogenic enzyme assay and capillary based H K cleavage immunoassay.

Catalytic activity of PKa in DXS-stimulated (Sigma; 6.25 pg/mL) plasma samples was determined by the time-dependent hydrolysis of fluorogenic substrate in all samples from all parts of the study.

The time until appearance of detectable amidolytic enzyme activity in DXS-stimulated plasma (lag time) was calculated from the catalytic activity assay. The detection sensitivity of the rate of catalytic activity in plasma based on using a Spark (Tecan) fluorimeter is a fluorescence increase to reach 1AF unit/sec.

Results

The mean plasma concentration profile for the non-placebo subjects in cohort 1 is shown in Figure 8. This figure shows that steady-state was achieved by day 2/3. This figure also shows that the Cmin was higher before the morning dose (i.e. during the night) compared with the Cmin before the evening dose (i.e. during the day).

Figure 9 overlays the Day 1, Day 14 PK profiles for the non-placebo subjects, with the PK profile of period 1 (from part 1). This shows that the MR formulations of the invention have a consistent PK profile over repeat dose indicating that there is insignificant impact of multiple dosing on rates of absorption and/or elimination. This reduces the potential for drug-drug interaction. Figure 10 shows the average plasma kallikrein activity levels compared to pre-dose levels for the non-placebo subjects in cohort 1. Figure 11 shows the average plasma kallikrein activity levels compared to pre-dose levels for the non-placebo subjects in cohort 1 for Days 1 and 14. The profile shows a fall in PKa activity in the subjects, which is indicative of plasma kallikrein inhibition by the compound of Formula A.

Figure 12 shows other reported PK parameters of cohort 1 in part 2, with periods 1, 4, and 6 in part 1.

No subjects were withdrawn from cohort 1. Any adverse events reported were mild and resolved without treatment or intervention.

Figure 13a shows the complete mean plasma concentration profile for the non-placebo subjects in cohort 2 in part 2. This figure shows that steady-state was achieved by day 2/3. This figure also shows that the Cmin was higher before the morning dose (i.e. during the night) compared with the Cmin before the evening dose (i.e. during the day).

Figure 13b shows the mean plasma concentration profile for the non-placebo subjects in cohort 2 for day 1 overlaid with the Day 1 PK profile from cohort 1. Figure 13c shows the average plasma kallikrein activity levels compared to pre-dose levels for the non-placebo subjects in cohort 2.

Figure 14a shows the mean plasma concentration profile for the non-placebo subjects in cohort 2 for days 1 to 7 overlaid with the Days 1 to 14 PK profile of Cohort 1. Figure 14b shows the complete mean plasma concentration profile for the non-placebo subjects in cohort 2 for Days 1 to 14 overlaid with the Days 1 to 14 PK profile of Cohort 1. Figures 14a and 14b show that steady state was achieved in cohort 2 by day 2/3. This figure also shows that the Cmin was higher before the morning dose (i.e. during the night) compared with the Cmin before the evening dose (i.e. during the day).

As shown in Figure 15a, where the Cmin is expressed as a fold IC50 value as tested in the undiluted plasma assay described in Example 1, the Cmin reported for both cohorts exceeded the minimum Cmin that can be considered suitable for prophylactic treatment (about 30 ng/mL). Indeed, the Cmin exceeded IC50 for the entire study. Thus, concentrations of the compound are maintained at least at levels equivalent to normal Clinh levels, and for large parts of the day, exceed that by many fold. Indeed, Figure 15a demonstrates that the steady state Cmin was at least ~2 times higher that approved the Ctrough for approved treatment Haegarda^® (by comparison of their respective fold IC50s). Figure 15b shows the complete 14 day data for cohorts 1 and 2.

Figure 16a shows the mean plasma concentration profile for the non-placebo subjects in cohort 3. Figure 16b shows the PK profile for Days 1, 10 and 14 for cohort 3. The PK profiles for Days 1 and 14 were recorded following the morning dose, whereas the PK profile for Day 10 was recorded following the night time dose.

Figure 17a shows the mean plasma concentration profile for the non-placebo subjects in cohorts 1 to 3 overlaid over each other for Days 1 to 14. Figure 17b shows the mean plasma concentration profile for the non-placebo subjects in cohorts 1 to 3 overlaid over each other for days 1 and 14. Figure 17c shows complete PK information of periods 1, 4, and 6 in part 1 and cohorts 1, 2, and 3 in part 2.

These data demonstrate that the oral modified release pharmaceutical dosage forms described herein provided a PK profile of the compound of Formula A that is suitable for prophylactic treatment of HAE.

Example 4 - Phase 2 Study of the Compound of Formula A

The example is based on a phase 2 clinical trial protocol that has received ethical approval from the Canadian Institutional Review Board (IRB), and has been approved by Canada's Office of Clinical Trials. The phase 2 protocol has also been granted a Clinical Trial Authorisation (CTA) by the UK's Medicines and Healthcare products Regulatory Agency (MHRA).

Aims: To evaluate the efficacy and safety of the compound of Formula A in the prophylactic treatment of angioedema attacks in adult subjects with hereditary angioedema type I or II.

Methods:

The study is a multicentre, randomized, double-blind, placebo-controlled, parallel group, phase 2 clinical trial to investigate the efficacy and safety of three dose levels of the compound, an oral plasma kallikrein inhibitor, for long-term prophylactic treatment of subjects with hereditary angioedema type I or II (EudraCT number: 2021-000136-59). Objectives:

Primary Objective:

• To demonstrate the clinical efficacy of prophylactic treatment with the compound compared with placebo in preventing hereditary angioedema (HAE) attacks.

Secondary Objectives:

• To further characterize the clinical efficacy of the compound.

• To investigate the safety and tolerability of the compound.

Benefit/Risk

The compound has been evaluated in two Phase 1 studies in adult healthy volunteers, one of which is described above. Pharmacodynamic evaluations of the compound have demonstrated that the compound inhibits plasma kallikrein activity ex-vivo at levels exceeding equivalent concentrations for berotralstat, a currently approved, once daily, oral plasma kallikrein inhibitor indicated for the prevention of HAE attacks. The compound achieved adequate plasma concentrations with sustained plasma kallikrein suppression over a 12- to 14-hour time interval. These data support further investigation of the compound as an orally administered treatment with adequate plasma kallikrein suppression to potentially prevent or reduce the occurrence of HAE attacks.

Preclinical investigations, including in-vitro and in-vivo safety pharmacology studies and animal studies in mice, rats, and non-human primates support administration of the compound in humans. The doses to be given in this trial were well tolerated in a previous clinical trial comprising 16 subjects who received single doses of the compound up to 900 mg and 21 subjects who received at least 600 mg twice a day for 14 days. All adverse events observed in these studies were of mild and of short duration. No Grade 3 (severe) or serious adverse events (SAE) were reported.

Setup:

This is a multicentre, randomised, double-blind, placebo-controlled, phase 2 clinical trial. Subjects with HAE will be recruited through HAE treatment centres worldwide. This trial will be conducted on an outpatient basis and will comprise in-clinic visits or home health visits when in-clinic visits cannot be conducted (e.g. in the event of a pandemic or other reason that prevents the subject from attending the in-clinic visits).

Screening Visit

The Screening Period includes the Screening Visit and Run-in Period. All subjects will sign an Informed Consent Form prior to any trial-related procedures being performed. Consent may be collected through a remote e-consenting solution if allowed through country and site regulations. Subjects will be 18 years of age or older at the time of screening and will have a diagnosis of HAE type I or II.

During the visit a physical exam, 12-lead electrocardiogram (ECG), laboratory tests, and other assessments will also be performed.

Site personnel will train subjects on the requirements for reporting attacks and the information subjects will be expected to provide in the electronic diary (eDiary) provided by the study sponsor. The subject will confirm understanding of what is required for reporting attacks.

Run-In Period

Screened subjects will enter a Run-in period of up to 8 weeks in duration. The start of the Run-in Period is determined by the type of HAE therapy being used by the subject at the time of Screening, as follows:

• Use of On-demand Therapy Only for Treatment of HAE Attacks: Subjects using only on-demand therapy will enter the Run-in Period upon completion of Screening Visit eDiary assessments.

• Use of Prophylaxis Therapy for Treatment of HAE Attacks: Subjects using any prophylaxis therapy will enter the Run-in Period following the first Investigator-confirmed HAE attack after discontinuation of all prophylactic therapy. This attack does not count towards the total attacks required to meet the run-in eligibility criteria. Subjects must enter the Run-in Period within 8 weeks of completion of Screening Visit eDiary assessments.

During the Run-in Period all subjects must meet one of the following eligibility criteria:

• Two Investigator-confirmed attacks in the first 4-week period.

• Three Investigator-confirmed attacks in <8 weeks. Once the above Run-In Period criterion is met subjects may proceed to the Randomization Visit. Subjects who do not meet the run-in criterion will be ineligible to randomize and will not be allowed to re-screen.

Randomization

Subjects will complete the Randomization Visit within 10 days of completing the Run-in Period. Subjects will be randomized 1:1:1:1 to receive one of the following treatments to betaken twice daily:

• 300 mg (1 x 300 mg tablet) of the compound

• 600 mg (2 x 300 mg tablets) of the compound

• 900 mg (3 x 300 mg tablets) of the compound

• Matching placebo

A balanced number of subjects assigned to placebo will receive either 1, 2 or 3 tablets.

Randomization will be stratified by the number of Investigator-confirmed HAE attacks during the Run- in Period (i.e. <3 attacks/4 weeks or >3 attacks/4 weeks).

Treatment Period

The Treatment Period will be 12 weeks in duration and will start with the first dose of the

Investigational Medicinal Product (IMP). Subjects will take their first dose with their next morning meal after receipt of the IMP. During the Treatment Period, subjects will self-administer IMP twice daily (either 300, 600 or 900 mg of the compound or matching placebo) approximately 12 hours apart with their morning and evening meals.

Use of the following treatments is not permitted during the trial:

• Long or short-term prophylaxis for HAE including: o Cl-esterase inhibitor (Cl-INH) for prophylaxis (e.g. Haegarda, Cinryze, Berinert, Ruconest) o Lanadelumab o Attenuated androgens (e.g. stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) o Anti-fibrinolytics (e.g. tranexamic acid) o Berotralstat o Other investigational therapies for HAE prophylaxis (e.g. garadacimab, PKK-LRx, PHVS416) • Angiotensin-converting enzyme (ACE) inhibitors

• Estrogen-containing medications with systemic absorption including: o oral contraceptives including ethinylestradiol or hormonal replacement therapy

• Strong CYP3A4 inhibitors and inducers.

• Narrow therapeutic index drugs metabolized by CYP3A4 or CYP2C9, or transported by OAT1, OCT2, and OATP1B1, as determined by the Investigator, are also prohibited throughout the trial.

Treatment of HAE attacks during the trial, including the Run-in period, should be managed according to the conventional care of each subject, including the use of on-demand therapies that are deemed medically appropriate. Use of Cl-INH will be permitted as an on-demand therapy but not as a long or short-term prophylaxis. Administration of the investigational product and trial procedures will continue without alteration to the protocol-specified schedule even if the subject requires an on-demand treatment for an HAE attack during the trial.

During the trial, subjects will be instructed to record details of each HAE attack into an eDiary. The Investigator (or qualified designee) will assess whether the reported attack was caused by HAE, as described below.

During the Treatment Period, subjects will complete an in-clinic or home health visit at Week 2, Week 6, and Week 12/Early Termination (ET). A 12-lead ECG, laboratory tests, and other assessments will be performed during the in-clinic or home health visit. Visits should occur within 3 days of the Week 2 and 6 visits. The Week 12/ET Visit should occur within 7 days after the final dose of IMP.

Subjects will also complete quality of life assessments at the Screening Visit, 4 and 8 weeks after the start of dosing, and at the final dose. The Treatment Satisfaction Questionnaire for Medication (TSQM) will be completed with the final dose.

Investigational Medicinal Product:

The compound of Formula A - 300 mg modified-release Tablet 4, as described above in Example 2, part II.

Placebo to the compound 300 mg modified release Tablet 4, as described above in Example 2, part II. Tablets must be swallowed whole; tablets are not to be crushed or modified in any way.

Number of Subjects:

Approximately 48 subjects will be randomized into the trial.

Population:

The trial population will include male and female subjects 18 years of age or older with HAE type I or

Inclusion Criteria:

1) Male or female subjects 18 years of age and older.

2) Confirmed diagnosis of HAE type I or II at any time in the medical history: a) Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling episodes without accompanying urticaria) AND EITHER b) Diagnostic testing results obtained during the Screening Period that confirm HAE Type I or II: Cl-INH functional level <40% of the normal level. Subjects with functional Cl-INH level 40- 50% of the normal level may be enrolled if they also have a C4 level below the normal range. Subjects may be retested during the Screening Period if results are incongruent with clinical history or believed by the Investigator to be confounded by recent prophylactic or therapeutic Cl-INH use, OR c) Documented genetic results that confirm known mutations for HAE Type I or II.

3) Subject has access to and ability to use conventional treatment for HAE attacks.

4) Subject is willing to cease any current medications being taken for HAE prophylaxis and Investigator determines that doing so would not place the subject at any undue safety risk.

5) Subject's last dose of attenuated androgens was at least 28 days prior to randomization.

6) During the Run-in Period subject meets one of the following criteria: a) Two Investigator-confirmed attacks in the first 4-week period. b) Three Investigator-confirmed attacks in <8 weeks.

7) Subjects who are fertile and heterosexually active must adhere to contraception requirements throughout the trial as follows: a) Female subjects must agree to use at least one highly effective contraception method from the Screening Visit until the end of the trial. Highly effective methods of contraception include: i) Progestogen-only hormonal contraception associated with inhibition of ovulation: oral/injectable/implantable (hormonal contraception that contains estrogen including ethinylestradiol is excluded per Exclusion 4). ii) Intrauterine device (IUD). iii) Intrauterine hormone-releasing system (IUS). iv) Bilateral tubal occlusion. v) Vasectomized partner (provided that the partner is the sole sexual partner of the female subject of childbearing potential and that the vasectomized partner has received medical assessment of surgical success). b) Male subjects with a female partner of childbearing potential must agree to use condoms for the entire Treatment Period AND for 90 days following the final dose of investigational medicinal product (IMP). Female partners are encouraged to use contraception as outlined in Inclusion 7a) from the Screening Visit until the end of the trial. Hormonal contraception that contains estrogen including ethinylestradiol is acceptable for the female partner.

8) Subjects who are not fertile or not sexually active, as defined below, do not require contraception. a) Subjects who refrain from heterosexual intercourse during the trial if the reliability of the heterosexual abstinence has been evaluated in relation to the duration of the clinical trial and is the preferred and usual lifestyle of the subject. b) Male subjects who are surgically sterile (e.g. vasectomized with medical assessment of surgical success). c) Female subjects who are surgically sterile (e.g. status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months.

9) Subjects must be able to swallow trial tablets whole.

10) Subjects assessed by the Investigator must be able to appropriately receive and store IMP, and be able to read, understand, and complete the eDiary.

11) Investigator believes that the subject is willing and able to adhere to all protocol requirements.

12) Subject provides signed informed consent and is willing and capable of complying with trial requirements and procedures.

Exclusion Criteria:

1) Any concomitant diagnosis of another form of chronic angioedema, such as acquired Cl inhibitor deficiency, HAE with normal Cl-INH (previously known as HAE type III), idiopathic angioedema, or angioedema associated with urticaria. 2) A clinically significant history of poor response to Cl-INH therapy or plasma kallikrein inhibitor therapy, for the management of HAE, in the opinion of the Investigator.

3) Use of angiotensin-converting enzyme (ACE) inhibitors after the Screening Visit or within 7 days prior to randomization.

4) Any estrogen containing medications with systemic absorption (such as oral contraceptives including ethinylestradiol or hormonal 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 starting at screening, as determined by the Investigator.

6) Use of strong CYP3A4 inhibitors and inducers during participation in the trial, starting at the Screening Visit.

Note: These medications include but are not limited to the following:

Inhibitors: boceprevir, clarithromycin, cobicistat, dasabuvir, denoprevir, 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.

7) Inadequate organ function including but not limited to: a) Alanine aminotransferase (ALT) > 2x ULN b) Aspartate aminotransferase (AST) > 2x ULN c) Bilirubin direct > 1.25x ULN d) International normalized ratio (INR) > 1.2 e) Clinically significant hepatic impairment defined as a Child-Pugh B or C f) eGFR <60 mL/min

8) Any clinically significant comorbidity or systemic dysfunction that, in the opinion of the Investigator, would jeopardize the safety of the subject by participating in the trial.

9) History of substance abuse or dependence that would interfere with the completion of the trial, as determined by the Investigator.

10) Known hypersensitivity to the compound or placebo or to any of the excipients.

11) Any prior use of any gene therapy treatment for HAE.

12) Participation in any interventional investigational clinical trial, including an investigational COVID- 19 vaccine trial, within 4 weeks of the last dosing of investigational drug prior to screening.

13) Any pregnant or breastfeeding subject. Assessments:

Subject Demographics and Medical History

Demographic and baseline data will include year of birth, height (meters [m]; without shoes), weight (kg), race and ethnicity (if allowed), and sex.

Medical history will capture any relevant previous and concurrent diseases, HAE disease history; therapies and supplements taken within the past 4 weeks; and participation in interventional clinical studies in the past 4 weeks.

Efficacy Assessments

When an attack of HAE occurs, the subject will provide a description of the HAE attack in the Subject eDiary. Should a subject become incapacitated during an attack and unable to record details, this information can be recorded once the incapacitation has resolved. This description will include:

• Start and stop date/time of each attack

• Location(s) of each attack

• Symptom(s) including prodromal

• Impact on activity

• Use of conventional treatment of each attack

• Subject assessment of attack severity

As soon as possible following the completion of each attack and within no more than 5 working days, contact will be made between the site staff and the subject to confirm, clarify, and correct any recorded eDiary data. Site staff who collect the HAE attack information from the subject must be designated and qualified to perform this task. Additionally, the designated site staff will ask questions about each attack to assist the Investigator (or qualified designee) with their confirmation of each attack.

The Investigator (or qualified designee) will assess whether the reported attack was caused by HAE. To be classified as an Investigator-confirmed HAE attack, the event must have symptoms or signs consistent with an attack in at least one of the following locations:

• Peripheral angioedema: cutaneous swelling involving an extremity, the face, neck, torso, and/or genitourinary region. • Abdominal angioedema: abdominal pain with or without abdominal distention, nausea, vomiting, or diarrhea.

• Laryngeal angioedema: stridor, dyspnea, difficulty speaking, difficulty swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx.

The investigator (or qualified designee) will rate the severity of each attack according to the following scale:

• Mild

• Moderate

• Severe

Despite the presence of these symptoms, the Investigator may clinically determine that the event did not represent an HAE attack if there are features that strongly refute such a diagnosis. For example, the reported event is accompanied by symptoms that are not consistent with an HAE attack (e.g. urticaria), the reported event persists well beyond the typical time course of an HAE attack, or there is a likely alternate etiology for the event (e.g. the subject's abdominal symptoms are attributable to a viral gastroenteritis).

HAE attack clarifications:

• To be counted as a unique attack and distinct from a previous attack, the new symptoms must occur at least 24 hours after resolution of the prior attack's symptoms.

• Prodromal symptoms by themselves are not considered an attack.

• Use of conventional medication for an acute HAE attack treatment by itself is not confirmation that an attack occurred.

• The attack start time is defined as the time the first symptoms were experienced or the time when the subject became aware of the symptoms (e.g., upon waking).

• The attack resolution is defined as no longer experiencing symptoms of the attack.

Angioedema Control Test (AECT)

The AECT is a validated, self-administered, retrospective 4-item patient-reported outcome measure for patients with recurrent angioedema used to quantify disease control and to aid treatment decisions (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 addresses the frequency of angioedema, angioedema-related quality-of-life (QoL) impairment, unpredictability of angioedema attacks, and angioedema control by the current treatment approach. Each of the 4 AECT items is scored from 0 to 4 points with higher scores indicating a higher level of angioedema control. The AECT score is calculated by summing up all 4 item scores, with a minimum and maximum possible score of 0 and 16 points.

1. In the last 4 weeks, how often have you had angioedema?

2. In the last 4 weeks, how much as your quality of life been affected by angioedema?

3. In the last 4 weeks, how much has the unpredictability of your angioedema bothered you?

4. In the last 4 weeks, how well has your angioedema been controlled by your therapy?

Angioedema Quality of Life Questionnaire (AE-QoL)

The AE-QoL is a symptom-specific health-related QoL instrument for patients with recurrent angioedema. It consists of 17 items that can be grouped together to a total score or to 4 different domain scores ("Functioning", "Fatigue/Mood", "Fears/Shame" and "Food") that collectively evaluate the extent of angioedema-dependent QoL impairment during the previous 4 weeks. Each AE-QoL question has 5 answer options (scored 1-5), with lower and higher scores indicting less and more adverse impact, respectively. The total score is calculated, which is then transformed into a linear scale that ranges from 0 to 100, with a score of 100 indicating the worst possible impairment. A minimal clinically important difference of 6 points 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).

Treatment Satisfaction Questionnaire for Medication (TSQM)

The TSQM is a psychometrically sound and valid measure of the major dimensions of patients' 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 comprises 14 questions that are scaled on a 7-point bipolar scale ranging from "Extremely Satisfied" to "Extremely Dissatisfied." How satisfied or dissatisfied are you with the ability of the medication to prevent or treat your condition?

How satisfied or dissatisfied are you with the way the medication relieves your symptoms?

How satisfied or dissatisfied are you with the amount of time it takes the medication to start working?

As a result of taking this medication, do you currently experience any side effects at all?

How bothersome are the side effects of the medication you take to treat your condition?

To what extent do the side effects interfere with your physical health and ability to function (i.e. strength, energy levels, etc.)?

To what extent do the side effects interfere with your mental function (i.e. ability to think clearly, stay awake, etc.)?

To what degree have medication side effects affected your overall satisfaction with the medication?

How easy or difficult is it to use the medication in its current form?

How easy or difficult is it to plan when you will use the medication each time?

How convenient or inconvenient is it to take the medication as instructed?

Overall, how confident are you that taking this medication is a good thing for you?

How certain are you that the good things about your medication outweigh the bad things? Taking all things into account, how satisfied or dissatisfied are you with this medication?

Safety Variables:

Physical examination findings.

Vital signs, including pulse rate, respiratory rate, and systolic and diastolic blood pressure after subject has been resting for at least 5 minutes.

12-lead electrocardiogram (ECG) results.

Laboratory test results (clinical chemistry, haematology, coagulation, liver enzymes, electrolytes and urinalysis).

Pregnancy test (female subjects of child-bearing potential).

Adverse Events (AEs), including serious adverse events (SAEs).

Criteria for Evaluation of Efficacy Primary Endpoint

• Rate of Investigator-confirmed FIAE attacks during the Treatment Period.

Secondary Endpoints

Proportion of subjects without Investigator-confirmed FIAE attacks during the Treatment Period. Rate of Investigator-confirmed FIAE attacks that require conventional treatment during the Treatment Period.

AE-QoL total score and domain scores during the Treatment Period.

AECT score and domain scores during the Treatment Period.

Proportion of subjects with an AECT score >12 at the end of the Treatment Period.

Exploratory Endpoints

Rate of Investigator-confirmed FIAE attacks during the Treatment Period, by severity.

Rate of conventional treatment used during the Treatment Period.

TSQM total scores at the end of the Treatment Period.

General Statistical Methods and Types of Analyses

Populations for Analyses

• Screened Set includes all subjects who have signed informed consent.

• Enrolled Set includes all subjects who have signed informed consent and begun the Run-In

Period.

• Randomized Set includes all subjects who are randomized.

• Safety Set (SAF) will include all subjects who are randomized and receive at least one dose of

IMP.

• Full Analysis Set (FAS) will include all subjects who are randomized, receive at least 1 dose of IMP, and have post baseline FIAE diary data recorded. Subjects will be analyzed according to randomized treatment. The FAS population will be the population for efficacy analyses.

• Per-protocol Set (PPS) includes all subjects from FAS who complete 12 weeks and who do not have pre-defined major protocol deviations that may affect primary efficacy endpoint.

Sample Size:

A total sample size of approximately 48 subjects (~12 randomized per dose-level) will provide at least

90% power to detect a 70% reduction in the monthly rate of attacks, between each active dose and placebo, using a two-sided 5% test, adjusted with Bonferroni correction. This assumes an average of at least 2 attacks/4 weeks on placebo and a Poisson distribution with approximately 90% subjects completing the 12 weeks. This sample size will also provide more than 80% power to detect a smaller effect of 50% reduction in attack rate. In addition, this sample size also ensures nearly 90% power to detect a 70% reduction should the attack rate in the placebo group be lower than expected at 1 attack/4 weeks. It is assumed that the rate of HAE attacks follows a Poisson distribution, therefore, the test for the ratio of two Poisson rates was used for the sample size calculation, however, negative binomial regression is used as a primary analysis to correct for potential overdispersion in the model. Sample size calculations were performed using PASS v20.0.3.

General Considerations

Qualitative data will be analyzed by number of observed values, and number and percentage of subjects per category.

Quantitative data will be analyzed by number of observed values, 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 have Bonferroni multiplicity adjustment for multiple dose levels, therefore pairwise comparison tests will be 2-sided with an alpha of 0.0167. The analysis of the secondary or exploratory endpoints will not have multiplicity adjustments.

The primary endpoint will be analyzed by negative binomial regression with randomization stratification factor of baseline attack rate per 4 weeks during the Run-In Period as a fixed covariate and treatment as a fixed factor and the logarithm of time each subject was observed "while on treatment" used as an offset variable in the model. This model will be used to estimate rate of HAE attacks while on treatment and rate ratio of HAE attacks (each of the dose groups of the compound versus placebo) with 95% confidence interval and 2-sided p-value.

Claims

1. A method for prophylactic treatment of hereditary angioedema (HAE) comprising: oral administration of the 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,

wherein, in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had (i) at least two attacks of FIAE in the first four weeks of the eight week period or (ii) at least three attacks of FIAE in the eight week period; or wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), and in the absence of another prophylactic treatment of FIAE, the patient would have had (i) at least two attacks of FIAE in the first four weeks or (ii) at least three attacks of FIAE in the eight week period.

2. The compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use in a method for prophylactic treatment of hereditary angioedema (FIAE) comprising: oral administration of the 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,

wherein, in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had (i) at least two attacks of HAE in the first four weeks of the eight week period or (ii) at least three attacks of HAE in the eight week period; or wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), and in the absence of another prophylactic treatment of HAE, the patient would have had (i) at least two attacks of HAE in the first four weeks or (ii) at least three attacks of HAE in the eight week period.

3. The use of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) in the manufacture of a medicament for prophylactic treatment of hereditary angioedema (HAE) comprising oral administration of the 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,

O Formula A ; and wherein, in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had (i) at least two attacks of HAE in the first four weeks of the eight week period or (ii) at least three attacks of HAE in the eight week period; or wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), and in the absence of another prophylactic treatment of HAE, the patient would have had (i) at least two attacks of HAE in the first four weeks or (ii) at least three attacks of HAE in the eight week period.

4. The method according to claim 1; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 2; or the use according to claim 3; wherein the prophylactic treatment is prophylactic treatment of an attack of HAE.

5. The method according to claims 1 or 4; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4; or the use according to claims 3 or 4; wherein the prophylactic treatment resulting from administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) reduces the mean number of FIAE attacks.

6. The method according to any of claims 1 or 4 to 5; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2, 4 or 5; or the use according to any of claims 3 to 5; wherein the prophylactic treatment resulting from administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) reduces the mean number of FIAE attacks requiring acute treatment.

7. The method according to claim 6; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 6; or the use according to claim 6; wherein the acute treatment that can be required is a rescue medication selected from the group consisting of pdClINFI, rhClINFH, icatibant, and sebetralstat (N-[(3-fluoro-4- methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-l-({4-[(2-oxopyridin-l- yl)methyl] phenyl }methyl)pyrazole-4-carboxamide).

8. The method according to any of claims 1 or 4 to 7; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 7; or the use according to any of claims 3 to 7; wherein the prophylactic treatment resulting from administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) reduces the mean number of moderate or severe FIAE attacks.

9. The method according to any of claims 1 or 4 to 8; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 8; or the use according to any of claims 3 to 8; wherein the prophylactic treatment resulting from administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) reduces the mean number of FIAE attacks progressing through the prodromal phase of an attack.

10. The method according to any of claims 1 or 4 to 9; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 9; or the use according to any of claims 3 to 9; wherein the prophylactic treatment resulting from administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) prevents any FIAE attack from progressing to the swelling stage of an attack.

11. The method according to any of claims 1 or 4 to 10; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 10; or the use according to any of claims 3 to 10; wherein the prophylactic treatment resulting from administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) prevents FIAE attacks.

12. The method according to any of claims 1 or 4 to 11; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 11; or the use according to any of claims 3 to 11; wherein the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is provided as the hydrochloride salt.

13. The method according to claim 12; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 12; or the use according to claim 12; wherein the hydrochloride salt is a solid form which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Ka radiation, expressed in degrees 2Q) at approximately 10.4, 15.6, 16.7, 17.3 and 20.8.

14. The method according to claim 13; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 13; or the use according to claim 13; wherein the solid form has an X-ray powder diffraction pattern substantially the same as that shown in Figure 5.

15. The method according to any of claims 12 to 14; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 12 to 14; or the use according to any of claims 12 to 14; wherein the solid form has an STA thermograph substantially the same as that shown in Figure 6.

16. The method according to any of claims 1 or 4 to 15; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 and 4 to 15; or the use according to any of claims 3 to 15; wherein the treatment provides a Cmin of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) of at least about 30 ng/(mL of the patient's blood plasma), wherein the Cmin is the Cmin of the free base form.

17. The method according to any of claims 1 or 4 to 16; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 16; or the use according to any of claims 3 to 16; wherein the treatment provides a Cmin of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) of between about 30 ng/mL and about 1000 ng/mL, wherein the Cmin is the Cmin of the free base form.

18. The method according to any of claims 1 or 4 to 17; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 17; or the use according to any of claims 3 to 17; wherein the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is administered twice daily.

19. The method according to claim 18; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 18; or the use according to claim 18; wherein the two daily dosage amounts are administered about 12 hours apart.

20. The method according to claim 19; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 19; or the use according to claim 19; wherein the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is administered with food.

21. The method according to any of claims 18 or 20; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 18 or 20; or the use according to any of claims 18 or 20; wherein one dosage amount is administered in the morning (after the patient wakes up) and one dosage amount is administered at night (before the patient's bedtime), and wherein the Cmin is higher before the patient takes their morning dosage amount compared with the Cmin before the patient takes their night time dosage amount, wherein the Cmin is the Cmin of the free base form.

22. The method according to any of claims 18 to 21; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 18 to 21; or the use according to any of claims 18 to 21; wherein one dosage amount is administered in the morning (after the patient wakes up) and one dosage amount is administered at night (before the patient's bedtime).

23. The method according to any of claims 1 or 4 to 22; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 22; or the use according to any of claims 3 to 22; wherein the total amount of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) administered per day is between about 300 and about 2400 mg, expressed as free base equivalent.

24. The method according to claim 23; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 23; or the use according to claim 23; wherein the total amount of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) administered per day is about 1,200 mg, expressed as free base equivalent.

25. The method according to claim 24; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 24; or the use according to claim 24; wherein the about 1,200 mg total daily amount is administered as a twice daily treatment with two dosage amounts of about 600 mg, expressed as free base equivalent.

26. The method according to claim 23; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 23; or the use according to claim 23; wherein the total amount of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) administered per day is about 1,800 mg, expressed as free base equivalent.

27. The method according to claim 26; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 26; or the use according to claim 26; wherein the about 1,800 mg total daily amount is administered as two dosage amounts of about 900 mg, expressed as free base equivalent.

28. The method according to any of claims 18 to 27; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 18 to 27; or the use according to any of claims 18 to 27; wherein each dosage amount comprises administering more than one unit dosage form.

29. The method according to claim 28; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to claim 28; or the use according to claim 28; wherein each dosage amount comprises unit dosage forms comprising 300 mg of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), expressed as free base equivalent.

30. The method according to any of claims 1 or 4 to 29; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 29; or the use according to any of claims 3 to 29; wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had (i) at least two attacks of FIAE in the first four weeks of the eight week period or (ii) at least three attacks of FIAE in the eight week period.

31. The method according to claim 30; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 30; or the use according to any of claims 30; wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had at least two attacks of FIAE in the first four weeks of the eight week period.

32. The method according to claim 30; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 30; or the use according to any of claims 30; wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), the patient has had at least three attacks of FIAE in the eight week period.

33. The method according to any of claims 1 or 4 to 29; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 29; or the use according to any of claims 3 to 29; wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), and in the absence of another prophylactic treatment of FIAE, the patient would have had (i) at least two attacks of FIAE in the first four weeks or (ii) at least three attacks of FIAE in the eight week period.

34. The method according to claim 33; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 33; or the use according to any of claims 33; wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) and in the absence of another prophylactic treatment of FIAE, the patient would have had at least two attacks of FIAE in the first four weeks.

35. The method according to claim 33; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 33; or the use according to any of claims 33; wherein in any eight week period prior to administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof), and in the absence of another prophylactic treatment of HAE, the patient would have had at least three attacks of HAE in the eight week period.

36. The method according to any of claims 1 or 4 to 35; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 35; or the use according to any of claims 3 to 35; wherein the prophylactic treatment resulting from the administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) leads to the patient having a score on the Angioedema Control Test (AECT) of at least 12.

37. The method according to any of claims 1 or 4 to 36; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 36; or the use according to any of claims 3 to 36; wherein the prophylactic treatment resulting from the administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) decreases the patient's score on the Angioedema Quality of Life Questionnaire (AE-QoL) by at least 6 points compared with the patient's score on the AE-QoL prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof).

38. The method according to any of claims 1 or 4 to 37; the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) for use according to any of claims 2 or 4 to 37; or the use according to any of claims 3 to 37; wherein the prophylactic treatment resulting from administration of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) increases the patient's score on the Treatment Satisfaction Questionnaire for Medication (TSQM) compared with the patient's score on the TSQM prior to prophylactic treatment with the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof).

39. The method according to any of claims 1 or 4 to 38, wherein the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is comprised within an oral modified release pharmaceutical dosage form.

40. An oral modified release pharmaceutical dosage form for use in a method for prophylactic treatment of hereditary angioedema (FIAE) according to any of claims 2 or 4 to 38, wherein the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is comprised within the oral modified release pharmaceutical dosage form.

41. The use of an oral modified release pharmaceutical dosage form in the manufacture of a medicament for prophylactic treatment of hereditary angioedema (HAE) comprising oral administration of the oral modified release pharmaceutical dosage form according to any of claims 3 to 38, wherein the oral modified release pharmaceutical dosage form comprises the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof).

42. The method according to claim 39; the oral modified release pharmaceutical dosage form for use according to claim 40; or the use according to claim 41; wherein the oral modified release pharmaceutical dosage form comprises a release modifying agent.

43. The method according to claim 42; the oral modified release pharmaceutical dosage form for use according to claim 42; or the use according to claim 42; wherein the oral modified release pharmaceutical dosage form comprises between about 1 and about 80 wt% release modifying agent.

44. The method according to claim 43; the oral modified release pharmaceutical dosage form for use according to claim 43; or the use according to claim 43; wherein the oral modified release pharmaceutical dosage form comprises between about 3 and about 30 wt% release modifying agent.

45. The method according to claim 44; the oral modified release pharmaceutical dosage form for use according to claim 44; or the use according to claim 44; wherein the oral modified release pharmaceutical dosage form comprises between about 3 and about 15 wt% release modifying agent.

46. The method according to claim 45; the oral modified release pharmaceutical dosage form for use according to claim 45; or the use according to claim 45; wherein the oral modified release pharmaceutical dosage form comprises between about 11 and about 13 wt% of the release modifying agent.

47. The method according to any of claims 42 to 46; the oral modified release pharmaceutical dosage form for use according to any of claims 42 to 46; or the use according to any of claims 42 to 46; wherein the release modifying agent is selected from one or more of the group consisting of polyethylene oxides such as Polyox WSR N750, or Polyox WSR 303, and hydroxypropyl methyl cellulose such as Methocel DC2 K4M, Methocel DC2 K100M, Methocel E4M CR, or Methocel EIOMCR.

48. The method according to claim 47; the oral modified release pharmaceutical dosage form for use according to claim 47; or the use according to claim 47; wherein the release modifying agent is hydroxypropyl methyl cellulose, for example, Methocel DC2 K4M.

49. The method according to any of claims 39 or 42 to 48; the oral modified release pharmaceutical dosage form for use according to any of claims 40 or 42 to 48; or the use according to any of claims 41 to 48; wherein the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) is provided as the hydrochloride salt.

50. The method according to claim 49; the oral modified release pharmaceutical dosage form for use according to claim 49; or the use according to claim 49; wherein the hydrochloride salt is a solid form which exhibits at least the following characteristic X-ray powder diffraction peaks (Cu Ka radiation, expressed in degrees 2Q) at approximately 10.4, 15.6, 16.7, 17.3 and 20.8.

51. The method according to claim 50; the oral modified release pharmaceutical dosage form for use according to claim 50; or the use according to claim 50; wherein the solid form has an X- ray powder diffraction pattern substantially the same as that shown in Figure 5.

52. The method according to any of claims 49 to 51; the oral modified release pharmaceutical dosage form for use according to any of claims 49 to 51; or the use according to any of claims 49 to 51; wherein the solid form has an STA thermograph substantially the same as that shown in Figure 6.

53. The method according to any of claims 39 or 42 to 52; the oral modified release pharmaceutical dosage form for use according to any of claims 40 or 42 to 52; or the use according to any of claims 41 to 52; wherein the dosage form is formulated to provide a Cmin of the compound of Formula A (or a pharmaceutically acceptable salt and/or solvate thereof) of at least about 30 ng/(mL of the patient's blood plasma), wherein the Cmin is the Cmin of the free base form.

54. The method according to any of claims 39 or 42 to 53; the oral modified release pharmaceutical dosage form for use according to any of claims 40 or 42 to 53; or the use according to any of claims 41 to 53; wherein the oral modified release pharmaceutical dosage form is a tablet.

55. The method according to any of claims 39 or 42 to 54; the oral modified release pharmaceutical dosage form for use according to any of claims 40 or 42 to 54; or the use according to any of claims 41 to 54; wherein the oral modified release pharmaceutical dosage form is bioequivalent to any of the oral modified release pharmaceutical dosage forms as defined in any of claims 39 to 54.