CN117999078A - Treatment and/or reduction of migraine occurrence - Google Patents
Treatment and/or reduction of migraine occurrence Download PDFInfo
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- CN117999078A CN117999078A CN202280018328.9A CN202280018328A CN117999078A CN 117999078 A CN117999078 A CN 117999078A CN 202280018328 A CN202280018328 A CN 202280018328A CN 117999078 A CN117999078 A CN 117999078A
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- migraine
- allodynia
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- headache
- hyperalgesia
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Abstract
The present invention describes methods of treating migraine in certain subjects suffering from migraine by administering to said subjects gempam. Methods of reducing the incidence of migraine in certain subjects suffering from migraine by administering gem to the subjects are also described. Methods for identifying certain subjects are also described. Other embodiments are also disclosed.
Description
Cross Reference to Related Applications
The present application claims paris convention priority and united states rights of U.S. provisional patent application No. 63/238448 filed on month 8 of 2021 and entitled "TREATMENT OF MIGRAINE" and 63/155310 filed on month 3 of 2021 and entitled "Method of TREATING MIGRAINE". The contents of these two provisional applications are incorporated herein by reference.
Background
Small molecules belonging to the gem class have been found to be effective in reducing the frequency of chronic migraine (Lipton RB et al Cephalgia 38:2S 18-9; dodick DW et al N Engl J Med,381 (23) (2019), pages 2230-2241; goadsby PJ Neurology (journal 15) (2019), article S17.001). However, while gempam has been found to be effective in treating certain headaches, patients may respond in different ways. For example, gempam may be fully effective, partially effective, or not effective at all in treating or preventing the occurrence of headache. If it can be determined whether the use of the antibody will be effective in treating and/or preventing the development of headache prior to treatment with gem, patient care can be beneficial, physician time can be saved, and unnecessary use of a particular course of therapy can be prevented.
Thus, there is a need for methods for determining whether a therapy comprising gempam will be effective in treating a patient suffering from or susceptible to headache.
Disclosure of Invention
The present invention relates to a method of treating migraine in a subject, the method comprising: determining or having determined whether the subject exhibits allodynia and/or hyperalgesia during an inter-episode of the migraine and administering gempam to the subject that does not exhibit signs of allodynia and/or hyperalgesia during the inter-episode of the migraine.
The invention also relates to a method of treating migraine in a subject, the method comprising: determining or having determined whether the subject exhibits allodynia and/or hyperalgesia during an inter-attack period of a migraine, and administering gempam to the subject that does not exhibit allodynia and/or hyperalgesia during the inter-attack period of the migraine.
The invention also relates to a method of treating migraine in a subject, the method comprising: determining or having determined whether the subject exhibits allodynia and/or hyperalgesia during the period of onset of the migraine, and administering gem to the subject that does not exhibit allodynia and/or hyperalgesia during the period of onset of the migraine.
Detailed Description
Provided herein are methods of treating migraine in a subject, the methods comprising: determining or having determined whether the subject exhibits allodynia and/or hyperalgesia during an inter-episode of the migraine and administering gempam to the subject that does not exhibit signs of allodynia and/or hyperalgesia during the inter-episode of the migraine.
Much evidence supports an important role for CGRP in the pathophysiology of migraine. This evidence has led to global efforts to develop new generation therapeutics that reduce the availability of CGRP in migraine sufferers. Recently, humanized monoclonal anti-CGRP antibodies and gempam were found to be effective in reducing the frequency of chronic or paroxysmal migraine.
The effect of the monoclonal anti-CGRP antibody freretshift mab (30 mg/kg, intravenous) and its isotype (control) on spontaneous and evoked activity in naive and CSD central trigeminal vascular neurons in bulbar and upper nuchal angles in anesthetized male and female rats was determined using single cell extracellular recording techniques (see, e.g., example 1).
The studies described herein demonstrate that freudenreichii inhibits naive High Threshold (HT) trigeminal vascular neurons, but does not inhibit wide power range (WDR) trigeminal vascular neurons, the inhibition is limited to activation from intracranial dura, but not facial skin or cornea, and when given for a sufficient time, this drug prevents HT but does not prevent WDR neurons from being activated and sensitized by cortical spreading inhibition. This inhibition was similar in male and female rats. For patients with chronic and paroxysmal migraine pain relief due to anti-CGRP active agents, this finding increases the likelihood of: HT neurons play a key, previously unidentified role in the initiation and chronicity of headache perception, whereas WDR neurons contribute to associated allodynia and central sensitization (see example 1). Clinically, this finding may help explain the therapeutic role of such agents in alleviating headache of intracranial origin (such as migraine) and headache due to meningitis, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, and certain brain tumors. This finding also explains why this treatment approach against anti-CGRP active agents may not be effective for every headache patient.
As used herein, "about" when used in reference to a numerical range, a cut-off value, or a particular value is used to indicate that the recited value can vary by up to 10% from the listed value. Thus, the term "about" is used to encompass a variation of + -10% or less, a variation of + -5% or less, a variation of + -1% or less, a variation of + -0.5% or less, or a variation of + -0.1% or less, as compared to the specified value.
An "antibody" is an immunoglobulin molecule capable of specifically binding to a target such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site located in a variable region of the immunoglobulin molecule. As used herein, the term encompasses not only intact polyclonal or monoclonal antibodies, but also fragments thereof (such as Fab, fab ', F (ab') 2, fv), single chain (ScFv), mutants thereof, fusion proteins comprising an antibody portion (such as a domain antibody), and any other modified configuration of an immunoglobulin molecule comprising an antigen recognition site. Antibodies include antibodies of any class, such as IgG, igA, or IgM (or subclasses thereof), and antibodies need not belong to any particular class. Immunoglobulins can be assigned to different classes based on the amino acid sequence of the constant domain of the antibody heavy chain. There are five main classes of immunoglobulins: igA, igD, igE, igG, and IgM, and several of them can be further divided into subclasses (isotypes), such as IgGl, igG2, igG3, igG4, igAl, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
As used herein, "monoclonal antibody" or "mAb" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific and thus are directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used according to the invention can be obtained by the method described by Kohler and Milstein,1975, nature,256:495, or may be prepared by recombinant DNA methods such as those described in U.S. Pat. No. 4,816,567. Use can also be made of, for example, mcCafferty et al, 1990, nature,348:552-554, and isolating monoclonal antibodies from the phage library generated by the technique described in the claims.
As used herein, "humanized" antibodies refer to non-human (e.g., murine) antibody forms that are specific chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, fab, fab ', F (ab') 2 or other antigen-binding subsequences of antibodies) containing minimal sequence derived from a non-human immunoglobulin. In most cases, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a Complementarity Determining Region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody), such as mouse, rat or rabbit, having the desired specificity, affinity and biological activity. In some cases, fv Framework Region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. In addition, humanized antibodies may comprise residues that are not present in both the recipient antibody and the imported CDR or framework sequences, but may also comprise such residues to further improve and optimize antibody performance. In general, a humanized antibody will comprise substantially all of at least one and typically two variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody will preferably also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Antibodies may have an Fc region modified as described in WO 99/58372. Other forms of humanized antibodies have one or more CDRs (one, two, three, four, five, six) that are altered relative to the original antibody, also referred to as one or more CDRs "derived from" one or more CDRs of the original antibody.
As used herein, "human antibody" means an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human and/or prepared using any of the techniques known in the art or disclosed herein for preparing human antibodies. This definition of human antibody includes antibodies comprising at least one human heavy chain polypeptide or at least one human light chain polypeptide. One such example is an antibody comprising a murine light chain and a human heavy chain polypeptide. Various techniques known in the art may be used to prepare human antibodies. In one embodiment, the human antibody is selected from a phage library, wherein the phage library expresses human antibodies (Vaughan et al, 1996, nat. Biotechnol,14:309-314; sheets et al, 1998, PNAS, (USA) 95:6157-6162; hoogenboom and Winter,1991, J.mol. Biol,227:381; marks et al, 1991, J.mol. Biol, 222:581). Human antibodies can also be prepared by introducing human immunoglobulin loci into transgenic animals (e.g., mice in which endogenous immunoglobulin genes have been partially or fully inactivated). U.S. patent No. 5,545,807;5,545,806;5,569,825;5,625,126;5,633,425; and 5,661,016 describes this method. Alternatively, human antibodies may be prepared by immortalizing human B lymphocytes (such B lymphocytes may be recovered from an individual or may have been immunized in vitro) that produce antibodies to the target antigen. See, e.g., cole et al Monoclonal Antibodies AND CANCER THERAPY, alan R.Lists, page 77 (1985); boerner et al, 1991, J.Immunol,147 (1): 86-95; U.S. patent No. 5,750,373.
As used herein, the terms "calcitonin gene-related peptide" and "CGRP" are used interchangeably to refer to any form of calcitonin gene-related peptide and variants thereof which retain at least part of the CGRP activity. For example, the CGRP may be an alpha-CGRP or a beta-CGRP. As used herein, CGRP includes the natural sequence CGRP of all mammalian species (e.g., human, canine, feline, equine, and bovine).
As used herein, an "anti-CGRP antibody" refers to an antibody that modulates CGRP biological activity or CGRP pathway, including downstream pathways mediated by CGRP signaling (such as receptor binding and/or elicitation of cell responses to CGRP). For example, an anti-CGRP antibody may block, inhibit, repress, or reduce the Calcitonin Gene Related Peptide (CGRP) pathway. The term anti-CGRP antibody encompasses both "anti-CGRP antagonist antibody" and "anti-CGRP receptor antibody". In some embodiments, the anti-CGRP antibody is a monoclonal antibody (i.e., an anti-CGRP monoclonal antibody).
An "anti-CGRP antagonist antibody" refers to an antibody capable of binding to CGRP and thereby inhibiting CGRP biological activity and/or one or more downstream pathways mediated by CGRP signaling. anti-CGRP antagonist antibodies encompass antibodies that modulate, block, antagonize, repress or reduce CGRP biological activity or otherwise antagonize CGRP pathways, including downstream pathways mediated by CGRP signaling (such as receptor binding and/or eliciting a cell response to CGRP). In some embodiments, the anti-CGRP antagonist antibody binds to CGRP and prevents binding of CGRP to the CGRP receptor. In other embodiments, the anti-CGRP antagonist antibody binds to CGRP and prevents activation of the CGRP receptor. Examples of anti-CGRP antagonist antibodies are provided herein.
An "anti-CGRP receptor antibody" refers to an antibody capable of binding to a CGRP receptor and thereby modulating the CGRP pathway. Examples of anti-CGRP receptor antibodies (e.g., errun MAb) are provided herein
"Gempam" refers to a small molecule CGRP antagonist. Examples of gempam are provided herein, and examples of gempam include ziram, ubenimpam, vazegepant, atopy Ji, oxepin Ji, teca Ji, BI 44370, and MK-3207, and pharmaceutically acceptable salts thereof.
By "anti-CGRP active agent" is meant an active agent selected from the group consisting of anti-CGRP antibodies and gempam.
As used herein, the terms "Gl", "antibody Gl", "TEV-48125" and "freudemumab" are used interchangeably to refer to anti-CGRP antagonist antibodies produced by the expression vectors having deposit numbers ATCC PTA-6867 and ATCC PTA-6866. Characterization of antibodies Gl (and variants thereof) and methods for making the same are described in PCT publication nos. WO2007/054809 and WHO Drug Information (2): 280-1 (2016), which are hereby incorporated by reference in their entirety.
The terms "ALD403" and "Ai Punai bead mab" refer to anti-CGRP antagonist antibodies, which are humanized IgG1 monoclonal antibodies from rabbit precursors. Characterization of Ai Punai bead mab and methods for preparing it can be found in U.S. publication nos. US2012/0294797 and WHO Drug Information 30 (2): 274-5 (2016), which are incorporated by reference in their entirety.
The terms "LY2951742" and "gammaglobumab" refer to anti-CGRP antagonist antibodies that are humanized IgG4 monoclonal antibodies from murine precursors. Characterization of gammaglobizumab and methods for preparing same can be found in U.S. publication nos. US2011/030571 1 and WHO Drug Information (4): 526-7 (2015), which are incorporated by reference in their entirety. The administration and formulation associated with gammaglobizumab can be found in PCT publication No. WO 2016/205037, which is also incorporated by reference in its entirety.
The terms "AMG334" and "erinumab" refer to anti-CGRP receptor antibodies, which are fully humanized IgG2 antibodies. Characterization of eriluumab and methods for preparing it can be found in U.S. publication nos. 2010/0172895, U.S. patent nos. 9,102,731 and WHO Drug Information 30 (2): 275-6 (2016), each of which is incorporated by reference in its entirety. Administration and formulations associated with eridecomab can be found in PCT publication No. WO 2016/171742, which is also incorporated by reference in its entirety.
The term "ramelteon" refers to specific small molecule CGRP antagonists and pharmaceutically acceptable salts thereof, the characterization and methods for preparation of which are found in U.S. patent nos. 8,314,117 and 8,759,372, each of which is incorporated by reference in its entirety.
The term "ubenimpam" refers to specific small molecule CGRP antagonists and pharmaceutically acceptable salts thereof, the characterization and methods for preparation of which are found in U.S. patent nos. 8,754,096, 8,912,210, and 9,499,545, each of which is incorporated by reference in its entirety.
The term "vazegepant" refers to certain small molecule CGRP antagonists and pharmaceutically acceptable salts thereof, the characterization and methods for preparation of which are found in PCT publication No. WO2011/123232, which is incorporated by reference in its entirety.
The term "atto Ji" refers to certain small molecule CGRP antagonists and pharmaceutically acceptable salts thereof, the characterization and methods for preparation of which are found in U.S. patent No. 8,754,096, which is incorporated by reference in its entirety.
The term "oses Ji" refers to certain small molecule CGRP antagonists and pharmaceutically acceptable salts thereof, the characterization and methods for preparation of which are found in U.S. patent No. 6,344,449, which is incorporated by reference in its entirety.
The term "ticagrelor" refers to certain small molecule CGRP antagonists and pharmaceutically acceptable salts thereof, the characterization and methods for preparation of which are found in U.S. patent No. 6,953,790, which is incorporated by reference in its entirety.
The term "BI 44370" refers to specific small molecule CGRP antagonists and pharmaceutically acceptable salts thereof, the characterization and methods for preparation of which are found in PCT publication No. WO2005/092880, which is incorporated by reference in its entirety.
The term "MK-3207" refers to certain small molecule CGRP antagonists and pharmaceutically acceptable salts thereof, the characterization and methods for preparing them are found in U.S. patent publication No. US2007/0265225, which is incorporated by reference in its entirety.
The terms "polypeptide", "oligopeptide", "peptide" and "protein" are used interchangeably herein to refer to amino acid polymers of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interspersed with non-amino acids. The term also encompasses amino acid polymers that have been modified naturally or by, for example, the following interventions: disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation to a labeling component. Also included within the definition are, for example, polypeptides containing one or more amino acid analogs (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. It will be appreciated that because the polypeptides of the invention are antibody-based, the polypeptides may exist in single or associated chain form.
As used interchangeably herein, "polynucleotide" or "nucleic acid" refers to a polymer of nucleotides of any length, and includes DNA and RNA. The nucleotide may be a deoxyribonucleotide, a ribonucleotide, a modified nucleotide or base and/or analogue thereof or any substrate that can be incorporated into a polymer by a DNA or RNA polymerase. Polynucleotides may comprise modified nucleotides, such as methylated nucleotides and analogs thereof. Modification of the nucleotide structure, if present, may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interspersed with non-nucleotide components. The polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component. Other types of modifications include, for example, "caps", substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as modifications with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidites, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), modifications containing pendant moieties such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), modifications with intercalators (e.g., acridine, psoralen, etc.), modifications containing chelators (e.g., metals, radiometals, boron, oxidative metals, etc.), modifications containing alkylating agents, modifications with modified linkages (e.g., alpha anomeric nucleic acids, etc.), and one or more polynucleotides in unmodified form. In addition, any of the hydroxyl groups typically present in the sugar may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages for additional nucleotides, or may be conjugated to a solid support. The 5 'and 3' terminal OH groups may be phosphorylated or partially substituted with an amine or an organic capping group of l to 20 carbon atoms. Other hydroxyl groups may also be derivatized to standard protecting groups. Polynucleotides may also contain ribose or deoxyribose in similar forms, which are generally known in the art, including, for example, 2 '-O-methyl-, 2' -O-allylribose, 2 '-fluoro-ribose or 2' -azido-ribose, carbocyclic sugar analogs, alpha-anomeric sugars, epimeric sugars such as arabinose, xylose or lyxose (lyxose), pyranose, furanose, sedoheptulose (sedoheptulose), acyclic analogs, and abasic nucleoside analogs such as methyl ribonucleoside. One or more of the phosphodiester linkages may be replaced by alternative linkage groups. These alternative linking groups include, but are not limited to, embodiments wherein the phosphate is replaced by P (0) S ("thioester"), P (S) S ("dithioester (dithioate)"), (0) NR2 ("amidate"), P (0) R, P (0) OR ', CO, OR CH2 ("formyl acetal"), wherein each R OR R' is independently H OR a substituted OR unsubstituted alkyl (1-20C) optionally containing an ether (-0-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl, OR aralkyl (araldyl). Not all linkages in a polynucleotide need be identical. The foregoing description applies to all polynucleotides referred to herein, including RNA and DNA.
Diagnosis or assessment of headache is well established in the art. The skilled practitioner can use references such as International Classification of Headache Disorders, 3 rd edition (ICHD-III. Beta.; CEPHALALGIA (2013) 33 (9): 629-808) to assess the type of headache experienced by a patient. Headaches within the scope of the present invention include headaches of intracranial origin. Non-limiting examples of headache of intracranial origin include migraine (e.g., chronic and paroxysmal) and headache due to meningitis, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, and certain brain tumors (where headache is caused by increased intracranial pressure).
For example, "chronic migraine" refers to headache that occurs for 15 or more days per month for more than three months, with migraine characteristics for at least 8 days per month, while "paroxysmal migraine" refers to headache that occurs for less than 15 days per month, and "high frequency paroxysmal migraine" refers to headache that occurs between 8 and 14 days per month. According to ICHD-III version beta, 2013, the diagnostic criteria for chronic migraine are as follows: A. monthly headaches (tension pattern and/or migraine pattern) > 15 days for > 3 months and meet criteria B and C (below). B. Occurs in patients with at least five episodes meeting certain criteria for non-predictive migraine and/or certain criteria for predictive migraine. C. Monthly > 8 days for > 3 months, satisfying any one of the following: 1. certain guidelines for non-predictive migraine; 2. there are certain criteria for predictive migraine; 3. at the time of onset the patient considers migraine and is relieved by triptan (triptan) or ergot derivatives; D. diagnosis by other headaches cannot be better explained.
The skilled practitioner will be able to readily identify a subject having any of the types of migraine as described herein. The assessment may be based on subjective measurements, such as patient symptom characterization. For example, migraine may be diagnosed based on the following criteria: 1) Paroxysmal headache episodes last from 4 to 72 hours; 2) Has two of the following symptoms: unilateral pain, pulsatility, post-exercise exacerbation, and moderate or severe intensity pain; and 3) one of the following symptoms: nausea or vomiting, photophobia or photophobia (Goadsby et al, N.Engl. J. Med. 346:257-2702002). In some embodiments, headache (e.g., migraine) can be assessed via headache hours as described elsewhere herein. For example, headache (e.g., migraine) can be assessed in terms of the number of headache hours per day, the number of headache hours per week, the number of headache hours per month, and/or the number of headache hours per year. In some cases, the number of headache hours may be as reported by the subject.
As used herein, "treatment" is a route for obtaining beneficial or desired clinical results. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: improvements in any aspect of headache (including lessening of severity, pain intensity, and relief of other related symptoms), reduced frequency of recurrence, improved quality of life for patients suffering from headache, and reduced dosages of other medications required to treat headache. Using migraine as an example, other related symptoms include, but are not limited to, nausea, vomiting, and sensitivity to light, sound, and/or motion. The terms "patient" and "subject" are used interchangeably herein. In some embodiments, the patient is a human.
As used herein, "acute treatment" is a method for achieving an immediate beneficial or desired clinical outcome. For the purposes of the present invention, directly beneficial or desired clinical results include, but are not limited to, one or more of the following: pain relief and the most annoying increase in symptomatic (MBS) relief two hours after administration, where pain relief may be defined as a reduction in moderate or severe headache to no headache, and MBS relief is defined as the absence of self-identifying MBS, such as photophobia, phonophobia, or nausea; an increase in pain relief at 2 hours, wherein the pain relief may be defined as a reduction in migraine from moderate or severe severity to mild or no pain; an increase in sustained pain relief at 2-48 hours; reduction in rescue medication usage within 24 hours; and an increase in the percentage of patients reporting normal function at two hours post-administration.
As used herein, "prophylactic treatment" is a method for obtaining beneficial or desired clinical results over time. For the purposes of the present invention, beneficial or desired clinical results over time include, but are not limited to, one or more of the following: improvements in headache include reduced recurrence frequency, reduced headache frequency, improved quality of life for headache patients, and reduced dosages of other medications required to treat headache.
As used herein, "preventing" is a way to prevent the occurrence or presence of headache in a subject prone to develop headache. For example, a patient may have been previously diagnosed with chronic or paroxysmal migraine. In other examples, the patient may have been diagnosed with meningitis, epidural bleeding, subdural bleeding, subarachnoid bleeding, or brain tumors.
By "reducing the incidence of headache" or "reducing the frequency of headache" is meant any of reducing the severity (which may include reducing the need and/or amount of (e.g., exposure to) other medications and/or therapies typically used for such headache disorders), reducing the duration, and/or reducing the frequency (including, e.g., delaying or increasing the time to the next headache episode in an individual). As will be appreciated by those of skill in the art, the response of an individual to treatment may vary, and thus, for example, a "method of reducing the frequency of headache in an individual" is considered administration of an anti-CGRP antagonist antibody based on the reasonable expectation that such administration would likely result in a reduction in the incidence of such headache in the particular individual.
By "ameliorating" a headache or one or more symptoms of a headache is meant a reduction or amelioration of one or more symptoms of a headache as compared to the absence of an anti-CGRP antagonist antibody. "ameliorating" also includes shortening or reducing the duration of symptoms.
As used herein, "controlling headache" refers to maintaining or reducing the severity or duration of one or more symptoms of headache or the frequency of onset of headache (e.g., migraine) in an individual (as compared to the level prior to treatment). For example, the duration or severity or frequency of episodes of headache in an individual is reduced by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to the duration or severity or frequency of episodes of headache prior to treatment.
As used herein, "headache hours" refers to an hour during which a subject experiences headache. The number of headache hours may be expressed in terms of the number of whole hours (e.g., one hour headache, two hours headache, three hours headache, etc.) or in terms of the number of whole and partial hours (e.g., 0.5 hours headache, 1.2 hours headache, 2.67 hours headache, etc.). One or more hours of headache may be described with respect to a particular time interval. For example, "number of headache hours per day" may refer to the number of headache hours a subject experiences over a day interval (e.g., 24-hour time). In another example, "number of headache hours per week" may refer to the number of headache hours a subject experiences over a week interval (e.g., 7-day time). As can be appreciated, the week interval may or may not correspond to a calendar week. In another example, "number of headache hours per month" may refer to the number of headache hours a subject experiences over a month interval. As can be appreciated, the number of days for a month interval (e.g., a time of 28, 29, 30, or 31 days) may vary, depending on the particular month and may or may not correspond to calendar months. In another example, "number of headache hours per year" may refer to the number of headache hours a subject experiences over an annual interval. As can be appreciated, the number of days of an annual interval (e.g., a time of 365 or 366 days) may vary, depending on the particular year and may or may not correspond to calendar years.
As used herein, "headache day" refers to the day during which a subject experiences headache. Headache days can be expressed in terms of total days (e.g., headache one day, headache two days, headache three days, etc.) or in terms of total and partial days (e.g., headache 0.5 days, headache 1.2 days, headache 2.67 days, etc.). One or more days of headache may be described with respect to a particular time interval. For example, "headache days per week" may refer to headache days that a subject experiences over a week interval (e.g., 7-day time). As can be appreciated, the week interval may or may not correspond to a calendar week. In another example, "headache days per month" may refer to headache days that a subject experiences over a month interval. As can be appreciated, the number of days for a month interval (e.g., a time of 28, 29, 30, or 31 days) may vary, depending on the particular month and may or may not correspond to calendar months. In another example, "headache days per year" may refer to headache days that a subject experiences over an annual interval. As can be appreciated, the number of days of an annual interval (e.g., a time of 365 or 366 days) may vary, depending on the particular year and may or may not correspond to calendar years.
As used herein, "delay" headache progression means delay, impediment, slowing, retardation, stabilization, and/or progression of a post-prandial disease. This delay may be of varying length of time depending on the medical history and/or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay may actually cover prophylaxis, as the individual does not develop headache. A method of "delaying" the development of symptoms is a method that reduces the likelihood of developing symptoms within a given timeframe and/or reduces the extent of symptoms within a given timeframe when compared to the absence of the method. Such comparisons are typically made based on clinical studies using a statistically significant number of subjects.
By "progression" or "progression" of a headache is meant the initial manifestation and/or subsequent progression of the disorder. The progression of headache can be detectable and assessed using standard clinical techniques as is well known in the art. However, development also refers to progress that may not be detectable. For the purposes of this disclosure, development or progression refers to the biological process of symptoms. "progression" includes occurrence, recurrence and onset. As used herein, "onset" or "occurrence" of headache includes initial onset and/or recurrence.
Migraine can be defined by its periodicity and its specific stage. As used herein, the "inter-episode" of migraine refers to the interval between two migraine attacks, the "pre-episode" refers to the time before onset of headache, at which time a patient may develop a symptom of aura, including appetite changes, thirst, yawning, etc., the "post-episode" refers to the time period during which the patient experiences headache for 4-72 hours, and the "post-episode" refers to the time within the inter-episode after cessation of headache, and is generally characterized by non-headache symptoms (such as cognitive deficit, fatigue, etc.).
"Respondent rate" refers to the proportion of patients whose average number of migraine days per month decreases by at least 50% during a predetermined treatment period. In one embodiment of the invention, the predetermined treatment period is 3 months. In another embodiment of the invention, the predetermined treatment period is 6 months. In yet another embodiment of the present invention, the predetermined treatment period is 12 months.
Migraine can be defined by its periodicity and its specific stage. As used herein, the "inter-episode" of migraine refers to the interval between two migraine attacks, the "pre-episode" refers to the time before onset of headache, at which time a patient may develop a symptom of aura, including appetite changes, thirst, yawning, etc., the "post-episode" refers to the time period during which the patient experiences headache for 4-72 hours, and the "post-episode" refers to the time within the inter-episode after cessation of headache, and is generally characterized by non-headache symptoms (such as cognitive deficit, fatigue, etc.).
As used herein, an "effective dose" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a beneficial or desired result. For prophylactic use, beneficial or desired results include, for example, the following: eliminating or reducing the risk of, lessening the severity of, or delaying the onset of a disease (including biochemical, tissue and/or behavioral symptoms of the disease; complications and intermediate pathological phenotypes that exist during the progression of the disease). For therapeutic use, beneficial or desired results include clinical results such as the following: reducing the intensity, duration, or frequency of pain in headache episodes, and alleviating one or more symptoms (biochemistry, tissue, and/or behavior) caused by headache, including complications and intermediate pathological phenotypes that exist during disease progression; improving the quality of life of a patient suffering from a disease; reducing the dosage of other drugs required to treat the disease; enhancing the effect of another drug; and/or delay progression of the disease in the patient. The effective dose may be administered in one or more administrations. For the purposes of this disclosure, an effective dose of a drug, compound or pharmaceutical composition is an amount sufficient to effect, directly or indirectly, prophylactic or therapeutic treatment. As understood in the clinical context, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective dose" may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective dose if the desired result is achieved or achieved in combination with one or more other agents.
As used herein, "allodynia" refers to pain experienced by a patient and caused by a stimulus that does not normally cause pain (International Association for the Study of Pain,2014-2015,"Allodynia and Hyperalgesia in Neuropathic Pain").
As used herein, "hyperalgesia" refers to an increase in pain experienced by a patient caused by a stimulus that would normally cause pain (International Association for the Study of Pain,2014-2015,"Allodynia and Hyperalgesia in Neuropathic Pain").
One skilled in the art can distinguish and quantify allodynia from hyperalgesia by methods such as Quantitative Sensory Testing (QST) (Rolke (2006) et al Pain 123:231-243). Rolke et al teach QST reference data for obtaining relative and absolute complete sensory phenotypes of patients. For example, rolke et al describe a test for Mechanical Pain Sensitivity (MPS) as a means for detecting needle-stick hyperalgesia. In such tests, MPS can be evaluated using a set of acupuncture stimuli to obtain a stimulus-response function for acupuncture-induced pain (where the strongest acupuncture force is about eight times the average mechanical pain threshold). The subject may be asked to give a score for pain for each stimulus on a scale of '0-100', where '0' indicates no pain and '100' indicates highest pain. A certain number of needle sticks are delivered to the subject at specific time intervals to avoid lifting (wind-up). After each needling, the subject provided a numerical pain score. MPS was then calculated as the geometric mean (composite measure) of all numerical scores for the acupuncture stimulation (Rolke et al at page 233).
As used herein, "sensitization" is the process of decreasing the intensity of stimulation required to produce a response over time, while increasing the amplitude of the response.
The phrase "experiencing headache primarily in a portion of the head" refers to a patient describing having headache (experiencing as, for example, pain) in a defined portion of the head. Examples of "head portions" include the unilateral periorbital, the unilateral temporal, one eye, a small region of the back of the head (e.g., just lateral to the midline), a small region of the top of the head, a small region of the middle of the forehead, the 'point' of the supraorbital nerve from the skull (e.g., 10x10 mm) (i.e., in the inner eyebrow end), and a small region on the forehead. One skilled in the art will be able to evaluate whether a patient experiences a headache in a portion of the head based on the patient's description (Noseda, R.et al (2016) brain.139 (7): 1971-1986).
Most paroxysmal migraine sufferers seeking secondary or tertiary medical care show signs of allodynia and/or hyperalgesia during the migraine attack phase, but do not show these signs during the inter-attack phase (Burstein et al 2000b; lipton et al 2008; bigal 2008; burstein et al 2000 a). In contrast, chronic migraine sufferers often exhibit signs of allodynia and/or hyperalgesia both during an acute migraine attack and during an inter-attack period. Allodynia is thought to be mediated mechanically by sensitization of central trigeminal vascular neurons in the spinal trigeminal nucleus (Burstein et al 1998). Furthermore, the presence of interseizure allodynia and/or hyperalgesia is mediated by central trigeminal vascular neurons whose sensitization status is independent of the afferent pain signal from the meninges, whereas the absence of interseizure allodynia and/or hyperalgesia in migraine patients is interpreted as the presence of central trigeminal vascular neurons whose sensitization status is dependent on the pain signal from the periphery.
Gempam is unlikely to cross the blood brain barrier and directly inhibit central trigeminal vascular neurons. The inventors of the present application have determined that the therapeutic capabilities of gempam indicate that in some paroxysmal, most likely high frequency and chronic migraine patients, central sensitization and allodynia and/or hyperalgesia are still dependent on pain signals derived from the meninges, and that patients who would respond to these agents will be those patients who require sustained peripheral input to maintain central sensitization, whereas non-responders will be those patients who do not require sustained peripheral input to maintain central sensitization. Thus, the peripheral site of action of the gem will allow these drugs to provide acute and prophylactic treatment for paroxysmal and chronic migraine patients in which the pivotal sensitization status depends on pain signals from the meninges, but not for those in which the pivotal sensitization status is independent of pain signals from the meninges. Such patients may appear to exhibit no allodynia and/or hyperalgesia during and/or between the episodes of migraine.
Provided herein is a method for reducing the frequency of headache (e.g., migraine) in a patient. The method comprises the following steps: determining whether the patient exhibits allodynia and/or hyperalgesia during an inter-attack period of migraine and administering gempam to the patient that does not exhibit signs of allodynia and/or hyperalgesia during the inter-attack period of migraine. In one embodiment of the invention, the treatment is prophylactic. In another embodiment of the invention, the treatment is acute.
Also provided herein are methods of treating migraine in a patient. The method comprises the following steps: determining whether the patient exhibits allodynia and/or hyperalgesia during an inter-attack period of migraine and administering gempam to the patient that does not exhibit signs of allodynia and/or hyperalgesia during the inter-attack period of migraine. In one embodiment of the invention, the treatment is prophylactic. In another embodiment of the invention, the treatment is acute.
Also provided herein is a method for reducing the frequency of headaches (e.g., migraine) in a patient suffering from migraine. The method may include: determining whether the patient exhibits or does not exhibit allodynia and/or hyperalgesia during the inter-attack period of the migraine, and administering gempam to the patient that does not exhibit signs of allodynia and/or hyperalgesia during the inter-attack period of the migraine. The method may further comprise: determining whether the patient exhibits or does not exhibit allodynia and/or hyperalgesia during the inter-attack period of the migraine, and administering gempam to the patient that does not exhibit signs of allodynia and/or hyperalgesia during the inter-attack period of the migraine. The method may further comprise: determining whether the patient exhibits or does not exhibit allodynia and/or hyperalgesia during the period of onset of the migraine, and administering gem to the patient that does not exhibit signs of allodynia and/or hyperalgesia during the period of onset of the migraine.
Also provided herein is a method for reducing the frequency of headache (e.g., migraine) in a patient. The method comprises the following steps: determining whether the patient exhibits allodynia and/or hyperalgesia during the inter-attack period of the migraine and administering gem to the patient who does not exhibit signs of allodynia and/or hyperalgesia during the inter-attack period of the migraine. In one embodiment of the invention, the treatment is prophylactic. In another embodiment of the invention, the treatment is acute.
Also provided herein are methods of treating migraine in a patient. The method comprises the following steps: determining whether the patient exhibits allodynia and/or hyperalgesia during the inter-attack period of the migraine and administering gem to the patient who does not exhibit signs of allodynia and/or hyperalgesia during the inter-attack period of the migraine. In one embodiment of the invention, the treatment is prophylactic. In another embodiment of the invention, the treatment is acute.
Also provided herein is a method for reducing the frequency of headache (e.g., migraine) in a patient. The method comprises the following steps: determining whether the patient exhibits allodynia and/or hyperalgesia during the period of onset of the migraine, and administering gempam to the patient that does not exhibit signs of allodynia and/or hyperalgesia during the period of onset of the migraine. In one embodiment of the invention, the treatment is prophylactic. In another embodiment of the invention, the treatment is acute.
Also provided herein are methods of treating migraine in a patient. The method comprises the following steps: determining whether the patient exhibits allodynia and/or hyperalgesia during the period of onset of the migraine, and administering gempam to the patient that does not exhibit signs of allodynia and/or hyperalgesia during the period of onset of the migraine. In one embodiment of the invention, the treatment is prophylactic. In another embodiment of the invention, the treatment is acute.
In one embodiment of the invention, the diazepam is administered within 3 hours of the onset of the migraine headache. In another embodiment of the invention, the gempam is administered within 150 minutes of the onset of migraine. In another embodiment of the invention, the gempam is administered within 120 minutes of the onset of the migraine headache. In another embodiment of the invention, the diazepam is administered within 105 minutes of the onset of migraine. In another embodiment of the invention, the gempam is administered within 90 minutes of the onset of migraine. In another embodiment of the invention, the gempam is administered within 75 minutes of the onset of migraine. In another embodiment of the invention, the gempam is administered within 60 minutes of the onset of migraine. In another embodiment of the invention, the gempam is administered within 45 minutes of the onset of migraine. In another embodiment of the invention, the gempam is administered within 30 minutes of the onset of the migraine headache. In yet another embodiment of the invention, the diazepam is administered within 15 minutes of the onset of the migraine headache.
In one embodiment of the invention Ji is administered at the time of onset prior to central sensitization of the patient. In another embodiment of the invention Ji is administered at the time of onset before the patient develops episodic allodynia and/or hyperalgesia.
In one embodiment of the invention, the subject suffers from paroxysmal migraine. In one embodiment of the invention, the subject suffers from high frequency episodic migraine. In another embodiment of the invention, the subject suffers from chronic migraine.
In one embodiment of the invention, the determination of whether a subject exhibits allodynia and/or hyperalgesia is made by a Quantitative Sensory Test (QST). In another embodiment of the invention, the determination of whether a subject exhibits allodynia and/or hyperalgesia is made by a survey. In another embodiment of the invention, the subject is determined whether or not the subject exhibits allodynia and/or hyperalgesia by both Quantitative Sensory Testing (QST) and questionnaires. In one embodiment of the invention, the QST and/or questionnaire is determined at the medical facility. In another embodiment of the invention, the QST and/or questionnaire is determined at the residence of the subject.
Quantitative Sensory Testing (QST) should preferably be performed in a quiet room remote from noise and interference. There, the patient should be allowed to choose his or her most comfortable posture (sitting in a chair or lying in a bed) during the sensory test. In each test, pain thresholds for thermal and mechanical stimulation were determined in the skin above the site involved in pain, with periorbital and temporal regions being the most common test sites. The pain threshold of the participants should be determined by delivering a hot skin stimulus through a 30x30mm 2 thermode (Q-Sense 2016, medoc) connected to the skin at constant pressure and by using a Limit of Limit analysis.
An allodynia test should be performed to determine the pain threshold, wherein the skin is allowed to adapt to a temperature of 32 ℃ for 5 minutes, then warmed up at a slow rate (1 ℃/sec) until pain sensation is perceived, at which point the subject will be allowed to stop stimulation by pressing a button on the patient's response unit. The thermal stimulus should be repeated three times each time and the average of the recorded temperatures will be regarded as the threshold. The pain threshold for mechanical stimulation can be determined by using a set of up to 20 corrected frey hairs (VFH, stoelting). Each VFH filament was assigned a scalar number in ascending order and each filament should be applied to the skin 3 times (for 2 sec). The minimum number of VFH that can cause pain in two-thirds of the trials will be considered the threshold. Skin sensitivity can also be determined by recording the subject's perception of a soft skin swipe, which is a dynamic mechanical stimulus, unlike VFH, which is a static mechanical stimulus.
Hyperalgesia tests should be performed to determine when a painful stimulus is perceived to be more painful than usual. The skin should be subjected to 3 thermal and mechanical stimuli above the threshold. The value of the suprathreshold stimulus may be determined during an allodynia test that the subject will have performed. In this test, the skin should be exposed to 3 suprathreshold stimuli (exceeding threshold 1), each lasting 10 seconds and separated by 10 seconds (i.e., 10 seconds between stimuli). At the end of each stimulus, the patient should have a Visual Analog Scale (VAS) of 0-10 (o=no pain, 10=maximum imaginable pain) for 10 seconds to determine pain intensity. Similar tests can be applied using a mechanical stimulus above the threshold.
In one embodiment of the invention, it is determined whether the subject exhibits allodynia and/or hyperalgesia by determining whether the subject has a hot pain threshold below 41 ℃ and/or a cold pain threshold above 21 ℃ and/or a mechanical pain threshold below 30g for skin pits using corrected frey.
In one embodiment of the invention, the subject is determined to exhibit allodynia and/or hyperalgesia by exhibiting a hot pain threshold below 41 ℃ and/or a cold pain threshold above 21 ℃ and/or a mechanical pain threshold below 30g for skin pits using corrected frey.
In one embodiment of the invention, it is determined that the subject does not exhibit allodynia and/or hyperalgesia by exhibiting a hot pain threshold above 40 ℃ and/or a cold pain threshold above 20 ℃ and/or a mechanical pain threshold above 30g for skin pits using corrected frey.
In one embodiment of the invention, the questionnaire is specifically designed to capture the presence or absence of allodynia and/or hyperalgesia between episodes. In another embodiment of the invention, a questionnaire is specifically designed to capture the presence or absence of narcotic allodynia and/or hyperalgesia, such as an allodynia symptom checklist (ASC-12) (Lipton RB et al 2008). In one embodiment of the invention, the questionnaire is incorporated as part of an electronic diary. In one embodiment of the invention, the subject records an electronic diary daily over a period of at least seven days, starting at least twenty-four hours from the post-migraine attack stage.
The specially designed questionnaire for identifying inter-seizure allodynia and/or hyperalgesia may be a modification of the allodynia symptom checklist (ASC-12) (Lipton RB et al 2008) that has been modified for inter-seizure intervals of migraine rather than for the seizure period in which ASC-12 is commonly used. Such modifications may result in the deletion of problems associated with wearing necklaces or contact lenses, and the scaling may rank in a similar manner as ASC-12, or it may be a more simplified ranking from never/few (score=0) and at least some time (score=0). With such modifications, no allodynia was found to be likely to be related to a score of 0, 1, 2, 3, 4, or 5.
In one embodiment of the invention, the absence of allodynia and/or hyperalgesia is determined by examination of a questionnaire by a properly qualified healthcare professional. In one embodiment of the invention, the absence of allodynia and/or hyperalgesia is determined by a questionnaire score of no more than 5. In one embodiment of the invention, the absence of allodynia and/or hyperalgesia is determined by a questionnaire score of no more than 5, no more than 4, no more than 3, no more than 2, no more than 1, or a questionnaire score of 0.
In one embodiment of the invention, the prophylactic treatment comprises a decrease in the rate of responders, i.e. a decrease in the proportion of patients whose average number of migraine days decreases by at least 50% during the treatment period. In another embodiment of the invention, the prophylactic treatment comprises a decrease in the number of migraine days per month over a treatment period of at least three months. In another embodiment of the invention, the prophylactic treatment comprises a reduction in the use of acute headache medications. In another embodiment of the invention, the prophylactic treatment comprises an improvement in the function of the subject. In another embodiment of the present invention, wherein the prophylactic treatment comprises an improvement in quality of life (QoL) of the subject. In another embodiment of the invention, the prophylactic treatment comprises an improvement in the severity of headache in the subject. In another embodiment of the invention, the prophylactic treatment comprises a decrease in the number of days of monthly non-migraine headaches over a treatment period of at least three months. In another embodiment of the invention, the prophylactic treatment comprises a decrease in photophobia, phonophobia and/or nausea in the subject.
In one embodiment of the invention, the acute treatment comprises an increase in pain relief. In another embodiment of the invention, the acute treatment comprises an increase in the elimination of the most annoying symptoms. In another embodiment of the invention, the acute treatment comprises pain relief and an increase in relief of the most annoying symptoms. In another embodiment of the invention, the acute treatment comprises an increase in pain relief. In another embodiment of the invention, the acute treatment comprises an increase in persistent pain relief. In another embodiment of the invention, the acute treatment comprises a reduction in the use of rescue medication. In another embodiment of the invention, the acute treatment comprises an increase in normal function. In one embodiment of the invention, the subject administered the gempam remains free of allodynia and/or hyperalgesia for at least three months after initiation of treatment. In one embodiment of the invention, the subject administered gempam remains free of allodynia and/or hyperalgesia for at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months or at least twelve months after initiation of treatment.
In one embodiment of the invention Ji is administered when the subject is not migraine.
Selecting the patient includes determining whether the headache of the patient is mediated by HT neurons. The skilled practitioner will appreciate that such determinations may be made in any number of ways described herein, such as by observing HT neuron activity and/or administering monoclonal antibodies that modulate CGRP pathways to a patient and determining whether the antibodies reduce hyperalgesia (e.g., as measured by QST) and/or determining that a patient's headache is confined to (e.g., most strongly or predominantly experienced) a portion of the head.
Example 1 describes a method by which neurons (HT and WDR neurons) can be identified and selected in rats. This example further describes observations related to activation and sensitization of each of these types of neurons after CSD induction.
Patients experiencing hyperalgesia, wherein hyperalgesia is reduced (e.g., reversed or eliminated) following administration of monoclonal antibodies that modulate (e.g., block, inhibit, suppress or reduce) the CGRP pathway, may be responsive to a course of treatment (e.g., longer course of treatment and/or higher dose course of treatment with an anti-CGRP active agent) comprising an anti-CGRP agent that modulates (e.g., blocks, inhibits, suppresses or reduces) the CGRP pathway. If the anti-CGRP active agent reduces headache in hyperalgesic patients, it is demonstrated that headache is mediated by HT neurons, as the anti-CGRP active agent does not inhibit another type of nociceptive neuron, WDR, as shown in example 1. Example 2 describes the experimental design of QST, which can be used to determine whether a patient experiences allodynia and/or hyperalgesia and whether it is reduced following treatment with gem.
Likewise, patients experiencing allodynia, wherein allodynia is reduced (e.g., reversed or eliminated) following administration of a gempam that antagonizes the CGRP pathway, may be responsive to a course of treatment comprising a gempam that antagonizes the CGRP pathway (e.g., a longer course of treatment and/or a higher dose course of treatment with an anti-CGRP active agent).
Thus, a patient who is responsive to treatment with gem may experience a reduction, reversal or elimination of both hyperalgesia and allodynia after the first course of treatment.
Furthermore, when there is no headache, i.e. during the inter-seizure period of migraine, patients not experiencing allodynia and/or hyperalgesia can be treated by administering gempam antagonizing the CGRP pathway. Identification of this patient population should allow for improved responsiveness to gempam and other anti-CGRP active drug therapies.
Furthermore, high threshold neurons are known to exhibit smaller receptive fields, while wide dynamic range neurons exhibit larger receptive fields. Thus, a headache that is confined to (or primarily experiences) a portion of the head may identify patients that will respond well to treatment with gempam that antagonizes the CGRP pathway.
In another embodiment, the patient is diagnosed with or has been previously diagnosed with paroxysmal or chronic migraine. In such patients, the anti-CGRP active agent may be administered when the patient has no migraine or experiences early stage migraine or mild migraine.
In another embodiment, the patient is diagnosed with or has been previously diagnosed with meningitis, epidural hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, or brain tumor. In other examples, the headache may be due to meningitis, epidural bleeding, subdural bleeding, subarachnoid bleeding, or brain tumors.
Thus, in certain methods described herein, the gempam to be used in the methods described herein may be selected from the group consisting of ramelteon, ubenimpam, vazegepant, atopy Ji, oseltamium Ji, teccard Ji, BI 44370, MK-3207, and bioequivalence thereof, and may be administered at a dose of about 10mg to about 250mg, e.g., a dosage of about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 160mg, about 165mg, about 170mg, about 175mg, about 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, or about 250 mg. The dosage may be administered once a day, more than once a day, or intermittently for a week or more.
Administration of the gempam may be by any means known in the art, including: oral, intravenous, subcutaneous, intra-arterial, intramuscular, intranasal (e.g., with or without inhalation), intracardiac, intraspinal, intrathoracic, intraperitoneal, intraventricular, sublingual, transdermal and/or via inhalation.
Administration may be systemic (e.g., intravenous) or local. In some embodiments, the initial dose and the one or more additional doses are administered via the same route (i.e., subcutaneously or intravenously). In some embodiments, the one or more additional doses are administered via a different route than the initial dose, i.e., the initial dose may be administered intravenously and the one or more additional doses may be administered subcutaneously.
In some cases, the methods described herein can further comprise administering a second dose to the patient simultaneously or sequentially with the diazepam. The second agent may be a non-steroidal anti-inflammatory drug (NSAID) and/or triptan and/or a 5-hydroxytryptamine IF receptor agonist (i.e., a serotonin receptor agonist). In some cases, the second agent is an agent that is administered to the patient prophylactically.
Non-limiting examples of NSAIDs that may be used in combination with the anti-CGRP antibody include aspirin (aspirin), diclofenac, diflunisal (bifusinal), etodolac (etodolac), fenbufen (fenbufen), fenoprofen (fenoprofen), flubensal (flufenisal), flurbiprofen (flurbiprofen), ibuprofen (ibuprofen), indomethacin (indomethacin), ketoprofen (ketoprofen), ketorolac (ketorolac), meclofenamic acid, mefenamic acid, nabumetone (nabumetone), naproxen (naproxen), oxaprozin (oxaprozin), phenylbutazone (phenylbutazone), piroxicam (piroxicam), sulindac (sulindac), tolmetin (tolmetin) or zomefenamic acid (zomepirac), cyclooxygenase-2 (COX-2) inhibitors, celecoxib (celecoxib), rofecoxib, meloxicam (meloxicam), JTE-522, 398, or pharmaceutically acceptable salts thereof. Non-limiting examples of triptans that may be used in combination with anti-CGRP antibodies include sumatriptan (sumatriptan), zolmitriptan, naratriptan (naratriptan), rizatriptan (rizatriptan), eletriptan (eletriptan), almotriptan (almotriptan), and frovatriptan (afrovatriptan). A non-limiting example of a5 hydroxytryptamine IF receptor agonist is masmiptan (lasmiditan).
The prevention, treatment, or alleviation of the methods provided herein may include reducing the number of headache hours of any severity, reducing the number of migraine days per month of any severity, reducing the use of any acute headache medications, reducing the 6-headache HIT test (HIT-6) dysfunction score, improving the 12-plain health survey (SF-12) score (Ware et al, med. Care 4:220-233, 1996), reducing the patient's overall change impression (PGIC) score (Hurst et al, j. Manual physical. Ter.27:26-35, 2004), improving the motor concussion assessment tool 3 (SCAT-3) score (McCrory et al British j. Sport. Med.47:263-266, 2013), or any combination thereof. In some embodiments, the monthly headache or migraine days may be reduced for at least seven days after a single administration.
In some embodiments, the number of monthly headache or migraine headache hours experienced by the subject is reduced by 40 or more hours (e.g., 45, 50, 55, 60, 65, 70, 75, 80 or more hours) after the administration compared to the pre-administration level in the subject. The number of headache or migraine hours per month can be reduced by more than 60 hours. In some embodiments, the number of headache or migraine hours experienced by the subject is reduced by 25% or more (e.g., 30%, 35%, 40%, 45%, 50% or more) after the administration relative to the pre-administration level in the subject. The number of headache or migraine hours per month can be reduced by 40% or more. In some embodiments, the number of days of monthly headache or migraine experienced by the subject is reduced by three or more days (e.g., 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more days) after the administration compared to the pre-administration level in the subject. In some embodiments, the monthly headache or migraine days can be reduced by at least about 50% compared to the pre-administration level in the subject. Thus, in some aspects, the number of headache or migraine days per month may be reduced by at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 90%.
The gempam and compositions thereof provided herein may also be used in combination with other agents for enhancing and/or supplementing the effectiveness of antibodies.
Kits for use in the methods are also provided herein. The kit may include one or more containers including an antibody described herein (e.g., gempam) and instructions for use according to any of the methods described herein. In general, these instructions include descriptions of administration of antibodies to select and treat patients according to any of the methods described herein. For example, the kit may include a description of how to select a patient suitable for treatment based on identifying whether the patient exhibits allodynia and/or hyperalgesia during its migraine attack interval. In other embodiments, the instructions include a description of how to administer gem to a patient to reduce headache frequency.
Thus, the kit may comprise, for example, a pre-filled syringe with needle safety, an injection pen or an automatic syringe comprising a dose of gem-pam; and instructions for determining whether allodynia and/or hyperalgesia in the patient occurred during the migraine attack interval thereof. Alternatively or additionally, the instructions may direct determining whether the patient exhibits allodynia and/or hyperalgesia (which may be reduced by administration of gem) and/or determining whether the patient's headache is experienced primarily in a portion of the head (e.g., periorbital, temporal or eye).
Another exemplary kit may include gempam antagonizing the CGRP pathway and detailed instructions on how to administer QST to the patient or instructions on conducting a patient questionnaire and analyzing the response to determine if allodynia and/or hyperalgesia in the patient of the patient occurred during its migraine attack interval.
In addition to instructions regarding identifying responders, the kit may further include instructions for further treatment with gempam, including information regarding the dosage, dosing regimen, and route of administration for the intended treatment (e.g., instructions for achieving a reduction in headache frequency once the patient is determined to be a responder according to the instructions of the kit).
In the kits provided herein, the gempam provided in the kit may include ziram, ubenimpam, vazegepant, atopy Ji, oxepin Ji, teca Ji, BI44370, MK-3207, or a pharmaceutically acceptable salt thereof.
The kit of the invention may be provided in a suitable package. Suitable packages include, but are not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar (Mylar) or plastic bags), and the like. Packages for use in combination with specific devices such as inhalers, nasal administration devices (e.g., nebulizers), or infusion devices (such as micropumps) are also contemplated. The kit may have a sterile access aperture (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container may also have a sterile access aperture (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is gempam. The container may further comprise a second pharmaceutically active agent. The kit may optionally provide additional components such as buffers and explanatory information. Generally, a kit includes a container and a label or one or more package inserts located on or associated with the container.
The following examples are provided to illustrate but not limit the application. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application. All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be so incorporated by reference.
Examples
Example 1: selective inhibition of trigeminal vascular neurons by humanized monoclonal anti-CGRP antibodies (furanezomib, TEV-48125).
The purpose of this study was to better understand how CGRP-mAb furosemide (TEV-48125) modulates the meningeal sensory pathway. To answer this question, single cell recordings were used to determine the effect of freudemumab (30 mg/kg, intravenous) and IgG2 isotype control antibodies (isotype-control abs) on spontaneous and evoked activity in the primary and CSD trigeminal vascular neurons in spinal nuclei of anesthetized male and female rats. Studies have demonstrated that in both sexes, freudetime mab inhibits the primary High Threshold (HT) trigeminal vascular neurons, but not the wide power range, and that inhibition of neurons is limited to its activation from intracranial dura mater rather than facial skin or cornea. In addition, when given for a sufficient time, the furanediol inhibits activation and sensitization of HT neurons by cortical diffusion inhibition.
A. Materials and methods
Surgical preparation
Experiments were approved by the belleville-female executive officer medical center (Beth Israel Deaconess MEDICAL CENTER) and the harvard medical college animal care institutes of health (HARVARD MEDICAL School standing committees on ANIMAL CARE) and were conducted according to the national institutes of health laboratory guidelines for animal care and use (U.S. national Institutes of Health Guide for THE CARE AND Use of Laboratory Animals). Male and female Sprague-Duoli rats (250-350 g) were anesthetized with carbamate (0.9-1.2 g/kg, intraperitoneally). They were equipped with an endotracheal tube allowing artificial ventilation (0.1L/min O 2) and a femoral intravenous tube for subsequent infusion of drugs. Rats were placed in a stereotactic instrument and the core temperature was maintained at 37 ℃ using a heated blanket. End-tidal CC was continuously monitored and maintained within the physiological range (3.5-4.5 pCC). After stabilization, rats were paralyzed and ventilated with rocuronium bromide (rocuronium bromide) (10 mg/ml,1 ml/hr continuous intravenous infusion). For subsequent cranial dura stimulation in the experiment, 5x5-mm openings were carefully cut in the parietal and occipital bones immediately anterior and posterior to the λ suture and above the left lateral sinus. The exposed dura mater was kept moist using modified synthetic interstitial fluid (135 mM NaCl, 5mM KCl, 1mM MgCh, 5mM CaCh, 10mM glucose, 10mM Hepes,pH 7.2). For single cell recordings in the spinal trigeminal nuclei, the spinal segment between the latch and C2 was torn away from the covered tissue, the dura was peeled away, and kept moist with mineral oil.
Neuron identification and selection
To record neuronal activity, tungsten microelectrodes (impedance 3-4mΩ) were repeatedly lowered into Spinal Trigeminal Nuclei (STN), looking for central trigeminal vascular neurons that receive convergent inputs from dura mater and facial skin. Trigeminal vascular neurons were first identified based on responses to dura electrical stimulation. They were selected for study if they exhibited multiple discrete discharges in response to ipsilateral electrical (0.1-3.0 ma,0.5 sec,0.5hz pulse) and mechanical (using corrected frey monofilaments) stimulation as well as mechanical stimulation of facial skin and cornea. The dural receptive field was located by recessing the dura (with 4.19g of VFH monofilament) at a point 1mm apart from the inside and outside and the head-to-tail. The points at which dural pits respond in > 50% of the trials were considered to be inside the neuronal receptive field. The skin receptive field is located by applying harmless and harmful mechanical stimuli to all facial skin areas and cornea. If no stimulus produced a response in > 50% of the trials, the region was considered to be outside the receptive field. The response to mechanical skin irritation was determined by applying short (10 s) harmless and harmful stimuli to the most sensitive parts of the skin receptive field. Harmless stimulation consisted of slow passage of the soft bristle brush over the skin receptive field (one 5-s brush stroke from tail to beak and one 5-s brush stroke from beak to tail) and application of pressure with a relaxing arterial forceps. The harmful stimulus consists of pinching with a strong arterial jaw (Pallecek et al 1992, J. Neurohysiol.67:1562-1573; dado et al 1994, J. Neurohysiol.71:981-1002; burstein et al 1998, J. Neurohysiol.79:964-982). No more intense or persistent stimulus is used to avoid inducing spontaneous neuronal firing or persistent changes in response characteristics. The response to the mechanical stimulation of the cornea consisted of a gentle and slow brushing impact using a fine brush (about 10 hair follicles). Two types of neurons were thus identified: wide power range (WDR) neurons (gradually responsive to brushing, pressure, and pinching), and High Threshold (HT) neurons (non-responsive to brushing). Using a real-time waveform discriminator to form and store templates of action potentials induced by electrical pulses to the dura mater in neurons under study; the activity spikes matching the template waveforms were obtained and analyzed online and offline using Spike 2 software (CED, cambridge, UK). Induction and recording of cortical diffusion inhibition.
Cortical diffusion inhibition (CSD) was induced mechanically by inserting a glass micropipette (end diameter 25 μm) into the visual cortex for about 1mm for 10 sec. At a propagation rate of 3-5mm/min, a single CSD wave is expected to enter the neuronal receptive field within 1-2min of cortical stimulation. For CSD validation, cortical activity (cortical electroencephalogram) was recorded, and a glass micropipette (0.9% saline, about 1 megaohm, 7um tip) was placed immediately below the cortical surface of the brain (about 100 μm). Cortical electroencephalogram electrodes were placed approximately 6mm in front of the visual cortex. Treatment with the monoclonal anti-CGRP antibody, furetastatin (TEV-48125). Furanavizumab (also known as TEV-48125/LBR-101/RN-307) (TEVA Pharmaceutical Industries Ltd., israel) was a humanized monoclonal anti-CGRP antibody (CGRP-mAb). It was diluted in saline to a final dose of 30mg/kg and administered intravenously (bolus injection, total volume 0.6-0.7 ml). The corresponding human IgG2 isotype control antibody (isotype-control Ab) was also diluted in saline to a final dose of 30mg/kg and administered intravenously (bolus injection, total volume 1.6-2.0 ml).
Experimental protocol
The experimental protocol consists of two parts. The first part was designed to compare the effect of CGRP-mAb and isotype-control Ab on spontaneous and induced activity of primary, tri-modal neurons, and the second part was designed to test the effect of CGRP-mAb and isotype-control Ab on activation and sensitization of tri-modal neurons by CSD. Both fractions included sampling of WDR and HT neurons in male and female rats. In the first part, a baseline neuron pattern is established as follows: (a) mapping dura mater, skin, and corneal receptive fields; (b) Measuring the response (average spikes per second) to mechanical stimulation of the dura (using fixation force), skin (brushing, pressure, pinching) and cornea (brushing) and (c) measuring the spontaneous discharge rate (recorded for more than 30min prior to treatment). After baseline establishment, CGRP-mAb or isotype-control Ab was administered and receptive fields were repositioned, neurons were re-examined for responses to dura mater, skin, and cornea stimuli, and re-sampled for spontaneous activity at 1, 2,3, and 4 hours post-treatment. The resulting value of each measurement is then compared to the respective baseline value obtained prior to processing. In the second part, CSD was induced 4 hours after CGRP-mAb or isotype-control Ab administration, and receptive field size, spontaneous motility, and magnitude of response to dura mater, skin, and cornea stimulation were measured again after 2 hours (i.e., 6 hours after treatment). The resulting post-CSD values for each measurement are then compared to the respective pre-CSD values obtained 4-hours after the treatment time. This fraction was initiated only if the physiological conditions (heart rate, blood pressure, respiration, end-tidal C02) and neuron separation signals (signal-to-noise ratio > 1:3) of the rats were stable 4 hours after the treatment time point.
When each experiment was completed, a small lesion was created at the recording site (anodic DC 15. Mu.A for 15 sec) and its localization in the dorsal horn was determined using histological analysis after death as described elsewhere (Zhang et al (2011) Ann. Neurol. 69:855-865). Only one neuron was studied in each animal.
Data analysis
To calculate the response values for each stimulus, the average discharge frequency occurring before the first stimulus (30 min for spontaneous activity and 10sec for mechanical stimulus of dura mater, skin and cornea) was subtracted from the average discharge frequency occurring for the duration of each stimulus. In the first part of the study, the corresponding values of each measurement (measured at 1, 2,3, 4 hours after treatment) were compared with the respective baseline values obtained prior to administration of freudenreichii or isotype-control Ab. In the second part of the study, the resulting values measured for each of the 2 treatment groups (freretastatin and isotype-control Ab) (measured 2 hours after CSD induction) were compared with the respective values obtained prior to CSD induction. Neurons were considered to be activated when their mean firing rate after CSD exceeded their mean baseline activity by 2 standard deviations of the mean for a period of >10 min (this translates to an activity increase of > 33%). Neurons showed enhanced response to at least 3 of the following 5 stimuli if 2 hours after CSD had occurred: dura mater dents, brushing, pressing or pinching the skin, and brushing the cornea, neurons are considered sensitized. The average discharge rate of the individual values was compared using non-parametric statistics (Wilcoxon signed-RANKS TEST). The two-tailed significance level was set to 0.05.
B. Results
The database used to test the effect of CGRP-mAb and isotype-control Ab on spontaneous and induced activity of primary, triple-nerve vascular neurons consisted of 63 neurons. Of these, 31 are classified as WDR and 32 are classified as HT. Of the 31 WDR neurons, 18 (11 in males, 7 in females) were tested before and after CGRP-mAb administration, and 13 (7 in males, 6 in females) were tested before and after isotype-control Ab administration. Of the 32 HT neurons, 18 (11 in males, 7 in females) were tested before and after CGRP-mAb administration, and 14 (8 in males, 6 in females) were tested before and after isotype-control Ab administration.
The database used to test the effect of CGRP-mAb and isotype-control Ab on neuronal activation and sensitization by CSD consisted of 50 neurons. Of these, 23 are classified as WDR and 27 are classified as HT. Of the 23 WDR neurons, 13 (7 in males, 6 in females) were tested in CGRP-mAb treated animals and 10 (5 in males, 5 in females) were tested in isotype-control Ab treated animals. Of the 27 HT neurons, 14 (8 in males, 6 in females) were tested in CGRP-mAb-treated animals, and 13 (7 in males, 6 in females) were tested in isotype-control Ab-treated animals. Recording sites, receptive fields, and neuronal types.
There was no difference in the recording sites, dura mater and skin receptive field patterns, and cell types between neurons tested against CGRP-mAb and neurons tested against isotype-control Ab. All identified recording sites were located in lamina I-II and IV-V of the first cervical spinal cord and in the caudal portion of the caudal nucleus. In all cases, the most sensitive area of the dural receptive field is along the transverse sinus and the most sensitive area of the skin receptive field is around the eye, in more than 90% of cases involving the cornea. Spontaneous activity of primordial trigeminal vascular neurons.
In male rats, intravenous administration of CGRP-mAb reduced spontaneous activity of HT, but not WDR neurons. In the HT group, neuronal firing was reduced by 90% within 3-4 hours (p=0.040). Occasionally, the firing rate of some HT neurons decreases within 1-2 hours after intravenous administration of CGRP-mAb. In contrast, intravenous administration of isotype-control abs did not alter spontaneous activity of either group of neurons.
In females, intravenous administration of CGRP-mAb does not reduce spontaneous activity of HT or WDR neurons, unlike in males. Similarly, intravenous administration of isotype-control abs did not alter spontaneous activity of either group of neurons. Importantly, the baseline (i.e., prior to any treatment) spontaneous firing rates of HT and WDR neurons did not differ between male and female rats (p=0.14).
For HT neurons, the average spikes per second before any treatment was 1.7±1.1 in males, compared to 1.9±1.0 in females (p=0.55). For WDR neurons, the average spikes per second before any treatment was 0.3±0.6 in males versus 2.2±1.1 (p=0.16) in females.
Sensitivity of primary and middle-aged trigeminal neurovascular neurons to dural depression
Intravenous administration of CGRP-mAb reduces sensitivity to mechanical stimulation of the dura mater in HT but not WDR neurons in both male and female rats. In males, the firing of HT neurons is reduced by 75% (p=0.047), while in females it is reduced by 61% (p=0.017). Intravenous administration of isotype-control abs did not alter the sensitivity to dural stimuli in either group of neurons, independent of gender. Sensitivity of primordial central trigeminal vascular neurons to periorbital skin and corneal mechanical stimuli. Intravenous administration of CGRP-mAb or isotype-control Ab did not alter the response of HT or WDR neurons to harmless (brushing, pressure) or harmful (pinching) skin or corneal mechanical stimuli in male or female rats.
Cortical diffusion inhibition
The effect of CGRP-mAb (n=27) or isotype-control Ab (n=23) on central trigeminal vascular neurons activated by CSD was tested in 50 neurons, with baseline firing rates (i.e., average spikes per second prior to CSD induction) being reliable and consistent over several hours. At baseline (i.e., prior to CSD), the spontaneous firing rates of HT and WDR neurons were not different between male and female rats (p=0.14). For HT neurons, the average spikes per second before CSD induction was 1.2±0.6 in males versus 3.3±1.7 in females (p=0.29). For WDR neurons, the average number of spikes per second before CSD induction was 1.5±0.6 in males versus 3.5±2.2 (p=0.37) in females.
CSD-induced activity in central trigeminal vascular neurons
In male rats, the average discharge rate of 7 HT neurons increased from 1.1±0.8 spikes/sec before CSD to 10.2±2.1 (p=0.019) after CSD, whereas the average discharge rate of 5 WDR neurons did not increase (0.5±0.3 spikes/sec before CSD compared to 1.6±0.5; p=0.14 after CSD) at two hours after CSD induction and 6 hours after isotype control Ab administration. In contrast, in CGRP-mAb treated rats, the magnitude of the response of 8 HT neurons remained unchanged at 2 hours after CSD induction and 6 hours after CGRP-mAb administration (1.2±0.6 spikes/sec before CSD compared to 1.9±1.5 after CSD, p=0.29). In other words, expected CSD-induced HT neuron activation was blocked by CGRP-mAb treatment.
In female rats, the average discharge rate of 6 HT neurons increased from 1.9±1.0 spikes/sec before CSD to 10.0±4.5 (p=0.027) after CSD, while the average discharge rate of 5 WDR neurons remained unchanged (2.6±1.2 spikes/sec before CSD compared to 2.2±0.9 after CSD, p=0.73) at two hours after CSD induction and 6 hours after isotype control Ab administration. In contrast, in CGRP-mAb treated rats, the magnitude of the response of 6 HT neurons remained unchanged at 2 hours after CSD induction and 6 hours after CGRP-mAb administration (3.3±1.7 spikes/sec before CSD compared to 5.0±3.4 after CSD, p=0.45). As in males, CSD-induced HT neuron activation is expected to be blocked by CGRP-mAb treatment. To further examine the effect of CGRP-mAb on WDR and HT neurons activation by CSD, a case-by-case analysis was also performed. Of all CGRP-mAb and isotype-control Ab treated WDR neurons, 5/13 and 4/10 were activated by CSD with only a 2% difference. In contrast, in all CGRP-mAb and isotype-control Ab treated HT neurons, 2/14 and 13/13 were activated by CSD, 86% different.
CSD-induced sensitization
Independent of activation by CSD, 11/13 HT neurons and no WDR neurons meet the criteria for sensitization (specified in the data analysis section). Thus, there is CGRP-mAb for HT that prevents the ability to produce sensitization after CSD, but not for WDR neurons. Expansion of the dural receptive field following CSD and enhanced response to dural mechanical stimulation. In the isotype-control Ab-treated group, the dural receptive field was enlarged in 5/7 HT neurons in males and 6/6 HT neurons in females. At two hours after CSD induction (6 hours after isotype-control Ab administration), the response of neurons to dural depression with VFH was increased in all 7 HT neurons in males (12.8±3.9 spikes/sec before CSD versus 22.0±3.7; p=0.026 after CSD) and 6 HT neurons in females (8.5±1.7 before CSD versus 21.6±5.1, p=0.047 after CSD).
In contrast, in the CGRP-mAb treated group, a smaller expansion of the dural receptive field when occurring was recorded in only 2/8 of HT neurons in males and 0/6 in females. At two hours after CSD induction (6 hours after CGRP-mAb administration), the response of neurons to dural depression using VFH remained unchanged in all HT neurons in both males (1.8±0.6 before CSD compared to 1.9±1.5 after CSD, p=0.83) and females (10.5±1.6 before CSD compared to 8.1±6.4 after CSD, p=0.72), indicating that sensitization was hindered. Thus, CGRP-mAb prevents the development of intracranial mechanical hypersensitivity in HT neurons in male and female rats. The skin receptive field following CSD expands and responds to enhanced mechanical stimulation of the periorbital skin (i.e., central sensitization).
In the isotype-control Ab-treated group, the facial receptive field was expanded in 5/7 HT neurons in males and 6/6 HT neurons in females. At two hours after CSD induction (6 hours after isotype-control Ab administration), the response to brushing and stress increased significantly in all 13 HT neurons (7 in males, 6 in females). In males, the response to brushing and pressure increased from 0.0 to 18.2±9.1 spikes/sec (p=0.046) and from 16.6±4.2 to 35.8±9.1 spikes/sec (p=0.045), respectively. In females, the response to brushing and pressure increased from 0.0 to 8±6.5 spikes/sec (p=0.027) and from 9.3±2.7 to 31.8±13.6 spikes/sec (p=0.016), respectively. In contrast, the response to pinching was significantly increased in all HT neurons in females (19.3±5.0 spikes/sec before CSD compared to 45.8±12.4 spikes/sec after CSD, n=6, p=0.027), but not significantly increased in males (33.8±7.1 spikes/sec before CSD compared to 52.4±10.3 spikes/sec after CSD, n=6, p=0.068).
In CGRP-mAb treated rats, the facial receptive field was enlarged in only 2/8 of HT neurons in males and 0/6 of HT neurons in females. At two hours after CSD induction (6 hours after CGRP-mAb administration), the response of neurons to brushing (p=0.35), pressure (p=0.63), and pinching (p=0.78) remained unchanged in all HT neurons in both males and females, indicating that CGRP-mAb prevented induction of sensitization.
Enhanced response to corneal stimulation after CSD
In isotype-control Ab treated rats, HT neurons significantly increased in response to corneal stimulation after CSD in females (7.6±1.9 spikes/sec before CSD compared to 21.0±6.4 spikes/sec after CSD, n=6, p=0.044), but not significantly increased in males (11.0±2.6 spikes/sec before CSD compared to 21.6±8.7 spikes/sec after CSD, n= 7,p =0.19). In CGRP-mAb treated female rats, the response to brushing the cornea remained unchanged in 6 HT neurons (p=0.51), indicating that sensitization was blocked; and as expected, also remained unchanged in 8 HT neurons in males (10.8±3.3 spikes/sec before CSDS compared to 9.±1.8 (spikes/sec, p=0.60) after CSD.) thus CGRP-mAb prevented corneal hypersensitivity in HT neurons in females but not in male rats.
C. Discussion of the invention
Studies have demonstrated that the humanized monoclonal anti-CGRP antibody, furanezomib, inhibits activation and sensitization of HT trigeminal neurons, but does not inhibit activation and sensitization of WDR trigeminal neurons. In males, CGRP-mAb inhibits spontaneous activity of naive HT neurons and its response to intracranial dural stimulation, but not to facial skin or cornea stimulation, whereas in females it inhibits only its response to intracranial dural stimulation. However, when given for sufficient time, CGRP-mabs prevent activation of HT neurons by CSD and subsequent sensitization in both sexes, but do not prevent partial activation of WDR neurons. These findings suggest that HT neurons mechanically play a key role in initiating headache perception and producing allodynia and central sensitization (previously unrecognized). Clinically, the findings of the present invention may help explain the therapeutic effectiveness of CGRP-mabs in preventing intracranial-derived headaches (such as migraine) and why this treatment may not be effective for every migraine patient.
This study tested the effect of CGRP-mAb on the reactivity of different classes of central trigeminal vascular neurons. Previously, storer and colleagues demonstrated that the CGRP-R antagonist BIBN4096BS inhibited the primary central trigeminal vascular neuron's response to the administration of L-glutamate by electro-stimulated upper sagittal sinus and micro-electrophoresis (Storer et al, 2004, br. J. Pharmacol.142:1171-1 181).
Effects of freudenreichii on HT and WDR
When administered intravenously, CGRP-mabs reduce baseline spontaneous activity in HT neurons, but not WDR neurons. Considering current and previous evidence that WDR trigeminal vascular neurons were used to study a variety of dural stimulus activations in migraine pathophysiology (Davis and Dostrovsky,1988, J.Neurohysiol.59:648-666; burstein et al, 1998, J.Neurohysiol.79:964-982; storer et al, 2004, brit.J.Phacol.142:1171-1181; zhang et al, 2011, ann.Neurol.69:855-865), it is reasonable to conclude that: activation of WDR alone is insufficient to induce headache perception in paroxysmal migraine patients who are completely or almost completely prevented from headache by CGRP-mAb therapy (Bigal et al, 2015,Lancet Neurol.14:1081-1090). Conversely, it is speculated that activation of WDR trigeminal neurons alone may be sufficient to induce headache perception in those paroxysmal migraine patients who do not benefit from CGRP-mAb therapy, as headache may not be affected by the elimination of signals sent from HT trigeminal neurons to the thalamus. Outside of migraine and trigeminal vasculature, HT and WDR neurons have been thought to play different roles in the processing of noxious stimuli and the perception of pain (Craig AD,2002,Nat.Rev.Neurosci.3:655-666;Craig AD,2003,Trends Neurosci.26:303-307;Craig AD,2003,Annu.Rev.Neurosci.26:1-30). while most HT neurons exhibit small receptive fields and respond exclusively to noxious mechanical stimuli, most WDR neurons exhibit large receptive fields and respond to both mechanical and thermal noxious stimuli (Price et al, 1976, J.Neurohysiol.39:936-953; price et al, 1978, J.Neurohysiol.41:933-947; hoffman et al, 1981, neurohysiology 46:409-427; dubner and Bennett,1983, annu.Rev.Neurosci.6:381-418; bushnell et al, 1984, J.Neurohysiol.52:170-187; surmeer et al, 1986, J.Neurohysiol.56:328-350; ferrington et al, 1987, J.Physiol. (Lond) 388:681-703; dubner et al, 1989, J.Neurohysiol.62:450-457; maixner et al, 1989, J.Neurohysiol.62:437-449; laird and Cervero,1991, J.Physiol.434). Based on these differences, it is widely believed that HT neurons make a large contribution to the spatial coding (size, location) of pain and a small contribution to the coding of pain patterns, while WDR neurons make a large contribution to the radiation properties of pain. As mentioned above, the following is also reasonable: those patients who do not respond to freretastatin are those whose headache affects a larger area of the head (i.e., frontal, temporal, occipital, bilateral), while those whose headache is well localized to a small and unique area will belong to the responders.
Effectiveness in headache
The freudemumab reduces responsiveness to mechanical stimulation of the dura mater (in both males and females), but does not reduce responsiveness to harmless or deleterious stimulation of the skin or cornea. This finding, together with the fact that CGRP-mAb also prevented activation of HT trigeminal vascular neurons by CSD, provides a scientific basis for the effectiveness of freudenreizumab in preventing headache of intracranial origin. Conversely, the lack of effect on modulating sensory and nociceptive signals produced in the facial skin and cornea predicts that this class of drugs will have little therapeutic effect on the treatment of long-term trigeminal neuralgia disorders such as dry eye and herpes-induced trigeminal neuralgia. Given that freudemumab inhibits activation of central trigeminal neurons from the dura mater (mechanical, CSD), but not from the skin or cornea, and that this molecule is too large in size to readily penetrate the blood brain barrier, it is reasonable to conclude that: the inhibition described above is a secondary inhibition of (primary) inhibition of peripheral trigeminal vascular system neurons responses to dural depression and CSD. In view of the wide distribution of CGRP fibers in vivo (Kruger et al, 1988, J. Comp. Nerol. 273:149-162; kruger et al, 1989, J. Comp. Neurol.280:291-302; silverman and Kruger,1989, J. Comp. Neurol. 280:303-330), which are present in multiple spinal cord segments (Hansen et al, 2016,Pain 157:666-676; nees et al, 2016,Pain 157:687-697) and in multiple sensory dorsal root ganglions (Edvinsson et al, 1998, J. Auton. Nerv. Syst.70:15-22; edvinsson et al, 2001, microsc. Res. Techniq.53:221-228; cho et al, 2015,J.Korean Med.Sci.30:1902-1910; kestell et al, 2015, J. Comp. Neurol.523:2555-2569; sprence et al, 2016, J. Comp. Neurol. 3083:3068) there is little or no adverse effect on the corneal or on the effects of the sensory nerve on the sensory nerve cells. If one accepts the insight that CGRP-mAb is mainly acting at the periphery, it may be reasonable to draw the following conclusions: the sensory dominance of the peripheral situation to the meninges and the manner in which this dominance affects sensory transmission in the dorsal horn are different from those involved in the generation of skin, cornea or other (somatic) pain. Studies of the effects of freudenreichii in animal models of other pain conditions will allow a more accurate interpretation of the differences between the effects of CGRP-mAb in dura mater and extracranial tissues not considered to have a unique initiating role in migraine.
Inhibition of CSD-induced activation and sensitization
This study demonstrates sensitization of central trigeminal vascular neurons by CSD. This sensitization observed in HT neurons but not WDR neurons in both males and females is blocked by CGRP-mAb administration. These findings indicate that skin allodynia preceded by a precursor at the time of onset (Burstein et al, 2000, ann. Neurol. 47:614-624) is mediated by HT neurons that are unresponsive to harmless mechanical stimulation of the skin at baseline (inter-onset in patients and prior to CSD induction in animals), but become mechanically reactive to brushing after CSD. According to this regimen, among patients with predictive migraine, the responders to prophylactic treatment with CGRP-mAb will not show signs of skin allodynia.
Male versus female
This study also tested the effect of CGRP-mAb in both male and female rats. While a comprehensive analysis by gender indicated that the therapeutic benefit of this class of drugs would be similar in male and female migraine sufferers, it also indicated that in the naive state CGRP-mAb reduced spontaneous activity in males, but not female HT neurons, and that after CSD-induced sensitization, only HT neurons recorded in females exhibited signs of sensitization to skin and cornea noxious stimuli. Given that migraine is more common in women than men, the differences may indicate that hyperalgesia (rather than allodynia) is more likely to develop in women than men during premonitory migraine, and that attempts to reduce neuronal excitability with CGRP-mAb in inter-seizure states (i.e., as a prophylactic) may also be more challenging in women than men. Mechanically, the three observed differences may be attributed to greater excitability of female HT neurons, either due to the internal nature of these neurons or to differences in the intensity of inputs they receive from peripheral nociceptors. Although there is no data to support the first selection, it is possible that a difference in activation of dural immune cells and inflammatory molecules in females compared to males (MCLLVRIED et al (2015) Headache 55:943-957) could support the second selection. Considering the ability of freudemumab to reduce spontaneous activity in male rats but not in female rats, data indicating that female rats express fewer CGRP receptors in the trigeminal ganglion and spinal trigeminal nuclei and higher levels of CGRP encoding mRNA in the dorsal horn can be taken into account (Stucky et al (2011) Headache 51:674-692).
Finally, it takes only a few hours for the inhibition of CGRP-mAb to reach significance. This relatively short time (hours instead of days) is achieved using intravenous administration.
Example 2 evaluation of anti-CGRP antibody (TEV-48125) responders Using behavioral and psychophysical tools
Most paroxysmal migraine sufferers seeking secondary or tertiary medical care show signs of skin allodynia and hyperalgesia during the acute phase of migraine, but not in the absence of pain (Burstein R et al (2000) Ann. Neurol. 47:614-624). In contrast, chronic migraine sufferers often exhibit signs of skin allodynia and hyperalgesia both during acute migraine attacks and during inter-attacks. Allodynia and hyperalgesia are thought to be mediated mechanically by sensitization of central trigeminal vascular neurons in the spinal trigeminal nuclei (Burstein R et al (1998) J.Neurohysiol.79 (2): 964-982; burstein R et al (2000) Ann. Neurol.47:614-624; and Lipton et al (2008) Ann. Neurol.63 (2): 148-58). In contrast, chronic migraine sufferers often exhibit signs of skin allodynia and hyperalgesia both during acute migraine attacks and during inter-attacks. Allodynia and hyperalgesia are thought to be mediated mechanically by sensitization of central trigeminal vascular neurons in the spinal trigeminal nucleus (see Burstein (1998)). Example 5 demonstrates that TEV-48125, through its inhibitory effect in peripheral meningiomotor, is able to prevent activation and sensitization of High Threshold (HT) neurons in the spinal trigeminal nuclei far beyond its ability to inhibit wide power range (WDR) neurons (see also Melo-Carrillo et al (2017) J.Neurosci.37 (30): 7149-63). Given that HT neurons react exclusively to noxious (painful) stimuli, while WDR neurons react preferentially to noxious stimuli (i.e., they react more than to harmless stimuli), it is reasonable to assume that blocking HT will be more effective in preventing hyperalgesia than allodynia.
To date, there is no example or suggestion in the literature of drug examples to reduce activation and sensitization of only one of these two types of nociceptive neurons in the spinal trigeminal nucleus. Whereas freudemumab inhibits meningeaδ but not C-fibers, selective inhibition of aδ -fibers potentially explains the selective inhibition of HT neurons by antibodies (see Melo-Carillo et al (2017) j. Neurosci.37 (44): 10587-96). In addition, since C-fibers may not affect the activity of HT neurons, freudenreichii may achieve a very selective effect on the ascending nociceptive trigeminal vascular pathways, which are those that depend on peripheral CGRP release for activity.
Without wishing to be bound by any particular theory, it is believed that responders are subjects that require continuous peripheral input to maintain central sensitization in WDR and HT neurons, while non-responders are subjects that do not require continuous peripheral input to maintain central sensitization in WDR and HT neurons. Because freudemumab blocks the activation of aδ -fibers, this blocking may be sufficient to render HT neurons completely quiescent (i.e., terminate their sensitization) in the responders. The furanezomib can also reduce the overall input driving the sensitized state of the WDR neuron to the point that the input received by the neuron from unlocking the C-fiber induces only excitatory postsynaptic potential (EPSP), but not the actual action potential. The sensitization status of both WDR and HT neurons can be reversed by freudenreichii, and thus allodynia/hyperalgesia will be reversed in the responders. In contrast, in non-responders, sensitization of HT or WDR neurons, or both, is completely independent of peripheral input, regardless of whether it originates from Aδ -fibers or C-fibers. Thus, non-responders will be allodynia and/or hyperalgesia after treatment. Other anti-CGRP active agents (e.g., gempam as described herein) are expected to exhibit the same properties as freudenreizumab.
Study design:
Overall policy: to determine the skin pain threshold (which tests allodynia), pain scores in response to repeated suprathreshold mechanical and thermal stimuli (which tests hyperalgesia) in chronic migraine patients under 4 different conditions: (a) before treatment in the absence of migraine, (b) after treatment in the absence of migraine, and (c) before and after treatment during an acute migraine attack, if possible. Note that: (c) Part is not necessary to identify a responder among a CM population. It may be relevant to identify responders among patients with high frequency of paroxysmal events.
Participant selection and recruitment: individuals with chronic migraine will be considered to participate in this study. The primary inclusion criteria will be (1) age 18-64 years, (2) chronic premonitory or non-premonitory migraine history for at least 3 years based on international headache disorder classification (International Classification of Headache Disorders) (3 rd edition), and (3) ability to communicate in english (to understand and follow test instructions). The exclusion criteria will include: (1) less than fifteen days per month of headache; (2) gestation; (3) There are history of coronary artery bypass surgery, history of heart disease, history of angina pectoris, history of stroke, history of severe gastrointestinal bleeding, history of peptic ulcer; or a history of chronic kidney disease; (5) With medical conditions requiring the use of diuretics or daily anticoagulants.
Open label design: following screening, which will be performed on a predetermined date (visit 1), a questionnaire will be used to obtain a migraine history of the study participants, and a quantitative sensory test will be performed for allodynia and hyperalgesia. When the participant has no headache, visit 1 will be performed at least 30 days before visit 2. The participant will be instructed to maintain a daily headache diary during this period.
Visit 2 will be performed when study participants have migraine and will include a pain score of 3 cycles and a QST for assessing allodynia and hyperalgesia. Pain scores for the first cycle will be performed at least 2 hours before treatment and after onset. Patients were randomized to receive placebo or 75mg of remigermpam orally. A second cycle of pain scoring will be performed two hours after treatment. A third cycle of pain scoring will be performed 4 hours after treatment.
Participants will be instructed to maintain daily headache diaries throughout the study.
Visit 3 will be performed 1 week after treatment and will include headache diary review, headache intensity scoring, and QST testing for allodynia and hyperalgesia.
Visit 3 will be performed 4 weeks after treatment and will include headache diary review, headache intensity scoring, and QST testing for allodynia and hyperalgesia. At each visit, baseline headache intensity, pain thresholds for quantitative mechanical and thermal stimuli, and headache intensity scores in response to suprathreshold mechanical and thermal stimuli will be recorded.
Quantitative Sensory Test (QST): the test will be conducted in a quiet room remote from noise and interference. The patient will be able to choose his or her most comfortable posture (sitting in a chair or lying in a bed) during the sensory test. In each test phase, the pain threshold for thermal and mechanical stimulation will be determined in the skin above the site called pain. This site most commonly includes the periorbital and temporal regions. The hot skin stimulus will be delivered by a 30x30mm 2 thermode (Q-Sense 2016, medoc) connected to the skin at constant pressure and its pain threshold will be determined by using the Method of Limit.
Allodynia test: to determine pain threshold, the skin will be allowed to adapt to a temperature of 32 ℃ for 5 minutes, then warm up at a slow rate (1 ℃/sec) until pain is perceived, at which point the subject stops stimulation by pressing a button on the patient's response unit. The thermal stimulus will be repeated three times each time and the average of the recorded temperatures will be regarded as the threshold. The pain threshold for mechanical stimulation will be determined by using a set of 20 corrected frey hairs (VFH, stoelting). Scalar numbers (1=0.0045g,2=0.023g,3=0.027g,4=0.07g,5=0.16g,6=0.4g,7=0.7g,8=1.2g,9=1.5g,10=2.0g,11=3.6g,12=5.4g,13=8.5g,14=11.7g,15=15.1g,16=28.8g,17=75g,18=125g,19=281g). are assigned to each VFH filament in ascending order because there is a linear relationship between the logarithm of the force and the number of digits arranged, the mechanical pain threshold is expressed in terms of the number of VFHs (#) rather than its force (g). The minimum number of VFHs per monofilament that would be applied to the skin 3 times (for 2 sec) and that could induce pain in two-thirds of the trials would be considered the threshold. Skin sensitivity will also be determined by recording the subject's perception of a soft skin swipe, a dynamic mechanical stimulus that is different from VFH, which is a static mechanical stimulus, which is different from VFH, which is a static mechanical stimulus.
Hyperalgesia test: a subject is considered hyperalgesic when the painful stimulus is perceived as more painful than usual. To determine if a subject is hyperalgesic, 3 thermal and mechanical threshold stimuli will be applied to the skin. The values of the above threshold stimulus will be determined during the above allodynia test. For example, if the thermal pain threshold is 45 ℃, we will use 46 ℃ in the hyperalgesia test. In this test, the skin will be exposed to 3 suprathreshold stimuli (exceeding threshold 1), each lasting 10 seconds and separated by 10 seconds (i.e., 10 seconds between stimuli). At the end of each stimulus, the patient will have 10 seconds to determine pain intensity using a Visual Analog Scale (VAS) of 0-10 (o=no pain, 10=maximum imaginable pain). Similar tests will be applied using a mechanical stimulus above the threshold.
Devices for quantitative sensory testing have been FDA approved. It is routinely used by neurologists, nurses and pain specialists throughout the country. It does not create a hazard or discomfort and because it is controlled by the patient, the stimulation can be stopped at any time.
Interpretation of QST:
Allodynia: because the detection of pain thresholds depends on subjective data input, several algorithms have been developed to minimize subjective variability and make the results as objective as possible. These algorithms are incorporated into the software program controlling the thermal and mechanical sensory analyzer (Q-Sense 2016). In healthy subjects, the pain threshold for thermal and mechanical skin irritation varies between 42-47℃ and 75-281g, respectively (see Lindblom(1994)Analysis of abnormal touch,pain,and temperature sensation in patients.In:Boivie J,Hansson P,Lindblom U. Touch, temperature AND PAIN IN HEALTH AND DISEASE: MECHANISM AND estimates, volume 3, progress in brain RESEARCH AND management. Seattle: IASP PRESS, pages 63-84), and Strigo et al (2000) analysis 92 (3): 699-707. Using stricter criteria, if the subject's pain threshold is below 41℃ for heat and below 30g for skin recessions using corrected French, then s/he will be considered as allodynic.
Hyperalgesia: any change in pain score of greater than 30% will be considered evidence of hyperalgesia (e.g., if the suprathreshold stimulus #1 is scored as 6/10 per VAS, then the suprathreshold stimulus #3 will necessarily be scored as 8/10 or higher).
The data analysis will take into account the values of mechanical and thermal pain thresholds before and after treatment.
Data analysis:
data analysis will include subjects completing all 4 visits and 6 test phases.
The primary outcome was measured as the presence or absence of allodynia in the responders after intervention (1 month) compared to non-responders. The responders were initially defined as experiencing a minimum 50% reduction in monthly headache days; non-responders were defined as experiencing a reduction in headache days per month of up to less than 50%. The secondary definition interprets the respondents as experiencing a minimum 60% reduction in monthly headache days; non-responders were defined as experiencing a reduction in headache days per month of up to less than 40%. Another secondary definition interpreted the respondents as experiencing a minimum of 75% reduction in the number of headache days per month; non-responders were defined as experiencing a reduction in headache days per month of up to less than 25%. When the participants were headache-free (migraine attack interval), the proportion of responders without allodynia and/or hyperalgesia was found to be significantly higher than the group of responders without headache.
The primary outcome measure will be examined using the chi-square (χ 2) test to assess the categorical association between the presence (yes/no) of allodynia and the subject's responsiveness (yes/no). Secondary results were measured as migraine duration (hours) before and after intervention (1 month) and headache intensity changes at 2 hours and 4 hours after intervention.
The normalization of the data of successive secondary result measurements will first be tested to determine if parametric or non-parametric analysis is appropriate.
Thus, the parameters of the center distribution (mean/median) will be used to evaluate the differences in these variables between the responders and non-responders.
The analysis will also check the effect of the following factors on primary and secondary outcome measurements: years with migraine, years with CM, family history, related symptoms (e.g., nausea, vomiting, photophobia, aphasia, premonition, muscle tenderness), common triggers (e.g., stress, persistent wakefulness, menstrual cramps), and history of acute treatment and history of prophylactic treatment.
Efficacy analysis:
Efficacy analysis was based on chi-square (χ 2) goodness of fit and Z-scale comparison test. Combine 5% a (significance level), 90% 1-beta error probability (efficacy), 0.36 w (impact size; χ 2 goodness-of-fit test), and 1:1 partition ratio (Z-scale comparison test). Stratified analysis includes variable groups (placebo versus treatment), responsiveness (responders versus non-responders; see definition above), and allodynia (present versus absent). The main assumption is that the proportion of dry prognosis responders in the treatment and placebo groups (50% reduction in headache days per month threshold according to the definition above) will be 55% and 25% respectively (based on data published by Bigal et al (2015) Lancet neurol.14 (11): 1091-100). This calculation resulted in the required number of 64 subjects in each of the placebo and treatment groups (df=5; critical χ < 2 > =11.07; non-central parameter λ=16.51). An additional 20% is considered to be a possible exit. Thus, a total of 77 patients were enrolled in each group, yielding a total of 144 patients throughout the study.
Example 3: clinical study of the reactivity of anti-CGRP drugs
Twenty-nine high frequency paroxysmal migraine patients who did not receive anti-CGRP agent treatment received QST testing for at least twenty-four hours after their migraine attack phase, and completed an electronic diary questionnaire for thirty days before beginning therapy with anti-CGRP agent. Three months after treatment with the anti-CGRP agent, patients were examined to determine if they responded to the agent. Effective treatment is determined by a number of factors, including headache intensity and frequency of headache, pain extraction, photophobia, phonophobia and reduction of nausea. Responders were defined as patients with an average migraine day reduction of at least 50% per month during a3 month treatment period. After determining the response to the treatment, the results are compared with the previously blinded allodynia/hyperalgesia evaluation. For patients exhibiting allodynia and/or hyperalgesia in the QST test for at least twenty four hours after the migraine attack, allodynia and/or hyperalgesia determination is completed based on an electronic diary questionnaire answer when the patient has no migraine for at least seventy two hours.
The results of the study are shown in table 1 and indicate that those patients who do not develop allodynia and/or hyperalgesia are significantly more likely to respond to anti-CGRP pharmacological therapy than those who develop allodynia and/or hyperalgesia.
TABLE 1
All patents, patent applications, and publications mentioned in this document are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
Claims (30)
1. A gempam for use in treating migraine in a subject having migraine, wherein prior to administration of said Ji, said subject is known to not exhibit allodynia and/or hyperalgesia during an inter-episode of said migraine.
2. The diazepam for use of claim 1, wherein the subject has paroxysmal migraine.
3. The diazepam for use of claim 1, wherein the subject has chronic migraine.
4. The diazepam for use of any preceding claim, wherein the subject is known to exhibit allodynia and/or hyperalgesia during the acute phase of the migraine.
5. The gem for use of any preceding claim, wherein the subject is determined to have a thermal pain threshold above 41 ℃ and/or a mechanical pain threshold above 30g for skin depressions using corrected frey during the inter-episode of the migraine.
6. The gempam for use according to any preceding claim, wherein the absence of allodynia and/or hyperalgesia during the inter-seizure period of the migraine is determined by Quantitative Sensory Testing (QST).
7. The diazepam for use of any preceding claim, wherein the absence of allodynia and/or hyperalgesia during the inter-episode of the migraine is determined by questionnaire.
8. The gempam for use of any preceding claim, wherein the Ji is selected from the group consisting of: rametadiazepam, ubbelopam, vazegepant, aoto Ji, orsat Ji, tica Ji, BI 44370, and MK-3207.
9. The gempam for use according to any preceding claim, wherein the Ji is administered in the absence of migraine in the patient.
10. The gempam for use according to any preceding claim, wherein the allodynia is skin allodynia.
11. The diazepam for use of claim 1, wherein said Ji is administered within 3 hours of the onset of said migraine.
12. The gempam for use of claim 11, wherein the Ji is administered within 60 minutes of the onset period of the migraine headache
13. Use of gempam in the manufacture of a medicament for treating migraine in a subject, wherein prior to administration of said Ji, said subject is known to not exhibit allodynia and/or hyperalgesia during the inter-seizure period of said migraine.
14. A method of treating migraine in a subject, the method comprising:
a) Determining or having determined whether the subject exhibits allodynia and/or hyperalgesia during the period of onset of migraine, an
B) Administering gempam to the subject that does not exhibit signs of allodynia and/or hyperalgesia during the inter-episode of the migraine.
15. The method of claim 14, wherein the subject has paroxysmal migraine.
16. The method of claim 14, wherein the subject has chronic migraine.
17. The method of any one of claims 14 to 16, wherein the subject is known to exhibit allodynia and/or hyperalgesia during the acute phase of the migraine.
18. The method of any one of claims 14 to 17, wherein the subject is determined to have a thermal pain threshold above 41 ℃ and/or a mechanical pain threshold above 30g for skin depressions using corrected frey during the inter-episode of the migraine.
19. The method according to any one of claims 14 to 18, wherein the absence of allodynia and/or hyperalgesia during the inter-seizure period of the migraine is determined by Quantitative Sensory Testing (QST).
20. The method of any one of claims 14 to 19, wherein the absence of allodynia and/or hyperalgesia during the inter-episode of the migraine is determined by questionnaires.
21. The method of any one of claims 14 to 20, wherein the Ji is selected from the group consisting of: rametadiazepam, ubbelopam, vazegepant, aoto Ji, orsat Ji, tica Ji, BI 44370, and MK-3207.
22. The method of any one of claims 14 to 21, wherein the Ji is administered when the patient is not migraine.
23. The method of any one of claims 14 to 22, wherein the allodynia is skin allodynia.
24. A method for reducing migraine frequency in a subject having migraine, the method comprising: determining or having determined whether the subject exhibits or does not exhibit allodynia and/or hyperalgesia during an inter-seizure period of the migraine, and administering gempam to the subject that does not exhibit signs of allodynia and/or hyperalgesia during the inter-seizure period of the migraine.
25. A method for reducing migraine frequency in a subject having migraine, the method comprising: a) Determining or having determined whether the subject exhibits allodynia and/or hyperalgesia during an inter-seizure period of a migraine, and b) administering gempam to the subject that does not exhibit signs of allodynia and/or hyperalgesia during the inter-seizure period of the migraine.
26. A method of treating migraine in a subject, the method comprising: a) Determining or having determined whether the subject exhibits allodynia and/or hyperalgesia during the inter-onset period of migraine, and b) administering gem to the subject that does not exhibit signs of allodynia and/or hyperalgesia during the inter-onset period of migraine.
27. A method of treating migraine in a subject, the method comprising: a) Determining or having determined whether the subject exhibits allodynia and/or hyperalgesia during the period of onset of the migraine, and b) administering gem to the subject that does not exhibit signs of allodynia and/or hyperalgesia during the period of onset of the migraine.
28. The method of claim 26 or 27, wherein the Ji is administered within 3 hours of the onset period of the migraine.
29. The method of claim 28, wherein the Ji is administered within 60 minutes of the onset of the migraine.
30. The method of any one of claims 26 to 29, wherein the treatment is acute treatment.
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PCT/IB2022/051820 WO2022185224A1 (en) | 2021-03-02 | 2022-03-02 | Treatment and/or reduction of occurrence of migraine |
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