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Pharmintel

Met & Unmet Medical Needs in Migraine Prevention: Approval of AJOVY

October 8, 2018

On September 14, 2018, the US Food and Drug Administration (FDA) has approved the humanized monoclonal antibody fremanezumab-vfrm (Ajovy, Teva Pharmaceuticals) for migraine prevention in adults.

Migraine is a complex disorder characterized by recurrent episodes of headache, most often unilateral and in some cases associated with visual or sensory symptoms. Migraine is most common in women and has a strong genetic component.

Migraine is a disabling neurological disease that affects more than 36 million people in the United States. About 40 percent of people living with migraine are appropriate candidates for preventive treatment, yet the majority of them are untreated. I am pleased to have another treatment option that may allow my patients to experience fewer monthly migraine days.”

In the United States, more than 30 million people have one or more migraine headaches per year. This corresponds to 18% of females and 6% of males. The estimated worldwide prevalence of migraine is 10%. Approximately 3000 migraine attacks per million persons worldwide occur every day.

Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy. Patients with frequent attacks usually require both. Measures directed toward reducing migraine triggers are also generally advisable.

Current issues in prevention of migraine are underdiagnosis, undertreatment, Lack of concordance between guidelines, limited efficacy, side effects of available therapies and restrictions due to comorbidities. All these factors are also reason for problematic long-term adherence.

Ajovy is an injectable calcitonin-gene-related peptide (CGRP) antagonist “is the first and only anti-CGRP treatment for the prevention of migraine. CGRP is a 37-amino acid neuropeptide derived from the gene encoding calcitonin. CGRP is a very potent vasodilator of the cerebral circulation. CGRP and CGRP receptors are expressed in the trigeminal ganglion. The trigeminovascular system has been identified as having a key role, both in the synthesis and release of CGRP, is a key target for CGRP inhibition. As the trigeminal ganglion is expressed outside the blood-brain barrier (BBB), therapeutic agents do not need to penetrate the BBB to act.

Ajovy inhibits the function of CGRP at all calcitonin-family receptors. AJOVY is available as a 225 mg/1.5mL single dose injection in a prefilled syringe with two dosing options – 225 mg monthly administered as one subcutaneous injection, or 675 mg every three months (quarterly), administered as three subcutaneous injections.

AJOVY was evaluated in two Phase III, placebo-controlled clinical trials in episodic & chronic migraine respectively. In these trials, patients experienced a reduction in monthly migraine days during a 12-week period. The most common adverse reactions (≥5 percent and greater than placebo) were injection site reactions.

In Study 1 (NCT 02629861), a total of 875 patients (742 females, 133 males), ranging in age from 18 to 70 years, were randomized. A total of 791 patients completed the 3-month double-blind phase. The mean migraine frequency at baseline was approximately 9 migraine days per month, and was similar across treatment groups. Both monthly and quarterly dosing regimens of AJOVY demonstrated statistically significant improvements for efficacy endpoints compared to placebo over the 3-month period.

Study 1 Efficacy Endpoint AJOVY 225 mg Monthly (N=287) AJOVY 675 mg Quarterly (N=288) Placebo (N=290)
Monthly migraine days (MMD)
Baseline migraine days 8.9 9.2 9.1
Change from baseline -3.7 -3.4 -2.2
Difference from placebo -1.5 -1.2
p-value <0.001 <0.001
≥50% MDD responders
% responders 47.7% 44.4% 27.9%
Difference from placebo 19.8% 16.5%
p-value <0.001 <0.001
Monthly acute migraine-specific medication days
Change from baseline -3.0 -2.9 -1.6
Difference from placebo -1.4 -1.3
p-value <0.001 <0.001

 

Study 2 (NCT 02621931) included adults with a history of chronic migraine (patients with ≥15 headache days per month). All patients were randomized (1:1:1) to receive subcutaneous injections of either AJOVY 675 mg starting dose followed by 225 mg monthly, 675 mg every 3 months (quarterly), or placebo monthly, over a 3-month treatment period. Patients were allowed to use acute headache treatments during the study. A subset of patients (21%) was allowed to use one additional concomitant, preventive medication.

 

Study 2

Efficacy Endpoint

AJOVY 225 mg

Monthly

(N=375)

AJOVY 675 mg

Quarterly

(N=375)

Placebo

(N=371)

Baseline headache days of any severity 20.3 20.4 20.3
Baseline headache days of at least moderate severity 12.8 13.2 13.3
Change from baseline in the monthly average number of headache days of at least moderate severity -4.6 -4.3 -2.5
Difference from placebo -2.1 -1.8
p-value <0.001 <0.001
Change from baseline in the monthly average number of migraine days in patients -5.0 -4.9 -3.2
Change from baseline in monthly average number of headache days of at least moderate severity at 4 weeks after 1st dose -4.6 -4.6 -2.3
Percentage of patients with ≥ 50% reduction in

monthly average number of headache days of at least moderate severity

40.8% 37.6% 18.1%
Change from baseline in monthly average number of days of acute headache medication -4.2 -3.7 -1.9

 

The most common treatment-related adverse events were injection-site reactions and infections.

There are other approved therapies available for migraine prevention. Current therapies approved for episodic migraine prevention are Topiramate & erenumab (Aimovig) and for chronic migraine are onabotulinumtoxin A & erenumab (Aimovig).

Erenumab (Aimovig) is the first monoclonal antibody that binds to the CGRP receptor approved by the FDA in May 2018 for migraine prophylaxis.

In March 2014, FDA approved first transcutaneous electrical nerve stimulation (TENS) device (Cefaly) for migraine prevention.

Comparison of AJOVY with currently approved therapies:

Episodic Migraine Topiramate 200 mg/day AIMOVIG 140 mg Once Monthly Cefaly AJOVY 225 mg Monthly
Change from baseline in Monthly migraine days (MMD)/ Migraine Headache Frequency 2.4 3.7 3.5 3.7
≥ 50% MMD responder 50.0% 75% 47.7%
Change from baseline in Monthly acute migraine-specific medication days 1.6 3

 

Chronic Migraine BOTOX (onabotulinumtoxin A) AIMOVIG 140 mg Once Monthly Cefaly AJOVY 225 mg Monthly
Change from baseline in Monthly migraine days (MMD)/ Migraine Headache Frequency 7 6.6 5
≥ 50% MMD responder 39.9%- 41.2% 35% 40.8%
Change from baseline in Monthly acute migraine-specific medication days 3.5-4.1 3.7-4.2

 

Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of the migraine attack, make acute attacks more responsive to abortive therapy, and perhaps also improve the patient’s quality of life.

Ajovy has better clinical efficacy as compared to Topiramate and comparable efficacy to Aimovig in episodic migraine prevention. Ajovy has shown comparable efficacy as compared to Botox and Aimovig in chronic migration prevention but Botox has shown secondary benefits on headache-related disability, improved functioning, vitality, and overall health-related quality of life which Ajovy & Aimovig is currently lacking.

To Summarise, Ajovy has shown moderate efficacy in migraine prevention. On primary endpoint it has provided 41% average reduction in monthly migraine days. On secondary end point, 47.7% of patients achieved at least a 50% reduction in monthly average number of migraine days and most common adverse reactions (≥5 percent and greater than placebo) were injection site reactions. Ajovy has to show long term safety & efficacy data long with impact on quality of life parameters.

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