The American Academy of Neurology (AAN) held its 69th annual meeting in Boston on April 22-28, 2017. This annual event serves as a forum for clinicians and members of industry and academia to come together to share information about the medical practice of all things neurology-related. Among the news from this year’s meeting that caught our attention were data on three late-phase therapies—notably the first monoclonal antibodies (MAbs) to be developed to treat migraine—that have the potential to transform how migraine is treated prophylactically. These therapies—Amgen/Novartis’s erenumab (AMG-334), Alder BioPharmaceuticals’ eptinezumab (ALD-403), and Eli Lilly’s galcanezumab (LY-2951742)—fall into a novel class of agents that target the calcitonin gene-related peptide (CGRP) signaling pathway. CGRP is the most potent vasodilatory neuropeptide, and numerous studies have suggested that it may play a central role in migraine propagation. Here, we provide DRG’s summary take on the results and provide some thoughts on the future outlook for these exciting, migraine-specific prophylactic alternatives.
Erenumab’s detailed Phase III efficacy results continue to look solid in episodic migraine: Amgen and Novartis presented complete results from the ARISE and STRIVE Phase III trials of erenumab in patients with episodic migraine (EM; defined as up to 14 migraine days per month), following the release of positive top-line results from these trials in late 2016. Efficacy results were modest but significant, consistent, and meaningful for episodic migraineurs’ quality of life. Complete results from the ARISE and STRIVE trials showed a significant reduction in monthly migraine days at end point from baseline (ARISE [70 mg]: -1.1 placebo-adjusted reduction at three months, P < 0.001; STRIVE [70 mg and 140 mg]: -1-4 and -1.9 days placebo-adjusted reduction at six months, P < 0.001) in EM patients who received erenumab as a once-monthly SC injection. In addition, treatment significantly increased the percentage of patients who achieved ≥ 50% reduction in monthly migraine days compared with placebo-treated patients, reduced use of acute medications, and increased the percentage of patients with improvement in physical impairment and activities of daily living (the latter in STRIVE).1,2 Importantly, the drug continues to appear generally safe and well tolerated. Although there were mixed levels of enthusiasm for the erenumab data in post-conference analyst coverage, the results appear mostly in line with Phase II data in EM, and with Amgen’s anticipated filing of an BLA in Q2 2017,3 the drug seems all but guaranteed to be first-in-class.
Additional Phase II data from Alder and Eli Lilly support promising clinical profiles in different migraine populations: Phase II data from the Alder and the Lilly programs presented at AAN lend further credence to the therapeutic potential of this mechanism of action in migraine prevention. Alder’s eptinezumab was effective in chronic migraine (CM) patients after just a single IV infusion, resulting in a significant reduction in migraine days (as assessed by the 75% responder rate, a high bar) between 1-4 weeks post-administration, with the efficacy maintained throughout the 12-week trial.4,5,6 Notably, the drug produced its prophylactic effect within just 24-48 hours after the first dose. The seemingly rapid onset of action, coupled with its every-three-months dosing schedule, could offset the potential drawbacks of its IV route of administration relative to its SC competitors (which can be self-administered) in patients’ and neurologists’ eyes. (A SC formulation of eptinezumab is in an earlier stage of development; Phase I data of this formulation suggest a three-month dosing schedule for this route of administration as well,7 a delivery profile which, of note, is similar to that of Botox and which is of a frequency that could represent a significant competitive advantage for the drug in the migraineur demographic.) No serious safety signals were reported. Top-line data of IV eptinezumab from its first Phase III trial (PROMISE-1) are expected by the end of the second quarter of 2017, and the company expects to file with the FDA in the second half of 2018.8
Lilly had rather nuanced coverage of galcanezumab at the meeting, presenting a post-hoc analysis of efficacy data in EM and additional safety information from its Phase II trials in migraine (as well as some patient-centric information in cluster headache). The data showed that 120 mg of galcanezumab administered SC every four weeks for 12 weeks improved function as measured by the Migraine-Specific Quality of Life Questionnaire (MSQ) v2.1 in patients with EM.9 Furthermore, preliminary data from Lilly suggest that certain patient characteristics (e.g., prior treatment failure; a history of migraine for > 20 years) may correlate with a good response to galcanezumab treatment.10 Predictive data on responders, if replicated on a larger scale, would be of high value for physicians, who will be challenged with identifying optimal candidates for this—and likely the other CGRP-targeted MAbs—versus the many other prophylactic options already at their disposal. Separately, pooled analysis of data from three Phase II studies suggested that galcanezumab was not associated with liver injury,11 an adverse event that has previously been associated with oral CGRP receptor antagonists being developed for migraine (e.g., Merck & Co.’s telcagepant, which was discontinued in 2011). The first Phase III trials of galcanezumab in migraine are expected to be complete this year.
It likely all comes down to differentiation: Proven efficacy coupled with generally acceptable tolerability and—to date—favorable safety will drive use of the anti-CGRP drugs, particularly for patients who fail or who cannot tolerate the plethora of generics that dominate migraine prophylaxis treatment today (e.g., topiramate [Ortho-McNeil/Janssen-Cilag’s Topamax, other brands, generics], propranolol [generics]). The adverse event profile of these new compounds, in particular, is key, especially if therapeutic benefits are somewhat modest, because many prophylactic mainstays come with unpleasant side effects or risks. Long-term safety is an open question for these compounds, but the data so far look good. In 2016, DRG forecasted the CGRP-targeted MAb class would have the largest impact on the migraine market through 2025, earning over $4.5 billion across the G7 and accounting for nearly 75% of the prophylactic migraine market in that year—this despite modest uptake projections—a dynamic largely driven by premium pricing (particularly as these therapies are biologics) and a large base patient population. Indeed, we expect that payers will enforce step therapy with less costly options, and potentially additional cost controls as well, before granting patient access to these new agents.
Assuming additional clinical successes of these MAbs are reported in 2017, we expect this space will quickly become crowded starting in 2018. In addition to erenumab, eptinezumab, and galcanezumab, a fourth MAb, from Teva (fremanezumab [TEV-48125]), is in late-phase development. Limited data on this drug were presented at AAN, but an extensive Phase III clinical trial program is ongoing, with the first trials expected to be completed later this year. Additionally, an oral prophylactic therapy from Allergan, atogepant, is in a Phase II/III trial in EM patients, with an anticipated completion date of December 2017.12 (Allergan has another oral anti-CGRP receptor antagonist, ubrogepant, in development for the acute treatment of migraine.)
Differentiation will be critical, but relative positioning in the class is very challenging to predict at this point. Phase III efficacy results are available for only one of these compounds and no head-to-head data will be available for years, if at all. To the best of our ability to discern, these drugs arguably look more similar than different, based on cross-trial comparisons (Table 1). There are mechanistic differences: erenumab acts on the CGRP receptor (as does atogepant), while eptinezumab, galcanezumab, fremanezumab target CGRP itself, but it remains unclear what, if any, effect this variation in target will have. Amgen’s ongoing study assessing erenumab in EM nonresponders to other prophylactic drugs13 could directly support the benefits of a switch to that drug. All things being equal, launch timing could give erenumab an edge, but labeling for CM (and, uniquely, episodic and/or chronic cluster headache for galcanezumab or fremanezumab) could open other agents to a broader market. Delivery route will be a means of distinguishing among the monthly injectable therapies, IV eptinezumab, and oral atogepant, and a three-month frequency of administration may prove an advantage to the SC formulation of eptinezumab (should it reach the market), but any variation in risk/benefits likely will outweigh delivery considerations.
Savvy positioning to physicians—particularly specialists—and to patients, together with successful negotiations with payers to secure favorable market access, are key to successful launches of these agents, which may not be strongly differentiated. Developers who can draw on launch experience in crowded, mature markets will possess an advantage (e.g., Lilly, with its experience in the antipsychotic and antidepressant markets), particularly those with existing relationships with neurologists (e.g., Teva and Novartis, which each have experience related to their respective multiple sclerosis drug franchises.)
Stay tuned, as later this year, DRG will field a survey with 100 neurologists specifically on CGRP-targeted drugs to assess their receptivity and anticipated use patterns for these products relative to each other, to Botox, and to today’s many generic stand-bys.
Table 1. Top-line comparison of MAbs targeting the CGRP pathway for the treatment of migraine
|Developers||Amgen/Novartis||Alder Biopharmaceuticals||Eli Lilly||Teva|
|Indications||Frequent EM & CM prevention||EM & CM prevention||EM & CM prevention, cluster headache prevention||High frequency EM & CM prevention, cluster headache prevention|
|Current phase||III (EM); II (CM)||III (IV; EM, CM); I/II (SC)||III (EM, CM, cluster headache)||III (EM, CM, cluster headache)|
|Efficacy: Change in migraine days/month||EM (PIII): -1.1 (70 mg); -1.4, -1.9 (70 mg, 140 mg) |
CM (PII): -2.4
|EM (PII): -1||EM (PII): -1.2a||EM (PII): -2.81 (225mg); -2.64 (675mg) |
CM (PII): -1.72 (675/225mg);
|Safety/tolerabilityb||Fatigue, influenza, nasopharyngitis, nausea, back pain||Upper respiratory tract infections, urinary tract infections, fatigue||Injection-site pain, abdominal pain, upper respiratory tract infections||Injection-site pain, dizziness, fatigue|
|Delivery profile||Once-monthly, SC||Once-every-3-months, IV/SC||Once-monthly, SC||Once-monthly, SC|
|CM = chronic migraine; EM = Episodic migraine; P = Phase. |
a. Bi-weekly administration.
b. Most commonly reported adverse events. All four therapies have been noted as being generally safe and well-tolerated with no serious adverse events reported from currently available clinical trial data.
Source: Decision Resources Group
- Dodick D, et al. A phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab in migraine prevention: primary results of the ARISE trial. Presented at: 2017 American Academy of Neurology Annual Meeting. April 25, 2017; Boston, MA.
- Goadsby P. Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab (AMG 334) in migraine prevention: Primary results of the STRIVE trial. Presented at: 2017 American Academy of Neurology Annual Meeting. April 25, 2017; Boston, MA.
- Q1 2017 Earnings Call Presentation. April 26, 2017. www.amgen.com
- Dodick D, et al. Randomized, double-blind, placebo-controlled trial of ALD403, an anti-CGRP peptide antibody in the prevention of chronic migraine. Presented at: 2017 American Academy of Neurology Annual Meeting. April 28, 2017; Boston, MA.
- Lipton R, et al. 75% responder rates provide improvement in HIT-6 scores from week 4 through 12 following a single infusion of ALD403, or placebo. 2017 American Academy of Neurology Annual Meeting. Poster P2.165. April 24, 2017; Boston, MA.
- Alder BioPharmaceuticals press release, April 28, 2017. alderbio.com
- Alder BioPharmaceuticals’ website. alderbio.com. Accessed May 4, 2017.
- Alder BioPharmaceuticals. Q1 2017 SEC filing. Filed April 27, 2017.
- Ford J, et al. Measures of functioning using MSQ v2.1 in patients with a history of episodic migraine and treated with galcanezumab or placebo injections in a Phase 2 clinical trial. 2017 American Academy of Neurology Annual Meeting. Poster P2.179. April 24, 2017; Boston, MA.
- Aurora S, et al. Factors associated with significant reduction in migraine headache days: A post hoc analysis of a Phase II placebo-controlled trial in patients treated with galcanezumab. 2017 American Academy of Neurology Annual Meeting. Poster P2.177. April 24, 2017; Boston, MA.
- Regev A, et al. Hepatic safety of galcanezumab in patients with migraine: Results of three Phase 2 double-blind placebo-controlled trials. 2017 American Academy of Neurology Annual Meeting. Poster P2.164. April 24, 2017; Boston, MA.
- clinicaltrials.gov. NCT02848326. Accessed May 5, 2017.
- clinicaltrials.gov. NCT03096834. Accessed May 3, 2017.
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