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Home , Eptinezumab, Fremanezumab

NEWS & ANALYSIS

From The AnalYst’s Couch The market for drugs

Angela M. Sparrow* and Jonathan W. Searles Images Perets/E+/Getty Credit:

Migraine is a highly prevalent disease, The most commonly prescribed drugs (Ajovy; Teva), (Emgality; affecting more than 33 million people for migraine prevention are antiepileptic Eli Lilly) — which all reached the US in the US alone, with three times greater drugs (such as ), beta blockers market in 2018 (European launches soon to prevalence in females. Migraine pain is (such as ) and tricyclic follow) — and Alder BioPharmaceuticals’ often debilitating. Individual attacks last antidepressants (including ), (phase III). Though far from for 4–72 hours, often accompanied by some of which have migraine prevention a cure, reported data have nausea, vomiting, photophobia and/or on their labels. Unfortunately, many of these stirred excitement. Topiramate and Botox phonophobia. agents have side effects including cognitive produce a 1–2 day reduction in monthly The market for prescription acute problems, fatigue, somnolence, weight gain migraine days in patients with CM, with a and preventive migraine treatments has and, particularly concerning in a largely response rate (≥50% reduction in monthly been stable — and largely generic — female population, a risk of teratogenic migraine days) of 12% for Botox and 22% for many years, but now stands poised for effects. Until 2018, the last meaningful for topiramate. In comparison, in phase III transformation. 2018 witnessed the launch innovation in this arena was the approval of data, the anti-CGRP​ mAbs resulted of the first novel preventive agents since Botox for CM in 2010. Botox is the only non-​ in an approximately 1.5–2 day reduction in 2010 and additional preventive and acute daily injectable preventive therapy, has far monthly migraine days in patients with EM agents are expected to launch in the next fewer side effects than daily oral agents and is and a 2–2.5 day reduction in patients with 5 years. Amongst these high-cost,​ innovative the only therapy specifically approved for CM CM; the response rate in both populations new drugs, seven or more therapies target (clinical trial data do not support its use in was 12–24%. Although these results are gene-​related (CGRP) — patients with EM). similar to those for topiramate and Botox a key pathological factor in migraine and a Despite the array of available, mostly (based on cross-trial​ comparison), in sought-after,​ but once elusive, drug target. inexpensive options, current prophylactics secondary end point analysis a portion These comprise the first new migraine-​ leave much to be desired in terms of efficacy; of patients treated with anti-CGRP​ mAbs specific class of drugs to launch in more than response rates fall well short of 100% and experience a 75–100% reduction in monthly two decades. breakthrough attacks are common, as is migraine days, patients administer fewer polypharmacy to achieve maximal results. doses of acute drugs, and some patients Current treatment Moreover, because of side effects, compliance There are two main clinical subtypes of and adherence are often low. 8 migraine based on headache frequency: Acute migraine Migraine prophylaxis 7 episodic migraine (EM), in which patients The (re)birth of CGRP-targeted​ therapies have <15 headache days per month, and CGRP is a potent vasodilatory . 6 chronic migraine (CM), in which patients Its release produces local vasodilation 5 have ≥15 headache days per month, with and extravasation of plasma and plasma 4 at least 8 of those days having migrainous proteins into surrounding tissue. Basal features. is divided into levels of peripheral CGRP are higher in 3 two paradigms: acute treatment, which is patients with CM than in patients with Sales (US$ billions) 2 taken as an abortive treatment at the onset of EM or healthy controls; intravenous 1 an attack, and prophylactic treatment, which administration of CGRP can trigger is administered chronically to prevent new in predisposed patients. In 0 2017 2027 2017 2027 migraine attacks. Acutely, many migraineurs the early 2000s, numerous oral CGRP Market 2017–2027 (G7) treat — sometimes exclusively — with antagonists were being developed for over-​the-counter medications, and some migraine. The leading candidate at the time Other new brands* Oral CGRP antagonists patients also rely on prescription . was Merck & Co.’s ; however, Oral CGRP antagonists Anti-CGRP mAbs The (named for the ending of hepatotoxicity issues surfaced in late-phase​ Triptans Other prophylactic the molecule names) are the mainstays trials and Merck discontinued their Other acute drugs drugs of prescription acute migraine treatment. CGRP programme. Other developers Botox launched in the early 1990s, followed suit. followed by six additional triptans, which Since then, there has been a resurgence Fig. 1 | Sales and predicted sales of key drug classes in G7 countries for migraine, by together revolutionized the acute migraine of interest in the class (Table 1). Several market segment. The G7 countries are the US, market. Since then, additional delivery monoclonal antibodies (mAbs) that target France, Germany , Italy , Spain, UK and Japan. routes have offered largely incremental CGRP or its receptor (hereafter collectively *Other new brands include Eli Lilly’s benefits. Novel non-​ alternatives are referred to as anti-CGRP​ mAbs) are in and several reformulations of existing drugs. needed for patients for whom triptans are development or have recently been approved CGRP, calcitonin gene-​related peptide, mAbs, contraindicated or who do not respond to for migraine prevention: monoclonal antibodies. Source: Decision or cannot tolerate them. (Aimovig; Amgen/Novartis), Resources Group.

Nature Reviews | DRuG DiSCoveRy volume 18 | MAY 2019 | 333 NEWS & ANALYSIS

Table 1 | Selected CGRP-targeted​ therapies in development for migraine in size to over $11 billion, spurred by CGRP-targeted​ drugs, which could Drug Developer Mechanism of action Market Status account for more than $6.5 billion of segment sales in 2027. Erenumab Amgen/Novartis Fully human mAb Prophylaxis Marketed (US) After much anticipation, erenumab (Aimovig) targeting the CGRP receptor launched in the US market in May 2018, followed by fremanezumab and Fremanezumab Teva Humanized mAb Prophylaxis Marketed (US) galcanezumab at the end of Q3 2018. (Ajovy) targeting CGRP Erenumab has also received European Galcanezumab Eli Lilly Humanized mAb Prophylaxis Marketed (US) Medicines Agency approval whereas (Emgality) targeting CGRP fremanezumab and galcanezumab are Eptinezumab Alder Humanized mAb Prophylaxis Phase III both under review. Eptinezumab is expected BioPharmaceuticals targeting CGRP to launch in the US in 2020. Given the Atogepant Allergan CGRP receptor Prophylaxis Phase III cost of these therapies (approximately antagonist $7,000 per year in the US), prescribing will Biohaven CGRP receptor Prophylaxis Phase III almost certainly be limited to patients who antagonist have failed prior treatments; however, even Allergan CGRP receptor Prophylaxis Phase III a small uptake will result in considerable antagonist revenue owing to the enormous population size. Initial indicators point to rapid, early BHV-3500 Biohaven CGRP receptor Prophylaxis Phase I antagonist adoption of anti-CGRP​ mAbs in the US, likely due to pent-up​ demand for improved CGRP, calcitonin gene-​related peptide; mAb, . options. Combined with the anticipated launch of atogepant in 2022, the migraine report that pain severity is decreased fremanezumab from its 2019 national prophylaxis market could nearly quadruple and breakthrough migraines are more preferred formulary. to $7 billion by 2027. manageable. Importantly, erenumab is Oral CGRP-​targeted therapies are also In the acute space, migraine experts effective in patients who have failed prior in development. In the post-telcagepant​ era, estimate that 15–20% of patients are preventive treatment either for efficacy or Allergan and Biohaven acquired the rights to candidates for non-triptan​ alternatives tolerability reasons. Another key feature is CGRP antagonists from Merck (ubrogepant) because of intolerability, ineffectiveness the excellent tolerability and safety of these and Bristol-​Myers Squibb (rimegepant), or contraindications. Ubrogepant and drugs; indeed, the FDA labels for erenumab, respectively; both companies believe that rimegepant are expected to launch in the fremanezumab and galcanezumab are free liver toxicity observed with telcagepant is US in 2020 (the timing of ex-US​ launches of warnings and precautions (aside from not a class effect. Phase III trials for the remains unclear owing to the absence hypersensitivity) and the adverse events are acute treatment of migraine are underway. of global trials). In addition, Eli Lilly’s largely confined to injection site reactions. Available efficacy data suggest the response lasmiditan, a novel 5-hydroxytryptamine 1F

All four mAbs have similar efficacy rates may be lower than those of triptans (5-HT1F) receptor agonist (phase III), could and tolerability data, so differentiation is (cross-trial​ comparisons), but the safety add to the crop of migraine-specific,​ non-​ critical. In addition to a short (a few months) and tolerability data are favourable, with no triptan options. However, as for the mAbs, first-​to-market advantage, erenumab is elevations in liver enzymes. In the prevention all three of these drugs will enter a heavily also the only fully human mAb and targets space, Allergan is developing atogepant, generic market, relegating them to second-​ the CGRP receptor rather than CGRP another Merck cast-off,​ currently in phase III line or later-line​ treatment. Nevertheless, the itself. The direct clinical benefits of this are development. In late 2018, Biohaven acute migraine market, driven by the oral unclear, but this distinction could support initiated clinical trials for rimegepant for CGRP antagonists, could more than double preferential prescribing of erenumab to migraine prophylaxis and has another to more than $4 billion by 2027. Payers patients who do not respond to a mAb phase I candidate, BHV-3500. Although could soon be bracing for the impact of that targets CGRP itself. The other main little is known about the efficacy of these CGRP-​targeted therapies in the acute differences are in delivery: erenumab and drugs, patients often prefer the oral route of realm, too. galcanezumab are offered as once-monthly,​ administration to s.c. injection. However, Angela M. Sparrow* and Jonathan W. Searles at-home​ subcutaneous (s.c.) injections via because the mAbs are infrequently dosed, Decision Resources Group, Burlington, prefilled autoinjectors; fremanezumab, efficacy will be the deciding factor for many Burlington, MA, USA. also a s.c. injection, is available only patients, especially those with severe or *e-mail:​ [email protected] in prefilled syringes, but can be dosed frequent migraines. https://doi.org/10.1038/d41573-018-00014-3 monthly or quarterly. Eptinezumab will be administered as a once-quarterly​ intravenous Market indicators Competing interests The authors declare no competing interests. infusion. Access and contract negotiation The 2017 migraine market is estimated at with payers will also be key drivers in US$3.8 billion in the seven major markets Related links treatment selection. In the US, payers are (US, France, Germany, Italy, Spain, UK and FDA label for erenumab: https://www.accessdata.fda.gov/ drugsatfda_docs/label/2018/761077s000lbl.pdf still finalizing their coverage decisions for Japan), with the acute market accounting FDA label for fremanezumab: https://www.accessdata.fda.gov/ 2019, and it is unlikely that any provider will for just over half of that (Fig. 1). However, drugsatfda_docs/label/2018/761089s000lbl.pdf include all three mAbs — as seen recently the market is primed for dramatic growth FDA label for galcanezumab: https://www.accessdata.fda. gov/drugsatfda_docs/label/2018/761063s000lbl.pdf with ExpressScripts’ decision to exclude over the next 10 years, potentially tripling

334 | may 2019 | volume 18 www.nature.com/nrd