For anyone following the migraine space, 2018 was poised to be a year of big change after a long period of stagnant innovation outside symptomatic treatment at the point of migraine onset. Within a short span of time, three medications belonging to a novel class of molecules aimed at targeting the Calcitonin Gene-Related Peptide (CGRP) emerged on the US market. This development marked a revolutionary shift in preventative migraine treatment, which had previously relied on continuous agents originally designed for depression or epilepsy, with questionable efficacy and significant baggage of safety concerns.
Five years down the line, the CGRP market has exploded, bringing close to $4bn expected sales in 2023 and predicted to reach $10bn by 2030 across both the acute and preventative segments [1]. For the latter, this certainly can be attributed to anti-CGRPs meaningfully raising the bar in terms of efficacy and safety. However, this raised bar has also become the de facto CGRP “ceiling”, with most of the now six approved treatments having relatively little differentiation in clinical effect and safety.
With the efficacy “ceiling” set across the competition, the opportunity for innovative go-to-market strategy has been in plain sight but which approaches have come on top? How did leveraging indication synergies, niches across the migraine spectrum and patient access advantages fare against traditional RoA positioning? Five years down the line – what have we learned?
Convenience, adherence, preference – the pill comes on top
When the first three anti-CGRPs launched on the US market, there was relatively little difference in terms of administration experience for patients taking either Aimovig (Amgen), Ajovy (Teva) or Emgality (Eli Lilly). All three were biologics delivered subcutaneously 1x a month, with Ajovy having the additional dosing option of receiving 3 injections once a quarter and Emgality needing a double injection loading dose. While unchallenged for 2 years, patient administration options have expanded further. First, Vyepti (Lundbeck), an IV biologic infused once a quarter, was FDA-approved in 2020. A year later, two additional small molecule oral options became available – Nurtec ODT (Pfizer) and Qulipta (AbbVie), taken as once every two days or once daily, respectively. While not targeting CGRPs, it is worth mentioning that patient preference in preventative migraine in terms of RoA is further complicated by AbbVie’s BOTOX, which offers a quarterly HCP-delivered treatment, consisting of 31 intramuscular injections. Another angle to consider is that convenience is not just for the patient but also the HCP, with treatments such as BOTOX still largely being delivered by dedicated specialists, potentially limiting access to treatment vs. an oral or SC option.
With all these options now available, manufacturers are keen to highlight the advantages and drawbacks of each approach, but the real win has perhaps been in favour of the patient and their individualized approach to treatment. No concerns about adherence? An oral option may be the most convenient. Less time spent managing your treatment and needle-phobia not an issue? Then an SC option may be desired. Closer interaction with your HCP and even less frequent treatments preferred – the IV route may address this need. Yet, which treatment has seen the most success so far?
At the lower end of the rankings, Lundbeck’s IV solution Vyepti has had a slow start, mainly due to unfavorable formulary access compounded by its launch timing in the middle of the COVID pandemic when elective care visits were significantly disrupted. However, IV delivery has shown potential advantages in speed of onset, which could be a critical advantage for clinic patients with severe disability, where fast-acting and effective treatments will be highly valued. Should Lundbeck capitalize on this patient segment, Vyepti’s growth trajectory may be accelerated.
While it may take another one or two years for the dust to settle and winners in the RoA arena to take the podium, the writing is on the wall regarding the prevalence of the oral options which are poised to continue rapidly gaining market share, surpassing SC and IV biologics [2]. According to analyst consensus, in 2028 more than 50% of all migraine sales (both acute and preventative) would be captured by orals. Currently, both HCPs preference and patient interest seem to gravitate towards Nurtec ODT and Qulipta [4], even despite recent setbacks inherent to the oral RoA such as Pfizer’s recall of 4.2 million units of Nurtec ODT due to non-child resistant packaging [5]. Another aspect that may play out as advantageous for the orals is the possibility of achieving better traction with PCPs, who, while increasingly familiar with the class, are less likely to prescribe it than specialists.
Pfizer is also set to continue pushing the envelope on RoA differentiation with its oral spray, Zavzpret recently approved for acute migraine. While still far from potential approval in migraine prevention, the ‘Nurtec Spray’ is generating interest with HCPs and could address the needs of patients who cannot take oral medications due to nausea or vomiting – both common in migraine sufferers.
I admit comparing preventative migraine treatments simply based on their RoA and dosing regimens is quite reductionist and somewhat dismissive of a much more complex puzzle. However, not many disease landscapes provide the opportunity for such “like-to-like” comparisons, which are usually overshadowed by considerations for clinical trial endpoint differentials and safety profiles. So letting ourselves indulge in this oversimplification, the lesson from the first five year of the CGRP revolution is clear – the oral formulations are set to reign supreme. Maybe it’s something about the simplicity and pain-free experience of taking a pill every day. Maybe it’s about sharing the patient journey of Lady Gaga [6]. Regardless, non-oral manufacturers should consider whether messaging on convenience for SC and IV treatments has the desired impact.
Across the migraine spectrum – the winner will be there for every step of the patient journey
Another way competitors have sought to distinguish their offerings is by seeking to broaden their migraine patient populations.
The biggest winner appears to be Nurtec ODT, which had already gained an FDA nod in acute migraine before entering the prevention space. The synergy of having one pill that can address both acute episodes of migraine and act on prevention has worked in favor of Pfizer’s oral CGRP offering, particularly with gaining HCP and patient familiarity. This has in turn blunted the uptake trajectory of Qulipta in preventative migraine, where AbbVie has sought to differentiate by gaining approval in chronic migraine, where Nurtec ODT is not approved. However, it is worth noting that while this has created a niche for Qulipta in the oral CGRP competition, chronic migraine accounts for only about 5% of frequencies, with episodic being the dominant frequency.
While acute treatment remains out of reach for the biologics, Lilly’s Emgality has sought the opportunity with a rarer form of headache, becoming the first and only FDA-approved treatment for episodic cluster headaches. While not directly related to migraine prevention, Emgality’s success in this area has definitely boosted its positioning. It’s worth noting that one of its rivals, Teva’s Ajovy, dropped out of the race in episodic cluster headache due to disappointing early results, giving Emgality free reign. Lundbeck’s Vyepti is also pursuing this space with results from its Ph3 trial expected in the coming months.
While creating niches has brought benefits for Qulipta and Emgality, the clear synergy of covering both the acute and preventative migraine segments stands to be a real game changer for Nurtec ODT and likely a guidepost for development programs to come. Look no further than Nurtec ODT’s follow-up Zavzpret.
And finally: what’s next?
CGRP treatments have undoubtedly reinvigorated and transformed the preventative migraine landscape. But as the migraine commercial engine is picking up steam, the pressure for further innovation and bursting through the “efficacy ceiling” is increasing while the opportunities for differentiation for the existing CGRP modality diminishing. So, what’s next? I will provide two developments which may significantly shift the landscape:
- Breakthrough with combinations: a landscape with a variety of MoA’s and RoA’s is ripe for exploring combination options. AbbVie is leading this effort for migraine, having the Qulipta, BOTOX and Ubrelvy (CGRP inhibitor for acute migraine) brands in-house. While none of the other major players in the space have this breath of portfolio, making collaborations for developing combo treatments unlikely, the expected entry of BOTOX biosimilars may be catalyst for change
- Breakthrough with new MoAs: the same as CGRPs revolutionized migraine, it may take another class to move the space forward. While the number of pipeline drugs in development is relatively small, one hopeful to take the CGRP mantle is Lundbeck’s Lu AG09222, an IV-delivered monoclonal antibody targeting a small peptide called PACAP, which is thought to be implicated in migraine pathophysiology. The company recently announced positive topline Ph2 data, supporting further development
While the clinical developers of today seek to raise the efficacy bar for tomorrow, they need to keep in mind the lessons of CGRP’s yesterday. Namely, that without unparalleled efficacy, convenience is king. In that regard, both new combination approaches and novel MoAs delivered via IV are not poised to meet this success criterion which may blunt their competitive edge. If the last five years of CGRP marketing are any indication, manufacturers eyeing the preventative migraine market of the future would be well advised to think about convenience early on in the development process.
Sources:
[1] UBS Global Research Sep, 2023
[2] Datamonitor Healthcare, Aug 2023
[3] Evaluate Pharma, Oct 2023
[4] Endpoint News, Oct 2023 – https://endpts.com/pfizer-and-abbvie-oral-migraine-drugs-earn-top-spots-with-physicians-survey-finds/
[5] Healthline News, Oct 2023 – https://www.healthline.com/health-news/pfizer-recalls-millions-of-packs-of-the-migraine-drug-nurtec-odt-due-to-child-safety-concerns
[6] Nurtec.com – accessed Oct 2023
[7] Lundbeck PR – https://news.cision.com/h–lundbeck-a-s/r/lundbeck-announces-positive-phase-ii-proof-of-concept-results-with-lu-ag09222-in-migraine-prevention,c3754245 – accessed Oct 2023