Alder Biopharmaceuticals had been hit hard when Bristol-Myers Squibb returned rights to its rheumatoid arthritis project clazakizumab, but now data with ALD403 in migraine prevention have propelled the stock up 12% to a record high since the group’s IPO a year ago.
However, Alder does not have this space to itself, and at the International Headache Society congress in Valencia, Spain, where ALD403 was profiled on Friday, Amgen also posted the first phase II data of its competing project, AMG 334. With Lilly and Teva MAbs waiting in the wings, migraine prevention could be carved up by disease subtypes and dosing advantages.
The Alder and Amgen data, for instance, relate to prevention of episodic migraine, defined as that in which a patient has fewer than 15 headache days per month. Chronic disease, meanwhile, implies a much more frequent and more debilitating disease, but there are fewer patients meeting this criteria.
In Alder’s 163-patient phase I safety study a single IV dose of ALD403 resulted in 50%, 75% and 100% reductions in migraine days in 25%, 19% and 11% of patients respectively, adjusted for placebo. These updated data added to previously disclosed three-month results and the overall finding that ALD403 resulted in a 1.2-day placebo-adjusted reduction in monthly migraine days.
While cross-trial comparisons are notoriously unreliable, Amgen posted broadly comparable results on Friday with AMG 334, which in its first phase II trial, in 483 patients, yielded a 1.1-day placebo-adjusted reduction for 70mg, the highest of three doses. There was a dose-response relationship, but only the highest dose seems to have shown statistical significance.
Both projects are MAbs against calcitonin gene-related peptide (CGRP), a vasodilator thought to play a central role in migraine. However, only AMG 334 targets the CGRP receptor; the other three projects – ALD403 as well as Lilly’s LY2951742 and Teva’s TEV-48125 – all target the peptide itself, which might explain dose differences.
For instance, ALD403 was dosed at 1,000mg IV versus Amgen’s 70mg SC. This, Evercore ISI’s Mark Schoenebaum suggests, might allow Amgen to dose even higher in phase III, seeking greater efficacy, as long as safety remained reasonable.
Interestingly, the fact that all these projects are MAbs means that they are too big to cross the blood/brain barrier, so targeting CGRP necessarily takes place outside the brain – theoretically also avoiding CNS-related side effects. Small-molecule approaches have fallen by the wayside (Therapeutic focus – Teva, Lilly and Amgen square up for battle in migraine prevention, June 10, 2014).
Alder plans to start a phase IIb study in frequent episodic migraine in the first half of this year, and is running a 600-patient chronic migraine prevention trial from which data should be available in the second half.
|The anti-CGRP MAb race|
|Project||AMG 334||ALD403||LY2951742||TEV-48125 (LBR-101)|
|Episodic migraine prevention|
|Chg in migraine days*||-1.1||-1.0||-1.2||NA**|
|Chronic migraine prevention|
|Trial ID||NCT02066415||NCT02275117||Not studied||NCT02021773|
|*Change in monthly migraine days at 3 mth, adjusted for placebo; **data possible at AHS meeting in June.|
Teva also presented data at the IHS congress, though this related to chronic migraine, and showed that both a 225mg and 900mg SC dose, following a 675mg loading dose, led to a statistically significant reduction in the number of headache hours after one week. The Israeli group said such results had not been seen in chronic migraine prevention, and backed progressing into phase III.
Data from a Teva study in episodic migraine are expected at the American Headache Society meeting next month. For its part, Lilly has not studied LY2951742 in chronic migraine, and its phase IIb trial in 402 episodic migraine patients is due to be completed in August.
With Amgen planning to move swiftly into phase III in episodic migraine Alder will have its work cut out. A key consideration is that late-stage migraine trials tend to be large, of the order of 1,000 patients, and of this quartet of companies Alder stands out as the smallest, and thus least well funded.
Still, it recently raised $204m, and now boasts positive ALD403 data, a phase IIb study showing clazakizumab to be nowhere near as bad as Bristol’s pullout had implied, and a stock nearly 300% above its float price. It might not take too long to attract a large partner to fund phase III.