Therapeutic focus – Teva, Lilly and Amgen square up for battle in migraine prevention

It is no coincidence that Teva’s $200m acquisition of Labrys’ anti-CGRP antibody last week came only a few months after Eli Lilly moved to take a similar project back into its pipeline. After years of substantial investment companies believe they have finally worked out how to effectively and safely hit this target, which has long been considered a clinically and commercially exploitable mechanism for migraine drugs.

The deals mean that three significant players will have their respective candidates in late-stage trials at around the same time; Amgen also has an in-house project that should generate data from a large phase II study later this year. Teva estimates peak sales of $2-3bn for its new drug, which points to a market big enough to encompass three players. But pivotal studies could still reveal important differences in terms of efficacy, dosing convenience and of course safety, so share of this space is still very much up for grabs (see table below).

Venture-backed progress

The initial $200m that Teva has agreed to pay represents a sizeable sum for an asset that only recently entered phase II – Labrys was a one asset company – and suggests that big things are expected. Up to $625m in contingent payments linked to sales milestones are also payable in the future.

LBR-101 was once spurned by big pharma – Labrys bought rights from Pfizer shortly before raising $31m in a series A round in early 2013. Pfizer remains eligible for milestones and sales royalties – and a cash payment on the takeover of Labrys – so the economics of the drug’s future success, should it arrive, will be shared three ways.

Lilly did not disclose what it paid to regain rights to LY2951742 but said it would take a pre-tax charge of $57.1m. It sold the asset to venture-backed Arteaus in 2011, which then worked with Lilly’s Chorus unit to develop the molecule to proof of concept; reacquiring the molecule at some stage was always a possible outcome.

Both these deals have been heralded as hugely successful results for the venture capital firms that took on the risks of these molecules, and provide some validation of the asset-centric model that investors have been pursuing in an attempt to improve their returns (F-star forges immuno-oncology spin off in latest test of asset-centric model, October 23, 2013).

The calcitonin gene-related peptide or CGRP is produced in neurons; it is a vasodilator and involved in pain transmission, and is known to play a central role in migraine. Drugs already used to treat migraine indirectly target CGRP. The triptans, for example, increase intracellular calcium, which acts to suppress the peptide's activity, while Botox stops its release.

Hence interest in targeting the peptide specifically. Commercial research initially focused on the development of small molecule receptor antagonists that could be used in an acute setting. Merck & Co got the furthest with a small molecule called telcegapant that completed a substantial pivotal programme in more than 10,000 patients. Efficacy was encouraging, but it was eventually shelved due to a liver safety signal (Merck’s results pain intensified by migraine troubles, April 22, 2009).

There are no longer any small molecules against CGRP in the clinic, according to clinicaltrials.gov, and the biologicals that now dominate the anti-CGRP pipeline are being tested in preventative settings for patients with chronic and persistent migraines. This is a logical positioning because they are antibodies with long half-lives, and as they need to be injected most have been formulated as self-administered subcutaneous shots.

LBR-101, the antibody now owned by Teva, stays in the body for more than 40 days and is being developed as a once-monthly injection. LBR-101 has successfully completed five phase I trials in healthy volunteers and two phase II studies are ongoing, seeking to recruit almost 500 patients in total with either chronic or episodic migraine, with results due early next year.

Lilly’s candidate was dosed once every other week in a 190-patient phase II study that completed last year, although a trial that was slated to start earlier this year describes a four weekly schedule to be tested.

AMG 334, which has the largest phase II programme currently underway, is also being tested with monthly dosing. A 468-patient study should complete shortly and the company has listed a second, similar study seeking to recruit 490 patients, although this does not appear to have started recruiting.

High hopes

Hopes are high after encouraging early data was presented earlier this year on the Lilly candidate and the fourth antibody candidate in the running, which is in the hands of private company Alder Biopharmaceuticals.

In a large, double-blind placebo-controlled phase Ib trial that recruited 163 patients with episodic migraines, ALD403 significantly reduced mean migraine days per month versus placebo, the primary endpoint. 60% of patients experienced a greater than 50% reduction in migraine days, compared to 33% in the placebo group.

A 217-patient phase II Lilly study also met the same primary endpoint, while 70% of patients in the trial experienced a greater than 50% reduction in migraine days, compared to 45% in the placebo group.

These results suggest that the class should be able to produce slightly better efficacy than Botox - the only treatment approved to prevent migraine – with a much improved dosing schedule. Safety and tolerability measures were also encouraging; developers believe that because the antibodies are not degraded in the liver they should avoid the safety signal that derailed the small molecules, and their greater specificity should mean fewer off-target effects.

Taking a punt

The AMG 334 data due later this year will allow the first rigorous look at the attributes of this class of antibody. However it will be some time before reliable comparisons of the candidates can be made. It is entirely possible that differentiating factors will emerge, an obvious source being the different binding sites they use. While AMG 334 blocks the CGRP receptor – working more like the small molecules – the other three candidates bind directly to the peptide.

With three big players in the space now it also leaves Alder as the sole independent. So far it has pursued a slightly different approach by testing an intravenous infusion and its next steps are awaited. With the trials of AMG 334 and LBR-101 due to generate data in the not too distant future, the results could well have a bearing on the future for ALD403, and the anti-CGRP space more widely.

Although none of these agents have sales forecasts attached at this stage – past failures are no doubt to blame –the data released by Alder and Lilly prompted some to predict big things. Analysts at Piper Jaffray estimate that a convenient, well tolerated sub-cutaneous treatment class could achieve peak global sales of $10bn. With Merck having got so close a few years ago with telcagepant, could it be tempted to take a second punt on Alder’s next generation approach?  

To contact the writer of this story email Amy Brown in London at [email protected] or  follow @AmyEPVantage on Twitter.