Achillion Pharmaceuticals still hopes to get the first oral complement inhibitor to market – it just might take a bit longer than expected, at least in one indication. The company yesterday discontinued work on its first-generation compound, ACH-4471, as a monotherapy in paroxysmal nocturnal haemoglobinuria (PNH), a disease dominated by Alexion’s Soliris.
Achillion talked up its next-generation factor D inhibitor, ACH-5228, but this is much earlier in development. Shares fell 13% this morning after plunging 23% yesterday ahead of the data release. It seems obvious that investors consider Achillion a long way from being a real complement contender.
The company is persevering with ACH-4471 in PNH patients not responding to Soliris, and as monotherapy in another disease, C3 glomerulopathy (C3G). Achillion released a smattering of phase II data yesterday in both indications, but shareholders will have to wait until next year to see if either of these uses truly holds potential.
Promising... if it weren't for Soliris
As for ACH-4471 monotherapy in PNH, this is heading for the scrapheap, although Achillion was adamant that data from a 10-patient open-label trial were encouraging. “ACH-4471 would potentially stand on its own in the absence of existing therapies,” said the group’s chief medical officer, Steven Zelenkofske, during a conference call yesterday – a reference to Soliris.
ACH-4471 has the advantage of being given orally, but its three-times-a-day dosing schedule would be burdensome for patients. Achillion’s next-generation candidate, ACH-5228, is more potent and could be dosed twice daily, the company hopes.
Whether this would be enough to allow ACH-5228 to compete with Soliris and, probably more importantly, Alexion’s follow-on candidate Ultomiris, is another matter. Both are given intravenously, Soliris every two weeks and Ultomiris every eight weeks, while a subcutaneous version of Ultomiris is also in the works.
To gain an edge on convenience with an oral candidate Achillion will surely have to work towards even less frequent dosing. But its work here is very early: ACH-5228 is slated to start a phase I multiple ascending dose study next quarter, while a potential once-daily project, ACH-5548, could enter the clinic in 2020. Liver toxicity will be closely watched with these assets; one patient in the ACH-4471 monotherapy trial discontinued owing to liver enzyme elevations.
Meanwhile, Achillion is not the only company hoping to challenge Alexion’s grip on the complement-mediated disease space: other contenders include Roche, Regeneron, Apellis and Ra Pharmaceuticals, and all are developing subcutaneous candidates (Ra joins the challenge to Alexion’s Soliris stranglehold, 12 December 2018).
Achillion believes that both '5228 and '5548 could have potential outside ultra-orphan diseases, but has yet to set out its intentions. Focusing on areas that Alexion does not already dominate seems a sensible move.
The company has already set ACH-4471 on this path in C3G, for which there are currently no approved therapies. However evidence of the project's utility here remains thin on the ground. Yesterday's announcement contained data from six patients in a 14-day biomarker study, which the company believes establishes proof of mechanism in this disease, and interim results from a 12-month open-label study; these concerned only three patients, however, making conclusions very hard to draw.
Final results from the latter trial are due towards the end of 2019, as well as from an ongoing six-month double-blind study, both of which are crucial to support any move into phase III.
Achillion is not out of the complement race, but yesterday’s setback draws attention to just how far it still has to travel.