Alexion has dominated complement-mediated diseases with Soliris, but it might not have the space to itself for much longer. A new challenger, Ra Pharmaceuticals’ subcutaneous zilucoplan, has reported what looks like a similar benefit to Soliris in a phase II trial in myasthenia gravis.
Of course this is a cross-trial comparison, and zilucoplan still has it all to do in phase III. But Ra’s chief executive, Doug Treco, is keen to take the battle to Soliris if zilucoplan is approved: he said on a conference call this week that the drug’s price should be much lower than that of Soliris, which at around $600,000 per year is one of the most expensive therapies available.
Another caveat is that the zilucoplan study showed significance thanks to a very generous statistical analysis. A far more stringent threshold will of course have to be cleared in the rigorous setting of phase III.
But Ra is not the only company that wants to take a piece of Soliris’s pie: the Ash meeting earlier this month saw data on complement-targeting projects from Roche, Regeneron and Apellis. Achillion is developing the complement D inhibitor ACH-4471, and Samsung Bioepis recently joined Amgen in the quest to develop a Soliris biosimilar.
Alexion is unlikely to give up without a fight, and has already lined up its Soliris successor, Ultomiris, previously known as ALXN1210. That project, which like Soliris is given intravenously, is due a US FDA approval decision by February 2019 in paroxysmal nocturnal haemoglobinuria (PNH), its lead use.
Meanwhile, Alexion plans to start a phase III trial of Ultomiris in myasthenia gravis next year; Soliris has been available in this indication since 2017.
One problem for the challengers and Alexion alike is whether there are enough patients with complement-mediated diseases to go around; Alexion has been notoriously aggressive in its sales practices, suggesting that it has needed to make the most of a small market.
But Ra, for one, believes that it has the answer: expanding the pool of addressable patients by moving therapy into those with earlier-stage disease. It claims that its candidate has a very high affinity for complement C5, the same component of the pathway inhibited by Soliris.
Ra’s phase II trial enrolled less severe subjects than those in Soliris’s pivotal myasthenia gravis study, Regain. Perhaps the most important difference was that patients in the zilucoplan trial did not need to have failed previous therapies. Ra estimates that the first-line population numbers 30,000, versus 3,000-5,000 with refractory disease.
Soliris is not restricted to refractory patients, but is generally used as a last-line therapy, according to Ra’s chief medical officer, Ramin Farzaneh-Far, “not so much because of the label, but because of its price and restrictions payers put around access”.
On the question of pricing, Ra’s Mr Treco said zilucoplan should come in “closer to” the $200,000 per year of IV immunoglobulins. And Ra’s drug, being subcutaneously delivered, could also be more convenient than Soliris and Ultomiris.
On the question of compliance with a SC therapy, Ra said that in phase II this had been “very high”. The company is also working on a weekly SC version, which should be close to the clinic by the end of next year. Alexion is also developing SC Ultomiris, which is slated to enter phase III in late 2018.
Low bar for success
The primary endpoint of zilucoplan's phase II trial was the QMG scale, where Ra claimed a win with both doses studied. However, it had set a low bar for success, prespecifying clearance of a one-sided, rather than the more stringent two-sided, p value of 1.0 (versus the commonly used 0.5).
On this basis both doses met both the QMG and the secondary MG-ADL endpoint. The group also carried out a pooled analysis of the two doses, and said this met the 12-week MG-ADL endpoint according to the "threshold for statistical significance used in pivotal studies", hitting a two-sided p value of 0.047.
A phase III trial is now planned, testing zilucoplan 0.3mg/kg and likely using MG-ADL as primary endpoint; importantly, MG-ADL is the standard approval measure in the disease, and was the primary endpoint of Soliris's Regain study.
|Cross-trial comparison of zilucoplan vs Soliris in myasthenia gravis|
|Endpoint||Zilucoplan phase II trial, 12 weeks (NCT03315130)||Soliris Regain trial, 26 weeks (NCT01997229)|
|0.1mg/kg SC||0.3mg/kg SC||1,200mg IV|
|Note: All placebo-adjusted. MG-ADL: Myasthenia gravis-specific activities of daily living scale; QMG: Quantitative myasthenia gravis score. Source: Soliris label, Ra Pharmaceuticals.|
Meanwhile, at Ash this month Roche unveiled clinical data from the Composer study of its Soliris rival RG6107, or SKY59, in PNH patients, some of whom were treatment naive and others who had been Soliris pretreated. SKY59 is long-acting and self-administered, said Dr Alexander Röth, from University Hospital Essen.
In Composer SKY59 was dosed SC as infrequently as once monthly, and completely blocked complement activity in naive as well as pretreated subjects.
Dr Röth said the project hit a different C5 binding site versus Soliris and Ultomiris, supporting its use in patients who do not respond to these drugs. The only issue with switching to SKY59 was skin adverse events, which were seen in two of 16 subjects and were transient.
Leerink analysts pointed out that SKY59’s half life was still only 50% of Ultomiris’s, but accepted that the Roche asset could seize at least part of the market for anti-C5 antibodies within a few years of approval.
Leerink rates SKY59 as Soliris’s “nearest real rival”, but other companies also got in on the act at Ash, with poster presentations featuring Apellis’s C3 complement C3 inhibitor APL-2, and Regeron’s C5-targeting project REGN3918 or pozelimab, both in PNH.
Perhaps not all of these projects will make it to market, but it will only take one to succeed for things to become tougher for Alexion.