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'Complementary' ticket: PNH pen to write Akari's own in better-Soliris bid?

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By Randy Osborne
Staff Writer

Akari Therapeutics plc CEO Gur Roshwalb told BioWorld Today that his firm "like[s] to think we'll be second to market" with once-daily, self-injected therapy Coversin for paroxysmal nocturnal hemoglobinuria (PNH), behind intravenous (I.V.) Soliris (eculizumab, Alexion Pharmaceuticals Inc.), given every other week. Coversin would be delivered by way of an "insulin-like" injector pen, he said, acknowledging "a lot of concern [among investors] with trying to go in front of the FDA with a drug-device combo" but saying the device would be an off-the-shelf item. "I don't think we have to re-invent the wheel here," he said.

"Granted, we have a lot more data we have to get" with Coversin in PNH, Roshwalb said, but "one thing that most people miss" in the disease is that "there is no placebo response. It doesn't happen" in phase III trials. "We actually have one PNH patient treated now going on five months, who is doing great," he said – an effect that therefore must be due to Akari's therapy, described as a second-generation complement inhibitor that acts on complement component-C5, preventing release of C5a and formation of C5b-9.

The firm, with offices in London and New York, disclosed positive interim data from the first cohort in its phase Ib trial that show maintenance of complement inhibition using Coversin in healthy volunteers. Akari execs said almost-entire complement inhibition is necessary to maintain adequate control in patients with certain conditions, including PNH and atypical hemolytic uremic syndrome (aHUS). Phase II studies in both indications are expected to start this year, Roshwalb said, with the PNH experiment to begin "imminently."

Soliris, from New Haven, Conn.-based Alexion, is a humanized mouse antibody that binds to C5 protein and inhibits breakdown to C5a and C5b. "Our drug binds to a different epitope on C5, but it's essentially doing the same thing," Roshwalb said. "Independently, though, it binds to leukotriene B4 [LTB4]" as well, which could help in preventing potentially fatal thrombosis among PNH patients. Soliris reduces thrombotic events, but maybe Coversin can "do it even better by soaking up LTB4," he said. Soliris has proven successful in the marketplace since its approval in March 2007. (See BioWorld Today, Oct. 3, 2011.)

As much as 30 percent of patients respond poorly to Soliris, and these may be candidates for a compound such as that developed by Alnylam Pharmaceuticals Inc., of Cambridge, Mass., which disclosed results last month from part C of its ongoing phase I/II trial with ALN-CC5, a subcutaneously administered RNAi drug that targets C5. "It may be that they'll have some benefit [in poor responders with Soliris] because they have already been given a boost, for lack of a better term," Roshwalb said. "You're still going to have the I.V. every other week, maybe at a lower dose so it will cost less, but I don't really see Alexion playing along with that. Certainly, when you have an option like ours, wouldn't you rather have one drug?"

BINDING AGREEMENT

Leerink Partners analyst Geoffrey Porges, in a June 12 research report, called the Alnylam results "worse than expected," noting that Alexion with Soliris is "setting [a] new bar" in PNH treatment. "One of the reasons for the continued weakness of Alexion's stock this year has been the fear of competition for Soliris in its core complement inhibition indications (PNH, aHUS)," he wrote. "The threat posed by these rivals all came together at [and before] this year's European Hematology Association [EHA] meeting, where a morning of presentations showcased the contenders and pretenders to the treatment of complement-mediated diseases, and Alexion presented the first clinical data for its own next-generation complement inhibitors. Overall, we believe that the rivals to Alexion's complement-inhibition market position are facing longer development paths, and more uncertainty, than investors understand at this stage."

Another PNH player is New Haven, Conn.-based Achillion Pharmaceuticals Inc., which at EHA offered interim results from a phase I study with its small molecule factor D inhibitor, ACH-4471. Across four patient groups, ACH-4471 achieved peak plasma concentrations between one and 2.5 hours after oral dosing. Up to 100 percent inhibition of complement activity was achieved in all dose groups, and duration of inhibition was dose dependent. Group 4, which evaluated 1,200 mg of ACH-4471 given every 12 hours for two doses, achieved a median 99.5 percent inhibition (range 96 percent to 100 percent) of hemolysis at 24 hours. "The company's strategy and product profile appears to be focused on capturing the minority of patients with PNH who 'escape' from control with Soliris via C3 activity, rather than competing directly with Soliris in the most common form of PNH [mediated by C5 over-activity], and to identify diseases that are more C3 (and thus factor D) dependent, rather than C5-dependent," Porges said. "Should ACH4471 survive the difficult transition from healthy subjects to actual patients," it might be used along side Soliris rather than competing, in his view. "Regardless, given its stage of development, we believe it has at least a five-year development timeline before it could realistically reach the market."

Akari CEO Roshwalb said his firm's Coversin could help PNH patients who are Soliris-resistant because of a polymorphism. "Their C5 is shaped a little differently, and Soliris doesn't bind perfectly there," though Coversin may bind nicely, as is the case with the star patient in the latest-reported results. "We don't really know exactly what percentage of patients" are resistant to Soliris because of the polymorphism. "I don't think it's all of them by a longshot. With some of them it may be underdosing, some of them may be bone marrow burnout," he said.