With safety and efficacy endpoints met in the Phase III trial testing Biogen Idec Inc.'s long-lasting rFVIIIFc (recombinant Factor VIII Fc fusion protein) for hemophilia A, investors were scrutinizing the candidate's odds in a market led by Advate, the serum-free, recombinant Factor VIII therapy from Baxter Healthcare Corp.

Cambridge, Mass.-based Biogen's stock (NASDAQ:BIIB) closed Wednesday at $138.21, down $4.72, amid a lukewarm sell-off that Robert Baird & Co. analyst Christopher Raymond blamed on investors' hopes for "something more definitive."

The treatment, like rFIXFc (recombinant Factor IX Fc fusion protein) for hemophilia B, is partnered with Swedish Orphan Biovitrum (Sobi), of Solna, Sweden. Positive data in the smaller market of hemophilia B were reported in late September. Analyst Robin Karnauskas, of Deutsche Bank, estimated 2020 potential peak sales of rFIXFc at $450 million, and rFVIIIFc at $2.4 billion. (See BioWorld Today, Sept. 27, 2012.)

The A-LONG study enrolled 165 male patients age 12 and older in three arms: individualized prophylaxis (118 patients, treated with 25-65 IU/kg of rFVIIIFc, at an interval of every three to five days, which was individualized to maintain factor trough levels sufficient to prevent bleeding); weekly prophylaxis (24 patients, treated with a weekly dose of 65 IU/kg); and on-demand, episodic treatment (23 patients, given rFVIIIFc as needed for bleeding). The trial began in summer 2010. (See BioWorld Today, July 12, 2010.)

The primary efficacy and safety measures were the annualized bleeding rate (ABR) and adverse events, including inhibitor development in patients studied for up to about a year. Secondary endpoints included response to treatment of bleeding episodes and the pharmacokinetics (PK) of rFVIIIFc vs. Advate.

Ninety-three percent of patients finished the study. RFVIIIFc controlled bleeding episodes in 98 percent of patients with one or two injections, and no patients turned up with inhibitors. The median ABRs, including spontaneous and traumatic bleeds, totaled 1.6 in the individualized prophylaxis, 3.6 in weekly prophylaxis and 33.6 in on-demand treatment.

In the finer-tuned, individualized prophylaxis arm, the median dosing interval was 3.5 days, which beats Advate, with its labeled dosing frequency of three to four times per week. Even better, during the last three months on study, 30 percent of patients in that arm reached a mean dosing interval of five days.

Of particular interest, too, is the weekly prophylaxis group.

"We knew going into that arm of the study that with the dose we had chosen, and with the increment between doses that we were looking at, not all of the patients were going to be protected for a full week, at least based on the PK of the molecule and [the patients'] trough levels," said Douglas Williams, vice president of research and development for Biogen.

Knocking down the median bleed from 33.6 to 3.6 "says to me we did have, in fact, a very meaningful clinical impact," a benefit that could encourage on-demand patients to switch over to a weekly dose, where appropriate, Williams said.

Weekly Dosing Data 'Intriguing'

Michael Yee, analyst with RBC Capital Markets, predicted in a research note that rFVIIIFc "could take 10 percent to 20 percent [of] market share or $500 million in sales," since the dosing every three or four days with low ABRs "appears comparable or better than Advate literature." Specifically, Advate's label calls for dosing thrice weekly, or every three days if trough levels stay at or above 1 percent, which gains a median ABR of 1.

Glenn Pierce, Biogen's chief medical officer, called the weekly data "really robust. Median [ABR] rates of one, two or three are all very low, compared to what episodic patients have. Patients who treat their bleeds will bleed anywhere from 30 to 40 and even 50 times per year. It's not infrequent that patients will bleed once a week and need to take a treatment," he told BioWorld Today.

Patients who treat themselves "by bleed" are usually adults who grew up with their condition and simply tolerate it, though almost all children in the U.S. and Europe take prophylaxis therapy, which has taken root in the U.S. for adults only in the past two decades, Pierce said.

Brian Abrahams, analyst with Wells Fargo, wrote in a research note that "given the need for more than once-weekly dosing to optimize bleeding rates for the majority of patients (as we expected), we would not anticipate rFVIIIFc to upend the treatment paradigm overnight." But Oppenheimer analyst Robert Ferreiro wrote that hematologists consulted by his firm deem even the twice-weekly dosing "a meaningful improvement" over Advate.

Sobi CEO Geoffrey McDonough told BioWorld Today, that "it appears many patients will be able to achieve dosing intervals better than two times per week – a major step forward, recognizing that they will do this without ever spending time between doses below 1 percent to 3 percent of factor activity.

"It is too early to speculate on the label, but I do think the data from the weekly arm [are] intriguing and could be highly relevant clinically," he said.

"Without getting into an analysis of competitor labels, looking at a variety of clinical studies, including Advate, the ABRs range from one to [about] 10, and this has been due to patient populations, design of study and other parameters" that don't allow fruitful comparisons between studies, McDonough added.

"To make the comparability question vivid, studying a 30-year-old man who has been on prophylactic treatment for two years prior to a prophylactic trial will reveal higher ABRs due to accumulated joint damage, whereas a 30-year-old man who has been on prophylactic treatment for 20 years prior to the same trial will perform better," McDonough said.

"This is why direct comparison across trials is so tough. Bottom line is that one needs a low, single-digit figure if one is going to develop a prophylactic in hemophilia A, and we have that," he noted.

Approvals by the FDA for both hemophilia therapies, A and B, will be sought during the first half of next year.