The "beautiful, eloquent" research that led to emicizumab for hemophilia A will "dramatically change the way they live," Nancy Valente with Roche Holding AG unit Genentech told BioWorld Today. "No one's ever used this approach to treat this disease."

Positive top-line data from the phase III HAVEN1 study, which tested emicizumab (also known as ACE910) prophylaxis in people 12 years of age and up who have developed inhibitors to factor VIII, had Wall Street speculating about what the full results might mean for the treatment's future as well as for others in the space.

"Patients develop inhibitors when they're only a year and a half to 2 years old," said Valente, vice president of global product development in hematology and oncology for Genentech/Roche. Bypassing agents are used, but they are burdensome and not very effective. Families of young patients must care for them "until they learn how to give themselves injections every other day." Emicizumab is given subcutaneously once a week.

A bispecific monoclonal antibody designed to bring together factors IXa and X, emicizumab "mimics the role of factor VIII in bringing these two proteins together," Valente said. HAVEN1 turned up a statistically significant reduction in the number of bleeds over time for emicizumab patients vs. those with no prophylactic treatment. The study also met all secondary endpoints, including a statistically significant reduction in the number of bleeds with emicizumab in an intra-patient comparison that brought aboard people who had received prior bypassing-agent prophylaxis. The most common adverse events were injection-site reactions, consistent with prior studies, the company said, and talks with regulators will begin "as quickly as possible," Valente said.

Two patients had thromboembolic events and two patients developed thrombotic microangiopathy (TMA), as previously reported. The common aspect between all cases of thromboembolic events and TMA is that they occurred in patients who were on emicizumab prophylaxis and also were given activated prothrombin complex concentrate to treat breakthrough bleeds. Neither of the thromboembolic events required anticoagulation therapy, and one patient restarted emicizumab. Both cases of TMA have completely resolved and here, too, one patient restarted emicizumab. "We're seeing something [in emicizumab's efficacy] that clearly has a great benefit for patients, but we take the safety very seriously and it's important to us," Valente said. "We're pleased that all the events are resolving."

Data will be presented at an upcoming medical meeting, though Genentech has not disclosed which one.

HAVEN1 is the first phase III study in the emicizumab program to report results. Specifically, the experiment is a randomized, multicenter, open-label evaluation of the efficacy, safety and pharmacokinetics of emicizumab. Included were 109 patients with hemophilia A with inhibitors to factor VIII previously treated with episodic or prophylactic bypassing agents. Patients previously treated with episodic bypassing agents were randomized in a 2-to-1 fashion to get emicizumab prophylaxis (arm A) or no prophylaxis (arm B). Patients previously treated prophylactically with bypassing agents received emicizumab prophylaxis (arm C). Per protocol, episodic treatment of breakthrough bleeds with bypassing agents was allowed. The primary endpoint of the study was the number of bleeds over time with emicizumab prophylaxis (arm A) vs. no prophylaxis (arm B). Secondary endpoints included all bleed rate, joint bleed rate, spontaneous bleed rate, target joint bleed rate, health-related quality of life/health status, intra-patient comparison to bleed rate on their prior prophylaxis regimen with bypassing agents (arm C) and safety. The development program also includes patients without inhibitors, those younger than 12 with inhibitors, and patients dosed as infrequently as once a month.

Need to 'characterize risk'

Leerink analyst Jason Gerberry noted that Genentech hasn't yet made known the magnitude or constitution of effect size, "making it difficult for investors to assess how the drug may fit into the hemophilia landscape. In our view, the non-disclosures increase the importance of the midyear updates," which he expects to include phase III top-line data with the compound in the larger hemophilia non-inhibitor population, along with a rollout of results at the International Society on Thrombosis and Hemostasis meeting in Berlin next July. So the "debate will linger into next year," he said.

RBC Capital Markets' Michael Yee "expect[s] the [full] data to be very strong and show minimal bleeds (phase II had 96-100 percent reduction in annual bleed rate) and in a high unmet-need population, which continues to have bleeds on standard-of-care therapy. And as a once-weekly subcutaneous injection, which is easy and convenient compared to current infusions multiple times per week, this drug will be FDA-approved for the 'inhibitor market' later, by 2018, and over time outside of the inhibitor market, and thus [will make] a future notable competitor in the larger $4 [billion to] $5 billion factor VIII market." Based on consultations with doctors at the American Society of Hematology meeting, he predicted the FDA will clear emicizumab.

Still, Yee said, "competitive dynamics abound. Emicizumab will be a key player that will take share over time from short-acting drugs from [Dublin-based Shire plc] and even longer-acting products such as Biogen Inc.'s Eloctate [antihemophilic factor (recombinant), Fc fusion protein], which is about to be spun out in a stand-alone hemophilia business."

For gene-therapy hemophilia players such as Biomarin Pharmaceutical Inc. and Spark Therapeutics Inc., "our physician expert consultants suggest and acknowledge that emicizumab will be a notable competitive player over traditional old-school infusions, but gene therapy offers a different potential solution as a single one-time administration 'cure-like' result, saving patients from hundreds of infusions per year per patient." The likes of Biomarin and Spark could even prove good takeout prospects, "either offensively or defensively, by existing players such as Shire to protect the business and/or offer a hedge on the threat," in his view.

Yee's colleague Douglas Miehm, who covers Shire, pointed out in a research report that prophylactic treatment with the latter's Feiba (factor VIII bypassing fraction) reduced the annual bleed rate (ABR) by 72.5 percent vs. on-demand treatment, "implying a greater than 72 percent ABR reduction" in HAVEN1. Thrombotic safety events remain troubling, "although we continue to believe that limiting access to Feiba is unlikely to resolve the issue," he said. In early December, Shire held a conference call to address "the concern that Novoseven [coagulation factor VIIa, Novo Nordisk A/S] could be used as the only bypassing agent to treat breakthrough bleeds in patients on emicizumab. Some patients respond better to Feiba and some react better to Novoseven."

In any case, Leerink's Gerberry found the TMAs with emicizumab worrisome. "Based on specialist feedback, more data in the broader hemophilia population are needed to better understand whether the TMA events are due to a drug-interaction issue or whether they will eventually emerge in emicizumab monotherapy patients," he wrote in a research report. "This is important, as the TMA signal from HAVEN has consistently been framed by specialists as 'too high' and will require more data to characterize the risk."