More than three months ahead of its Feb. 23, 2018, PDUFA date, Hemlibra (emicizumab-kxwh), a bispecific monoclonal antibody that brings together factors IXa and X to mimic the role of factor VIII (FVIII) and restore blood clotting, was green-lighted by the FDA to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A who develop FVIII inhibitors. The product was advanced by Roche Holding AG's Genentech unit in collaboration with Chugai Pharmaceutical Co. Ltd., which discovered the asset.

Nearly one in three people with severe hemophilia A can develop inhibitors to FVIII replacement therapies.

"This is really an exciting day for people with hemophilia A and, in particular, for these patients with inhibitors," said Gallia Levy, Genentech's associate group medical director, who led global development of Hemlibra. As the news sank in, Levy called approval of the first new treatment option in some two decades "a career-defining day for me" and acknowledged feeling moved about prospects to improve the clinical care and quality of life for affected patients.

"There's been very little innovation for patients with inhibitors," Levy told BioWorld. "Most of the innovation has been concentrated on the factor VIII products. The community has been waiting a long time for this."

With Hemlibra, granted priority review, orphan drug and breakthrough therapy designations by the FDA, Genentech is seeking to revolutionize treatment in the hemophilia A space. Prepared for an imminent launch, the company set the price at a wholesale acquisition cost (WAC) of approximately $482,000 for the first year of treatment, dropping to about $448,000 per year for the average weight hemophilia A inhibitor patient (58 kg). That price, according to Genentech, amounts to less than half of the WAC of Shire plc's FEIBA, an activated prothrombin complex concentrate and the only other approved prophylactic treatment for the affected population of hemophilia A patients.

The safety and efficacy of Hemlibra were evaluated in the phase III HAVEN 1 and 2 trials. In HAVEN 1, which enrolled 109 males 12 years or older with hemophilia A with inhibitors, those who received Hemlibra prophylaxis showed a statistically significant reduction in treated bleeds of 87 percent (95 percent CI: 72.3; 94.3, p<0.0001) compared to those who received no prophylaxis. In a first-of-its-kind intrapatient analysis, Hemlibra prophylaxis resulted in a statistically significant reduction in treated bleeds of 79 percent (95 percent CI: 51.4; 91.1, p=0.0003) compared to previous treatment with bypassing agent (BPA) prophylaxis collected in a non-interventional study (NIS) prior to enrollment.

HAVEN 1 also included patient-reported quality-of-life metrics as secondary endpoints. Individuals treated with Hemlibra reported improvement in hemophilia-related symptoms, such as painful swellings and joint pain, and physical functioning, such as pain with movement and difficulty walking, compared to those who did not receive prophylactic treatment. Some of the quality of life improvement is described in the label, which Levy called "quite unusual" and "meaningful to the community."

Interim results from the ongoing pivotal HAVEN 2 study in children younger than 12 with hemophilia A with inhibitors showed that 87 percent (95 percent CI: 66.4; 97.2) who received Hemlibra prophylaxis experienced zero treated bleeds. In an intrapatient analysis of 13 children who participated in the NIS, Hemlibra prophylaxis resulted in a 99 percent reduction in treated bleeds compared to previous treatment with a BPA as prophylaxis (n=12) or on-demand (n=1).

The most common adverse events (AEs), occurring in 10 percent or more of those treated with Hemlibra in pooled studies, were injection site reactions, headache and joint pain.

Hemlibra was approved for use at all ages among hemophilia A patients with inhibitors, a critical factor in the drug's marketing approach.

"These inhibitors develop, usually, in the first 50 to 100 times that people receive factor, so that is at a very young age – usually about 18 months," Levy said. "That is the population with the highest unmet need for therapies that work and that can be administered."

The prophylactic treatment is dosed weekly through subcutaneous injections, compared to FEIBA, which is delivered intravenously every few days.

'We've very happy with the label'

Genentech is conducting two additional phase III studies of Hemlibra. HAVEN 3 is evaluating the therapy as prophylaxis dosed once weekly or once every other week in people 12 or older with hemophilia A without inhibitors to FVIII, and HAVEN 4 is evaluating Hemlibra prophylaxis dosed every four weeks in people 12 or older with hemophilia A with or without inhibitors.

Although the agent goes directly to the site of the missing FVIII and mimics its function, Hemlibra's distinct mechanism of action enables the company to pursue the broader hemophilia A patient population, Levy said. Because the antibody binds to two other anticoagulation factors rather than replacing FVIII, "it doesn't get recognized by those inhibitors, so it really doesn't matter whether there's an inhibitor present or not for Hemlibra to work," she explained.

The HAVEN 3 data are expected to read out by year-end, "and we're really excited to see those results," Levy added.

Hemlibra was approved with a boxed warning that thrombotic microangiopathy (TMA) and thromboembolism were observed in patients taking the drug who were also given FEIBA as a rescue treatment to treat bleeds for 24 hours or more.

"We're very happy with the label," Levy said. "We feel that we have very well characterized the safety profile and that risk is well-described in the label. The black box warning helps to clearly communicate the risk to physicians and allow them to avoid it. We think that is actually the best way to educate the community."

Genentech has seen no additional TMA events in its trials since instituting a risk evaluation and mitigation strategy nearly a year ago that closely reflects the language in the boxed warning, she pointed out, and the company is continuing to monitor outcomes as studies of the agent – including those enrolling patients outside the U.S. – continue.

Still, the TMA events gave some analysts pause when the HAVEN 1 data were reported last year.

"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," observed Leerink analyst Jason Gerberry at the time. "This is important," he added in a research report, "as the TMA signal from HAVEN has consistently been framed by specialists as 'too high' and will require more data to characterize the risk." (See BioWorld Today, Dec. 23, 2016.)

The safety overhang also prompted Dublin-based Shire plc to challenge Roche's encroachment on the hemophilia A market by slapping a preliminary injunction on the Basel, Switzerland-based pharma, alleging that the description of AEs in HAVEN 1 was "inaccurate and misleading" and could compromise patient safety. (See BioWorld, July 11, 2017.)

Shire's FEIBA primarily contains non-activated forms of factors II, IX, X and activated factor VII.

The effort to stem competition proved fruitless, however. During an oral hearing at the Court of Hamburg in September, the court reviewed evidence from both parties and concluded that Roche did not engage in inappropriate promotional activities related to the HAVEN 1 data. Shire subsequently withdrew its application, closing the case, according to Genentech, which said Shire was liable for Roche's court and legal fees in relation to the proceedings.

Peak sales could reach $5 billion

Little second guessing was evident among analysts following Thursday's approval.

"Hemlibra (emicizumab) was approved three months before its PDUFA date, with a solid label, and it was priced to penetrate the non-inhibitor patient population, which is a bit of a risk since HAVEN 3 has yet to report, but may reflect Roche's confidence in the data," Cowen and Co.'s Steve Scala wrote in a company update. "[Key opinion leaders] with whom we checked cited no issues with the label, including the black box," he added, noting that surveyed physicians "expect substantial uptake in inhibitor patients and solid uptake in non-inhibitor patients."

The rapid approval "is testament to the significant unmet need," added Jefferies analyst Jeffrey Holford in a flash note. "Beyond its superior efficacy, Hemlibra's simple weekly subcutaneous injection will help transform the lives of patients that would otherwise require multiple infusions a week."

Pricing at an average discount of at least 50 percent over the current standard of care "on top of the superior clinical and dosing profile will aid rapid adoption and penetration of the market," Holford added, estimating a peak sales opportunity of $5 billion.

For Shire, Hemlibra's approval suggested more than a flesh wound in its important hemophilia franchise.

"Overall, we see the news as neutral/slightly negatively for Shire simply due to the early launch date," RBC Capital Markets analyst Douglas Miehm wrote in a first glance. "Our current forecasts already reflect a significant (73 percent) decline in inhibitor revenues for Shire from 2017 through 2025, with a more modest (24 percent) decline in non-inhibitor revenues. We would like to reiterate our view that the current share price implies a more extreme scenario for the company – one in which the hemophilia segment ceases to exist as of Q3/18 based on our outlook."

Piper Jaffray's David Amsellem laid out a more sobering forecast for Shire.

"In the wake of the approval of Roche's Hemlibra (emicizumab) in hemophilia A, we continue to believe that Shire faces an uphill battle regarding its ability to drive significant value creation given several longer-term challenges: (1) the obvious pressure that is looming on its hemophilia business, particularly considering that Roche is pricing Hemlibra competitively (not to mention the additional pressure associated with a favorable outcome from the HAVEN 3 study in non-inhibitor patients); (2) competitive headwinds associated with the HAE franchise, namely Haegarda and longer-term, potentially Biocryst's oral kallikrein inhibitor BCX-7353; (3) the loss of Vyvanse exclusivity in 2023 and the reality that Mydayis volumes are tracking well behind Intuniv in a similar stage of that product's launch; and (4) the potential for less aggressive volume growth for Xiidra once Restasis loses exclusivity."

In conclusion, he said, Shire's long to-do list represents "too many fires for management to put out."

In June, Shire tried another competitive tack when its Baxalta unit filed suit against Chugai over patent infringement claims involving emicizumab. The complaint, registered in the U.S. District Court for the District of Delaware, requested an injunction to prevent Chugai from manufacturing, using, offering or selling emicizumab in the U.S. or importing the drug to the U.S. Genentech also is listed in the suit. (See BioWorld, June 8, 2017.)

Undeterred, Genentech and Chugai are moving ahead with ex-U.S. filings. The marketing authorization application for emicizumab is already under review by the EMA, with a decision expected in the first half of next year.

On Thursday, shares of Roche, which trade on the Six Swiss Exchange (ROG.S), closed at CHF229.00 (US$230.32) for a gain of CHF1.20 (US$1.21). Shire's shares (NASDAQ:SHPG) gained $4.60 to close at $144.63.