Should regulatory authorities agree with favorable results from Genentech’s ongoing Phase 3 studies of Hemlibra (emicizumab-kxwh), hemophilia A patients may have a treatment they can use regardless of inhibitor status, with a choice of three dosing schedules that might better match their lifestyle and preferences.
“The ultimate goal for the development program, when we started, was to have Hemlibra approved for hemophilia A patients with and without inhibitors, with three dosing schedules: every week, every two weeks, and every four weeks,” Gallia Levy, a hematologist and associate group medical director for Genentech, said in an interview with Hemophilia News Today. “The Haven 3 and 4 trials will hopefully support” this expansion, that “ultimate vision” since the therapy’s start almost 20 years ago.
Hemlibra is already approved as prophylaxis — or preventive treatment — for hemophilia A with factor VIII inhibitors in the U.S. (in November 2017), across the European Union (in March 2018), and in Australia, Japan, and elsewhere. Inhibitors are antibodies that prevent clotting factor therapies from working as they should.
Its approval, based on data from the Phase 3 HAVEN 1 and HAVEN 2 studies, marked the first new hemophilia A treatment in almost 20 years. It was a landmark event, particularly for patients with inhibitors, since for long “all research was focused on prolonging the half-life of factor VIII therapies … there was very little research focused at the inhibitor population, which is the population really with the highest unmet need in hemophilia,” Levy said.
Now, new and full data from the ongoing clinical trials — HAVEN 3 and HAVEN 4 — show that the therapy greatly outperforms current standard-of-care therapies, and its use leads to significant reductions in the number of bleeds both in hemophilia A patients with inhibitors and in those without them.
The population with inhibitors was the initial target for Hemlibra, intentionally.
“In our view, that was a population of highest unmet need, with an even higher need — the highest of the high — being in children with factor VIII inhibitors,” Levy said. “Because in those children, the burden of therapy causes really significant challenges for the family, especially the really young ones.” Patients with inhibitors need to use bypassing agents as prophylaxis, she said, and such agents can require every-other-day dosing for 45 minutes at a time.
No changes at molecular level were needed to make Hemlibra suitable to patients without inhibitors, meaning the therapy and its mechanism of action is exactly the same in both hemophilia A groups.
HAVEN 3 (NCT02847637), enrolled patients ages 12 and older without inhibitors. After an an initial loading dose of 3 mg/kg once a week for four week, they were randomized to receive no prophylaxis (i.e., treatment as-needed for bleeds), or to receive Hemlibra prophylaxis every week or every other week.
Treatment, given as a subcutaneous injection, will be maintained until the study’s end.
The new data covered HAVEN 3 patients treated every week for a median of 29.6 weeks, and every other week for a median of 31.3 weeks. They were shared at the World Federation of Hemophilia (WFH) 2018 congress that closed May 24 in Glasgow, Scotland, and which Levy was attending.
Researchers saw a 96% reduction in treated bleeds among those on weekly treatment (1.5 mg/kg), and a 97% reduction in patients treated every two weeks (3 mg/kg) compared to patients in the control, or as-needed, study arm.
Moreover, in a subgroup with prior factor VIII preventive use, patients underwent a 68% reduction in the number of bleeds.
“One of the interesting things that was not mentioned in the presentation,” Levy said, “is that all of the patients in HAVEN 3 remained on Hemlibra after 24 weeks, when they don’t have to stay in the study anymore.”
Hemlibra took about 10 years to fully develop, but the work began in 2001 with scientists at Chugai Pharmaceuticals, a member — like Genentech — of the Roche Group. The scientists worked to create and optimize a molecule “with all the properties they wanted to address this unmet need in both hemophilia populations.”
Next came “a Phase 1 trial in Japanese patients — treated 18 patients with and without inhibitors in Japan — and already there, even in the lowest dose cohort which was 0.3 mg per kilo, they saw really promising efficacy with many patients not having any more bleeds,” Levy said. “So, expectations were high” as the treatment advanced in studies.
Importantly, its long half-life allowed the current trials to test Hemlibra’s safety and effectiveness well beyond its approved once-a-week prophylaxis use. HAVEN 3 pushed treatment to twice monthly, while HAVEN 4 stretches it out to a possible once-a-month injection. (Both trials are due to conclude in the second half of 2019.)
Genentech set up the open-label, non-randomized HAVEN 4 (NCT03020160) study for patients with and without factor VIII inhibitors, given Hemlibra prophylaxis at 6 mg/kg every four weeks after the monthlong loading period.
The most recent results showed that 56.1% had zero bleeds, and 90.2% had three or fewer bleeds over at least 24 weeks of treatment.
“With a long half-life of 30 days, that’s the beauty of this. We can explore these different schedules,” Levy said. “The predictions were that the efficacy would be similar between the three dosing regimens, and it was wonderful to see that that bore out in the clinical trials.”
“Why just not select one?” we asked.
“Because ideal dose, it’ll be different for different people. For a young child at home, parents might think that Sunday night, while we’re packing the backpack for school, this is the time to do this — we’ll remember this. You go off to school and don’t think about it until next week,” Levy said. “For someone traveling with business, like me, you might prefer a monthly regimen … and then don’t worry about until four weeks later.
“It really is to provide patients with an option that works best for them and their lifestyle. Which one they choose is up to them in discussions with their physician,” she added.
Adverse effects, a key measure of safety, seen in each dosing regimen are in agreement with those previously reported.
“Most frequent are injection site reactions and there was not a difference — or not a meaningful one, anyway — in patients treated weekly, every other week and every four week regimens. We didn’t see that, which is good, and again supports the flexibility of the regimens,” Levy said.
No HAVEN 4 patients have opted to discontinue treatment and only one patient to date has done so in HAVEN 3 — important results given recent published reports of five deaths in patients on Hemlibra treatment. A sixth — an elderly patient with acquired hemophilia A — has also died since those March reports, Levy said.
Acquired hemophilia is more common in older patients with comorbidities like cancer, or autoimmune diseases, and differs from the congenital disease.
In all cases, a physician-led exam determined the cause of death was not related to Hemlibra, and “our own investigations agree with that assessment,” Levy said.
“We’ve gotten quite fond of the hemophilia community and quite close to some people, and we never want to hear about anybody having an adverse event. Having a fatality is always something that’s hard to hear about, and we take it very seriously,” she added, noting that Genentech has opened a website for healthcare professionals to periodically track fatalities, thrombotic events and the like. A similar site for patients and caregivers is planned.
The company also plans to ask authorities in the U.S., EU and elsewhere — “all again and more,” as Levy put it — to approve Hemlibra prophylaxis for hemophilia A patients without inhibitors and to add the new dosing regimens.
“Obviously, it will be up to the health authorities to look at the data and determine what the final indication will be,” she said. “We’re working with health authorities to file as quickly as possible. Ultimately, after that, it’s in their hands and we can’t speculate on timing.”
HAVEN 3 and 4 enrolled only patients 12 and older, but Hemlibra is approved for children under 12 with inhibitors, based on HAVEN 2 results. No new trials in pediatric patients are planned, she said.
Patient questionnaires show clear preference for Hemlibra over previous therapies, although their data — which will include differences in missed school and work days — are still being analyzed and not ready for release.
But stories from patients and physicians regarding the impact Hemlibra’s has had on their lives point to likely good results there, too.
“There’s one that I heard just a few minutes ago,” Levy said,” of a “little boy with an inhibitor whose parents are divorced and live sort of far away from each other. The treatments were so burdensome that the father couldn’t really take care of him and do all the injections. So he really was not seeing his dad all that much.
“Now that he’s on Hemlibra, he’s getting to spend more time with his dad, actually can spend weekends with his dad. And his mom is now able to apply for a job, something she hasn’t been able to do because she’s been staying home take care of him.
“Those sorts of stories are so touching to hear, and that’s what we hope,” Levy said, “for Hemlibra to be able to bring that kind of success to patients with hemophilia A, and those types of changes, to their lives.”