‘Huge Step Back’ for Hemophilia Gene Therapy, Expert Says of FDA Delay on Roctavian

The U.S. Food and Drug Administration (FDA)’s request for two years of additional clinical trial data on Roctavian, a potential gene therapy for hemophilia A, took its developer — BioMarin — and others in the hemophilia community by surprise.

That decision, announced in a complete response letter of Aug. 18 to BioMarin, likely pushed an approval decision back until 2022. It was expected on Aug. 21.

“I’m honestly shocked,” Guy Young, MD, a professor of pediatrics at the Keck School of Medicine of the University of Southern California and director of the Hemostasis and Thrombosis Program at the Children’s Hospital of Los Angeles, said in an Aug. 19 phone interview with Hemophilia News Today just hours after the news broke.

“I’ve been working in hemophilia for 22 years now, and this is the first product that I can recall that came through the FDA specifically for hemophilia, that was not approved right away,” Young said.

“I’m deeply disappointed, in particular for the people in the hemophilia community who have been waiting patiently to have a treatment … that could offer them the benefits of not having to use factor … of an improved quality of life.”

Trial data to date had “not a single report of a major safety issue,” he added, noting that safety is the FDA’s primary charge in evaluating a potential treatment’s value.

Young’s disappointment is shared by patients and their families, the Hemophilia Federation of America (HFA) said in a statement posted on its website.

The HFA added the community expects the FDA will “adhere to its established ‘gold standard’ review processes and rigorous science” in continuing evaluations of Roctavian. It will be following news of BioMarin and agency meetings closely.

Roctavian uses a harmless version of an adeno-associated virus (AAV), called AAV5, to deliver a shorter but functional copy of F8 — the gene that provides instructions to make factor VIII (FVIII) — to liver cells. FVIII is the blood clotting protein missing in people with hemophilia A.

Its goal is to restore the production of FVIII, lowering both the frequency of spontaneous bleeds and the need for repeated infusions of FVIII (replacement therapy), a current standard care for hemophilia A.

“It’s a setback of two years, and that’s a long time,” Young said.

Factor VIII durability a ‘concern’

In rejecting BioMarin’s biologics license application (BLA), filed in December 2019 and accepted by the agency under priority review, the FDA said it needed longer-term results from the Phase 3 GENEr8-1 clinical trial (NCT03370913), in addition to the six-month interim data on 16 patients that supported the BLA.

It was also concerned with differences between this trial, and an earlier Phase 1/2 study (NCT02576795) whose findings also supported BioMarin’s BLA.

Those differences, the agency said, limited its ability to judge Roctavian’s durability in raising factor levels.

Durability is a legitimate concern, Young said, noting dropping levels were seen in the earlier trial. “We in the academic community have questions about the durability of this product.”

But Phase 3 trial data reaching out two years after the last of its 134 patients is treated cannot definitively answer this concern.

“There is a continuing drop, and it is a slow but steady decrease,” he said. “I don’t see what the additional two-year data is going to offer.”

Questions posed by academic researchers center on “how long” this gene therapy will last, Young said. “When will patients drop to [factor VIII] levels when they’ll really need to start using [replacement therapy] again? Is it five years, is it eight years? Is it 10 years, is it 15 years?”

“Those are the questions we have,” he added.

Even with recorded drops, reassuring effectiveness over years was being shown by Roctavian.

Six of seven patients treated at the highest 6e13 vector genomes/kg dose in the Phase 1/2 study, which is the dose used in the Phase 3 trial, were free of spontaneous bleeds at a four-year trial update, as were five of six treated at a lower dose.

“There’s not a single report of a major safety issue,” Young said. And “if we look at factor usage and bleeds, they’re down to close to 100% — 96%, 97%.”

Factor VIII activity levels dropped from a mean of 64.3 IU/dL (international units per deciliter) one year after high-dose treatment to a mean of 24.2 IU/dL at four years post-treatment, a 63% decline, a company investor update on the World Federation of Hemophilia 2020 summit shows.

To Young, reasons for these declines are multiple and complex. Possible causes, he said, range from cell toxicity caused by the amount of viral vector introduced to liver cells — which are not the natural site of factor VIII production — that could trigger immune responses or a cell death process called apoptosis, to cell damage due to misfolding of the “complicated” factor VIII protein.

“Yes, we see declining levels,” Young said. “And what this information tells me, at least about this product, is this is not going to be a lifelong cure.”

“The vast majority of patients get into a good factor level, whether it’s a normal level or a close to normal level … and this could be a key benefit,” he said. “You can always go back to whatever treatment they’re getting now … It’s not like factor therapy is disappearing.”

Whatever price BioMarin planned to place on Roctavian upon approval — which reports indicated could be as high as $2 million to $3 million for one-time treatment — should not be part of the FDA’s decision.

“Their edict is to look at data being submitted, and determine if this treatment is safe,” Young said. “I think that, over the duration of time we have, which is close to five years, the treatment is safe.

“Long term we’re not going to know, but the FDA approves many drugs that we have no idea what the long-term effects are.”

No cure, but welcome ‘factor holiday’

Young is not an investigator on any of Roctavian’s trials, although he is working in a study of uniQure’s gene therapy AMT-061 for hemophilia B. He also has “hundreds of people with hemophilia that I take care of,” including multiple members of the same family with this genetic disease.

He sees gene therapy’s importance as offering not necessarily “a lifelong cure” — at least not for now — but a much needed “factor holiday” for adults who are either fed up with repeat factor infusions or too busy going about their lives to be properly adherent.

“I’m disappointed for my patients,” Young said, noting that he’s talked about this gene therapy with good number of them — setting expectations that now cannot be met.

“I was just talking to a patient literally yesterday at the clinic, thinking what a good candidate he would be. He’s not very adherent with his treatment,” Young said, “and he was all excited about it. Now I have to tell him, ‘remember what we talked about? Sorry, maybe in another couple of years.’

“The community had an expectation that we would have a product available this year,” he added.

Young faults himself and the pharmaceutical community for having raised expectations among patients of an “unmet need” being finally met to a reasonable degree. And he faults the FDA for apparently setting guidelines for data submission for an approval application — three- or four-year Phase 1/2 data, six-month interim Phase 3 data — then changing course.

“If the FDA at least had told” BioMarin of a need for longer-term data “at the beginning, then we would have known,” he said. “We wouldn’t have been expecting any approval this week.”

A possible setback for other gene therapies

In Young’s opinion, Roctavian’s setback will likely affect approval application requirements for other hemophilia gene therapies currently in development, particularly those at more advanced stages of testing.

Included in this category are uniQure’s AMT-061 for hemophilia B, and SB-525 for hemophilia A, which began under Sangamo Therapeutics and recently was taken over by Pfizer.

“If I were a Pfizer medical director working on [SB-525], I’d be really concerned right now,” Young said. “Why would the FDA not say the same thing to them? Why would they not tell Pfizer we want two-year Phase 3 data?”

The agency “put out guidance about gene therapy for hemophilia. And BioMarin followed that guidance, and yet here we are,” Young added. “That’s not fair to the company, never mind to my patients.”

“Personally, I think this is a huge step back for gene therapy in general in hemophilia.”