The Pennsylvania biotech company CSL Behring says it is on track to file for approval of its hemophilia B gene therapy by the end of June after releasing pivotal data showing statistical superiority over current standard-of-care treatment 18 months after infusion.

The Phase III HOPE-B trial (NCT03569891) showed that a single infusion of EtranaDez (etranacogene dezaparvovec) generated a stable and durable increase in mean Factor IX (FIX) activity and hemostatic protection that outperformed prophylactic infusions of FIX intended to temporarily replace or supplement low levels of the blood-clotting factor.

According to CSL Behring, EtranaDez produced mean FIX activity of 39.0 IU/dL at six months and 36.9 IU/dL at 18 months post-infusion. After the six-month lead-in period post-infusion, the adjusted annualized bleeding rate (ABR) (1.51) for all bleeds was reduced by 64%, while ABR for all FIX-treated bleeds was reduced by 77%, from 3.65 to 0.83 over months 7–18.

CSL Behring added that 98% of subjects treated with a full dose of EtranaDez stopped their use of prophylaxis, with an overall 97% reduction from lead-in period to months 13–18 in mean unadjusted annualized FIX consumption, from 257,338 IU/yr/participant to 8,486 IU/yr/participant.

Steven Pipe, MD, principal investigator of the HOPE-B trial assessing CSL Behring’s gene therapy candidate EtranaDez in Hemophilia B patients

“This met the highest expectations of what we were looking for from a gene therapy intervention,” Steven Pipe, MD, the principal investigator of the HOPE-B trial, told GEN Edge. Pipe is Pediatric Medical Director of the Hemophilia and Coagulation Disorders Program at the University of Michigan, where he is a professor of pediatrics and pathology.

Pipe said the decline of investigator adjudicated FIX treated bleeds, to less than one annualized bleed rate per year, highlights “how impressive the efficacy is for the patients and really good correlation with the Factor IX levels.”

EtranaDez is a gene therapy that uses adeno-associated virus type 5 (AAV5) to deliver to patients the Padua gene variant of Factor IX (FIX-Padua), a gain-of-function protein variant also known as FIX-R338L. FIX-Padua has 5-8 times more activity than normal FIX.

CSL Behring cites preclinical and clinical data that have shown AAV5-based gene therapies to be clinically effective in up to 95% of hemophilia B patients with pre-existing antibodies to AAV vectors—thus potentially increasing patient eligibility for treatment compared to other AAV gene therapy product candidates.

“If you look at the people we screened for this trial, 42.6% of them had neutralizing antibodies that, in any other trial, would have excluded them from participating. This brings promise that we can greatly expand the eligibility of this treatment to a broader population of patients,” Pipe said.

Stopping FIX infusions

HOPE-B was an open label, single-dose, single-arm trial designed to assess EtranaDez in 54 male participants with severe or moderately severe hemophilia B. Of the 54 participants, 52 (96.3%) were able to stop prophylactic FIX infusions, with none of the 52 returning to prophylaxis during the study period.

Of the two who did not respond to treatment, one showed an AAV5 neutralizing antibody titer of 3,212, while the other received part (~10%) of the planned dose.

“It was anticipated that AAV5 might have a lower overall serial prevalence of neutralizing antibodies in the population compared to other vectors like AAV8 or AAV2 that have been used in some trials. That was the original hypothesis,” Pipe said. “AAV5 had shown that it can direct transgenes to the liver, and so that was part of its choice.”

“But the other thinking, which I think has been realized in this trial, is that even if patients did have cross reacting antibodies to AAV5, those antibodies originally wouldn’t have developed in those patients because of a specific response to a wild type in the community AAV5 virus,” Pipe explained. “These neutralizing antibodies we’re measuring in vitro are cross-reacting antibodies that were derived from exposure to other AAVs. These may actually have a lower affinity for the AAV5 vector. And this may be what’s allowing us to treat through these high titers of AAV5 neutralizing antibodies, and still get a good efficacy result.”

CSL Behring researchers presented final data from HOPE-B at the European Association of Haemophilia and Allied Disorders (EAHAD) 2022 Annual Meeting, after the company announced topline results in December.

Brahm Goldstein, MD, MCR, CSL Behring’s Vice President, Hematology Research and Development

“It’s actually in line with what we were expecting, so it was very reassuring that our due diligence proved to be accurate,” CSL Behring’s vice president, Hematology Research and Development Brahm Goldstein, MD, told GEN Edge. “It’s just a really novel, almost revolutionary, first gene therapy program for hemophilia B patients that really is going to impact many, many lives.”

Based on the trial data, Goldstein said, CSL Behring is planning to submit applications for approval of EtranaDez to the FDA and European Medicines Agency (EMA) during the first half of the year. EtranaDez has been granted the FDA’s Breakthrough Therapy designation as well as access to the EMA’s Priority Medicine (PRIME) program.

EtranaDez is one of two gene therapies for hemophilia B that are in late-stage development.

The other is fidanacogene elaparvovec (PF-06838435), a gene therapy developed by Spark Therapeutics, a member of the Roche Group, under the name SPK-9001, but whose clinical development is now overseen by Pfizer under a collaboration launched in 2014. Pfizer agreed to pay Spark $20 million upfront and up to $260 million in development and commercialization milestone payments for fidanacogene elaparvovec and “multiple” hemophilia B product candidates.

Pfizer data delay

EtranaDez’ chances of crossing the proverbial finish line to approval first were brightened last November: Mikael Dolsten, MD, PhD, Pfizer’s chief scientific officer and president of Worldwide Research, Development & Medical, told analysts that it was delaying its interim readout of Phase III data from 40 participants in BENEGENE-2 to the first quarter of 2023 from 2021 “based on recent interaction with the FDA.”

Fidanacogene elaparvovec is a bioengineered AAV vector designed to deliver a high-activity F9 transgene for hemophilia B. The gene therapy has received both breakthrough therapy and orphan product designations from the FDA. Pfizer is leading the Phase III BENEGENE-2 trial (NCT03861273), designed to evaluate the efficacy and safety of fidanacogene elaparvovec in 43 adult men with moderately severe to severe hemophilia B (FIX circulating activity of 2% or less).

Also developing a gene therapy for hemophilia B is Freeline Therapeutics. Freeline’s FLT180a is a liver-directed AAV gene therapy consisting of a proprietary engineered capsid (AAVS3) containing an expression cassette encoding FIX-Padua.

Freeline is carrying out the Phase I/II dose-confirmation B-LIEVE trial (NCT05164471) designed to confirm a dose and immune management for a future Phase III pivotal trial of FLT180a. The trial will use commercial scale manufacturing and a starting dose of 7.7e11 vg/kg and a short course of prophylactic immune management. The first patient was dosed this week. The company has said it expects to complete dosing and report data from the first dose cohort in B-LIEVE in the first half of 2022.

B-LIEVE was launched in the fourth quarter of 2021—a quarter ahead of its guidance to investors—after identifying a sufficient number of patients to fully enroll the trial through its ECLIPSE run-in study (NCT04272554). In December at the 63rd American Society of Hematology (ASH) Annual Meeting in Atlanta, Freeline presented positive data from the Phase I/II B-AMAZE dose-finding trial (NCT03369444) where patients showed sustained expression of Factor IX up to three and a half years after treatment with FLT180a.

CSL Behring already markets a therapeutic for hemophilia B, IDELVION® [Coagulation Factor IX (Recombinant), Albumin Fusion Protein]. Launched in 2016, IDELVION is one of two marketed products accounting for more than $1.1 billion in hemophilia product sales in the fiscal year ending June 30, 2021, down 4% from a year earlier (The other is AFSTYLA®, a recombinant Factor VIII product for Hemophilia A).

Growing Sales

Parent company CSL does not break down how much of that was IDELVION sales, but has disclosed that sales of that product grew 17% in the second half of 2021 and two percent in FY 2020–21, when according to the company IDELVION commanded a 45% global share of recombinant FIX prophylaxis patients, including a 44% share in the U.S.

Goldstein said CSL Behring is also continuing its clinical program for EtranaDez, with plans for a longer-term “rollover” extension study of patients currently in HOPE-B, and plans to proceed with studies in younger patients over several years. The extension study will start when patients get through the five-year period for HOPE-B and “roll over” if they choose.

“In terms of the pediatric studies, we’re currently moving forwards with the next lower age group, and hope to have that moving significantly moving forward within the next year or so,” Goldstein said.

EtranaDez (also known as CSL222) was originally developed by uniQure as AMT-061. uniQure has licensed exclusive global rights to the gene therapy program to CSL Behring for up to $2 billion consisting of $450 million in upfront cash, and up to $1.6 billion in payments tied to achieving regulatory and commercial milestones, plus royalties. The licensing deal was announced in June 2020, but took effect last year after completion of antitrust review in the U.S., the United Kingdom, and Australia.

Under the companies’ licensing agreement, uniQure agreed to complete the HOPE-B trial and scale up manufacture for early commercial supply under an agreed plan with CSL Behring.

Because EtranaDez came from uniQure, its AAV5 platform differs from CSL Behring’s other candidates. CSL Behring added capabilities to develop ex vivo hematopoietic stem cell (HSC) gene therapies for incurable genetic diseases in 2017 when it acquired Calimmune for up to $416 million, including $91 million upfront.

“We have a different platform that we have developed internally. However, this program [EtranaDez] was so compelling and we thought the promise was such that it was worth the investment in obtaining this, and getting the licensing, so that we can help our hemophilia B patients,” Goldstein said.

“We are still determining if we would be expanding our platforms moving forward,” he added. “Obviously we have expanded it to AAV, and we’ll just have to see what other opportunities may arise that are associated with this.”

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