Not Such A Sure Thing: FDA Knocks Back BioMarin’s Roctavian
Company’s Hemophilia A Gene Therapy Gets A CRL
Executive Summary
BioMarin’s confidence that its first-ever hemophilia gene therapy would be cleared by the US FDA was shaken by a complete response letter that the company claims changed the requirements for approval.
BioMarin Pharmaceutical Inc. insists that it did not know that the US Food and Drug Administration wanted to see longer-term data on its gene therapy Roctavian (valoctocogene roxaparvovec) for severe hemophilia A until it received a complete response letter from the agency.
The CRL, announced 19 August and received a day earlier, was a complete surprise. BioMarin had been very confident, and publicly so, that the agency would approve Roctavian, which would be the first gene therapy for hemophilia, on its 21 August user fee date.
“Having previously agreed with the agency on the extent of data necessary to support the BLA, the FDA introduced a new recommendation for two years of data from the company's ongoing 270-301 study (Phase III) to provide substantial evidence of a durable effect using annualized bleeding rate (ABR) as the primary endpoint,” BioMarin said. “The agency first informed the company of this recommendation in the CRL, having not raised this at any time during development or review.”
Chairman and CEO Jean-Jacques Bienaime added that BioMarin is “surprised and disappointed that the FDA introduced new expectations for the first time in the complete response letter.”
Investors were surprised and disappointed as well. San Rafael, CA-based BioMarin’s stock closed down 35.3% at $76.72 on 19 August after the company revealed that it received the CRL. The FDA previously indicated available data from the Phase I/II and ongoing Phase III clinical trials would be sufficient to support the BLA filing, the company said, but now the agency wants two-year results from the Phase III trial, which won’t be available until late 2021. Analysts now anticipate Roctavian won’t launch in the US until 2023.
“The FDA rejection of BioMarin’s Roctavian isn’t so much of a surprise based on facts as it is a surprise relative to the company’s extreme level of confidence that the product would be approved,” Evercore ISI analyst Josh Schimmer commented in a 19 August note.
Phase I/II And III Differences Drive CRL
The CRL said differences between the Phase I/II and Phase III studies made it difficult to rely on data from the earlier study showing the durability of Roctavian’s effect on ABR, according to the company. One difference is that the gene therapy was produced for the Phase III trial using BioMarin’s commercial manufacturing process.
“While no details as to the specific differences between studies were provided, we see the main differences as being the change from one-stage to chromogenic assay, and the change to using a commercial-grade product in the Phase III study, which the FDA may be effectively viewing as a different product to that used in the Phase I/II study, especially in light of modestly lower FVIII expression at 12 months,” William Blair analyst Tim Lugo said in a 19 August note.
“We always had concerns whether the very disparate results between the Phase I/II dataset for Roctavian compared to the far less impressive interim Phase III results would support approval,” Evercore ISI’s Schimmer said.
BioMarin reported updated results from the Phase I/II trial from 13 hemophilia A patients treated with two different doses of the gene therapy in June, including seven patients treated with the higher dose for four years and six who received the lower dose for three years. While patients’ levels of Factor VIII expression had declined over time, all of the patients remained free from prophylactic use of infused Factor VIII products and the ABR was less than one bleeding event per year across both doses.
The 134-patient Phase III 270-301 trial testing the higher dose enrolled its last patient in November 2019, so two-year data won’t be available until November 2021 at the earliest.
“Accelerated approval was widely expected given robust durability data from the Phase I/II study and interim results from the ongoing Phase III study that met the pre-specified criteria agreed to with the FDA,” Baird analyst Michael Ulz said in a 19 August note.
“Overall, while we believe the CRL does create some near-term uncertainty, we believe [Roctavian] will ultimately be approved, supported by the ongoing Phase III study,” Ulz wrote. “Given the two-year data will not be available until late 2021, followed by a refiling, we anticipate at least a two-year delay in approval timelines with a launch in early 2023.”
BioMarin said it will meet with the FDA “in the coming weeks to align on next steps to obtain approval.”
EMA Review Pending, Delayed By COVID-19
Meanwhile, the European Medicines Agency (EMA) review of the Roctavian marketing authorization application (MAA) began in January and is ongoing, but the company said in June that while the EMA granted Priority Medicines (PRIME) status for the gene therapy and the MAA remains under accelerated assessment, the review may be extended by at least three months due to the COVID-19 pandemic.
Between a potential shift to standard review – which BioMarin said is the case with most filings that initially receive accelerated assessment – and COVID-19-related delays, the company noted that the EMA’s Committee for Medicinal Products for Human Use (CHMP) may not make its recommendation regarding approval until late 2020 or early 2021.
One benefit of a delayed launch, whether it’s in the EU next year or in the US in two or three years, is that patients may no longer be reluctant to visit health care facilities for infusions out of fear of exposure to the novel coronavirus. If the gene therapy had been approved in the US as planned in August, BioMarin expected the COVID-19 pandemic to be somewhat of a barrier to Roctavian treatment.
The gene therapy is expected to become a blockbuster, with analysts projecting peak annual sales in the $2bn range, but the size of Roctavian’s potential market is in question. There are about 20,000 people in the US with hemophilia A, but BioMarin has said the number of patients with severe disease and who fit the likely parameters for treatment is more like 5,000 people. The gene therapy is expected to be limited to hemophilia A patients age 18 and up who have never had Factor VIII inhibitors and who don’t have antibodies to the adeno-associated virus (AAV) that is used to deliver Roctavian. (Also see "BioMarin All Set For Hemophilia Gene Therapy Approval, But Is It Overestimating Demand? " - Scrip, 27 Feb, 2020.)
Patient numbers may also be limited by reimbursement challenges as payers struggle to reckon with the number of new high-cost cell and gene therapies reaching the market for more diseases and for indications with more patients than currently approved cell and gene therapies. (Also see "Progress Being Made With Cell And Gene Therapy Market Access, But Challenges Remain" - Scrip, 8 Oct, 2019.) and (Also see "Gene Therapies Will Be A Bigger Cost Issue In 2021, PwC Predicts" - Scrip, 24 Jun, 2020.)
Evercore ISI’s Schimmer said the readthrough from Roctavian’s CRL to other gene therapies is unclear.
“In particular, the two-year safety data requirement for Roctavian could be relevant, particularly for settings where there is already an established treatment option,” the analyst wrote. “But where there are no alternatives and a high unmet need, we believe programs will be reviewed on a case-by-case basis.”
However, at least one gene therapy company is sticking to its plans for accelerated approval without multiple years of safety and efficacy data. Baird analyst Madhu Kumar said in a 19 August note that uniQure N.V. has not received notice from the FDA or any other regulator that 26-week interim data will be insufficient for accelerated approval of its gene therapy candidate for hemophilia B. UniQure recently licensed global rights for etranacogene dezaparvovec to CSL Behring. (Also see "uniQure Hemophilia B Deal With CSL Leaves M&A Fans Miffed" - Scrip, 25 Jun, 2020.)
BioMarin Still In Hemophilia A Lead
BioMarin has a significant lead over other hemophilia A gene therapies. A Phase III registrational trial for SB-525 from Pfizer Inc. and Sangamo Therapeutics, Inc. will not start until later this year and a BLA filing isn’t expected until 2023, according to Biomedtracker. Roche Holding AG’s SPK-8011, which it acquired with the purchase of Spark Therapeutics, Inc. last year, also is expected to initiate dosing in a Phase III study this year. (Also see "Roche $4.8bn Buy Sparks Hemophilia Gene Therapy Race " - Scrip, 25 Feb, 2019.)
Roctavian is an important product for BioMarin, not just because of its blockbuster potential, but because it was expected to help offset future declining revenue for the company’s second-biggest seller, Kuvan (sapropterin dihydrochloride), after the phenylketonuria (PKU) drug loses patent exclusivity 1 October. Kuvan net sales of $244.6m in the first half of 2020 were up 11% from the first half of 2019.
“Given the significant [Roctavian] setback, we note that the company’s earnings will be more exposed to the upcoming generic competition to Kuvan, a product that we estimate will bring in $448 million in product revenue in 2020 or roughly 24% of the company’s revenue, which we now estimate to be $1.867 billion in 2020,” William Blair’s Lugo said.
He noted that “we see no easy fix to the negative impact on the company. We note that the company continues to expect to file a BLA for vosoritide in the United States within the quarter, and that the EMA recently validated its vosoritide application, though we expect the launch of vosoritide to be a much more modest ramp and upcoming Kuvan generic competition will likely dampen any meaningful ramp in revenue.”
BioMarin has said it expects to launch vosoritide for achondroplasia in late 2021. (Also see "BioMarin Eyes Late 2021 Launch As Achondroplasia Drug Succeeds In Phase III " - Scrip, 16 Dec, 2019.)