Gene Therapy Development Should Involve Fewer Surprises, Says US FDA’s Marks
Executive Summary
Regulators want to help smooth the process of bringing a gene therapy to market, hoping to iron out ‘surprises’ and even address reimbursement issues for the sake of patients.
Amid an ongoing crisis of confidence in the gene therapy field, senior regulators from the US and the EU have expressed willingness to help biopharma to reduce the hold-ups and surprises which have plagued the sector in recent times.
Speaking at a cell and gene therapy conference this week, the US Food and Drug Administration’s Peter Marks and the European Medicines Agency’s Ana Hidalgo-Simon said that regulators and industry needed to work together to address bottlenecks, such as trial endpoints, manufacturing issues and even market access.
These comments will be encouraging for the many gene therapy companies that are running low on cash and investor confidence. (Also see "Is The Downturn A ‘Darwinian Moment’ For Biotech? The View From The Frontline" - Scrip, 21 Apr, 2022.)
Among the potential blockbuster products which have suffered serious delays are BioMarin’s potential first-in-class hemophilia A therapy Roctavian (valoctocogene roxaparvovec) and bluebird bio’s beta thalassemia treatment Zynteglo (betibeglogene autotemcel), over efficacy and safety and quality control issues respectively.
Consistency Is Key
Clinical holds that the FDA imposed on trials surged last year, and research conducted by Jefferies analysts found that 40% of these were for cell and gene therapies.
Marks, who is director of the Center for Biologics Evaluation and Research at the FDA, said that a recent survey of trial sponsors conducted by the agency’s Office of Tissues and Advanced Therapies revealed a clear message – give us more consistent rulings and better communication.
“Sponsors were very vocal about the fact that they found it highly problematic when one of their gene therapy programs got advice on, for example, manufacturing, that was different than another one of their gene therapies that were very similar,” Marks told delegates at the American Society of Gene & Cell Therapy conference on 17 May.
However, he and his European counterpart Hidalgo-Simon said that agency “bandwidth” was finite, and sponsors could not expect regulators to replicate the 24/7 communications established for COVID-19 vaccines during the pandemic.
The FDA is nevertheless undertaking an internal review to help free up its experts’ time and allow for greater engagement with industry. Meanwhile, the EMA is spreading its workload out on this front across more of the regulatory agencies in the 27 EU member states.
Marks said problems of quality control in manufacturing, clinical trial endpoints and durability of efficacy were the biggest causes for regulatory delay to both clinical trials and the review of marketing applications. In manufacturing, the US regulator has frequently found inconsistencies between gene therapies in early studies and those manufactured later at a larger scale, raising questions about safety and efficacy.
The FDA was also sufficiently alarmed about the safety of AAV gene therapies to convene a panel of outside experts to review the issue in September 2021. (Also see "Gene Editing: Off-Target Effects Should Be A Key Safety Focus During Development, US FDA Says" - Pink Sheet, 16 Mar, 2022.)
Agreeing Surrogate Markers Upfront
The CBER director said one simple improvement to the gene therapy pathway would be to agree on surrogate endpoints before trials are begun, as presently these are often suggested once studies are underway.
This would allow sponsors to be “eyes wide open” as the gene therapy is developed, and would eliminate the chances of surprises, he said.
That point might raise eyebrows at some companies, which claim the FDA has sometimes moved the goalposts on pre-agreed trial data requirements, and sprung surprises in complete response letters (CRLs).
BioMarin is one such company; it raised objections after valrox received a CRL in August 2020. The firm claimed the agency had previously asked for one year’s post-treatment data, and that the first mention of the need for two-year follow-up data came only in the CRL.
Referring to the hemophilia field, Marks confessed that the agency had been surprised a number of issues, including problems of durability in the AAV candidates and measurements of Factor VIII. He said assays had not always provided an accurate picture of the patient’s condition, but nevertheless expressed confidence that these issues would be only a ”bump in the road.”
He added that the FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation allowed many ways for post-approval commitments to be met and could be agreed in advance.
Key reference points in this debate are drugs that have been granted accelerated approval by the FDA but where the companies in question have failed to meet post-marketing data commitments – for example, Biogen, Inc.’s Alzheimer’s disease treatment, Aduhelm (aducanumab-avwa), Sarepta Therapeutics, Inc.’s Duchenne muscular dystrophy drugs and numerous cancer therapies. This has generated so much controversy that the US Congress will now review whether to limit the accelerated approval pathways.
Marks said he hoped no major changes would be made, but admitted that the FDA needed to become “better policemen” to ensure confirmatory studies are completed in good time. (See sidebar.)
Confronting The Gorilla
While market access issues are traditionally outside the remit of regulators, both Marks and Hidalgo-Simon said these were a big stumbling block to bringing more cell and gene therapies to patients with rare or uncurable diseases.
Marks called reimbursement for the often very high cost treatments was “the 800-pound gorilla in the room” and said it was the reason why there was so much nervousness about drugs that are granted accelerated approval in the US.
Peter Marks
On the other hand, he noted that the value proposition for Novartis AG’s spinal muscular atrophy therapy, Zolgensma (onasemnogene abeparvovec), had been “overwhelming” – even with its record-breaking $2.1m cost. (Also see "US Vs. EU: Is Cell And Gene Therapy Reimbursement Easier Stateside?" - Scrip, 14 Oct, 2021.)
However, a therapy’s value remains more contentious for diseases that are not a matter of life or death. “How that issue is resolved, will potentially affect how many people go into this field to try to develop therapies,” he said.
In Europe, the problem has been even more stark, with health technology assessment (HTA) bodies setting a high bar for cost effectiveness evidence, and uncomfortable with accelerated approval based on surrogate endpoints. Last year, bluebird announced it was withdrawing its EU-approved gene therapies Zynteglo from all EU countries after failing to secure reimbursement in the key German market. (Also see "Bluebird Bio Decision in Europe Is A Wake-Up Call For Payers and Industry" - Pink Sheet, 30 Aug, 2021.)
It has also withdrawn from Europe another of its EU-approved gene therapies – Skysona (elivaldogene autotemcel), for the treatment of cerebral adrenoleukodystrophy. Hidalgo-Simon, who is head of advanced therapies at the EMA, said there had been several examples of rare disease therapies which had gained EU approval, only for companies to decide they were not commercially viable.
“That is a catastrophe for everybody, above all for the patients,” she said, adding that efforts of companies, regulators and patients in clinical trials must not go to waste.
Hidalgo-Simon and Marks agreed that international “convergence” on regulation was needed to help support global gene therapy studies for smaller, rare disease patient groups, and make the research more commercially viable. In addition, they called for more early discussions between sponsors and HTA organizations.
The fortunes of the sector could also be lifted by some expected marketing approvals. Three of the next biggest milestones will be for BioMarin’s Roctavian, which was filed with the EMA in June 2021 and is expected to be filed with the FDA at the end of June, and the US agency’s decision on two of bluebird’s candidates: Zynteglo for beta-thalassemia and Skysona, the latter two both to be reviewed by an FDA advisory committee on 9-10 June.