"If we don't move toward accelerated approval, many patients will not be able to receive treatment in a timely manner. For many initial approvals of gene therapies, accelerated approval will become the standard process." Peter Marks said at a seminar held by the Reagan-Udall Foundation in Washington last week .

There are currently more than 10,000 rare diseases, but companies often struggle to bring treatments for these diseases to market due to small patient populations and financial constraints. Accelerated approval is a tool that can advance the development of innovative treatments and ensure that companies do not abandon promising treatments. Peter Marks said: "There are many gene therapies for rare diseases that are almost successful. The key question now is, how do we push them to the finish line smoothly?"

For gene therapy for rare diseases, a balance between supervision and science is needed. How to supervise gene therapy more scientifically is still a major issue that needs to be continuously explored, and the FDA’s regulatory stance is also constantly evolving. If there is no strict regulation, patients may have false hope and it will also bring a heavy burden on the medical system.

Confirmatory trials are required as part of the accelerated approval pathway, typically randomized controlled trials, to verify clinical benefit. But because these populations with life-threatening diseases are small, and it would be unethical to conduct placebo-controlled trials in some populations, the way these trials are conducted needs to be adjusted.

Marks' comments also reflect CBER's desire to research new biomarkers that could shorten the years-long approval process. He also announced that he will serve as chair of the FDA's new Accelerated Approval Committee to help advance reforms around accelerated pathways. It is important to note that the use of biomarkers that have not yet been certified is already common in the industry and is not a requirement prior to accelerated approval. Peter Marks believes that as long as the company can prove that it has an accurate and reproducibly measured biomarker, it does not necessarily require all the additional work to meet the standards.

Gavin Imperato of CBER's Office of Clinical Evaluation also said at the seminar that the regulatory system must evolve with the development of science. "That's why we favor the use of biomarkers and accelerated approval in some gene therapy cases." he explained.

Reactions to this signal have been mixed. Sarepta's Duchenne gene therapy Elevidys received accelerated approval last June, but Peter Marks said at a separate event on Monday that the treatment's approval should not be viewed as a typical approval, despite his previous pledge that even if confirmatory trials failed ,it will also expand the application scope of this therapy.

BIO's John Crowley, who will take over as CEO of BIO next month, disputes the idea that the FDA is using flexibilities or lowering barriers to treatment for certain rare diseases, saying: "We have at least 200 rare disease programs that have been halted, and we have There's so much hope and commitment and we're moving forward in our own way."

Ultragenyx CEO Emil Kakkis disclosed in an interview that he is developing an AAV gene therapy that has been preliminarily shown to rapidly reduce heparan sulfate levels in the cerebrospinal fluid of patients with Sanfilippo syndrome type A (MPS IIIA). He hopes the therapy will be approved in 2025, but the company has yet to formally submit an application. His understanding is that the person in charge of CBER has a very clear positive attitude towards accelerating approval. Enterprises cannot give up and need to continue to advance and take action.

Promising gene therapy for rare diseases

RP-L201 is a lentiviral gene therapy developed by Rocket Pharma for the rare genetic immune disease severe leukocyte adhesion deficiency type I (LAD-I). It uses lentiviral vectors to genetically modify autologous hematopoietic stem cells, which can make ITGB2 Genes are expressed normally.

Data from a global pivotal Phase I/II clinical study showed that after 12 months of treatment with RP-L201, 9 patients had a 100% survival rate, and all 9 LAD-I patients had hospitalizations, infections and inflammation-related hospitalizations. Hospitalizations and prolonged hospital stays were significantly reduced. At the same time, there is evidence that LAD-I-related rashes are resolved, symptoms of LAD-I-related skin lesions subside, and wound repair capabilities are restored.

Currently, Rocket has submitted a Biologics License Application (BLA) for RP-L201 to the FDA and received priority review, with a Prescription Drug User Fee Act (PDUFA) target action date of March 31, 2024.

SPK-9001 is a gene therapy drug developed by Pfizer/Spark for hemophilia B. It consists of liver-specific bioengineered capsid AAV2, liver-specific promoter and codon-optimized FIX-Padua transgene. The drug reduced the annual bleeding rate in treated patients by 71% and the rate of bleeding requiring treatment by 78% compared with standard care.

Last year, the BLA application for SPK-9001 for the treatment of hemophilia B was accepted by the US FDA and granted priority review. The FDUFA date is Q2 2024. After its launch, it will compete with existing gene therapies already on the market.

EB-101 is an autologous, COL7A1 gene-corrected epidermal patch for the treatment of patients with recessive dystrophic epidermolysis bullosa (RDEB). It can be described as a different kind of gene therapy. A clinical data study showed that the majority (81%) of pz-cel-treated wounds showed ≥50% healing, and greater pain severity was observed in pz-cel-treated wounds compared with control wounds of relief. The BLA submitted by Abeona has been accepted and granted priority review status. The PDUFA target date is May 25, 2024.

In addition, in February this year, REGENXBIO announced that the gene therapy RGX-121 under research achieved the primary endpoint in a pivotal clinical trial for the treatment of mucopolysaccharidosis type II (MPS II). The patients' cerebrospinal fluid D2S6 levels were reduced by an average of 86%. At close to normal levels, D2S6 is one of the key biomarkers of disease activity in the brain. In addition, the previous phase 1/2/3 trial data of RGX-121 for the treatment of MPS II patients under the age of 19 were positive, and reports showed that RGX-121 has continued to benefit patients for three years. These data will support the company's use of the accelerated approval pathway to submit a BLA to the US FDA in 2024, which is also a gene therapy that is expected to qualify.

Summarize

Overall, the signals revealed by Peter Marks are still very positive, which will help promote the development and marketing of gene therapies for rare diseases. Not only that, this is beneficial to the Sino-US dual reporting layout of domestic gene therapy companies or their overseas strategies. The development of gene therapies for rare diseases itself requires a lot of time and money, and clinical verification may be more difficult than for common diseases. Policies that are tilted when considering such therapies can better promote the enthusiasm of enterprises for research and development. Perhaps, for gene therapies whose costs cannot be significantly reduced for a while, in the future when the FDA accelerates approval and is more optimized, more companies will choose to list overseas, and this choice already has relatively successful precedents.

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