Earlier this year, the FDA granted approvals for two noteworthy gene therapy products. In one case, the product received accelerated approval with a review time of approximately 9 months and included an advisory committee meeting during the review cycle. The other product received full approval after a much longer review time that included a complete response letter and resubmission of the application.
ELEVIDYS (delandistrogene moxeparvovec-rokl)
On June 22, 2023, FDA granted accelerated approval for ELEVIDYS (delandistrogene moxeparvovec-rokl) for treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.
The BLA submission included data from three clinical studies: Study SRP-9001-101 (NCT03375164), Study SRP-9001-102 (NCT03769116) Part 1 and Part 2, and Study SRP-9001-103 (NCT04626674). As Studies SRP-9001-101 and SRP-9001-103 were open label, they were not considered by FDA as providing primary evidence of efficacy. Study SRP-9001-102 included a 48-week randomized, double-blind, placebo-controlled Part 1, and a “cross-over” in Part 2 (i.e., patients who received delandistrogene moxeparvovec-rokl in Part 1 were then administered placebo in Part 2, and vice-versa) with an additional 48-week treatment period. This allowed for patients who received placebo in Part 1 access to the gene therapy treatment without breaking the blind.
The primary efficacy review was based solely on the results of Part 1 of Study SRP‑9001-102. The primary efficacy endpoints of this study included change in the quantity of ELEVIDYS micro-dystrophin protein from baseline to Week 12, as measured by Western blot; and change in North Star Ambulatory Assessment (NSAA) Total Score from baseline to Week 48.
The FDA summary basis of regulatory action provides a summary of study design implications that are important learnings for sponsors to keep in mind in the design of clinical studies, especially in rare disease studies in which data from every patient is extremely important. These comments, which are provided below, further highlight the role of controlled studies in the assessment of efficacy and the pitfalls of open-label study designs. As I do not think that I could phrase the guidance better, it is repeated here.
“Study design has important implications for the interpretability of efficacy data for ELEVIDYS. Under certain circumstances, data obtained from open-label studies are readily interpretable: when the disease being studied is homogeneous, the treatment has a large effect, and the clinical endpoint can be objectively assessed. Those conditions, however, are not present here: progression of DMD is heterogeneous; improvement on the NSAA occurs with standard-of-care alone in patients aged about 4 to 6 years, such as those in the Applicant’s studies; any effect of ELEVIDYS is likely to be moderate; and the NSAA is effort-dependent and process-dependent. Thus, randomized, double-blind, placebo-controlled studies are necessary to clearly ascertain the effect of ELEVIDYS. The only data available that can provide reliable assessment of NSAA performance are those from Study 102 Part 1; these results constitute the primary basis for the recommendation by the Clinical and Statistical review teams for Complete Response for BLA STN 125781.”
This approval is noteworthy for the following reasons:
- It is the first accelerated approval for a gene therapy product;
- The efficacy is based on a surrogate endpoint, expression of ELEVIDYS micro-dystrophin in skeletal muscle at Week 12 in a subset of the patients included in the clinical program;
- The approval decision was made by Dr. Peter Marks, the Center Director, overriding the recommendation of some members of the FDA review team.
There are three criteria that must be fulfilled for accelerated approval. The indication must be serious or life‑threatening, there must be no available therapy or the new product must represent a significant improvement over currently available therapy, and efficacy based on a surrogate endpoint must be likely to predict clinical benefit.
In reading the review documents for this application, there is agreement among agency reviewers on the first two criteria. The point of dissention was the strength of the information that demonstrated that the surrogate endpoint (expression of ELEVIDYS micro-dystrophin in skeletal muscle at Week 12) was likely to support clinical benefit (increased mobility as measured by NSAA).
As always, the devil is in the details. The summary review documents state the following:
“As detailed in Section 5 Clinical Pharmacology, expression of ELEVIDYS micro-dystrophin was demonstrated, and increased with increasing dose of ELEVIDYS. However, no clear association was evident overall between expression of ELEVIDYS micro-dystrophin at Week 12 and change in NSAA Total Score at Week 48. Exploratory analysis of the limited data from patients aged 4 to 5 years (n = 8) suggested improvement in the NSAA Total Score with increased expression of ELEVIDYS micro‑dystrophin; no such association was observed in patients aged 6 to 7 years (n = 11).”
The Cellular, Tissue, and Gene Therapies 74th Advisory Committee reviewed the application on May 12, 2023 and the committee voted 8 to 6 in favor of accelerated approval in the subpopulation of patients 4‑5 years of age.
While it is the exception rather than the norm for FDA to accept data from a subset of the study population as the basis for a primary efficacy determination, a rationale was proposed based on the disease progression in DMD pediatric patients. The Center Director’s review memo states the following: “Because this clinical observation of physical decline after age 6 years may reflect a change in the underlying disease pathology related to any one of several different potential mechanisms of irreversible muscle injury, an analysis of the data confined to ages 4 through 5 years is not unreasonable.”
There were three prior products approved for DMD under accelerated approval based using a similar endpoint (EXONDYS 51 (eteplirsen) injection initially approved in 2016, VYONDYS 53 (golodirsen) injection approved in 2019, and AMONDYS 45 (casimersen) injection approved in 2021). These were antisense products, each of which targeted a confirmed mutation of the DMD gene that was amenable to that specific exon skipping. All three approvals included the requirement to confirm clinical benefit in a randomized placebo-controlled study using either the 6‑minute walk test or the NSAA. While these accelerated approvals provide a basis for the use of dystrophin production in the muscle as a surrogate endpoint, the validity of this endpoint has not been documented in confirmatory studies to date. As of the information posted in May 2023 on FDA’s website regarding post-marketing commitments, a study required to fulfill this requirement had not yet been received by FDA for any of the three products.
ROCTAVIAN (valoctocogene roxaparvovec-rvox)
The second approval granted this year was for ROCTAVIAN (valoctocogene roxaparvovec-rvox) for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency). In contrast to the previous application, this application, approved June 29, 2023, was for full approval and came after a longer review period. The application was initially received by FDA on December 23, 2019, a complete response letter followed, dated August 18, 2020, and resubmission occurred on September 29, 2022.
The clinical efficacy review focused on 112 patients in the “rollover population” in the Phase 3 Study-270-301 (NCT03370913). This was a single-arm, open-label, multinational trial that enrolled a total of 134 patients from 48 sites worldwide. Of the 134 patients (ITT population) in this study, 112 patients participated in Study 270-902, a non-interventional study wherein annualized bleeding rate (ABR) on routine FVIII prophylaxis was prospectively collected for at least 6 months prior to patients “rolling over” to Study 270-301 to receive valoctocogene roxaparvovec-rvox. Again, the devil is in the details. While Study 270-301 is a single arm study, in essence, the 112 patients whose data provided primary evidence of efficacy served as their own controls by virtue of the data collected in Study 270-902.
During the review of this application, there were additional submissions by the sponsor to provide longer follow-up of the patients in the studies. This included 2-year outcomes from the Phase 3 study, supportive data from 5 years of follow-up from the Phase 1/2 dose escalation study, and agreement to conduct a long-term extension study to follow all patients up to 15 years. Agreement was also reached on two post-approval registries. At the request of FDA, the application was again updated in November 2022 with 3-year data from the Phase 3 study and the Prescription Drug User Fee Act (PDUFA) date (the date by which the FDA must respond to a New Drug or Biologics License Application) was extended to June 2023. It is interesting to note that this product had Regenerative Medicine Advanced Therapy (RMAT) and Breakthrough Therapy designations granted by FDA.
In the EU, valoctocogene roxaparvovec-rvox received conditional approval (similar to accelerated approval in the US) in August 2022, almost 1 year prior to the FDA approval. In reviewing the European Public Assessment Report (EPAR), it is interesting to see the similarities and differences in the approach to the review taken by the two agencies.
An EU Marketing Authorization Application (MAA) had been previously submitted and was withdrawn on November 4, 2020. The MAA was resubmitted on June 25, 2021 including efficacy data up to 1 year in the Phase 3 study and up to 4 years in the Phase 1/2 study in patients who were treated at the intended dosage. During the review period, updated clinical data were submitted to include 2 years of data in all patients in the Phase 3 study, and up to 5 years of data from the Phase 1/2 study.
In consultation with the sponsor, a conditional marketing authorization was proposed and granted. The requirements to confirm the efficacy and safety included the submission of the final results, which included 5 years of follow-up in the Phase 3 study.
One of the considerations in the review of this application by both FDA and EMA was the durability of the effect; thus, the request for long‑term data.
While both products discussed here were for serious and life-threatening conditions, ELEVIDYS was designed to improve function in DMD patients. In contrast, for patients with severe hemophilia A, there are approved products to treat the condition; nevertheless, failure to control bleeding can be a life-threatening event, so potentially better-acting treatments such as ROCTAVIAN are still needed. Gene-therapy products promise the distinct advantage of one treatment providing a lasting benefit; yet, the need to follow patients to confirm long-term effect is one of the issues regulators face in determining approvability. We are reminded that the long-term (15 years) follow-up data FDA requests of sponsors of gene therapy trials serves two purposes: safety and demonstration of continued efficacy.
In conclusion, these two gene therapy products, for the treatment of two very different serious indications, were approved within a week of each other after very different review cycles. While these approvals represent great strides in the treatment of patients with these conditions, they remind us of what we know and what we need to continue to learn as we approach the development of gene therapies that will revolutionize the treatment of serious, debilitating and life-threatening conditions.
