Yesterday July 11, 2018 the FDA FDA issues 6 new draft guidance documents for gene therapy, clinical development and manufacturing guidance.
Pre-existing antibody to the GT product may limit its therapeutic potential. Sponsors may choose to exclude patients with pre-existing antibodies to the GT product. In such cases, the sponsor should strongly consider contemporaneous development of a companion diagnostic to detect antibodies to the GT product. If an in vitro companion diagnostic is needed to appropriately select patients for study (and later, once the GT product is approved, for treatment), then submission of the marketing application for the companion diagnostic and submission of the biologics license application for the GT product should be coordinated to support contemporaneous marketing authorizations.The FDA prefer randomized & controlled study, and I believe Cohort C of the micro-dystrophin study can be used as pivotal
for a BLA filing under accelerated approval conditions.
Treatment arm, n=12, Placebo arm, n=12 then Crossover at 1 year
So, this trial can be used as the base for the registration study – which is supported by the FDA guidance published today.
- The randomized, concurrent-controlled trial is generally considered the ideal standard for establishing effectiveness and providing treatment-related safety data. Randomization in early stages of development is strongly encouraged when feasible.
- Sponsors should consider designing their first-in-human study to be an adequate and well-controlled investigation that has the potential, depending on the study results, to provide evidence of effectiveness to support a marketing application.
- To promote interpretability of data for studies that enroll subjects with different disease stages or severities, sponsors should consider stratified randomization based on disease stage/severity.
- A single-arm trial using historical controls, sometimes including an initial observation period, may be considered if there are feasibility issues with conducting a randomized, controlled trial
- If use of a type of single-arm trial design with a historical control is necessary, then knowledge of the natural history of disease is critical. Natural history data may provide the basis of a historical control, but only if the control and treatment populations are adequately matched, in terms of demographics, concurrent treatment, disease state, and other relevant factors. In circumstances where randomized, concurrent controlled trials cannot be conducted and the natural history is well characterized, sponsors may consider the clinical performance of available therapies (if there are any) when setting the performance goal or criteria against which the product effect will be tested.
- A small sample size, together with high inter-subject variability in clinical course, diminishes a study’s power to detect treatment-related effects. Therefore, alternative trial designs and statistical techniques that maximize data from a small and potentially heterogeneous group of subjects should be considered. Ideally, utilizing as an endpoint a treatment outcome that virtually never occurs in the natural course of the disease would greatly facilitate the design and cogency of small trials.
- Adequate measures to minimize bias should be undertaken. The preferred approach to minimize bias is to use a study design that includes blinding
These points should be discussed with the FDA. CK is the way the kids get diagnosed, it’s the best marker of muscle damage, and it should be used as a validated endpoint, but they have to get the agencies position. It’s good to have such a compelling data like the CK levels reduction in hand to show to the FDA rather than only having a theoretical discussion. During the meeting they will discuss the requirements for the trial design and the FDA will need to decide the surrogate markers and endpoints that will allow full approval.
We already know that truncated Dystrophin (shortened dystrophin via exon skipping) was used as the biomarker for AA for Eteplirsen. So why would micro-dystrophin not be approved by the FDA as a biomarker? The most skeptical of FDA officials said during the AdCom, “If the drug made 10% of normal we wouldn’t even be here right now” – I.e. we wouldn’t even hold an AdCom to decide the approval question. So how about 4 times that amount with micro-dystrophin? Will these officials keep their word to the DMD patient community?
Our expectation are getting the micro-dystrophin gene-therapy full approved by late 2019 – early 2020.
We learned from Eteplirsen that truncated dystrophin is functional, but we don’t know yet if the micro-dystrophin is functional. But in light of the data already presented at the R&D day, it is hard to say micro-dystrophin is not functional; you see a drop in CK level which is very clear and remarkable, as well as demonstration of the DAPC (Dystrophin-Associated Protein Complex) being formed, you see alpha and beta-Sarcoglycan, two important components of the dystrophin-associated complex are completely restored, which is critical for function. Added to that is the reciprocal stair climbing by patients after dosing which is not something seen with the natural history of the disease at the ages of these patients.
LGMD – Limb-Girdle Muscular Dystrophy
The same way we consider the new FDA guidance as bullish for SRPT’s DMD program, we should also notice the LGMD study and similarity with the DMD micro-dystrophin study. SRPT already moved on with the LGMD2E study, the FDA granted permission to move directly to a systemic, IV delivery Phase 1/2a study; as a result, LGMD2E will move into systemic trials before other LGMD programs.
The use of AAVrh74.MHCK7 micro-dystrophin paves the way with modular design that decreases time for approval, rh74 AAV was chosen due to superior skeletal muscle transduction in preclinical testing. Muscle cells do not divide and rh74 AAV transduced muscle fibers should be protected indefinitely, rh74 provides superior systemic delivery, including to the heart muscle. and from the R&D day slides we saw that the systemic delivery of the construct reduces CK, a muscle damage biomarker as well.
SRPT will start the study in 3Q-2018, the study MYO-101 (LGMD2E) IV Phase 1/2a design. Cohort 1 with 60-day biopsy and the data will be presented in early 1Q-2019.
The LGMD2E trial protocol:
Randomized, double-blind, placebo-controlled
• Single IV infusion of the construct or placebo
- 9 subjects: 2 cohorts, 2 dose levels
- 2:1 active:placebo cohort 1 @ 5 x 1013 vg/kg
- 4:2 active:placebo cohort 2 @ 2 x 1014 vg/kg if <50% fiber expression
- 3 placebo crossovers after 1-year reading of Subject 9
• Primary: Safety and Gene expression (≥20% of muscle fibers expressing β-sarcoglycan vs baseline)
• Secondary (functional): 100-meter time, workspace volume, 6MWT, NSAA, MVIC, testing of knee extensors and flexors, cardiac ejection fraction by MRI, TUG, ascend 4 stairs.
Disclosure: Author is Lon SRPT.