PPMD is delighted to learn that the FDA has lifted the hold on Solid Biosciences’ IGNITE-DMD clinical trial for their gene therapy product (SGT-001) delivering a micro-dystrophin transgene via AAV9. Solid has worked diligently to address the concerns raised by the FDA shared in their July 2020 communication around the issues of manufacturing, safety, and efficacy.
As detailed in the press release below Solid has refined their manufacturing process, leading to less empty capsids being delivered in their product, a topic we covered during PPMD’s virtual conference. Solid has also adjusted their protocol to include additional preventative safety measures to help combat potential adverse reactions that can result from any high dose gene therapy delivery. For additional information on their clinical mitigation strategy, total viral load, and empty capsids, please see the glossary included in the community letter below.
These improvements in manufacturing and safety have prompted Solid to resume dosing patients at their pre-defined high dose of 2e14 vg/kg. Solid expects to resume dosing in the first quarter of 2021. The first two patients dosed with SGT-001 at that time will have a maximum weight of 18kg, this is part of their design to understand safety with their new manufacturing and mitigation strategies and will be evaluated before expanding to heavier patients.
We are hopeful that these improvements to their platform will enable safe and efficacious delivery SGT-001 and continue to drive our community towards a landscape where multiple gene therapy treatments are available for all.
Read Solid’s Community Letter:
Letter to the Duchenne Community: FDA Lifts Clinical Hold on IGNITE DMD Clinical Trial
Dear Duchenne Community,
We are pleased to announce that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold on IGNITE DMD, our Phase I/II clinical trial. We appreciate this community’s support, input and trust as we have worked hard these past several months to remove the clinical hold. We are relentless and motivated to make a meaningful impact on the lives of patients living with Duchenne.
As we shared in July 2020, in addition to requesting further manufacturing information and updated safety and efficacy data for all patients dosed, the FDA also provided direction on total viral load* to be administered per patient. Following its review, the FDA acknowledged that we have satisfactorily addressed all questions related to the clinical hold. We are looking forward to screening patients as soon as possible, with anticipated dosing in the first quarter of 2021.
After consultation with clinical and scientific experts, we have amended our protocol to strengthen the clinical risk mitigation strategy** to enhance patient safety. Our long-term goal is to treat every patient living with Duchenne, but we must work toward this goal in a stepwise manner. To support safe and continued dosing of SGT-001, we are reducing the maximum weight of the next two patients dosed to 18 kg per patient, with safety outcomes from these two patients driving potential weight increase of patients dosed subsequently.
Additionally, we provided updated safety and functional efficacy data for all patients dosed to date in IGNITE DMD. Of note, there have been no additional drug-related adverse events up to 30 months post dosing.
As part of our commitment to continuously improve our manufacturing processes, we have implemented changes that refine the purity of our product. This includes removing the majority of empty viral capsids*** in SGT-001, allowing target dosing to be achieved with fewer viral particles. Reducing the total amount of virus delivered to each patient is intended to support patient safety. Additionally, Solid submitted data from a new microdystrophin expression assay that demonstrates comparability between SGT-001 manufactured by the two processes.
By reducing the maximum weight of the next two patients and improving our manufacturing process to reduce the number of viral particles being delivered, we have addressed the FDA’s guidance on total viral load while allowing continued dosing at the 2E14 vg/kg dose.
We remain encouraged by the differentiated nature of SGT-001 and its potential to benefit patients living with Duchenne. We understand there are many questions regarding our next steps. While we do not have all of those answers at the moment, what we can tell you is that we are working with a sense of urgency with all necessary parties to get back into the clinic safely. We recognize the challenges that COVID-19 presents in all clinical trials and are working closely with our clinical sites and experts to make it as easy as possible for both existing and new patients to participate in the clinical trial.
We are looking forward to providing you with further information in the near future and encourage you to regularly visit the IGNITE DMD landing page for updates as they become available. If you have any questions, please feel free to contact us directly at Community@solidbio.com.
Your Solid Biosciences Team
Glossary of Terms
*Total viral load – also known as viral burden or viral titer, is a numerical expression of the quantity of virus in a given volume of fluid. For SGT-001 a benign virus (AAV9) is used to carry and deliver microdystrophin into all muscle cells. The amount of virus a person has inside them is referred to as their ‘viral load’.
**Clinical Mitigation Strategy – a detailed description of the activities and interventions in place to prevent or minimize risks of using a first in human medicine. For SGT-001 that now includes preventive use of both anti-complement inhibitor eculizumab and C1 esterase inhibitor, and an increase in prednisone in the first month post dosing.
***Empty viral capsids – A peculiar feature of AAV vector manufacturing is the formation of an excess of “empty” capsids, which in the case gene therapy for DMD means the viral carrier does not contain the microdystrophin and are therefore is unable to provide a therapeutic benefit but still adds to the viral load. By reducing the empty viral capsids the purity and potency of a drug can be increased which means less AAV is needed to deliver the same dose of drug.
Read Solid’s Press Release:
Solid Biosciences Announces FDA Lifts Clinical Hold on IGNITE DMD Clinical Trial
October 1, 2020 at 7:30 AM EDT
– Modifications to IGNITE DMD trial protocol and improvements to manufacturing processes enable continued program development –
CAMBRIDGE, Mass., Oct. 01, 2020 (GLOBE NEWSWIRE) — Solid Biosciences Inc. (Nasdaq: SLDB), a life sciences company focused on advancing meaningful therapies for Duchenne muscular dystrophy (Duchenne), today announced that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold placed on the Company’s IGNITE DMD Phase I/II clinical trial. As announced in July 2020, the FDA had requested further manufacturing information, updated safety and efficacy data for all patients dosed, and provided direction on total viral load to be administered per patient. Based on the Company’s response to these requests, the FDA acknowledged that the Company satisfactorily addressed all clinical hold questions.
“We are pleased that our team was able to address the FDA’s clinical hold questions, allowing us to restart the trial,” said Carl Morris, PhD, Chief Scientific Officer at Solid Biosciences. “We are working diligently to complete all activities necessary to resume dosing, which we expect to occur in the first quarter of 2021.”
As part of its commitment to continuously improve its manufacturing processes, Solid implemented and shared with the FDA manufacturing process changes that remove the majority of empty viral capsids, allowing target dosing to be achieved with fewer viral particles. This reduction in the total amount of virus delivered to each patient is intended to support safe dosing of SGT-001 for the duration of the IGNITE DMD trial. In its July 2020 communication, the FDA requested additional information regarding the comparability between SGT-001 made using Solid’s prior manufacturing process and its current, improved process. In response to this request, Solid submitted data from a new, quantitative, in vitro microdystrophin expression assay that demonstrates comparability between SGT-001 manufactured by the two processes.
Solid is reducing the maximum weight of the next two patients dosed to 18 kg per patient, with safety outcomes from these two patients driving potential weight increase of patients dosed subsequently. This reduction, in conjunction with the delivery of fewer viral particles as a result of the Company’s manufacturing process improvements, will reduce patients’ total viral load while continuing dosing at the 2E14 vg/kg dose.
Solid provided the FDA with updated safety and functional efficacy data (including 6-Minute Walk Test and North Star Ambulatory Assessment data) for all patients dosed to date in IGNITE DMD. There have been no additional drug-related adverse events up to 30 months post dosing. Additionally, to mitigate the risk of serious drug-related adverse events, Solid is amending the IGNITE DMD clinical protocol to include the prophylactic use of both anti-complement inhibitor eculizumab and C1 esterase inhibitor, and increasing the prednisone dose in the first month post dosing.
Solid’s SGT-001 is a novel adeno-associated viral (AAV) vector-mediated gene transfer therapy designed to address the underlying genetic cause of Duchenne. Duchenne is caused by mutations in the dystrophin gene that result in the absence or near absence of dystrophin protein. SGT-001 is a systemically administered candidate that delivers a synthetic dystrophin gene, called microdystrophin, to the body. This microdystrophin encodes for a functional protein surrogate that is expressed in muscles and stabilizes essential associated proteins, including neuronal nitric oxide synthase nNOS. Data from Solid’s preclinical program suggests that SGT-001 has the potential to slow or stop the progression of Duchenne, regardless of genetic mutation or disease stage.
SGT-001 is based on pioneering research in dystrophin biology by Dr. Jeffrey Chamberlain of the University of Washington and Dr. Dongsheng Duan of the University of Missouri. SGT-001 has been granted Rare Pediatric Disease Designation, or RPDD, and Fast Track Designation in the United States and Orphan Drug Designations in both the United States and European Union.