The DMD treatment pipeline boasts a number of therapeutics with varying mechanisms of action and delivery systems, pointing to a promising future for treatment.
Over the course of the last year, the pipeline for Duchenne muscular dystrophy (DMD) treatments has been supported by a number of ongoing assessments of investigational therapies for the neuromuscular disease.
In the second half of 2020, the first patient was enrolled into the phase 3 LELANTOS trial (NCT04371666) of pamrevlumab (FibroGen), phase 2a data (NCT02760277) on vamorolone (Santhera Pharmaceuticals) were released, and the FDA lifted a clinical hold on the phase 1/2 IGNITE DMD trial (NCT03368742) of the gene therapy SGT-001 (Solid Biosciences). Then, in January, the phase 3 CIFFREO study (NCT04281485) of another gene therapy, PF-06939926 (Pfizer), was launched, and open-label gene transfer study data suggested that SRP-9001 (Sarepta Therapeutics) holds promise as a therapeutic option.1-5
All of these pipeline updates came on the heels of the FDA approval of viltolarsen (Viltepso; NS Pharma) in August 2020, which marked just the second such approval for patients amenable to exon 53 skipping, a gene mutation that affects 8% to 10% of patients. The recent activity in the research and development of these therapies has brought some hope to those treating DMD, a disease that Amy D. Harper, MD, associate professor and medical director of the Muscular Dystrophy Association Care Center at Children’s Hospital of Richmond at Virginia Commonwealth University, once said “takes a village” to treat properly.
The treatments being evaluated are also reflective of the many novel approaches being taken to the disease. Three of the agents: SGT-001, PF-06939926, and SRP-9001, are microdystrophin gene therapies, with the first being AAV9-mediated, the second rAAV9-mediated, and the third rAAVrh74-mediated. Meanwhile, both pamrevlumab and vamorolone are first-in-class therapies, with the former an anti-inflammatory agent and the latter a connective tissue growth factor (CTGF) inhibitor.
The FibroGen therapy pamrevlumab is an antibody inhibitor of CTGF and is being assessed in roughly 90 patients in the LELANTOS study. Each will be randomized to receive either pamrevlumab plus systemic corticosteroids, or placebo plus systemic corticosteroids, for up to a 52-week treatment period. Patients will be evaluated on the change in the total score of performance of upper limb assessment from baseline. Elias Kouchakji, MD, senior vice president, clinical development, drug safety, and pharmacovigilance at FibroGen, told NeurologyLive in late 2020 that pamrevlumab’s unique formulation is what separates it from currently FDA-approved DMD treatments.1
“We’ve seen that this monoclonal antibody can block that CTGF from continuing to activate the myofibroblasts, reduce the motility and invasion, or the proliferation of the fibrosis,” he explained at the time. “There are many diseases that fibrosis is well defined, including idiopathic pulmonary fibrosis, interstitial lung diseases in general, DMD, invasive liver cirrhosis, and other cardiovascular diseases. By blocking CTGF, we are reducing the invasion of the fibrosis, blocking the activation of myofibroblasts, and reducing the deposition in the remodeling of the fibrosis.”
Kouchakji noted that replacing the dystrophin in some patients has led to improvements little by little, which blocking the fibrosis also achieves. Additionally, the trial of pamrevlumab is assessing the therapy by focusing on treating non-ambulatory patients—one of the least addressed populations in DMD clinical trials. This, Kouchakji explained, is the first step in beginning to really concentrate on how to modify this disease from fatal to chronic.
Santhera Pharmaceuticals published data from a multicenter, open-label, 24-week trial (VBP15-003; NCT02760277) and its accompanying 24-month long-term extension (VBP15-LTE; NCT03038399) that suggest that patients with DMD who were treated with vamorolone experienced motor outcome improvements compared to corticosteroid-naïve individuals, offering Class III evidence to support the benefit of motor function in boys with DMD with a 2- to 6-mg/kg per day dose. Notably, those data also showed that fewer physician-reported adverse events (AEs) occurred with the agent compared to reports of treatment with prednisone and deflazacort, nor was vamorolone treatment associated with stunted growth observed with those agents.2
At the time, Edward C. Smith, MD, associate professor of pediatrics, Duke University, and clinical investigator and lead author of the publication, noted that “treatment-related efficacy responses with vamorolone were similar to those seen in an external control group with corticosteroid-treated patients. Both 4-stair climb and 10-meter run/walk tests were significantly improved when compared to steroid-naïve natural history control subjects.”
Preliminary findings in February 2019 from IGNITE-DMD showed positive signs for Solid Biosciences’ microdystrophin gene transfer therapy SGT-001, which led to the company’s desire to dose escalate as planned and as soon as possible. Specifically, all 3 patients who were dosed with 5E13 vg/kg—the lowest dose in the study protocol—showed promising levels of microdystrophin protein expression. In a single patient, microdystrophin was detected via western blot below the 5% level of quantification of the assay, and via immunofluorescence in approximately 10% of fibers.3
The trial was then placed on hold in November 2019, after the third serious safety incident in the trial. In July of last year, the regulatory agency requested further information about manufacturing, as well as updated safety and efficacy data on all dosed patients, after which it offered direction on total viral load to be administered per patient. Solid’s response to the requests was deemed satisfactory by the FDA, and the hold was lifted.
“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, Solid Biosciences, in a statement in October 2020. “We are working diligently to complete all activities necessary to resume dosing, which we expect to occur in the first quarter of 2021.”
On December 29, 2020, the first patient was dosed in the double-blind, placebo-controlled CIFFREO study of Pfizer’s gene therapy, which is expected to enroll 99 ambulatory male patients aged 4 through 7 years, across 55 clinical trial sites in 15 countries. Researchers will use change from baseline in the North Star Ambulatory Assessment (NSAA) at 1 year as the primary end point of the study. In May 2017, the investigational agent received orphan drug and rare pediatric disease designations, and 3 years later, PF-06939926 received fast track designation from the FDA.4
“The initiation of our pivotal trial, which is the first phase 3 DMD gene therapy program to being enrolling eligible participants, is an important milestone for the community because there are currently no approved disease-modifying treatment options available for all genetic forms of DMD,” Brenda Cooperstone, MD, chief development officer, Rare Disease, Pfizer Global Product Development, said in a statement at the time.
Participants will be randomized into 2 cohorts, with treatment consisting of 2 single intravenous infusions, 1 of PF-06939926 and 1 of placebo. The first group will receive the investigational gene therapy at the start of the study and placebo after 1 year, while the reverse will happen in the second group, where the patients will start with placebo and then receive the gene therapy.
The Sarepta Therapeutics rAAVrh74-mediated gene therapy has recently shown promise in those who are ambulatory with DMD without preexisting AAVrh74 antibodies and on a stable corticosteroid dose. Findings from an open-label gene transfer study in adolescent patients with DMD announced in January 2021 suggest that microdystrophin gene transfer using rAAVrh74, driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression, is an effective therapeutic option for patients with DMD.
The Systemic Gene Delivery Clinical Trial for DMD showed robust transgene expression on muscle biopsy (74% to 96%) of fibers, but biopsy data reflects a small sample of muscle where muscle quality in large muscle groups can be objectively and noninvasively measured using quantitive MRI (qMRI) and spectroscopy (qMRS). Investigators wrote that qMRI and qMRS measures—including muscle fat fraction and bulk MRI transverse relaxation time—could be reduced in children treated with SRP-9001 compared to an age-matched natural history cohort treated with standard of care, as well as a control group of individuals without DMD.
Sarepta also has SRP-5051 in its pipeline, which recently showed promise in those amenable to exon 51 skipping, demonstrating proof-of-concept in this population with the data from the phase 2 MOMENTUM study (NCT04004065). The results of the study, announced in December 2020, support continued dose escalation.6