Sarepta Therapeutics, Inc. (NASDAQ: SRPT), positioning itself as a leader in precision genetic medicine for rare diseases, recently announced positive results from the ongoing study of SRP-9003 (rAAVrh74.MHCK7.hSGCB), the company’s investigational gene therapy for limb-girdle muscular dystrophy Type 2E (LGMD2E). Results included 18-month functional data from three clinical trial participants in the low-dose cohort and 6-month functional data from three participants in the high-dose cohort. SRP-9003 is in development to treat LGMD2E (also known as beta-sarcoglycanopathy and LGMDR4), a devastating monogenic neuromuscular disease caused by a lack of beta-sarcoglycan proteins. SRP-9003 is a gene construct that transduces skeletal and cardiac muscle, delivering a gene that codes for the full-length beta-sarcoglycan protein, the absence of which is the sole cause of the progressive degeneration and a shortened lifespan characterized by the disease. The research is conducted at the world’s top gene therapy research center: Nationwide Children’s Hospital. In fact, the LGMD2E gene therapy program was developed at the Abigail Wexner Research Institute at Nationwide Children’s Hospital. Sarepta has secured the exclusive rights to this gene therapy.
No Approved Treatments
An inherited condition, this disease triggers deterioration of the skeletal muscles, particularly around the hips and shoulders. The disease materializes when the individual struggles to walk, climb stairs, and other basic tasks, most commonly diagnosed in childhood. But there are exceptions: mild cases are known to materialize in adulthood. A progressive disease, LGMD2E as muscles waste to the point that the patient requires a wheelchair. A weakening heart muscle represents another challenging feature of this genetic disease; hence physicians must monitor cardiac function. With no cure, physical therapy is employed to help patients retain mobility. The disease doesn’t impact intelligence or mental function, for that matter. It often leads to early mortality.
Limb-girdle muscular dystrophies are genetic diseases that cause progressive, debilitating weakness and wasting that begin in muscles around the hips and shoulders before progressing to muscles in the arms and legs. Patients with limb-girdle muscular dystrophy Type 2E (LGMD2E) begin showing neuromuscular symptoms such as difficulty running, jumping, and climbing stairs before age 10. The disease, which is an autosomal recessive subtype of LGMD, progresses to loss of ambulation in the teen years and often leads to early mortality. There is currently no treatment or cure for LGMD2E.
Sarepta has five LGMD gene therapy programs in development, including subtypes for LGMD2E, LGMD2D, LGMD2C, LGMD2B, and LGMD2L, and holds an option for a sixth program for LGMD2A.
Executive Point of View
Louise Rodino-Klapac, PhD senior vice president of gene therapy, Sarepta Therapeutics, commented on the progress “It’s very encouraging that we continue to see consistent, positive data from our investigational gene therapy SRP-9003 across several measures, as we know the community needs more options.” Mrs. Rodino-Klapac continued, “The improvements in functional measures at 18- and 6- months in participants from both cohorts who received SRP-9003 are distinctly different from what an age-matched, natural history group would predict with LGMD2E. This sustained durability of the response in functional outcomes reinforces that SRP-9003 is getting to the muscle and suggestive of improvement against disease-mediated muscle damage. When coupled with the strong expression results and encouraging safety profile seen to date, today’s results increase our confidence in the construct and provide additional evidence as we advance the higher dose of SRP-9003 into the next stage of clinical testing.”
Efficient transduction in skeletal muscle and robust beta-sarcoglycan protein expression was seen in both dose cohorts following infusion with SRP-9003, and significant creatine kinase (CK) reductions were observed at 90 days. Cohort-specific results as follows:
Cohort 1 (low dose), at 18 months:
· All three participants continued to show improvements from baseline across all functional measures, including the North Star Assessment for Dysferlinopathies (NSAD), time-to-rise, four-stair climb, 100-meter walk test, and 10-meter walk test.
· The mean NSAD improvement from baseline was 3.0 at six months and 5.7 at 18 months.
· There have been no new drug-related safety signals observed since the one-year update in June 2020, and no decreases in platelet counts outside of the normal range or signs of complement activation were observed.
Cohort 2 (high dose), at six months:
· All three participants demonstrated improvements from baseline across all functional measures, including the NSAD, time-to-rise, four-stair climb, 100-meter walk test, and 10-meter walk test.
· The mean NSAD improvement from baseline was 3.7.
· There have been no new drug-related safety signals observed since expression results were shared in June 2020, and no decreases in platelet counts outside of the normal range or signs of complement activation were observed.
About SRP-9003 and the study
SRP-9003 uses the AAVrh74 vector, designed to be systemically and robustly delivered to skeletal, diaphragm, and cardiac muscle, making it an ideal candidate to treat peripheral neuromuscular diseases. AAVrh74 has lower immunogenicity rates than reported with other human AAV vectors. The MHCK7 promoter has been chosen for its ability to robustly express in the heart, which is critically important for patients with limb-girdle muscular dystrophy Type 2E (LGMD2E), also known as beta-sarcoglycanopathy and LGMDR4, many of whom die from pulmonary or cardiac complications.
This first-in-human study is evaluating a single intravenous infusion of SRP-9003 among children with LGMD2E between the ages of 4 and 15 years with significant symptoms of the disease. The SRP-9003 study has two cohorts, each studying a different dose-per-kilogram based on the patient’s weight. Three participants in the low-dose cohort (Cohort 1) were treated with a one-time infusion of SRP-9003 dosed at 5×1013 vg/kg, and an additional three participants in the high-dose cohort (Cohort 2) received a one-time infusion dosed at 2×1014 vg/kg. The six participants were between the ages of 4 and 13. Post-treatment biopsies were taken at 60 days.
About Sarepta Therapeutics
At Sarepta, they declare the drive toward a revolution in precision genetic medicine, and every day is an opportunity to change the lives of people living with rare diseases. The company has built an impressive position in Duchenne Muscular Dystrophy (DMD) and gene therapies for Limb-Girdle Muscular Dystrophies (LGMDs), Mucopolysaccharidosis type IIIA, Charcot-Marie-Tooth (CMT), and other CNS-related disorders, with more than 40 programs in various stages of development. The company’s programs and research focus span several therapeutic modalities, including RNA, gene therapy, and gene editing.
The company was founded across the country in Corvallis, Oregon back in 1980, originally as Antivirals Inc. A couple of decades later, the company was rebranded as AVI BioPharma, Inc. by 2002 and made headlines by 2003, announcing its pursuit for treatments of SARS and West Nile virus. By 2009, the company packed up and moved from its headquarters at the time, Portland, Oregon, to Bothell, Washington, in the Seattle area biotech cluster. Reports at that time indicated the company generated $3.2 million and employed 83: it still had no commercial products nor profits 29 years since its inception. A capital infusion came with the $11.5 million winning bid with the U.S. Department of Defense Threat Reduction Agency by Q4 2009. By 2012, the company was pivoting toward rare diseases and picked up and moved its headquarters to Cambridge, MA. Then CEO Chris Garabedian pointed out that the expertise necessary for such a transition existed in greater numbers in the Boston-area biotech cluster.
By Q1 2019, the company put the pedal to the metal toward gene therapy, acquiring five gene therapy candidates for $165 million as one of them, MYO-101, produced results with a new gene therapy candidate for patients with Limb-Girdle Muscular Dystrophy. Just a couple of months after gene therapy treatment, all three patients’ muscles produced the specific protein that the rare disease impeded.
Business & Finance
The company’s share price as of this writing, $143.20, leaves its market capitalization at $11.24 billion with $450.2 million—staggering revenue multiples typically only seen with specialized biotech, often such as gene or cell therapy ventures such as this one. Losses are considerable (just over half-billion), and the cash position is about $2 billion.
Call to Action: Those suffering from these genetic diseases have potential promise in this potential gene therapy breakthrough. TrialSite will continue to monitor trials, research centers, and investigators involved, including Abigail Wexner Research Institute at Nationwide Children’s Hospital.