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Clinical Trials

Date: 2018-10-03

Type of information: Presentation of results at a congress

phase: 1-2

Announcement: presentation of results at the 23rd International Congress of the World Muscle Society

Company: Sarepta Therapeutics (USA - MA)

Product: AAVrh74.MHCK7.micro-Dystrophin

Action mechanism:

  • gene therapy.

Disease: Duchenne muscular dystrophy (DMD)

Therapeutic area: Rare diseases - Genetic diseases - Neuromuscular diseases

Country: USA

Trial details:

  • The proposed clinical trial is a single-dose controlled trial using rAAVrh74.MHCK7.micro-dystrophin for DMD subjects. Cohort A will include six subjects ages 3 months to 3 years, and Cohort B will include six subjects ages 4 to 7 years old. All subjects will receive intravenous micro-dystrophin vector (2X10e14 vg/kg in 10mL/kg). (NCT03375164)

Latest news:

  • • On October 3, 2018, Sarepta Therapeutics announced that at the 23rd International Congress of the World Muscle Society in Mendoza, Argentina, Jerry Mendell, M.D., of Nationwide Children’s Hospital presented positive updated results from its gene therapy clinical trial assessing AAVrh74.MHCK7.micro-Dystrophin in individuals with Duchenne muscular dystrophy (DMD). Dr. Mendell presented the following updated data on the four patients enrolled in the study:
  • All patients showed robust expression of transduced micro-dystrophin, which is properly localized to the muscle sarcolemma, as measured by immunohistochemistry. Mean gene expression for the study, as measured by percentage of micro-dystrophin positive fibers was 81.2% and the mean intensity of the fibers was 96.0% compared to normal control.
  • All post-treatment biopsies showed robust levels of micro-dystrophin as measured by Western blot, with a mean of 74.3% compared to normal utilizing Sarepta’s method, or 95.8% compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue.
  • Gene expression for the fourth patient was robust, as follows: As measured by immunohistochemistry, micro-dystrophin positive fibers was 96.2% and the mean intensity of the fibers was 160.0% compared to normal control.
  • As measured by Western blot, patient 4 showed robust levels of micro-dystrophin, with a mean of 182.7% compared to normal utilizing Sarepta’s method, or 222% compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue.
  • In all patients, expression of micro-dystrophin was associated with significant expression and up-regulation of the dystrophin-associated protein complex, an additional indication of functionality of dystrophin.
  • All patients showed significant decreases of serum creatine kinase (CK) levels at last measure, with a mean reduction of CK of over 78% from baseline.
  • Dr. Mendell also provided an update on functional endpoints for all four patients, including North Star Ambulatory Assessment (NSAA), Time to Rise, 4 Stairs Up, and 100M. Patients showed improvements across all measured functions, with boys showing an average NSAA raw score improvement of 6.5 points from baseline to last measure, or on a linearized NSAA basis, 12 points of improvement in the first 90 days. While results suggest functional improvements across all measures significantly greater than natural history predictions, it should be cautioned that this is a small, uncontrolled data set and these positive results must be reconfirmed in the larger, controlled registration trial.
  • No serious adverse events (SAEs) were observed in the study. Three patients had elevated gamma-glutamyl transferase (GGT) that resolved with increased steroids within a week. There were no other significant laboratory findings. Patients had transient nausea generally during the first week of therapy coincident with increased steroid dosing.
  • Dr. Mendell, the study’s principal investigator, in collaboration with Louise Rodino-Klapac, Ph.D., empirically optimized the AAVrh74.MHCK7 specifically for DMD: The AAVrh74 vector is designed to be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle without promiscuously crossing the blood brain barrier, making it an ideal candidate to treat peripheral neuromuscular diseases.
  • As a rhesus monkey-derived AAV vector, AAVrh74 has lower immunogenicity rates than reported with other common 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 DMD, who typically die from pulmonary or cardiac complications. In pre-clinical models, micro-dystrophin expression in the heart was observed to be up to 120% of the micro-dystrophin levels observed in skeletal muscles.
  • The transgene was designed to maintain spectrin-like repeats 2 and 3, which has been reported to be critical to maintaining the protective functional characteristics of dystrophin.
  • • On September 24, 2018, Sarepta Therapeutics announced that the FDA has lifted the clinical hold for its Duchenne muscular dystrophy (DMD) micro-dystrophin gene therapy program. In July the FDA placed the program on clinical hold due to the presence of trace amounts of DNA fragment in research-grade third-party supplied plasmid in a manufacturing lot. In response, and in collaboration with Nationwide Children’s Hospital, an action plan was developed and submitted to the FDA, including an audit of the plasmid supplier and a commitment to use GMP-s plasmid for all future production lots. “Our focus now is on meeting with the Division to take guidance and gain alignment around what we hope to be our registration trial for our micro-dystrophin program and achieving our goal of commencing that trial by year-end 2018,” stated Doug Ingram, Sarepta’s president and chief executive officer.
  • • On July 25, 2018, Sarepta Therapeutics announced that the company has been notified by the Research Institute at Nationwide Children’s Hospital (the Research Institute) that they have received a letter from the FDA on July 24, 2018, stating that their Phase 1/2a Duchenne Muscular Dystrophy (DMD) Micro-Dystrophin Gene Therapy Trial has been placed on clinical hold due to the presence of a trace amount of DNA fragment in research-grade third-party supplied plasmid. Preliminary in-vivo testing performed by the Research Institute indicates that the trace fragment does not result in protein expression and is quickly cleared. The Research Institute, working with Sarepta, has developed their action plan with immediate plans to submit for review by the FDA, which will include the use of GMP-s plasmid for the program. Subject to the FDA’s acceptance of the action plan, Sarepta does not anticipate any material delay in dosing patients as originally planned by year-end 2018.
  • • On June 19, 2018, Sarepta Therapeutics announced that at the company’s R&D Day, Jerry Mendell, M.D. of Nationwide Children’s Hospital presented positive preliminary results from its Phase 1/2a gene therapy clinical trial assessing AAVrh74.MHCK7.micro-Dystrophin in individuals with Duchenne muscular dystrophy (DMD). Dr. Mendell presented the following preliminary data on the first three patients enrolled in the study:
  • All patients showed robust expression of transduced micro-dystrophin, which is properly localized to the muscle sarcolemma, as measured by immunohistochemistry. Mean gene expression, as measured by percentage of micro-dystrophin positive fibers was 76.2% and the mean intensity of the fibers was 74.5% compared to normal control.
  • All post-treatment biopsies showed robust levels of micro-dystrophin as measured by Western blot, with a mean of 38.2% compared to normal utilizing Sarepta’s method, or 53.7% compared to normal pursuant to Nationwide Children’s quantification of Sarepta’s method that adjusts for fat and fibrotic tissue.
  • A mean of 1.6 vector copies per cell nucleus was measured in patients, consistent with the high micro-dystrophin expression levels observed.
  • All patients showed significant decreases of serum creatine kinase (CK) levels, with a mean reduction of CK of over 87% at Day 60. CK is an enzyme associated with muscle damage and patients with DMD uniformly exhibit high levels of CK. Indeed, significantly elevated CK is often used as a preliminary diagnosis tool for DMD, which is then followed by confirmatory genetic testing.
  • No serious adverse events (SAEs) were observed in the study. Two patients had elevated gamma-glutamyl transferase (GGT) that resolved with increased steroids within a week and returned to baseline levels. There were no other significant laboratory findings. Patients had transient nausea generally during the first week of therapy coincident with increased steroid dosing.
  • Dr. Mendell, the study’s principal investigator, in collaboration with Louise Rodino-Klapac, Ph.D., empirically optimized the AAVrh74.MHCK7 specifically for DMD:
  • The AAVrh74 vector can be systemically and robustly delivered to skeletal, diaphragm and cardiac muscle without promiscuously crossing the blood brain barrier, making it an ideal candidate to treat neuromuscular diseases.
  • As a rhesus monkey-derived AAV vector, AAVrh74 appears to show lower immunogenicity rates in existing early-stage clinical studies than expected 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 DMD, who typically die from pulmonary or cardiac complications. In preclinical models, micro-dystrophin expression in the heart was observed to be up to 120% of the micro-dystrophin levels observed in skeletal muscles.
  • The transgene was designed to maintain spectrin-like repeats 2 and 3, which has been reported to be important for maintaining the protective functional characteristics of dystrophin.

Is general: Yes