DMD Gene Therapy Showing ‘Very Encouraging’ Results at 9 Months in Phase 1/2 Study, Sarepta Reports

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |


New nine-month data on four boys with Duchenne muscular dystrophy (DMD) enrolled in Study-101 testing Sarepta Therapeutics‘ micro-dystrophin gene therapy continues to show “very encouraging” results, company officials said.

These updated data, given in a recent investors’ webinar, show the gene therapy resulted in 81.2% increase in dystrophin protein expression in the muscles, accompanied by marked improvements in boys’ functional performance, and without signs of adverse effects.

“The data remain very encouraging with continuing improvement on functional endpoints, unprecedented biomarker results and on safety as well,” Doug Ingram, Sarepta’s president and CEO, said during the webinar.

Sarepta hopes to confirm these results in a new Phase 2 trial – called Study-102 (NCT03769116) – now looking to enroll 24 boys with DMD between 4 and 7 years old. This trial, still recruiting participants, is taking place at Nationwide Children’s Hospital in Ohio under the direction of Jerry Mendell, MD, its principal investigator. (Contact and other enrollment information is available here.)

“Our goal right now is to take what we see is very exciting results from these four patients and to confirm them in our placebo controlled, blinded trial,” Ingram.

The gene therapy, called AAVrh74.MHCK7.micro-dystrophin, uses an adeno-associated virus, or AAV, to deliver micro-dystrophin, a shorter version of the dystrophin gene. Although shorter, the micro-dystrophin gene contains enough information to produce and restore the function of dystrophin.

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Developed by researchers at the Nationwide Children’s and licensed by Sarepta, the gene therapy delivers the micro-dystrophin gene exclusively to the muscle tissue — in particular, the heart muscle. Rescuing heart muscle function is vital since DMD patients frequently die of heart disease.

Study-101 (NCT03375164) enrolled four boys with DMD, also ages 4 to 7, with blood levels of creatine kinase (CK) — a marker of muscle inflammation — at the beginning of the trial (baseline) between 20,000 and 35,000 U/L.

Each was given a single dose of the gene therapy administered into the bloodstream. To prevent their immune system from targeting and destroying the therapy, they also receive corticosteroids. A high dose was given through first 30 days, followed by their  their standard-of-care corticosteroid dose.

The study’s primary goal was safety, but several secondary endpoints focused on changes in muscle function, including the 100-meter timed test, time to rise, four-stair climb test, as well as the North Star Ambulatory Assessment (NSAA).

NSAA is a 17-item rating scale used to measure motor abilities – such as ability to rise from the floor, to get from lying to a sitting position and from sitting to standing – in ambulant patients. Scoring ranges from zero (patients unable to perform any of these activities) to 34, when all are achieved.

As previously reported, analysis of muscle biopsies done at 90 days post-gene therapy injection showed a widespread localization of dystrophin at the sarcolemma (muscle membrane). Researchers quantified the amount (called intensity) of micro-dystrophin at the muscle membrane, and reported a 96% increase compared to baseline or pre-treatment.

They also detected 81.2% of micro-dystrophin-positive muscle fibers across the four patients at 90 days post-treatment.

Another technique, called western blot, was used to quantify the total amount of micro-dystrophin protein. After adjusting for fat and fibrosis, a 95.8% increase in micro-dystrophin was seen compared to study start. An increase of 74.3% was still seen when not adjusting the results.

The micro-dystrophin gene was present at 3.3 copies per cell.

“All of this biopsy data taken together is very consistent in terms of the number of copies we see and the amount of dystrophin present, so we see high level, widespread micro-dystrophin expression 90 days post-biopsy,” said Louise Rodino-Klapac, PhD, senior vice president of Sarepta.

Almost nine months (270 days) after treatment, NSAA scores showed a significant improvement in  motor abilities. (Sarepta had previously reported data for patient one, this update covered data on patients two, three and four.)

NSAA data from patients one, two and four — ages 4 to 5 — showed that the score increased by eight points in about nine months, “well beyond what we would predict from natural history,” said Rodino-Klapac.

Natural history data on 4- to 5-year-olds with DMD shows that steroid treatment leads to an improvement of two points in the NSAA score.

Patient number three, 6 years old at the trial’s beginning, had the highest baseline NSAA score  — 26 — and still showed an improvement of two points at nine months. This smaller improvement is important, as “we know that 6- and 7-year old’s from natural history data are actually declining over the course of a year by four points,” Rodino-Klapac added.

Pooled data from all patients showed a mean of improvement of 6.5 points from baseline (study start) in the NSAA score.

These results mean that “these patients can do six activities independently that other untreated DMD boys cannot do,” Rodino-Klapac said.

Findings across every additional functional measure — time to rise, four-stair climb test, and the 100-meter timed test — also showed an improvement from baseline until day 270 across all four patients.

According to the new data, the time to rise improved by 0.8 seconds, time in four-stair climb test improved by 1.2 seconds, and the 100-meter test by 7.95 seconds.

The inflammation biomarker CK showed an overall decreasing trend over time. Although there was some variability, which researchers linked to a break in protocol guidance — namely, patients engaging in these activities before CK was measured (activity can induce a spike in biomarker levels), the data shows an overall trend toward decreased levels of CK, which researchers deem encouraging.

While CK levels in DMD boys ages 4 to 7 is between 20,000 to 40,000 U/L, but this range was only detected at the study’s start. In later measurements, the values were always declining. Most importantly, when looking at the improving NSAA scores in relation to lowering CK levels during this nearly nine-month period, there is a clear consistent improvement.

Researchers saw that the decrease in CK was linked with steroid use, a finding seen in other studies.

No immune responses against micro-dystrophin were seen throughout the trial, company officials said.

Safety signals remains positive, with patients continuing to do well and free of evidence of adverse side effects. As previously reported, three patients had elevated gamma-glutamyl transferase (GGT), a marker of liver damage, but these levels returned to normal within a week after increasing the dose of steroids.

The study will follow these patients for a total of three years. No further biopsies are scheduled for intermediate time-points.

“No plan for 12-month biopsies for these children and the reason is the very invasive nature of the procedure for children … Sarepta is, however, looking at ways to find a good non-invasive marker for the therapy’s durability in the long-term,” Ingram said.

Sarepta plans no further updates in these first patients, with focus now shifting to the Phase 2 placebo-controlled trial.

“While preliminary, these functional results are better than anything has has ever been seen in Duchenne before, and better even than what we’ve anticipated at the outset,” Ingram said.“The CK drop are unprecedented and (…) we are very encouraged by the safety profile that has been observed.”

The Study-102 (NCT03769116) – looking to enroll 24 boys with DMD, ages from 4 to 7 years old – will randomize participants to gene therapy or placebo. The trial main outcome is to continue to assess the therapy’s safety and changes in micro-dystrophin protein expression after 12 weeks. Around 13 patients have already enrolled the trial and recruitment is still open. Information available at the trial’s official page.

Sarepta is also planning a multi-center trial before the end of 2019 to test a commercial supply of the micro-dystrophin therapy. The trial will undergo in at least 10 clinical sites in the U.S. and potentially sites outside the U.S.

Overall, these results “are completely unprecedented in any of Duchene’s trial, so we want to be careful at not overanalyzing four patients’ preliminary results, but it certainly gives us some confidence that we’re on the right track” said Ingram.

“It is our goal and certainly our subjective belief that from everything we’ve seen that we have a therapy that can truly transform and extend and improve the quality of lives of DMD children,” he added.