New nine-month data from a Phase 1/2 trial show that a single administration of the gene therapy SRP-9003 (formerly, MYO-101) at low dose significantly improved functional measures and lowered the levels of a biomarker of muscle damage in three children with limb girdle muscular dystrophy (LGMD) type 2E.
These latest preliminary results are “very encouraging,” a Sarepta researcher said. The company is looking forward to treating a second patient group, who will receive higher therapy doses to determine the best dose for further clinical testing.
“We have now observed consistent functional improvements, in addition to high levels of expression of the missing protein of interest and strong results in related biomarkers,” Doug Ingram, Sarepta’s president and chief executive officer, said in a press release.
“We intend to test one higher dose of SRP-9003 in LGMD2E participants, select our clinical dose and then advance our SRP-9003 program, along with our other five LGMD programs, as rapidly as possible,” Ingram added.
Limb-girdle muscular dystrophy type 2E (LGMD2E) is caused by mutations in the SGCB gene, which codes for one of the components of the beta-sarcoglycan protein complex, important for maintaining the structure of muscle tissue.
SRP-9003 is a gene therapy that acts to restore levels of the beta-sarcoglycan protein in skeletal and cardiac muscles in order to reverse the symptoms of the disease. The gene therapy was designed initially by a research team led by Louise Rodino-Klapac, PhD, with the clinical guidance of Jerry Mendell, MD, at Nationwide Children’s Hospital Center for Gene Therapy.
The gene is introduced using a specific modified, harmless virus (known as a viral vector), called AAVrh74, which delivers genes efficiently to muscles without crossing the blood-brain barrier. The promoter — a DNA sequence that controls gene activity — allows significant expression of the gene in both cardiac and skeletal muscle. Furthermore, the vector is derived from the rhesus monkey, lowering the risk of the therapy triggering an immune response.
Its safety and effectiveness is being assessed in this randomized, double-blinded, and single-dose study taking place at the Nationwide Children’s Hospital, led by Mendell. The trial is enrolling about nine children, ages 4 through 15, with LGMD2E.
Therapy’s effects at two months
In the first cohort, three patients, ages 4 (one patient) and 13 (two), were treated intravenously (into a vein) with a single low dose of 5×1013 vg/kg of SRP-9003. This dose is actually a fourth of the dose used in Sarepta’s micro-dystrophin gene therapy program.
Researchers previously reported that two months after treatment, 51% of the patients’ muscle fibers expressed beta-sarcoglycan (as shown by an analysis of muscle biopsies). This exceeded the 20% threshold level of protein expression that had been shown in preclinical (lab) studies to result in significantly improved function. The mean intensity of protein expression compared to control levels was 47%. The overall protein expression level was 36.1% compared to controls.
Further analysis confirmed a good insertion of the gene into the muscle cells, as shown by a mean of 0.6 copies of the vector carrying the gene across the three patients.
Compared to baseline (pre-treatment) levels, researchers also saw a 90% decrease in blood levels of creatine kinase, a muscle damage biomarker, whose levels are elevated in LGMD2E. Normal levels of CK is of 150 units (U)/l or less, but in the LGMD2E patients these levels exceed 10,000 U/L.
An increase in the blood levels of liver enzymes (an indicator of liver damage) occurred in two patients, but was resolved with steroid treatment. Furthermore, two patients reported transient nausea, which usually occurred in the first week after treatment. No other serious side effects were observed.
And at nine months post-treatment
Sarepta now is reporting nine-month results in these three patients. These results were shared by Rodino-Klapac, now head of the gene therapy program at Sarepta, in an investor’s webinar on Oct. 4. (A slide presentation can be found here.)
These data showed a significant reduction of 82% in mean blood creatine kinase levels compared to starting (baseline) levels.
“We see a significant and consistent decrease in CK over the course of the nine months, with an 82% reduction,” Rodino-Klapac said.
Patients also showed improvements in functional measures, including the North Star Assessment for Dysferlinopathy (NSAD, a 54-point scale measuring motor abilities), time to rise, the four-stair climb, the 100-meter walk test, and the 10-meter walk test.
These results positively differ from what would be predicted in an age-matched, natural history group where, for example, NSAD is expected to decline by 6 to 8 points in patients in the trial’s age range.
Instead, all the three children showed significant increases in NSAD scores. In patient 2, in particular, “we saw a 6-point gain,” Rodino-Klapac said, from 48 to 54, meaning this score reached its maximum — i.e., it achieved the level considered normal, according to the NSAD. A six-point gain was also seen in patient 3, rising from 41 to 47 points.
In all the other functional measures — time to rise, four-stair climb, 100-meter and 10-meter walk tests — where a decline over time is expected, “we saw dramatic increases,” said Rodino-Klapac. No new safety signals were seen in the patients compared to the earlier trial report.
“The take home-message,” Rodino-Klapac said, was that “in every single measure from all the three patients is that we see a significant improvement in all of the functional tests that we conducted.”
She added: “These preliminary results are very encouraging.”
Next steps include a four-fold dosage increase that will be tested in the second patient group (cohort 2). This dose is equivalent to that being tested in Sarepta’s micro-dystrophin trial. Sarepta also plans to discuss future trial designs for LGMD2E with regulatory agencies.
“It is our intention to meet with the agency in the near future and to have a discussion about the development pathway, first of course, for our 2E program and then beyond that for the rest of our Limb Girdle programs,” Ingram said in the webinar.
Sarepta has four other limb-girdle muscular dystrophy programs: SRP-9004 (MYO-102) for LGMD type 2D, SRP-9005 for LGMD type 2C, MYO-201 for LGMD type 2B, and SRP-9006 for LGMD type 2L. These use the same gene delivery system.
SRP-9003, then known as MYO-101, was designated an orphan drug designation by the U.S. Food and Drug Administration (FDA) in April 2018. The therapy’s development program was also granted a rare pediatric disease designation by the FDA, which makes it eligible for priority review, potentially accelerating its approval.
This Phase 1/2 study is expected to conclude on Dec. 31, 2020.