Early Work Supports Apitegromab’s Safety as SMA Muscle Therapy

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by Steve Bryson, PhD |

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A series of toxicology studies in rats and macaque monkeys confirmed the safety and tolerability of apitegromab, an investigational spinal muscular atrophy (SMA) therapy, supporting its ongoing assessment in patient trials, a study reported.

The study, “Preclinical Safety Assessment and Toxicokinetics of Apitegromab, an Antibody Targeting Proforms of Myostatin for the Treatment of Muscle-Atrophying Disease,” was published in the journal International Journal of Toxicology.

In SMA, muscle tissue is atrophied and weakened. One potential treatment approach is to increase muscle mass by blocking myostatin — a protein secreted by muscle cells that acts to suppress muscle cell growth.

Apitegromab (SRK-015) is an antibody-based therapy designed to bind to the inactive precursor of myostatin — called promyostatin — and prevent its conversion to its active form in muscle tissue.

The therapy is currently being evaluated in the Phase 2 TOPAZ trial (NCT03921528) in children and young adults with SMA type 2 and type 3. Recent top-line data show apitegromab effectively improved or stabilized motor function.

In support of such clinical studies, scientists at Scholar Rock, the therapy’s developer, reported on the preclinical investigations of apitegromab’s pharmacological properties and safety across two animal models.

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“The nonclinical safety studies were designed to enable clinical trials with apitegromab across both adult and pediatric … patients with SMA,” the team wrote.

The first series of experiments confirmed the in vitro (test tube) binding and activity of apitegromab to prevent activation of myostatin in humans, rats, and a type of macaque (cynomolgus) monkey “suggesting potentially similar activity of apitegromab across these species,” the researchers wrote.

Worked in human tissue from three different donors showed apitegromab did not bind to other tissue targets.

Four-week toxicology studies were then conducted in cynomolgus monkeys and rats, which supported an early Phase 1 safety trial in healthy adult volunteers.

Male and female monkeys were given weekly infusions of apitegromab at increasing doses (0, 10, 30, and 100 mg/kg) into the bloodstream for four weeks, followed by a four-week treatment-free recovery phase.

At all doses, no apitegromab-related adverse effects were observed regarding food consumption, eye exams, blood tests, clinical chemistry, or urine analysis. Adverse effects were likewise not evident in neurological exams, respiration rates, or with electrical studies of the animals’ heart function.

In apitegromab-treated animals, muscle mass was slightly higher than in non-treated monkeys (a control group), an improvement ranging from 5% to 25%, but without a dose response.

Male and female rats were infused weekly with apitegromab, also at the same increasing doses for four weeks, followed by a recovery period. Again, no apitegromab-related adverse effects were reported, even at the highest dose. Slightly elevated levels of blood proteins were seen. The body weight of rats increased at higher doses, and researchers thought this likely due to the greater muscle weight that came from treatment.

A long-term toxicology study was conducted in male and female adult rats, with weekly infusions (30, 100, and 300 mg/kg) for 26 weeks, followed by an eight-week recovery phase. No treatment-related deaths were reported, and no adverse events regarding clinical tests were observed.

Similar to the four-week rat study, minimally higher total blood protein levels were seen, as was an increase in muscle weight, which persisted into the recovery phase. No dose-related responses in increased muscle mass were reported.

To support the treatment’s use with children, juvenile rats at seven weeks of age were tested. Consistent with the findings in older rats, no significant apitegromab-related adverse effects were observed, even at the highest dose of 300 mg/kg. Further, breeding treated males and females with unexposed animals showed no adverse effects on reproductive factors.

A series of experiments next assessed apitegromab’s pharmacokinetics, or how the treatment enters the body, is metabolized, and excreted.

First, male and female cynomolgus monkeys were infused with weekly apitegromab (10, 30, and 100 mg/kg). A maximum level was seen one hour after infusion, which was dose-dependent and dose-proportional. All animals maintained exposure after the dosing and recovery phases, and no monkeys developed antibodies targeting apitegromab, which would reduce its effectiveness.

Similar findings were observed in adult rats over four- and 26-week studies, as well as in juvenile rats. Two female rats, which were antibody-negative during the dosing phase of the four-week study, were positive for anti-apitegromab antibodies in the recovery phase, which correlated with the lower concentrations of apitegromab measured.

The medicine’s half-life — time for it concentration to drop to half of its starting dose — ranged between about 10 to 15 days.

Finally, target engagement was confirmed by showing promyostatin remained elevated throughout the dosing and recovery phases in rats and monkeys, as apitegromab prevented its conversion to active myostatin. Promyostatin increased with increasing doses, but the levels were not proportional to the doses used.

“In summary, the nonclinical pharmacology, pharmacokinetic, and toxicology data demonstrate that apitegromab is a selective inhibitor of proforms of myostatin that does not exhibit toxicities observed with other myostatin pathway inhibitors,” the researchers wrote. “These data support the conduct of ongoing clinical studies of apitegromab in adult and pediatric patients with spinal muscular atrophy.”