New top-line data from Scholar Rock Holding Group’s phase II Topaz trial of apitegromab (SRK-015) in patients with type 2 and type 3 spinal muscular atrophy (SMA) generated enough proof-of-concept results for the company to plan on initiating a phase III for later this year.

But the 12-month data didn’t stop the Cambridge, Mass.-based company’s stock (NASDAQ:SRRK) from struggling mightily on April 6 as shares closed 20.3% lower at $35.97 each. The stock received a massive upsurge in October when Scholar Rock announced positive six-month interim analysis results from the Topaz study. On Oct. 19, shares were going for $14.14 and later peaked at $70.

SRK-015, a myostatin activator inhibitor, demonstrated no safety signals for the period, and all 57 patients in three cohorts completing the study said they would return for the extension period.

Key findings from cohort 1, whose subjects were ages 5 to 21 with ambulatory type 3 disease and received 20-mg/kg dose monotherapy in conjunction with Spinraza (nusinersen, Biogen Inc.) saw a mean change from baseline in Revised Hammersmith Scale (RHS) of a 0.3-point decline. The majority of patients across the cohort (57%, 13/23 of patients) maintained or improved their motor function, as reflected by a greater than 0-point change from baseline in RHS score, and 22% of patients (5/23) attained a greater than three-point increase from baseline.

Stuart Anthony Kingsley, CEO, Scholar Rock

In cohort 2 – also ages 5 to 21 but with type 2 and non-ambulatory type 3 disease who initiated nusinersen at age 5 and older and received a 20-mg/kg dose – the findings showed a mean change from baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) of a 0.6-point improvement. The majority of patients (64%, 9/14 of patients) attained a great than one-point increase from baseline and 29% of patients (4/14) attained a greater than three-point increase from baseline. Those results support the potential durability of improvements in motor function observed at the six-month interim analysis, the company said.

In cohort 3, which enrolled subjects ages 2 and older with type 2 disease who initiated nusinersen under age 5, the data showed a mean change from baseline in HFMSE of 7.1-point and 5.3-point improvements in the 20-mg/kg dose and the 2-mg/kg dose arms, respectively. The benefit of nusinersen treatment, according to Stuart Anthony Kingsley, Scholar Rock’s CEO, was prominently seen in that cohort.

“Consistent with the six-month data, it's most pronounced in cohort 3,” Kingsley told investors in an April 6 conference call. “Cohort 3 is a younger cohort and there's more dynamic muscle growth. We've always expected that you'd see better performance in that group.”

Across the full cohort, 59% of the patients (10/17) saw a greater than five-point increase and 35% of patients (6/17) attained a greater than 10-point increase from baseline.

The five most frequently reported treatment-emergent adverse events were headache, pyrexia, upper respiratory tract infection, cough and nasopharyngitis.

Spinraza, a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide, gained the green light for SMA in December 2016. Also in play are Zolgensma (onasemnogene abeparvovec-xioi), the one-time gene therapy from Basel, Switzerland-based Novartis AG, cleared by the FDA in May 2019, and Evrysdi (risdiplam), from Roche Holding AG, an SMN2 splicing modifier approved in August 2020 that is given daily at home.

DRG noted that drivers in the SMA space include a continued high unmet need for effective therapies, a significant uptake of SMA disease-modifying therapies (DMTs) in previously underserved niches, and high prices for Spinraza and emerging DMTs. Constraints include the potential for decline in the treatable patient pool, DRG noted, plus a decreasing treatment-naive patient pool for clinical trial recruitment. There is also a challenging reimbursement environment due to a high cost of treatment. DRG added.

The most promising emerging therapies, according to DRG, are AVXS-101 from Novartis and Avexis Inc., risdiplam, branaplam from Novartis and reldesemtiv from Cytokinetics Inc. and Astellas Pharma Inc.