SRRK stock exploded higher on October 28, 2020, after the company received a price target hike from BMO Capital.

BMO Capital analyst Do Kim raised the firm’s price target on Scholar Rock to $52 from $33 and keeps an Outperform rating on the shares. The analyst cites the company’s “positive” interim phase 2 data of SRK-015 in patients with Type 2 and Type 3 Spinal Muscular Atrophy and believes that the 6-month outcomes for all cohorts “comfortably beat motor function and responder rate hurdles”. Kim also increases his probability of success for the program to 50% from 33% following yesterday’s update.

On October 27, 2020, Baird analyst Madhu Kumar raised the firm’s price target on Scholar Rock to $39 from $35 and keeps an Outperform rating on the shares. The analyst notes that Scholar Rock has announced 6-month interim data from the Phase 2 TOPAZ trial of antipromyostatin mAb SRK-015 in spinal muscular atrophy types 2/3. Overall, he was pleased by the early clinical POC shown in all cohorts of TOPAZ, especially the dose-dependent improvement in motor function observed in cohort 3. Kumar reiterates the stock status as a Fresh Pick.

On October 27, 2020, cholar Rock (NASDAQ: SRRK), a clinical-stage biopharmaceutical company focused on the treatment of serious diseases in which protein growth factors play a fundamental role, announced positive six-month interim analysis results from the TOPAZ Phase 2 clinical trial. Treatment with SRK-015 led to improvements in Hammersmith scale scores (primary efficacy endpoint) in all three cohorts of patients with Type 2 and Type 3 Spinal Muscular Atrophy (SMA). Dose response in the primary efficacy endpoint was observed across all evaluated timepoints in the double-blind, randomized portion of the trial (Cohort 3). The high-dose arm of Cohort 3 attained a 5.6 point mean improvement from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) as compared to the low dose arm, which attained a 2.4 point mean improvement at the six-month interim analysis timepoint. No safety signals were identified from the interim analysis.

“These interim results are important because they demonstrate the potential of this muscle-directed approach to improve motor function of individuals with Type 2 and Type 3 SMA,” said Thomas Crawford, M.D., Professor of Neurology at the Johns Hopkins University School of Medicine and Lead Investigator of the TOPAZ trial. “In the last few years, we’ve celebrated the remarkable success in treating SMA with SMN-upregulating approaches that stabilize against neurodegeneration. These findings highlight the potential for a whole new approach to SMA therapy, used in conjunction with the SMN-enhancing therapies, to address the persistent and significant unmet needs of individuals weakened by SMA.”

“This is an exciting and important step towards establishing SRK-015 as the potential first muscle-directed therapy for patients with SMA, while also providing important validation of our scientific approach of targeting the latent forms of growth factors,” said Yung Chyung, M.D., Chief Medical Officer of Scholar Rock. “These interim data support the continuation of the TOPAZ trial and we look forward to engaging with regulatory authorities regarding our registrational trial plans.”

TOPAZ Phase 2 Six-Month Interim Results

SRK-015 is a highly selective inhibitor of the activation of latent myostatin. The TOPAZ Phase 2 proof-of-concept trial enrolled 58 patients with Type 2 and Type 3 SMA across 16 study sites in the U.S. and Europe. The trial is evaluating the safety and efficacy of intravenous SRK-015 dosed every four weeks (Q4W) over a 12-month treatment period. A pre-planned interim analysis was conducted following a six-month treatment period across all three study cohorts. Three patients (one in Cohort 2 and two in Cohort 3) each missed three doses of SRK-015 and the six-month interim analysis timepoint due to COVID-19-related site access restrictions; the six-month timepoint from these patients was not included in the interim analysis.

At the six-month interim analysis timepoint:

Mean increases from baseline in Hammersmith scale scores were observed in all three cohorts.

  • 67% of total patients achieved ≥1 point improvement in Hammersmith scores.

Substantial proportion of patients in each cohort achieved a ≥3 point increase in Hammersmith scores.

  • 35% of total patients achieved ≥3 point increase in Hammersmith scores.

Dose response in the primary efficacy endpoint was observed in the randomized, double-blind cohort; numerically greater improvements in HFMSE scores were observed for high-dose (20 mg/kg) arm across all evaluated timepoints.

Detailed Summary of Interim Results by Cohort

Cohort 1: This open-label, single-arm cohort enrolled 23 patients with ambulatory Type 3 SMA. Patients are being treated with 20 mg/kg of SRK-015 Q4W either as a monotherapy or in conjunction with an approved SMN upregulator therapy (nusinersen). The primary objectives of the cohort are to assess safety and the mean change from baseline in Revised Hammersmith Scale (RHS).

At baseline, patients across both subgroups of patients had a mean age of 12.6 years (range 7-21 years) and a RHS score of 49.6 (range 26-63) out of a total possible score of 69. Patients in the SRK-015 monotherapy group had a mean age of 12.1 years (range 7-19 years) and a mean RHS score of 47.6 (range 26-63). Patients in the group treated with SRK-015 and receiving an SMN upregulator (nusinersen) had a mean age of 13.1 years (range 7-21 years) and a mean RHS score of 51.3 (range 43-62). One patient discontinued from the trial for reasons that were assessed to be unrelated to SRK-015 but was included in the intent-to-treat interim analysis.

At the six-month interim analysis timepoint:

Mean change from baseline in RHS score:

  • SRK-015 pooled (n = 23): +0.5 points (95% CI of -1.1, +2.2)
  • SRK-015 monotherapy (n = 11): +0.7 points (95% CI of -2.5, +4.0)
  • SRK-015 + nusinersen (n = 12): +0.3 points (95% CI of -1.4, +2.0)

Proportion of patients attaining ≥1 point increase in RHS score:

  • SRK-015 pooled: 52% (12/23)
  • SRK-015 monotherapy: 64% (7/11)
  • SRK-015 + nusinersen: 42% (5/12)

Proportion of patients attaining ≥3 point increase in RHS score:

  • SRK-015 pooled: 26% (6/23)
  • SRK-015 monotherapy: 36% (4/11)
  • SRK-015 + nusinersen: 17% (2/12)

Proportion of patients attaining ≥5 point increase in RHS score:

  • SRK-015 pooled: 9% (2/23)
  • SRK-015 monotherapy: 9% (1/11)
  • SRK-015 + nusinersen: 8% (1/12)

Cohort 2: This open-label, single-arm cohort enrolled 15 patients with a mean age of 11.7 years (range 8-19 years) with Type 2 or non-ambulatory Type 3 SMA and who are already receiving treatment with an approved SMN upregulator. Patients are being treated with 20 mg/kg of SRK-015 Q4W in conjunction with an approved SMN upregulator therapy (nusinersen). At baseline, patients had a mean HFMSE score of 22.7 (range 13-39) out of a total possible score of 66. One patient missed three doses of SRK-015 and the six-month interim analysis timepoint due to COVID-19-related site access restrictions; the six-month timepoint from this patient was not included in the interim analysis. The primary objectives of the cohort are to assess safety and the mean change from baseline in HFMSE.

At the six-month interim analysis timepoint:

Mean change from baseline in HFMSE score (n = 14): +1.4 points (95% CI of +0.1, +2.7)
Proportion of patients attaining ≥1 point increase in HFMSE score: 71% (10/14)
Proportion of patients attaining ≥3 point increase in HFMSE score: 21% (3/14)
Proportion of patients attaining ≥5 point increase in HFMSE score: 14% (2/14)
Improvements in HFMSE scores progressively increased over the six-month treatment period, and a plateau in improvement appears to not have yet been reached. Twelve-month data may provide additional insights evaluating the potential for durability of effect and for further motor function gains.
Cohort 3: This randomized, double-blind, portion of the trial enrolled patients with Type 2 SMA who had initiated treatment with an approved SMN upregulator (nusinersen) before five years of age. Twenty patients were randomized in a 1:1 ratio to receive the low dose (2 mg /kg SRK-015 Q4W) or high dose (20 mg/kg SRK-015 Q4W); both treatment arms are in conjunction with an approved SMN upregulator therapy (nusinersen). Two patients (one in high-dose arm and one in low-dose arm) each missed three doses of SRK-015 and the six-month interim analysis timepoint due to COVID-19-related site access restrictions; the six-month timepoint from these patients was not included in the interim analysis. The primary objectives of the cohort are to assess safety and the mean change from baseline in HFMSE.

At baseline, patients in the high-dose arm had a mean age of 3.8 years (range 2-6 years) and mean HFMSE score of 23.5 (range 14-42) out of a total possible score of 66 points, while patients in the low dose arm had a mean age of 4.1 years (range 2-6 years) and a mean HFMSE score of 26.1 (range 12-44).

At the six-month interim analysis timepoint:

Mean change from baseline in HFMSE score:

  • 20 mg/kg dose (n = 9): +5.6 points (95% CI of +2.5, +8.7)
  • 2 mg/kg dose (n = 9): +2.4 points (95% CI of -0.9, +5.8)

Proportion of patients attaining ≥1 point increase in HFMSE score:

  • 20 mg/kg dose: 100% (9/9)
  • 2 mg/kg dose: 67% (6/9)

Proportion of patients attaining ≥3 point increase in HFMSE score:

  • 20 mg/kg dose: 67% (6/9)
  • 2 mg/kg dose: 44% (4/9)

Proportion of patients attaining ≥5 point increase in RHS score:

  • 20 mg/kg dose: 56% (5/9)
  • 2 mg/kg dose: 33% (3/9)

Greater improvement achieved with high dose: Patients treated with high dose (20 mg/kg) achieved numerically greater improvements from baseline in HFMSE scores as compared to the low dose (2 mg/kg) at all assessed timepoints (week 8, week 16, and the six-month interim analysis timepoint).

Numerically greater improvements with high dose were observed both in terms of mean change from baseline and in proportions of patients attaining ≥3 point increase in HFMSE score.
Plateau in improvement appears to not have yet been reached: Improvements in HFMSE scores progressively increased over the six-month treatment period. Twelve-month data may provide additional insights evaluating the potential for durability of effect and for further motor function gains.

PK and PD results are supportive of the observed dose response in efficacy:

Treatment with the high dose led to higher levels of drug exposure than with the low dose.
Treatment with high dose achieved higher levels of target engagement, and treatment with low dose did not attain full target saturation.
Overall Safety and Tolerability: No safety signals were identified during the interim analysis.

Incidence and severity of adverse events were consistent with underlying patient population and background therapy.
Five most frequently reported TEAEs: Headache, upper respiratory tract infection, pyrexia, nasopharyngitis, and cough.
No grade 3 (severe) or higher adverse events were reported.
One patient (Cohort 1) experienced a serious treatment-emergent adverse event (TEAE) of Grade 2 viral upper respiratory tract infection leading to hospitalization. The event was resolved without sequelae and was assessed by the trial investigator as unrelated to study drug.
One patient (Cohort 1) discontinued from the trial due to Grade 2 muscle fatigue that started prior to initiation of dosing with study drug; assessed by the trial investigator as unrelated to study drug.
Top-line data from the 12-month treatment are expected in the second quarter of 2021. Twelve-month data may provide additional insights evaluating the potential for durability of effect and for further motor function gains.

As of October 23, 2020, 39 of 39 patients who have completed the 12-month treatment period have opted into the extension period.

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