Phase 2 Trial Planned for SRK-015 in SMA Patients After Positive Phase 1 Data

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by Alice Melão |

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SRK-015 clinical trial

Positive interim data from an ongoing Phase 1 trial in healthy volunteers supports the continued development of Scholar Rock’s investigational candidate SRK-015 as a treatment for spinal muscular atrophy (SMA).

The company is now planning to launch a Phase 2 trial to assess the safety and efficacy of SRK-015 in patients with SMA type 2 and type 3 by the end of the first quarter of 2019.

“We are very excited with the progress to date in the Phase 1 trial of SRK-015 as we continue to work towards developing our lead antibody candidate as a potential first muscle-directed therapy for the treatment of SMA,” Yung Chyung, MD, chief medical officer of Scholar Rock, said in a press release. “We look forward to initiating the Phase 2 proof-of-concept trial to evaluate SRK-015’s potential to address the functional deficits that continue to represent a significant unmet need in SMA.”

SRK-105 is a man-made antibody engineered to selectively inhibit the activation of myostatin, a negative regulator of muscle mass primarily produced in skeletal muscle cells. Excessive activation of myostatin is known to induce muscle atrophy, while loss or reduced activity of this protein is associated with increased muscle mass and strength.

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In preclinical studies, SRK-105 prevented additional atrophy in mice with muscle wasting and demonstrated the potential to improve muscle mass and function in healthy animals.

The investigational antibody has received orphan drug status from both the U.S. Food and Drug Administration and European Commission for the treatment of SMA. Scholar Rock believes that SRK-105 has the potential to become the first muscle-directed treatment to reverse or prevent additional muscle atrophy in SMA patients.

Researchers are currently evaluating the safety, tolerability, and overall antibody stability, action, and secretion in healthy volunteers in an ongoing Phase 1 trial. The study was also designed to establish the optimal dose and treatment regimen to be used in future clinical studies.

The Phase 1 trial was divided into two parts. The first part was a single-ascending dose (SAD) study, which included 40 healthy adult volunteers who were randomly assigned to receive a single intravenous (into-the-vein) administration of one of the five tested doses of SRK-015 — ranging between 1 and 30 mg/kg — or a placebo.

The second part was a multiple-ascending dose (MAD) study, in which 26 healthy adult volunteers were randomized to receive SRK-015 at 10, 20, and 30 mg/kg — or a placebo every two weeks for a total of three doses.

Preliminary analysis of the completed SAD and ongoing MAD studies revealed that SRK-015 was well-tolerated, with no dose-limiting toxicities reported even in participants treated with the highest tested dose.

SRK-015 was shown to have a good safety profile. No discontinuations due to treatment-related adverse events and no hypersensitivity reactions were reported. Assessments of possible immune reactions triggered by SRK-015 therapy were all negative, with no participant showing increased production of autoantibodies against the treatment.

SRK-015 was generally stable and reactive for about 23 to 33 days across the different tested dosages, supporting its administration once every four weeks in the next trials.

In addition, a single administration of 3 mg/kg of SRK-015 was found to be enough to support and sustain a durable increase of latent myosin in the blood. This indicates that, even at a low concentration, SRK-015 can effectively inhibit myosin activity for an extended period of time.

Scholar Rock anticipates the announcement of full Phase 1 study data at a scientific conference later this year.

“These interim Phase 1 data provide initial proof-of-mechanism for the pharmacologic potential of SRK-015, and more broadly, Scholar Rock’s therapeutic approach of specifically targeting the latent forms of growth factors,” said Nagesh Mahanthappa, PhD, president and CEO of Scholar Rock.

Supported by positive preclinical data, as well as these Phase 1 safety and stability results, Scholar Rock is planning a proof-of-concept Phase 2 trial, called TOPAZ, to explore the potential of SRK-015 in SMA patients.

The study is expected to enroll approximately 50–60 patients with SMA types 2 and 3 who will all receive intravenous injections of SRK-015 every four weeks either alone or in combination with an approved SMN upregulator therapy.

The treatment will be given for up to 12 months, during which researchers will assess changes in motor function using the Hammersmith Functional Motor Scale Expanded (HFMSE) in non-ambulatory patients and the Revised Hammersmith Scale (RHS) in ambulatory patients.

Preliminary safety and efficacy results from the Phase 2 trial are expected to be announced during the first half of 2020, and the study should be completed by the first half of 2021.

“Through our discovery efforts, we have built a robust pipeline of highly specific growth factor modulators across a diverse range of therapeutic areas and are eagerly working to advance these potential therapies to serve patients with unmet medical needs,” Mahanthappa said.

More information about the TOPAZ trial will be announced closer to its launch, according to the company.