Juvenile Spinal Muscular Atrophy

The Rainbowfish trial enrolled babies aged from birth to six weeks who had not yet shown symptoms of SMA. Credit: Studio Romantic via Shutterstock. Roche’s spinal muscular atrophy (SMA) drug Evrysdi (risdiplam) has helped pre-symptomatic babies reach rare milestones after two years of treatment in a Phase II trial. The Rainbowfish trial (NCT03779334), run by the Roche subsidiary Genentech, enrolled babies aged from birth to six weeks who had not yet shown symptoms of SMA. After two years, all 26 children were able to swallow and feed orally, and none required permanent ventilation. This is a significant contrast to untreated Type 1 SMA, where children would typically not reach these milestones and rarely survive past two years old, according to natural history studies. The cognitive development of the children was also comparable to babies without SMA, as measured by the Bayley Scales of Infant and Toddler Development, third edition (BSID-III). According to Genentech, this is the first clinical trial in SMA to evaluate cognitive skills as an exploratory endpoint using a standardised scale. The data was presented at the World Muscle Society (WMS) Congress 2024, in Prague, Czech Republic, from 8 to 12 October. This builds on previously announced one-year data, where the trial met its primary endpoint with 80% of patients sitting without support for at least five seconds after one year of Evrysdi treatment, measured by BSID-III. Of the 26 babies, 81% could sit independently for 30 seconds. Adverse events (AEs) for the drug included teething, Covid-19, fever, eczema, and constipation. See Also: CPHI Europe: Gummies as a drug delivery system could improve compliance Sterilisation Solutions, Equipment and Services for the Pharmaceutical Industry SMA is a genetic disorder characterised by the loss of motor neurons, leading to muscle weakness and progressive physical disability. It is caused by mutations in the SMN1 gene, resulting in a deficiency of SMN protein, which is critical for muscle function. Evrysdi is an oral survival motor neuron 2 (SMN2) splicing modifier that targets mutations in chromosome 5q, which is implicated in survival motor neuron (SMN) protein deficiency. It was approved by the US Food and Drug Administration (FDA) in 2022 to treat SMA in patients of all ages, including infants under two months with Type 1, Type 2, or Type 3 SMA, or those with one to four SMN2 copies. Genentech’s chief medical officer Levi Garraway highlighted the potential of Evrysdi in combination with newborn screening programmes : “These two-year findings confirm the potential of early intervention with Evrysdi to meaningfully improve the lives of children with SMA. Working in tandem with newborn screening programs, Evrysdi is the only non-invasive SMA treatment that can be administered during a child’s first hours of life.” Evrysdi generated CHF 1.4bn ($1.64bn) in 2023 for Genentech, as per the company’s annual report, with projections from GlobalData estimating $2.8bn in revenue by 2030. Evrysdi’s main competitor, Biogen ’s Spinraza (nusinersen) won FDA approval in 2016 for infants, children, and adults with SMA. Spinraza is projected to generate less than Evrysdi in 2030, at $1.13bn, mainly due to the favourable oral delivery of Evrysdi compared to the intrathecal route (via a lumbar puncture) for Spinraza. GlobalData is the parent company of Pharmaceutical Technology. In addition to SMN-targeting treatments like Evrysdi and Spinraza, Novartis’ gene therapy Zolgensma (onasemnogene abeparvovec) can also be administered to infants with SMA. Zolgensma delivers a new, working copy of a human SMN gene which is administered in a one-time infusion to children under two years of age. Despite its effectiveness, some infants may be unable to access the gene therapy due to its invasive nature, cost, and accessibility. Evrysdi is also being evaluated in other clinical trials, including the Phase II Jewelfish trial (NCT03032172) in people with SMA aged six months to 60 years who received other investigational or approved SMA therapies for at least 90 days prior to receiving Evrysdi.

CAMBRIDGE, MA, USA I October 07, 2024 I Scholar Rock (NASDAQ: SRRK), a late-stage biopharmaceutical company focused on advancing innovative treatments for spinal muscular atrophy (SMA), cardiometabolic disorders, and other serious diseases where protein growth factors play a fundamental role, today announced positive topline results from the Phase 3 SAPPHIRE clinical trial (NCT05156320) evaluating the efficacy and safety of apitegromab, an investigational muscle-targeted therapy, in patients with SMA. The study achieved its primary endpoint demonstrating a statistically significant and clinically meaningful improvement for apitegromab versus placebo in motor function as measured by the gold standard HFMSE in SMA patients on chronic dosing of standard of care therapies (either nusinersen or risdiplam). Based upon the similar pharmacological profile of the 20 mg/kg and 10 mg/kg doses of apitegromab, the statistical analysis plan was prespecified to analyze both the combined dose (10 mg/kg and 20 mg/kg) compared to placebo, and 20 mg/kg dose each compared to placebo. Statistical significance is achieved per the prespecified statistical analysis plan (Hochberg multiplicity adjustment) where the p-value (≤0.025) is more rigorous if only one prespecified analysis crosses the statistical significance boundary of ≤ 0.05. Motor function outcomes were meaningful and consistent across the main efficacy population and in the ages 13-21 exploratory population, favored apitegromab (n=22) compared to placebo (n=10). Thirty percent of patients receiving apitegromab had >3 point improvement in HFMSE versus 12.5% of patients on placebo. Patients receiving apitegromab demonstrated early motor function improvement compared to placebo from the first measured time point at 8 weeks, benefit expanded at 52 weeks as measured by HFMSE. Following trial completion, 98 percent of SAPPHIRE patients (185/188) enrolled in the ongoing ONYX open-label expansion study. “We are thrilled that apitegromab met the primary endpoint in our Phase 3 SAPPHIRE clinical study. The results clearly demonstrate robust and clinically meaningful improvement in motor function in patients with SMA,” said Jay Backstrom, M.D., MPH, President and Chief Executive Officer of Scholar Rock. “At Scholar Rock, we are working with urgency to deliver the potentially transformative benefits of apitegromab to children and adults with SMA in the US, Europe, and around the world.” Treatment with apitegromab was well-tolerated across all age groups. There were no clinically relevant differences in the adverse event profile by dose, 10 mg/kg versus 20 mg/kg. No new safety findings were observed in the SAPPHIRE clinical trial; the profile was consistent with that observed in the Phase 2 TOPAZ clinical trial, including an extension study which had over four years of treatment as of the cut-off date. Serious adverse events (SAEs) were consistent with the underlying disease and current standard of care received by patients; no SAEs were assessed as related to apitegromab. There were no study drug discontinuations due to adverse events. “We are grateful to the families and investigators who participated in our trials. The positive Phase 3 SAPPHIRE trial, along with over 4 years of TOPAZ clinical trial data, clearly demonstrate the potentially transformative benefit of apitegromab to drive clinically meaningful improvements in motor function as measured by HFMSE in a broad SMA population, where motor function would normally be expected to generally decline over time,” said Jing Marantz, M.D., Ph.D., Chief Medical Officer at Scholar Rock. “We look forward to submitting our applications to the FDA and the EMA in Q1 2025.” The U.S. Food and Drug Administration (FDA) has granted Fast Track, Orphan Drug, and Rare Pediatric Disease designations, and the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) and Orphan Medicinal Product designations, to apitegromab for the treatment of SMA. The Company plans to submit a U.S. Biologics License Application (BLA) and a European Union marketing authorisation application (MAA) in Q1 2025. “It’s a great day for people living with SMA and their families. These encouraging trial results mark a critical milestone for the SMA community,” said Kenneth Hobby, President of Cure SMA. “Declining motor function and hopes for reversing losses associated with muscle weakness are significant unmet needs, impacting activities of daily living, from breathing, eating, self-care, to working and social interactions. We need an approved therapy that can support motor function and further improve daily activities for people with SMA.” Analyses of the full Phase 3 SAPPHIRE data are ongoing, and Scholar Rock plans to present detailed results at an upcoming medical conference in early 2025. Preliminary baseline characteristics from the trial will be presented during a poster presentation at the upcoming 29 th Annual Congress of the World Muscle Society on Friday, October 11, 2024, being held in Prague, Czech Republic. Conference Call Information Scholar Rock will hold an investor conference call today, October 7 at 8:00 am ET. To access the live conference call, participants may register here . The live audio webcast of the call will be available under “Events and Presentations” in the Investor Relations section of the Scholar Rock website at http://investors.scholarrock.com . To participate via telephone, please register here . Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. An archived replay of the webcast will be available on the Company’s website for approximately 90 days. Presentation at Annual Congress of the World Muscle Society Scholar Rock will present baseline characteristics from the SAPPHIRE trial in a poster presentation at the 29 th Annual Congress of the World Muscle Society. Details of the presentation are as follows: Title: Apitegromab in Spinal Muscular Atrophy: baseline characteristics of participants enrolled in the phase 3 SAPPHIRE study Presentation type: Poster presentation Presenter: Thomas O. Crawford, M.D., Professor of Neurology and Pediatrics, Johns Hopkins University Date and time: Friday, October 11, 2024, 3:45 PM CET Location: Prague, Czech Republic About Apitegromab Apitegromab is an investigational fully human monoclonal antibody inhibiting myostatin activation by selectively binding the pro- and latent forms of myostatin in the skeletal muscle. It is the first muscle-targeted treatment candidate to demonstrate clinical proof-of-concept in spinal muscular atrophy (SMA). Myostatin, a member of the TGFβ superfamily of growth factors, is expressed primarily by skeletal muscle cells, and the absence of its gene is associated with an increase in muscle mass and strength in multiple animal species, including humans. Scholar Rock believes that its highly selective targeting of pro- and latent forms of myostatin with apitegromab may lead to a clinically meaningful improvement in motor function in patients with SMA. The U.S. Food and Drug Administration (FDA) has granted Fast Track, Orphan Drug and Rare Pediatric Disease designations, and the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) and Orphan Medicinal Product designations, to apitegromab for the treatment of SMA. Apitegromab has not been approved for any use by the FDA or any other regulatory agency. About SAPPHIRE SAPPHIRE was a randomized, double-blind, placebo-controlled Phase 3 clinical trial that evaluated the safety and efficacy of apitegromab in nonambulatory patients with Types 2 and 3 SMA who are receiving current standard of care (either nusinersen or risdiplam). SAPPHIRE enrolled 156 patients aged 2-12 years old in the main efficacy population. These patients were randomized 1:1:1 to receive for 12 months either apitegromab 10 mg/kg, apitegromab 20 mg/kg, or placebo by intravenous (IV) infusion every 4 weeks. An exploratory population that enrolled 32 patients aged 13-21 years old was also evaluated. These patients were randomized 2:1 to receive either apitegromab 20 mg/kg or placebo. About SMA Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disease that afflicts an estimated 30,000 to 35,000 people in the United States and Europe. The disease is characterized by the loss of motor neurons, atrophy of the voluntary muscles of the limbs and trunk, and progressive muscle weakness. While there has been progress in the development of therapeutics that address the loss of motor neurons, there continues to be a high unmet need for therapies that directly address the progressive muscle weakness that leads to loss of motor function in SMA. About Scholar Rock Scholar Rock is a biopharmaceutical company that discovers, develops, and delivers life-changing therapies for people with serious diseases that have high unmet need. As a global leader in the biology of the transforming growth factor beta (TGFβ) superfamily of cell proteins and named for the visual resemblance of a scholar rock to protein structures, the clinical-stage company is focused on advancing innovative treatments where protein growth factors are fundamental. Over the past decade, Scholar Rock has created a pipeline with the potential to advance the standard of care for neuromuscular disease, cardiometabolic disorders, cancer, and other conditions where growth factor-targeted drugs can play a transformational role. This commitment to unlocking fundamentally different therapeutic approaches is powered by broad application of a proprietary platform, which has developed novel monoclonal antibodies to modulate protein growth factors with extraordinary selectivity. By harnessing cutting-edge science in disease spaces that are historically under-addressed through traditional therapies, Scholar Rock works every day to create new possibilities for patients. Learn more about our approach at ScholarRock.com and follow @ScholarRock and on LinkedIn. SOURCE: Scholar Rock

CAMBRIDGE, Mass.--( BUSINESS WIRE )--Scholar Rock (NASDAQ: SRRK), a late-stage biopharmaceutical company focused on advancing innovative treatments for spinal muscular atrophy (SMA), cardiometabolic disorders, and other serious diseases where protein growth factors play a fundamental role, today announced it has completed enrollment in the Phase 2 EMBRAZE trial designed to show proof-of-concept of apitegromab, an investigational selective myostatin inhibitor antibody, to safely preserve lean muscle mass in individuals on GLP-1 receptor agonist (GLP-1 RA) therapy for obesity. Results from this trial are expected in the second quarter of 2025 and will inform the development of SRK-439, a novel, investigational selective myostatin inhibitor, which the Company plans to advance specifically for the treatment of cardiometabolic disorders, including obesity. EMBRAZE is a randomized, double-blind, placebo-controlled, Phase 2 trial evaluating the efficacy, safety and pharmacokinetics of apitegromab in adults who are overweight or obese without diabetes and taking a GLP-1 RA. The trial fully enrolled participants aged 18-65 to assess the primary endpoint of change in lean mass by DEXA scan at 24 weeks. Initiation of enrollment was announced in May 2024. “ We believe the rapid enrollment of the EMBRAZE trial speaks to the unmet need to preserve lean muscle mass for patients experiencing significant weight loss on GLP-1 therapies. As a leader in myostatin inhibition, Scholar Rock is uniquely positioned to play a meaningful role in the cardiometabolic space. Preserving muscle has the potential to improve the quality of weight loss as well as attenuate the weight regain often observed when people come off GLP-1 therapy,” said Jing Marantz, M.D., Ph.D., Chief Medical Officer at Scholar Rock. “ We anticipate reporting results from EMBRAZE in the second quarter of 2025 and plan to use the data to further inform Scholar Rock’s development of SRK-439, which was designed specifically for the treatment of obesity.” The Company also announced today that it will present new preclinical SRK-439 data in a poster presentation entitled, “ SRK-439 Selectively Inhibits Myostatin to Promote Healthy Body Composition During Metformin Therapy” at The Obesity Society’s Annual Meeting at ObesityWeek®, November 3-6, in San Antonio, Texas. Preclinical data presented earlier showed that SRK-439 maintained lean mass and improved fat mass loss when used in combination with a GLP-1 RA in diet-induced obesity (DIO) mice. Preclinical data also supported the potential for SRK-439 to increase lean mass and attenuate fat mass regain, thus contributing to a favorable body composition following withdrawal from GLP-1 RA treatment. The Company plans to file an IND for SRK-439 in 2025. Apitegromab is being developed as potentially the first muscle-targeted therapy for the treatment of spinal muscular atrophy (SMA) and is the only muscle-targeted therapy to show clinical proof-of-concept in SMA. The Company is on track to report topline data in the fourth quarter of 2024 from the pivotal Phase 3 SAPPHIRE clinical trial in patients with SMA. If the trial is successful and apitegromab is approved by the U.S. Food and Drug Administration (FDA), the Company expects to initiate a commercial product launch in 2025. About Apitegromab Apitegromab is an investigational fully human monoclonal antibody inhibiting myostatin activation by selectively binding the pro- and latent forms of myostatin in the skeletal muscle. It is the first muscle-targeted treatment candidate to demonstrate clinical proof-of-concept in spinal muscular atrophy (SMA). Myostatin, a member of the TGFβ superfamily of growth factors, is expressed primarily by skeletal muscle cells, and the absence of its gene is associated with an increase in muscle mass and strength in multiple animal species, including humans. Scholar Rock believes that its highly selective targeting of pro- and latent forms of myostatin with apitegromab may lead to a clinically meaningful improvement in motor function in patients with SMA. The U.S. Food and Drug Administration (FDA) has granted Fast Track, Orphan Drug and Rare Pediatric Disease designations, and the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) and Orphan Medicinal Product designations, to apitegromab for the treatment of SMA. The efficacy and safety of apitegromab have not been established and apitegromab has not been approved for any use by the FDA or any other regulatory agency. About the Phase 3 SAPPHIRE Trial in Spinal Muscular Atrophy SAPPHIRE is an ongoing randomized, double-blind, placebo-controlled, Phase 3 clinical trial evaluating the safety and efficacy of apitegromab in nonambulatory patients with Types 2 and 3 SMA who are receiving SMN-targeted therapy (either nusinersen or risdiplam). SAPPHIRE targeted enrolling approximately 156 patients aged 2-12 years old in the main efficacy population. These patients were randomized 1:1:1 to receive for 12 months either apitegromab 10 mg/kg, apitegromab 20 mg/kg, or placebo by intravenous (IV) infusion every 4 weeks. An exploratory population that targeted enrolling up to 48 patients aged 13-21 years old will also separately be evaluated. These patients were randomized 2:1 to receive either apitegromab 20 mg/kg or placebo. For more information about SAPPHIRE, visit www.clinicaltrials.gov . Apitegromab has not been approved for any use by the US FDA or any other health authority, and its safety and efficacy have not been established. About the Phase 2 EMBRAZE Trial in Obesity EMBRAZE is a randomized, double-blind, placebo-controlled, Phase 2 proof-of-concept trial evaluating the efficacy, safety and pharmacokinetics of apitegromab in adults with a body mass index (BMI) of >27 (overweight) or a BMI of >30 (obese) and taking a GLP-1 RA (tirzepatide or semaglutide). The target enrollment of EMBRAZE is 100 subjects aged 18-65 who are overweight or obese without diabetes. As part of the study design, the treatment period is 24 weeks, and all subjects will receive a GLP-1 RA. In addition, all subjects will be randomized 1:1 to receive either apitegromab or placebo by intravenous (IV) infusion every four weeks during the 24-week treatment period. The primary endpoint is change from baseline at Week 24 in lean mass assessed by dual-energy X-ray absorptiometry. Secondary endpoints include additional weight loss measures, safety and tolerability, and pharmacokinetic outcomes. Exploratory endpoints at Weeks 24 and 32 include cardiometabolic parameters (e.g. HbA1c), body composition, and physical function. About SRK-439 SRK-439 is a novel, preclinical, investigational myostatin inhibitor that has high in vitro affinity for pro- and latent myostatin and maintains myostatin specificity (i.e., no GDF11 or Activin-A binding), and is initially being developed for the treatment of cardiometabolic disorders, including obesity. Based on preclinical data, SRK-439 has the potential to support healthier weight management by preserving lean mass during weight loss. The efficacy and safety of SRK-439 have not been established and SRK-439 has not been approved for any use by the FDA or any other regulatory agency. About Scholar Rock Scholar Rock is a biopharmaceutical company that discovers, develops, and delivers life-changing therapies for people with serious diseases that have high unmet need. As a global leader in the biology of the transforming growth factor beta (TGFβ) superfamily of cell proteins and named for the visual resemblance of a scholar rock to protein structures, the clinical-stage company is focused on advancing innovative treatments where protein growth factors are fundamental. Over the past decade, Scholar Rock has created a pipeline with the potential to advance the standard of care for neuromuscular disease, cardiometabolic disorders, cancer, and other conditions where growth factor-targeted drugs can play a transformational role. Scholar Rock is the only company to show clinical proof-of-concept for a muscle-targeted treatment in spinal muscular atrophy (SMA). This commitment to unlocking fundamentally different therapeutic approaches is powered by broad application of a proprietary platform, which has developed novel monoclonal antibodies to modulate protein growth factors with extraordinary selectivity. By harnessing cutting-edge science in disease spaces that are historically under-addressed through traditional therapies, Scholar Rock works every day to create new possibilities for patients. Learn more about our approach at ScholarRock.com and follow @ScholarRock and on LinkedIn. Availability of Other Information About Scholar Rock Investors and others should note that we communicate with our investors and the public using our company website www.scholarrock.com , including, but not limited to, company disclosures, investor presentations and FAQs, Securities and Exchange Commission filings, press releases, public conference call transcripts and webcast transcripts, as well as on Twitter and LinkedIn. The information that we post on our website or on Twitter or LinkedIn could be deemed to be material information. As a result, we encourage investors, the media and others interested to review the information that we post there on a regular basis. The contents of our website or social media shall not be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended. Scholar Rock® is a registered trademark of Scholar Rock, Inc. Forward-Looking Statements This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Scholar Rock’s future expectations, plans and prospects, including without limitation, Scholar Rock’s expectations regarding its growth, strategy, progress and timing of its clinical trials for apitegromab and its preclinical programs, including SRK-439, and indication selection and development timing, including the therapeutic potential, clinical benefits and safety thereof, expectations regarding timing, success and data announcements of current ongoing preclinical and clinical trials, expectations regarding the achievement of important milestones, the ability of any product candidate to perform in humans in a manner consistent with earlier nonclinical, preclinical or clinical trial data, and the potential of its product candidates and proprietary platform. The use of words such as “may,” “might,” “could,” “will,” “should,” “expect,” “plan,” “anticipate,” “believe,” “intend,” “future,” “potential,” or “continue,” and other similar expressions are intended to identify such forward-looking statements. All such forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, without limitation, that preclinical and clinical data, including the results from the Phase 2 clinical trial of apitegromab are not predictive of, may be inconsistent with, or more favorable than, data generated from future or ongoing clinical trials of the same product candidates, including, without limitation, the Phase 3 clinical trial of apitegromab in SMA; Scholar Rock’s ability to provide the financial support, resources and expertise necessary to identify and develop product candidates on the expected timeline; the data generated from Scholar Rock’s nonclinical and preclinical studies and clinical trials; information provided or decisions made by regulatory authorities; competition from third parties that are developing products for similar uses; Scholar Rock’s ability to obtain, maintain and protect its intellectual property; Scholar Rock’s dependence on third parties for development and manufacture of product candidates including, without limitation, to supply any clinical trials; and Scholar Rock’s ability to manage expenses and to obtain additional funding when needed to support its business activities and establish and maintain strategic business alliances and new business initiatives, and our ability to continue as a going concern; as well as those risks more fully discussed in the section entitled "Risk Factors" in Scholar Rock’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as well as discussions of potential risks, uncertainties, and other important factors in Scholar Rock’s subsequent filings with the Securities and Exchange Commission. Any forward-looking statements represent Scholar Rock’s views only as of today and should not be relied upon as representing its views as of any subsequent date. All information in this press release is as of the date of the release, and Scholar Rock undertakes no duty to update this information unless required by law.