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Muscular Dystrophy Association Clinical and Scientific Conference (MDA)

This content originally appeared on our sister site,

New data from the phase 3 SPR1NT trial (NCT03505099) of onasemnogene abeparvovec (Zolgensma; Novartis Gene Therapies) were recently published, suggesting that the therapy is efficacious for presymptomatic patients with spinal muscular atrophy (SMA) with 3 copies of 

. Additionally, the gene-splicing modifier was well-tolerated in this population.

The results of the multicenter, open-label study were presented at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, March 13-16, in Nashville, Tennessee.

 The dataset presented included 15 patients, with Zolgensma treatment meeting both primary and secondary end points statistical significance (

 <.001). The therapy was compared with a cohort from the Pediatric Neuromuscular Clinical Research natural history data set.

Every patient was alive at the time of reporting, and no patients required ventilation or feeding tube support at any time point. Additionally, 100% of the treatment group achieved the ability to stand alone, and 93% (n = 14) of those patients achieved this within the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS) developmental window. Fourteen patients walked alone—11 within the WHO-MGRS developmental window.

As for safety, every patient reported an adverse event (AE), of which 53% (n = 8) had at least 1 treatment-related AE. Three patients reported serious AEs, but none were considered treatment-related by the investigators.

Shephard Mpofu, MD, senior vice president and chief medical officer, Novartis Gene Therapies, offered his perspective on the data in detail in this conversation, providing more context about the findings and their significance for the clinical community.

What should the clinical community take away from the data for the SPR1NT 3 copy cohort?

 The completed Phase 3 SPR1NT data presented at MDA show that children with three copies of the 

 back-up gene treated presymptomatically achieved age-appropriate milestones, including standing and walking. This is a stark contrast with the natural progression of SMA. Without treatment, most children with three copies of the 

 back-up gene develop SMA Type 2, characterized by the inability to walk independently. Results from SPR1NT reinforce that early treatment is critical regardless of medication and further demonstrates the outstanding impact Zolgensma can have on children with SMA.

Were there any particularly exciting data points or unique aspects of this assessment?

We are excited that the results from the SPR1NT trial once again confirm the transformative impact of Zolgensma for children with SMA, and now in patients who were treated presymptomatically.

Fourteen of 15 children (or 93%) went on to walk independently, most (11 of 15, or 73%) within the World Health Organization window of normal development. All 15 children met the primary end point of standing alone 3 or more seconds, including 14 of 15 (or 93%) within the WHO window of normal development. All children were free of feeding tube support and ventilatory support of any kind during the study, and no serious, treatment-related adverse events were reported

These results are in sharp contrast to the natural history of the disease—and they again reinforce the value of early diagnosis and treatment of SMA.

How would you describe the overall data profile on Zolgensma to this point?

Zolgensma has demonstrated consistent, transformative, and clinically meaningful therapeutic benefit in presymptomatic and symptomatic SMA, including prolonged event-free survival and achievement of motor milestones unseen in natural history of the disease.

The data presented at MDA continue to reinforce the benefit of Zolgensma in the real-world setting, including in patients outside of our current clinical trial experience.

We believe that all patients diagnosed with SMA should be able to benefit from the transformative impact of gene therapy, and we continue to study its effect in patient groups where unmet needs remain. The data presented at MDA continue to reinforce the benefit of Zolgensma in the real-world setting, including in patients outside of our current clinical trial experience.

In addition to the SPR1NT data, Novartis also presented a descriptive post hoc analyses of START, STR1VE-EU and STR1VE-US that indicated children with SMA Type 1 achieved or maintained important measures of bulbar function following treatment with Zolgensma, including ability to speak; swallow and meet nutritional needs; and maintain airway protection. Bulbar motor neurons control muscles required for functions like swallowing, speaking, and chewing, and impairment from SMA can lead to choking, malnutrition, infection and death.

In April 2021, we announced plans to initiate SMART, a phase 3b clinical study to evaluate the safety and efficacy of Zolgensma in young children with SMA weighing 8.5 kg or more and 21 kg or less. Additionally, in August 2021, we announced plans to initiate STEER, a global pivotal phase 3 registration-enabling study to evaluate the clinical efficacy, safety, and tolerability of OAV101 intrathecal in treatment-naïve patients who are between 2 and 18 years of age, able to sit, but have never walked.

REFERENCES
1. Strauss K, Mutoni F, Farrar MA, et al. Onasemnogene abeparvovec in presymptomatic spinal muscular atrophy: SPR1NT study update in children with three copies of SMN2. Presented at: MDA 2022; March 13-16; Nashville, TN. Virtual Poster. https://mdaconference.org/node/1708
2. Novartis data again demonstrate age-appropriate development when Zolgensma is used presymptomatically, and post-hoc data reveal SMA Type 1 patients could speak, swallow and maintain airway protection. News release. Novartis. March 14, 2022. Accessed April 11, 2022. https://www.novartis.com/news/media-releases/novartis-data-again-demonstrate-age-appropriate-development-when-zolgensma-used-presymptomatically-and-post-hoc-data-reveal-sma-type-1-patients-could-speak-swallow-and-maintain-airway-protection

Shephard Mpofu, MD, part of the Novartis Gene Therapies leadership, shared his thoughts on the latest phase 3 data on onasemnogene abeparvovec (Zolgensma) from the SPR1NT trial.

Zolgensma Shows Efficacy in SMA With 3 SMN2 Copies

’ investigational gene therapy for treating Duchenne muscular dystrophy (DMD), improved outcomes in treated patients over 2 years, according to new data from the phase 1/2 IGNITE-DMD study (NCT03368742).

Updated 2-year data from the first 3 patients treated in the high-dose cohort (2E14vg/kg) were presented at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, March 13-16, in Nashville, Tennessee, by Roxana Donisa Dreghici, MD, senior vice president and head, clinical development, Solid Biosciences.

“We are encouraged by the motor function, pulmonary function and patient reported outcome data which show that patients continue to experience durable benefit across all reported measures two years after SGT-001 dosing,” Dreghici said in a statement.

“This is important as the evidence suggests that these patients treated with SGT-001 show potentially sustained or improved performance at a time when expected natural history would suggest a decline.”

The updated, 2-year data for the 3 patients are in line with previous data reported from the 12- and 18-month time points and continue to show durable benefit. Differing from natural history, these patients exhibited improved motor function, with a mean 16-meter improvement (range, -12 to 39; mean difference from natural history, +100.6) in 6-Minute Walk Test from baseline and a –1.7 change (range, -3 to –1; mean difference from natural history, +4.3) in North Star Ambulatory Assessment from baseline.

SGT-001 Improves Pulmonary Function in Duchenne Muscular Dystrophy

These patients also showed improvements from baseline differing from natural history in pulmonary function with a mean 9.2% improvement in forced vital capacity (range, -1.4 to 29.0; mean difference from natural history, +19.2) and a 6.5% improvement in peak expiratory flow (range, -5.8 to 14.8; mean difference from natural history, +16.5).

“We are especially pleased that the data suggests sustained benefit of pulmonary function at the 2-year timepoint, which may lead to delayed ventilation and improved quality of life, as well as potentially an increased life expectancy,” Dreghici added.

Patient reported outcome measures as assessed in key functional domains of the Pediatric Outcomes Data Collection Instrument (PODCI) also were improved when compared with both baseline and natural history, with a mean 6.3-point improvement in PODCI global function (range, 0-13; mean difference from natural history, +16.4), a 0.7-point improvement in PODCI transfer/basic mobility (range, -4 to 6; mean difference from natural history, +20.6), and a 13.3-point improvement in PODCI sports/physical functioning (range, 12-15; mean difference from natural history, +19.5).

SGT-001 continues to be well-tolerated, with no new treatment-related adverse events in the 9 patients dosed so far, with follow-up for up to 4 years. The IGNITE-DMD trial will finish dosing patients in 2022 and will commence further discussions with the FDA at that time.

Solid also reported data from skeletal muscle biopsies from the 3 patients most recently treated with the high dose of SGT-001, collected 3 months after treatment. Immunofluorescence and western blot findings were within the range of the first 3 patients in the higher-dose cohort. All patients in this cohort have demonstrated microdystrophin expression and proper membrane localization. 

1. Dreghici R, Redican S, Lawrence J, et al. Ignite DMD phase I/II study of SGT-001 microdystrophin gene therapy for DMD: 2-year outcomes update. Presented at MDA Clinical and Scientific Conference; March 13-16. Poster 46.
2. Solid Biosciences reports fourth quarter and full-year 2021 financial results and 2-year efficacy and safety data from the ongoing phase I/II IGNITE DMD clinical trial of SGT-001. News release. Solid Biosciences. March 14, 2022. https://www.solidbio.com/about/media/press-releases/solid-biosciences-reports-fourth-quarter-and-full-year-2021-financial-results-and-2-year-efficacy-and-safety-data-from-the-ongoing-phase-i-ii-ignite-dmd-clinical-trial-of-sgt-001

Data presented at MDA 2022 show improvements in motor and pulmonary function and patient-reported outcomes. 

2-year Data for Duchenne Muscular Dystrophy Gene Therapy Shows Durable Improvements 

This content originally appeared on our sister site, 

Sarepta Therapeutics has launched the phase 3 EMBARK study (NCT05096221) to evaluate their gene therapy delandistrogene moxeparvovec (SRP-9001), for the potential treatment of Duchenne muscular dystrophy (DMD).

The trial design was presented by Francesco Muntoni, MD, chair, pediatric neurology, University College London Institute of Child Health and Great Ormond Street Hospital for Children, at the 2022 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, March 13-16, Nashville, Tennessee. 

Doug Ingram, president and chief executive officer, Sarepta, said in a statement that "The launch of the pivotal trial “represents the culmination of enormous effort and success from a research, development, and manufacturing perspective and is an extraordinarily important moment for the patient community and a leap forward in our effort to change the course of Duchenne."

SRP-9001 uses the adeno-associated virus serotype rh74 (rAAVrh74) vector to deliver the micro-dystrophin-encoding gene to skeletal and cardiac muscle tissue.

The EMBARK study will enroll up to 120 patients, boys with a DMD mutation within exons 18-44 or 46-79. Participants must be ambulatory and between 4 to 8 years of age. Participants will be dosed with a single, intravenous dose of 1.33x10

The study was initiated in Novermber 2021 and will consist of 2, 52-week phases. Participants randomized to placebo will receive SRP-9001 in the second phase. 

EMBARK is primarily assessing change in North Star Ambulatory Assessment (NSAA) total score from baseline to week 52. Secondary end points include micro-dystrophin protein expression at week 12 as measured by western blot and number of skills gained or improved at week 52 as measured by NSAA. 

Investigators will also assess timed function tests such as Time to Rise, 100-Meter and 10-Meter Walk/Run, and 4-Stair Climb, as well as stride velocity as measured by a wearable device and Patient-Reported Outcomes.

Sarepta presented additional information from Study 101 (NCT03375164) that evaluated SRP-9001 at MDA 2022. This open-label trial evaluated  a dose of 2x10

 vg/kg via peripheral arm vein in 4 ambulatory patients with DMD between the ages of 4 and 7 without preexisting AAVrh74 antibodies and a stable corticosteroid dose of ≥12 weeks.Participants were also given daily prednisolone, 1 mg/kg, at day 1 prior to gene delivery and also underwent a 30-day taper after infusion.

SRP-9001 was well tolerated in this study with minimal adverse events (AEs). There were no serious AEs or discontinuations from the study after 3 years on SRP-9001. Treatment-emergent AEs, mild or moderate in severity, mostly occurred during the first 90 days post-infusion and were all resolved by the end of the study period.

Safety was the primary outcome, but investigators observed biomarker efficacy via secondary outcomes that included micro-dystrophin expression by Western blot and immunohistochemistry. Robust transgene expression in all patients was observed after 12 weeks, with a mean of 81.2% of muscle fiber micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. 

Notably, all patients had confirmed vector transduction and showed functional improvement of NSAA at posttreatment compared with baseline that was maintained for 1 year. All 4 patients demonstrated general improvements in functional measures compared with baseline that appeared to me maintained 3 years after infusion. 

Led by Jerry Mendell, MD, neurologist, Nationwide’s Children Hospital, the study authors concluded that these new findings provide proof-of-concept support for the continuation of trials looking at SRP-9001 in patients with DMD.

REFERENCES
1. Muntoni F, Mercuri E, Schara-Schmidt U, et al. EMBARK study design: phase 3 trial evaluating the safety and efficacy of delandistrogene moxeparvovec (SRP-9001) in Duchenne muscular dystrophy. Presented at MDA Clinical and Scientific Conference; March 13-16. Poster 28
2. Sarepta Therapeutics announces initiation of EMBARK, a global pivotal study of SRP-9001, a gene therapy for the treatment of Duchenne muscular dystrophy. News release. Sarepta Therapeutics. November 4, 2021. Accessed March 14, 2022. 

https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-initiation-embark-global-pivotal


3. Sarepta Therapeutics announces positive safety and efficacy data from the SRP-9001 micro-dystrophin gene therapy trial published in JAMA neurology. News release. Sarepta Therapeutics. June 15, 2020. Accessed March 14, 2022. globenewswire.com/news-release/2020/06/15/2048220/0/en/Sarepta-Therapeutics-Announces-Positive-Safety-and-Efficacy-Data-from-the-SRP-9001-Micro-Dystrophin-Gene-Therapy-Trial-Published-in-JAMA-Neurology.html
4. Mendell JR, Sahenk Z, Lehman KJ, et al. Phase 1/2a trial of delantistrogene moxeparvovec (SRP-9001) in patients with Duchenne muscular dystrophy: 3-year safety and functional outcomes. Presented at MDA Clinical and Scientific Conference; March 13-16. Poster 47

Sarepta also presented updated data from Study 101 of SRP-9001 at MDA 2022.

EMBARK Study Evaluates DMD Gene Therapy

Pediatric patients with spinal muscular atrophy (SMA) treated presymptomatically with

(Zolgensma; Novartis) continue to demonstrate age-appropriate development, according to new data from the phase 3 SPR1NT study (NCT03505099).

These data were presented at the 2022 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, March 13-16, in Nashville, Tennessee.

“Results from SPR1NT again confirm the remarkable impact of Zolgensma for children at risk for SMA who are treated before the onset of symptoms. In sharp contrast to the natural course of SMA, children treated preemptively with Zolgensma are standing and walking, with few or no signs of neuromuscular disease. Many of these children achieve patterns of motor development indistinguishable from their healthy peers without SMA,” Kevin Strauss, MD, medical director, Clinic for Special Children, Pennsylvania, said in a statement. “These data clearly demonstrate the value of newborn screening for SMA, which is vital to affording children the earliest diagnosis and treatment to ensure the best possible outcomes.”

The phase 3, open-label, SPR1NT trial evaluated presymptomatic= treatment of patients with SMA with either 2 or 3 copies of SMN2 less than 6 weeks of age. New data reported is from the 3-copy cohort, who had a mean age of dosing of 28.7 days (range, 9-43). Most patients with 3 copies of the gene develop SMA type 2.

Gene Therapy Updates in Neuromuscular Diseases

Investigators found that almost all treated children (n = 14/15; 93%) with 3 copies of the SMN2 back-up gene developed independent walking skills and 11 (73%) developed this skill within the World Health Organization (WHO) window of normal development, differing from natural history. The study met its primary endpoint, and all children were able to stand alone for at least 3 seconds, most (n = 14) within the WHO window of normal development.

No patients required nutritional and respiratory support during the study. There were no serious, treatment-related adverse events (AEs) but 3 patients did experience unrelated serious AEs. All patients experienced at least 1 AE after dosing and 8 (53%) were treatment-related.

Novartis also presented descriptive post-hoc analyses of the START (NCT02122952), STR1VE-EU (NCT03461289), and STR1VE-US (NCT03306277) trials, with data from 65 treated children. Altogether, investigators found that of 20 evaluable, treated children with SMA type 1 from the studies, 16 of 20 (80%) achieved the bulbar function endpoint, a composite score of communication, swallowing, and maintenance of airway protection.

Specifically, 19 of 20 evaluable patients (95%) met the communication endpoint, 60 of 65 evaluable patients (92%) met the swallowing endpoint, and 60 of 65 evaluable patients (92%) were able to maintain airway protection.

“The effect of SMA Type 1 on bulbar function often leads to debilitating complications, such as increased risk of aspiration, as well as social consequences from impairment of speech development. These post-hoc data suggest Zolgensma can have an important impact on a child’s well-being,” Shephard Mpofu, MD, senior vice president and chief medical officer, Novartis Gene Therapies, added to the statement. “Additional data presented at MDA continue to reinforce the consistent, significant and clinically meaningful therapeutic benefit of Zolgensma in the real-world setting, including in patients outside of our current clinical trial experience.”

Novartis data again demonstrate age-appropriate development when Zolgensma is used presymptomatically, and post-hoc data reveal SMA Type 1 patients could speak, swallow and maintain airway protection. News release. Novartis. March 14, 2022. https://www.novartis.com/news/media-releases/novartis-data-again-demonstrate-age-appropriate-development-when-zolgensma-used-presymptomatically-and-post-hoc-data-reveal-sma-type-1-patients-could-speak-swallow-and-maintain-airway-protection

New data presented at MDA 2022 showcased positive motor and bulbar function data. 

Presymptomatic SMA Treatment With Zolgensma Associated With Normal Development 

The AAV9-mediated microdystrophin gene therapy SGT-001 elicited promising improvements in functional and biomarker end points for patients with Duchenne muscular dystrophy (DMD), according to updated findings from the ongoing phase 1/2 IGNITE DMD trial presented at the 2021 MDA Virtual Clinical & Scientific Conference.

In data from 6 patients treated with SGT-001 at high and low doses, there was an improvement in North Star Ambulatory Assessments (NSAA) compared with a delayed treatment control group (n = 3) and historical controls. Moreover, average 6-minute walk test (6MWT) distance was above 30 meters in both cohorts compared with a decline of 8.5 meters in the control group. Additionally, biomarker findings showed wide distribution of microdystrophin-positive muscle fibers and promising creatine kinase (CK) findings, suggesting disease stabilization with SGT-001.

“IGNITE DMD has demonstrated some meaningful evidence of benefits in multiple outcome measures across a wide age range of patient,” principal investigator Barry Byrne, MD, PhD, associate chair of Pediatrics and Director of the Powell Gene Therapy Center at the University of Florida, said during a presentation of the findings. “Some things are not easily captured in time function tests or quality of life measures. One of the most significant is that boys with Duchenne rarely run. It has been very rewarding to hear from families when these new-found abilities to run and other skills have led to the ability to participate in sports or even ride a bike. These moments are a really important part of childhood.”

Data presented at the meeting from the phase 1/2 study were from 9 patients aged 4 to 17 across 2 cohorts that analyzed different doses of SGT-001. In cohort 1, 3 patients were randomized to low-dose SGT-001 at 513 vg/kg or to a delayed treatment control group (n = 3). In cohort 2, 3 patients received SGT-001 at a higher dose of 214 vg/kg. The study has since been adapted to be an open-label, non-randomized trial and the control arm has been closed.

For functional outcomes, data were available for 2 patients each in the low-dose and control arms and for all 3 in the high-dose cohort. The mean change in NSAA total score at 1-year in the control arm was -1 and -7 compared with -3 and +5 in the low-dose cohort. By month 24, both patients in the low-dose cohort showed an improvement in NSAA total score (+1 and +5). In the high-dose cohort at 12 months, NSAA total score was +1, -1, and +1. Longer-term data were not yet available in this group. “It will be important to continue to examine the entire cohort over time,” Byrne noted.

For 6MWT, total distance declined in the control arm at 1-year compared with baseline by -8 and -9 meters. In the low-dose cohort, distance walked at 1-year increased from baseline by +12 and +62 meters (average, +37). At 2 years, this was +62 and +133 meters (average, +97.5). In the high-dose cohort, distance walked increased by +12, +52, and +85 meters at 1 year (average, +50).

Improvement in pulmonary function tests were observed with SGT-001 compared with natural history at 1-year, Byrne noted. Data for this end point were available for all 9 patients. Improvements in forced vital capacity (FVC) were seen in most patients treated with SGT-001. In the low-dose group, FVC at 1-year was -2.4%, 5.3%, and 8.9%. In the high-dose group, FVC was 3.1%, 10.2%, and 36.7% at 1 year. In the control arm, mean percent change in FVC at 1-year was -7.6%, -9.6%, and -15.0%.

In cohort 2, there was wide distribution of microdystrophin-positive muscle fibers at 90 days, with distribution ranging from 10% to 70%. By western blot analysis, the average microdystrophin level at 90 days was within 10% of normal dystrophin levels (range, ~5% to 17.5% of normal). Additionally, there was a 55% decline in CK levels 1 year after infusion of high-dose SGT-001, from an average baseline of 13,288 to 5908 following treatment. In cohort 1, a CK decrease was not observed. Patients went from an average baseline CK of 7774 to an average of 16,654 at 1 year (166% increase).

"There is a meaningful decrease in CK for patients in the high-dose group. While this biomarker can be variable, the average sustained decline of about 50% in the high-dose cohort seen after 1 year suggests improved integrity of the muscle fibers and a potential protective effect of the treatment," Byrne said.

The most common drug-related adverse events (AEs) were nausea (100%), vomiting (83%), and fever (67%). Less common events included cytokine release syndrome, generalized edema, hepatotoxicity, systemic inflammatory response, and thrombotic microangiopathy. These AEs are common in other systemic gene therapy studies, Byrne said. The most common treatment-related laboratory abnormalities included thrombocytopenia, increased fibrin D dimer, increased soluble C5b-9, increased LDH, and proteinuria.

There were 4 serious AEs in 3 of the 6 patients, 1 of which was deemed unrelated to SGT-001 and 2 were related to the activation of the soluble C5b-9 terminal complement system. The other serious AE was a case of immune hepatitis 4 weeks post treatment, which resolved rapidly with corticosteroids. "No new drug-related safety findings have been identified post-infusion in these 6 patients, between 17 and 37 months of follow up," Byrne said.

"The IGNITE DMD study included patient-reported outcome measure from 4 motor function domains from the Pediatric Outcomes Data Collection Instrument, or PODCI," said Byrnes. "Consistent with what would be expected with natural history data, the 2 patients in the control cohort had declines in scores in all 4 domains. In contrast, patients in the high-dose cohort had significant improvements in all 4 domains and the patients in the low-dose cohort improved in a minority of domains as well."

There have been several amendments to the IGNITE DMD study protocol, in response to serious AEs that occurred earlier in the study. Some of these concerns led to a clinical hold on the trial in the middle of 2020. The study subsequently resumed in October 2020. “The changes included a pretreatment regimen with complement inhibitors, transient increase in steroid use, and a second-generation manufacturing process to reduce the total viral capsid level per kilogram,” Byrne said.

Since reopening the study in October, an additional patient was enrolled and treated in the high-dose SGT-001 treatment arm. At this point, safety assessments on the seventh patient treated with SGT-001 have been promising and the patient has only experienced transient adverse events, according to Solid Biosciences, the company developing the gene therapy.

“We are encouraged with the successful resumption of dosing in the IGNITE DMD trial under our amended clinical protocol and using SGT-001 manufactured with a second-generation process," Ilan Ganot, chief executive officer, president and co-founder of Solid Biosciences, said in a statement. “We look forward to continuing to dose patients and reporting clinical outcomes from additional patients in the second half of 2021.”

SGT-001 elicited promising improvements in functional and biomarker end points for patients with Duchenne muscular dystrophy.

SGT-001 Shows Promising Functional Improvements in DMD

The AAV-based gene therapy SRP-9003 elicited sustained protein expression in muscle tissue and stabilized North Star Assessment for Dysferlinopathies (NSAD) scores at 2 years in patients with limb-girdle muscular dystrophy Type 2E (LGMD2E), according to updated findings from a phase 1/2 study presented at the 2021 Muscular Dystrophy Association (MDA) Annual Clinical and Scientific Conference.

In a low-dose cohort with 2 years of follow-up, mean beta-sarcoglycan (beta-SG) expression was 54% by western blot in patients receiving SRP-9003, which was an increase from 36% at day 60. In a high-dose cohort, the 60-day beta-SG expression was 62%. Two-year findings were not yet available. There was a mean improvement from baseline in NSAD score at 2 years of 5.7 points with low-dose SRP-9003. In the high-dose arm, there was a 4.0-point increase at 1 year.

SRP-9003 elicited improvements for functional measures in all patients in the phase 1/2 study. These included improvements in time-to-rise, four-stair climb, 100-meter walk test, and 10-meter walk test. These improvements were more pronounced in the high-dose group. Across all 6 patients in the phase 1/2 study, a comparison to historical controls showed a marked improvement in NSAD score with SRP-9003. For those treated with SRP-9003, the mean improvement in NSAD was 4.6 points compared with a decline of 4.6 points for matched historical controls, for an absolute difference of 9.2 points.

“This data is the first look at longer-term expression data with any gene therapy for muscular dystrophy,” Louise Rodino-Klapac, PhD, executive vice president and chief scientific officer, Sarepta Therapeutics, the company developing the therapy, said in a statement. “The meaningful and sustained levels of beta-sarcoglycan protein expression at 2 years and continued strength of the functional outcomes measured are tremendously positive and support continued advancement of this investigational treatment for patients.”

LGMD2E is characterized by mutations in the sarcoglycan beta (

) gene, disrupting production of key proteins in the dystrophin-associated protein complex (DAPC). SRP-9003 was developed to restore function to 

 transgene mediated by the AAVrh74 vector. The therapy is targeted to cardiac and skeletal muscle expression specifically through the MCHK7 promoter.

"LGMD2E is one of the most severe forms of LGMD and causes significant disability in children while frequently leading to early mortality and the data continue to suggest this treatment could bring much needed hope to these patients," Rodino-Klapac said.

The phase 1/2 study contained 2 cohorts, each exploring a different dose of the gene therapy. In cohort 1, patients received 1.85 × 10

 vg/kg as a single intravenous infusion and in cohort 2 treatment was given at 7.41×10

 vg/kg. The dose in the second cohort was based on safety and efficacy findings from cohort 1. The study enrolled children between the ages of 4 and 15 years with significant symptoms.

In cohort 1 (n = 3) there were 24 months of follow-up. The percent of immunofluorescent (IF)-positive fibers for beta-SG expression was 48%. At 60 days, this was 51%, showing stabilization with additional follow up. The mean fluorescent beta-SG intensity at 2 years was 35% and was found to be localized to muscle sarcolemma, suggesting efficacy of the MCHK7 promoter. At 60 days, the intensity was 47%. By PCR, there were 0.59 vector copies per nucleus at 60 days and 0.13 at 2 years.

In cohort 2 (n = 3) there were 12 months of follow up. At 60 days, approximately 72% of fibers had beta-SG expression with a mean fluorescent intensity of 73%. There were 4.24 vector copies per nucleus. Other proteins encoded by the 

 gene were also elevated, namely delta-SG and gamma-SG, which could indicate a reconstitution of the DAPC. Expression for these proteins was 65.3% mean positive fibers and 103% intensity for delta-SG and 60% mean positive fibers and 97% intensity for gamma-SG.

“In cohort 2, we also saw strong expression of delta-sarcoglycan and gamma-sarcoglycan proteins in addition to beta-sarcoglycan, which suggests that SRP-9003 is working to restore the dystrophin associated protein complex, or DAPC, which provides biological support for the sustained functional benefits observed in both cohorts," Rodino-Klapac said.

Adverse events remained consistent with the additional follow-up, and there were no new safety events. Earlier in the study, in cohort 1, there were 2 cases of liver enzyme elevation, 1 of which was deemed a serious adverse event (SAE). There was 1 elevation in liver enzyme in cohort 2. All of these cases occurred when patients were tapered off steroids and both resolved with supplemental steroid treatment. In cohort 2, there was 1 SAE of dehydration due to vomiting 3 days post-infusion.

SRP-9003 elicited sustained protein expression in muscle tissue and stabilized North Star Assessment for Dysferlinopathies scores at 2 years in patients with limb-girdle muscular dystrophy Type 2E.



SRP-9003 Efficacy, Tolerability Sustained at 2 Years in LGMD2E

Updated findings from across a number of studies presented at the 2021 Muscular Dystrophy Association (MDA) Virtual Clinical and Scientific Conference highlighted the significant benefits of onasemnogene abeparvovec (Zolgensma) for children with spinal muscular atrophy (SMA).

In findings from the phase 3 SPR1NT trial, presymptomatic children with a genetic diagnosis of SMA achieved age-appropriate developmental milestones with onasemnogene abeparvovec treatment. In long-term findings with a mean follow-up of 5 years, 100% of children treated with a therapeutic dose of the gene therapy remained alive and free of permanent ventilation and previously achieved milestones were sustained with the longer follow up. Adding to these findings, data from the RESTORE registry showed CHOP INTEND improvement or maintenance in 96% of children treated with onasemnogene abeparvovec.

“When treated with Zolgensma prior to the onset of symptoms, children in the SPR1NT trial achieved milestones like sitting, standing, and walking at an appropriate age, grew as expected without nutritional assistance, and remained free of all forms of mechanical ventilatory support,” Kevin Strauss, MD, medical director, Clinic for Special Children in Pennsylvania, said in a statement. “This stands in sharp contrast to the natural progression of SMA Type 1, which would otherwise render them helpless within the first year of life and unable to swallow, breathe, or survive without mechanical support. The transformative benefit of early intervention, as seen in SPR1NT, further underscores the urgent need for newborn screening.”

The ongoing phase 3 SPR1NT trial included presymptomatic patients ≤6 weeks in age with biallelic deletions of 

 gene. "Without the benefit of disease-modifying therapy, newborns with biallelic 

 would normally develop SMA type 1 and SMA type 2, respectively," Strauss noted.

 (n = 14), the median age of patients was 15.6 months (range, 8.8-18.8). The primary end point of sitting without support for at least 30 seconds was achieved by 79% of patients (11 of 14), with 10 of the 11 achieving this milestone within the World Health Organization (WHO) criteria for normal development. The remaining 3 patients continued to be assessed.

Additionally, 36% of patients (5 of 14) could stand independently, with 3 achieving this milestone within WHO criteria for normal development. Of the remaining 9 patients, 7 were still in the window for normal development at the follow-up. Additionally, 4 of 14 patients (29%) could walk independently, of which 3 were within WHO criteria for normal development. Of the remaining 10 patients, 7 were still within the window for normal development.

 (n = 15), the median age was 15.2 months (range, 3.3-21.1). Overall, 53% of patients met the primary end point of standing alone for at least 3 seconds (8 of 15) and 40% walked independently (6 of 15). These achievements were all within WHO definition for normal development. Patients who had not yet achieved this end point were still within the window at the time of follow-up.

Across both groups, 100% of those treated with onasemnogene abeparvovec remained alive and free of ventilatory support and 100% did not require a feeding tube. As a single-arm study, there were not a comparator arm; however, in historical controls, 60% of patients with 2 copies of 

 would typically require feeding support by 15 months of age.

Additionally, 100% of patients had steady gains in mean raw score of Bayley-III fine and gross motor scales. Moreover, in the 2-copy group, 100% of patients achieved CHOP INTEND scores of ≥50 and 93% achieved scores ≥58. All patients experienced at least 1 adverse event and there were 7 reported serious adverse events in the study; however, all resolved and were deemed unrelated to onasemnogene abeparvovec.

Long-term findings were from LT-001, a long-term follow-up study of patients that completed the START study, and LT-002, which includes patients from other phase 1 and phase 3 studies of onasemnogene abeparvovec (STRONG, STR1VE, and STR1VE-EU). Data were presented for 13 patients from LT-001 with a mean age of 36.42 months (standard deviation [SD], 8.523) and 31 patients in LT-002 with a mean age of 33.6 months (SD, 12.92).

In LT-001, 8 patients reported SAEs, none of which led to study discontinuation or death and all of which were considered unrelated to treatment. The most common were acute respiratory failure, pneumonia, and dehydration. In LT-002, 2 patients reported SAEs and 1 AE of special interest was reported.

As of data cutoff dates, 2 of 3 patients (66.7%) remained free of permanent ventilation in the low-dose cohort of LT-001, and all patients in the therapeutic dose cohort (n = 10) were alive and free of permanent ventilation. Half the patients (n = 5) in the therapeutic dose cohort did not use respiratory support and 1 required it only when ill. The mean age at data cutoff was 5.2 years (range, 4.7-6.1) and mean time since dosing was 5.0 years (range, 4.6-5.6) as of data cutoff, June 11, 2020.

Among patients in LT-002 from the STR1VE studies, none of the 16 patients required permanent ventilation while 9 reported baseline respiratory support. The intravenous (IV) cohort had a mean age of 2.3 years (range, 1.6-3.2) at data cutoff and the mean time since dosing was 2.0 years (range, 1.5-2.7). The intrathecal cohort had a mean age of 4.3 years (range, 2.8-6.1) at data cutoff and the mean time since dosing was 2.4 years (range, 1.8-2.8).

No previously achieved motor milestones were lost during long-term follow-up in LT-001, with 2 patients gaining the milestone of standing with assistance without ever receiving nusinersen (Spinraza). In LT-002, 11 new milestones were achieved during long-term follow-up in 4 patients in the IV cohort, the highest of which was sitting without support, achieved without nusinersen or risdiplam (Evrysdi; Genentech) support in 3 patients and with risdiplam in 1.

The RESTORE observational registry trial included 70 patients ≥6 months in age with a diagnosis of SMA. Overall, 64% of participants (n = 45) had SMA type 1. At the time of treatment with onasemnogene abeparvovec, 48.5% of patients were aged ≥6 to 12 months, 43% were ≥12 to 24 months, and 8.5% were ≥24 months of age. This study also revealed the efficacy of newborn screening for SMA. Overall, 28 of patients in the registry were identified during newborn/prenatal screening. These patients received treatment at a mean of 1.7 months of age versus 4.4 months for those clinically diagnosed.

At the assessment, 23 patients had at least 2 CHOP INTEND assessments. Of these, 22 had improved or maintained scores (96%), including 15 (65%) with a clinically meaningful ≥4-point increase. Overall, CHOP INTEND increases of ≥4 points were experienced by 68% of those clinically identified (15 of 22) and for 89% of those identified through newborn or prenatal screening (8 of 9).

“With more than 1,000 patients now treated, these data presented at MDA further reinforce what we’ve come to expect from Zolgensma," Shephard Mpofu, MD, SVP, chief medical officer, Novartis Gene Therapies, the company developing onasemnogene abeparvovec, concluded in a statement. "[There was] consistent, significant, and clinically meaningful therapeutic benefit in SMA, including prolonged event-free survival, achievement of motor milestones unseen in natural history of the disease, and durability now more than 5 years post-dosing."

Onasemnogene abeparvovec was approved in the United States in May 2019 for the treatment of SMA in children less than 2 years of age. Prior to this approval, the gene therapy was granted fast track, orphan drug, priority review, and breakthrough therapy designations. Studies will continue to assess the treatment.

Updated findings from across a number of studies highlighted the significant benefits of onasemnogene abeparvovec for children with spinal muscular atrophy.