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Real-World Trials Show Sustained Durability, Improved Outcomes in Children With SMA

April 06, 2021

By Julie Gould

Shephard Mpofu, senior vice president and chief medical officer, Novartis Gene TherapiesShephard Mpofu, MD, senior vice president and chief medical officer, Novartis Gene Therapies, discusses various trials—SPR1NT, LTFU, and RESTORE from Muscular Dystrophy Association Virtual Clinical and Scientific conference—that examined a treatment for spinal muscular atrophy (SMA), which demonstrated age-appropriate development in children with SMA when used early, as well as real-world benefits in older children and durability more than five years post-treatment. 

What existing data led you and your co-investigators to conduct this research?

It has been a decade since findings were first published that AAV9 was able to cross the blood-brain barrier. Since then, we’ve conducted several clinical studies evaluating the use of an AAV9 vector to deliver a functional copy of the SMN gene to a patient’s neurons, starting with our completed Phase 1 START and pivotal Phase 3 STR1VE studies. As you may know, Zolgensma is the only gene therapy for SMA and the only SMA treatment designed to directly address the genetic root cause of the disease by replacing the function of the missing or non-working SMN1 gene with a single, one-time dose. As a transformative gene therapy designed to provide a lifetime of benefit, Zolgensma is an essential one-time treatment for patients with SMA, representing a completely new class of SMA treatment. 

These trials evaluated the efficacy and safety of a one-time IV infusion of Zolgensma in patients with SMA Type 1 who showed symptoms of SMA at less than six months of age, with one or two copies of SMN2 in the STR1VE trial or two copies in the START trial, and who have bi-allelic SMN1 gene deletion or point mutation.  

Since then, we’ve started three additional clinical trials, two long-term observational studies and one non-interventional registry study to evaluate treatment with Zolgensma. At this year’s 2021 Muscular Dystrophy Association (MDA) Virtual Clinical and Scientific conference, we were proud to share interim results from our SPR1NT study as well as our two Long-Term Follow-Up (LTFU) Studies and emerging findings from the RESTORE Registry.

Please briefly describe the study and its findings. Were any of the outcomes particularly surprising? What are the possible real-world applications of these findings in clinical practice? 

These new data show that Zolgensma demonstrates age-appropriate development in children with SMA when used early, real-world benefit in older children and durability more than five years post-treatment.  

The new data underscore the critical importance of identifying and treating SMA as early as possible. Patients treated presymptomatically in our SPR1NT trial are achieving age-appropriate motor milestones including sitting, standing and walking, were able to eat exclusively by mouth and did not require ventilatory support of any kind – a sharp contrast to the natural history of this devastating disease. This underscores the important need for widespread implementation of newborn screening for SMA, so we can detect and treat this disease before symptoms appear. In addition, children identified via newborn screening enrolled in the RESTORE real-world registry were significantly less likely to receive more than one SMA therapy compared with those who were diagnosed clinically.

Our two LTFU studies demonstrated that Zolgensma led to achievement of new milestones years after treatment and resulted in sustained durability in children with SMA now up to six years old and more than five years post-treatment. In LT-002 (Phase 3 IV studies), eleven new milestones were achieved by four patients (17%), including sitting without support by all four patients (three were not receiving concomitant disease-modifying SMA therapy). In LT-001 (START study) as of the December 2019 data cut, no previously achieved motor milestones were lost, and two patients (20%) had gained the milestone of standing with assistance (neither of whom had received treatment with nusinersen) during the follow-up period. In both LT-001 and LT-002, all patients were alive and long-term follow-up does not show evidence of new or delayed safety signals, supporting a favorable benefit-risk profile.  

Real-world data from our RESTORE registry indicate older children (aged ≥6 months) achieved a clinically meaningful benefit from Zolgensma alone, after switching to gene therapy or in combination with another SMA therapy, with events consistent with the previously described safety profile. Nearly all children with two or more CHOP INTEND assessments available improved or maintained their scores, and most had a clinically meaningful ≥4-point increase. These data are an important indication that the real-world experience for these older patients mirrors what we have seen in clinical trials of younger patients.  

Do you intend to expand upon this research?

SPR1NT is an ongoing Phase 3, open-label, single-arm, multi-center trial that is currently evaluating 14 patients with two copies of SMN2 and 15 patients with three copies of SMN2. Data presented at the 2021 MDA Virtual Conference is from a June 11, 2020 data cut. We expect the study to conclude in 2021 and will plan to share updated findings once it’s completed.  

This is the first time we are reporting early interim data from RESTORE and expect to report more patients with longer follow-up durations as the study progresses. The RESTORE registry is an ongoing, prospective, multicenter, multinational, observational study of patients with a diagnosis of SMA, including patients from the Zolgensma managed access programs and from partnering clinical sites with a planned follow up of 15 years.

LT-001 is an ongoing, observational, long-term follow-up study of patients who completed START and electively enrolled in the study. Patients from the completed and ongoing Phase 3 IV studies (STR1VE-US, STR1VE-EU, STR1VE-AP, SPR1NT) and the Phase 1 intrathecal study (STRONG–currently on partial clinical hold) are now enrolling in a long-term follow-up extension study (LT-002). We look forward to reporting future results from these studies, as well as the rest of our clinical program. Novartis is unwavering in our commitment to using science-based innovation to improve outcomes for SMA patients and address the unmet medical needs of SMA. 

Is there anything else pertaining to the research and findings that you would like to add?

With more than 1,000 patients treated to date with Zolgensma worldwide across clinical trials, managed access programs, and in the commercial setting, these data presented at MDA further reinforce what we’ve come to expect from Zolgensma–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 five years post-dosing.

Please share any necessary disclosures.

I am employed by Novartis Gene Therapies.

About Dr Mpofu

Shephard Mpofu is the Senior Vice President and Chief Medical Officer at Novartis Gene Therapies. He oversees medical affairs for Novartis Gene Therapies’ spinal muscular atrophy (SMA) treatment, Zolgensma® (onasemnogene abeparvovec), and leads clinical development for the pipeline of promising gene therapies for rare genetic diseases. He also serves as an extended member of Novartis’ Development Committee.  

He has deep clinical and industry experience, having served in a variety of roles at Novartis since 2006. Most recently, he has served as Novartis’ Senior Global Program Head in the Immunology, Hepatology and Dermatology Franchise, where he played an instrumental role in the clinical development of our company’s medicines. 

He has a medical degree from the Godfrey Huggins School of Medicine and received a Certificate in Clinical Development from the University of Basel. He is a board-certified rheumatologist and a Fellow of the Royal College of Physicians UK.

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