Zolgensma is the only approved gene therapy for SMA and designed to directly address the genetic root cause of the disease by replacing the function of the missing or non-working SMN1 gene.
The world’s most expensive drug at the time of approval (2019 in the US and 2020 in the EU) with a $2.1m price-tag, it is now approved in more than 47 countries and more than 3,000 patients have been treated.
Maintaining motor milestones
SMA is a rare, genetic neuromuscular disease and a leading genetic cause of infant death. The most severe forms of SMA results in the rapid and irreversible loss of motor neurons, affecting muscle functions including breathing, swallowing and basic movement.
The most common type, Type 1, is severe and, left untreated, leads to death or the need for permanent ventilation by the age of two in more than 90% of cases.
Loss of motor neurons cannot be reversed, so diagnosing SMA as early as possible is important to halt motor neuron loss and disease progression.
Zolgensma is a one-time adeno-associated virus vector-based gene therapy indicated for the treatment of pediatric patients under 2 years old.
Releasing the latest data from two Long-Term Follow-Up (LTFU) studies (LT-001 and LT-002) this morning, Novartis says the data show ‘the continued efficacy and durability of Zolgensma across a range of patient populations, with an overall benefit-risk profile that remains favorable’.
LT-001, an ongoing 15-year LTFU study of patients who completed the Phase 1 START study, showed that up to 7.5 years post-dosing, children who were treated after presenting symptoms of SMA maintained all previously achieved motor milestones. During the time of LT-001, three additional patients also achieved the key milestone of 'standing with assistance.'
The mean age of enrolled patients was 7.1 years.
“I have had the privilege of observing some of the children included in the LTFU studies since they started their Zolgensma clinical trial journey, and the fact that we’re seeing them maintain and, in some cases, gain motor milestones when they are nearly eight years old is truly transformational,” said Dr. Jerry R. Mendell of Nationwide Children’s Hospital.
“These children now have an improved quality of life, vastly different from what would have been expected for them if they had not received treatment."
15-year study
Interim results from the 15-year Phase 4 LT-002 study, which includes both presymptomatic and symptomatic patient populations, as well as intravenous (IV) and intrathecal (IT) showed that all patients (100%) maintained motor milestones achieved during their respective parent studies (namely, Phase 3 IV studies STR1VE-US, STR1VE-EU, STR1VE-AP, SPR1NT and the Phase 1 IT study STRONG) in the follow-up period.
Results from the IV cohort, which included 63 patients, demonstrated how a single administration of Zolgensma provided 'consistent, substantial and durable efficacy over time'.
In the pre-symptomatic IV cohort (n=25), all children either maintained the highest milestone achieved during the parent study (walking alone) or achieved the milestone by the data-cut off. In total, six patients treated prior to SMA symptom onset and 16 treated after SMA symptom onset achieved new motor milestones in the follow-up period.
For the 18 children who were treated with one-time investigational OAV101 IT (for patients with later onset forms of SMA), all were alive, free from permanent ventilation and continued to show incremental gains in motor function as of the May 2022 data cut-off. Five of 16 patients who had a milestone assessment achieved new milestones during the long-term follow-up period, such as crawling, walking or standing with assistance.
The majority of patients in LT-002 (70.4%, 57/81) never received add-on therapy (76.2% of the IV cohort, 50% of the investigational OAV101 IT cohort). Among patients in the intravenous cohort, 24 of 25 (96%) patients treated before symptom onset achieved the motor milestone of walking alone prior to or without add-on therapy, and 30 of 32 (93.8%) patients treated after SMA symptom onset achieved the milestone of sitting without support prior to or without add-on therapy.
These data are being presented during the 2023 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference in Texas this week.