Treatment of presymptomatic babies with the investigational gene therapy Zolgensma provides rapid improvement in motor function in infants with spinal muscular atrophy (SMA) types 1, 2 and 3, according to preliminary results of a Phase 3 trial.
The study, named SPR1NT (NCT03505099), is enrolling participants at locations in the U.S., Australia, Canada, and Japan. Other study sites in the U.S., Europe, Israel, Republic of Korea and Taiwan are yet to open. More information on locations and contacts can be found here.
The findings, “AVXS-101 Gene-Replacement Therapy (GRT) in Presymptomatic Spinal Muscular Atrophy (SMA): Study Update,” were presented in a scientific poster by Kevin A. Strauss during the 2019 American Academy of Neurology (AAN) Annual Meeting, being held in Philadelphia.
SMA is caused by a faulty SMN1 gene, which leads to lower levels of the SMN protein and subsequent loss of motor nerve cells, muscle weakness and atrophy. In its pivotal Phase 1 trial (NCT02122952), Novartis’ Zolgensma markedly improved survival and motor function of symptomatic SMA type 1 patients, who were up to six months of age when dosed.
Zolgensma comprises the shell of a genetically engineered virus, the adeno-associated virus (AAV) 9, called a capsid, which delivers a normal copy of the SMN1 gene to the target motor neurons. Once the SMN1 gene reaches patients’ cells, it supplements those cells’ own production of SMN protein.
As loss of motor neurons can be subtle and SMA progression is rapid, early intervention with a disease-modifying therapy is key. As such, the multi-center, open-label SPR1NT trial is testing intravenous infusion of Zolgensma in infants age six weeks or less who still do not present symptoms of SMA.
“Once motor neuron death occurs it is irreversible. That cannot be recovered. To be able to intervene before motor neuron death occurs, you really need to be able to do that before the child presents with symptoms: we have to move to a diagnosis at the time of birth,” Olga Santiago, MD, chief medical officer of AveXis, said in the company’s phone call-in briefing during AAN.
The study — sponsored by AveXis, the company that first developed Zolgensma and was purchased by Novartis in 2018 — is assessing Zolgensma in at least 27 patients with either two or three copies of the SMN2 gene. A higher number of copies of SMN2 —a gene that creates a shorter and less stable version of the SMN protein – is associated with reduced SMA severity.
Safety and efficacy will be analyzed at 18 or 24 months in patients with two or three SMN2 copies, respectively. SPR1NT’s primary outcomes are independent sitting for 30 seconds or longer at 18 months for infants with two SMN2 copies and standing with assistance at 24 months in those with three copies of this gene.
From April 10, 2018 to March 8, 2019, 18 patients with SMA (seven males, 11 females) have been dosed: eight (44%) had two copies of SMN2, nine (50%) three copies and one (6%) four copies of SMN2. All patients are alive and free of permanent ventilation and all are feeding on their own (have intact swallowing).
The mean age at dosing was 21 days, range 8–37 days. All patients with two copies of SMN2 (type 1) achieved or maintained a CHOP-INTEND score — an assessment of motor function — 50 points or higher. Six patients achieved a score higher than 60 points and three patients reached the maximum score of 64 points. According to natural history, SMA type 1 children do not achieve/maintain scores higher than 40 points, while healthy children have a score greater than 60 points beyond 3 months of age.
Among patients with two copies of SMN2, a mean score of 8.4 points in the Bayley-III Gross Motor score (which assesses gross motor function) was achieved by month two. These patients are reaching age-appropriate motor milestones, including four patients who could sit without support for at least 30 seconds (average age when milestone achieved 7.5 months) and one patient who could stand with assistance for more than two seconds (average age when milestone achieved 7.5 months).
Untreated natural history shows that patients with two copies of SMN2 will never sit without assistance.
Early increases in Bayley-III Gross Motor scores were also observed in SMA patients with three copies of the SMN2 gene.
“The main thing to understand here is that 100% of these patients were detected either by newborn screening or because they had one sibling who was affected by SMA. This really emphasizes the importance of early screening,” Strauss told José Lopes, SMA News Today on-site reporter.
Immune reactions against AAVs typically develop at around age 2. However, antibodies from the mothers — which usually disappear after a few months — have been found in infants. In SPR1NT, the biological mother is tested for AAV9 antibodies to determine whether a patient can participate in the trial.
Of the 24 biological mothers tested during trial enrollment screening, two (8%) had antibodies against AAV9 and only one SMA patient (out of four directly tested) had antibody levels that were high enough to result in trial exclusion.
“Preliminary data from SPR1NT show rapid motor function improvements in presymptomatic SMA patients, which may be associated with future survival and motor milestone achievement,” researchers said. “[This] evidence demonstrates a dramatic response when patients are treated presymptomatically with [Zolgensma].”
Serious adverse events included croup (one patient), lethargy (one patient), and hypercalcemia (elevated blood calcium levels, one patient), all of which were resolved and were considered unrelated to treatment. Other observed adverse events included elevated transaminases (which may indicate liver damage), elevated blood creatine phosphokinase-muscle/brain (which may indicate muscle damage) and elevated troponin (which may indicate heart muscle damage).
“SMA is rapidly progressive, and we know that intervening as early as possible in the disease course is critical to rescue motor neurons and preserve motor function,” Olga Santiago, MD, Chief Medical Officer of AveXis, said in a press release. “Patients treated with Zolgensma before the onset of symptoms are achieving age-appropriate motor milestones in line with normal development. These SPR1NT data reinforce the potential Zolgensma has as a foundational treatment for patients with SMA.”
“When we treat under six weeks, from what we can see so far, the children who are achieving milestones do that in a normal timeframe of childhood development. We think this is the best chance for these kids to get on a normal path of development,” David Lennon, president of AveXis, added during the company’s phone call-in briefing.