Update on the SPR1NT study
Dr. Kevin Strauss
Interim safety and efficacy data from the ongoing SPR1NT study, which includes presymptomatic patients, also were scheduled to be presented. The trial “was built on the basic premise that spinal motor neuron degeneration associated with SMN protein deficiency begins in utero, continues to progress rapidly during the first months of life, and is irreversible,” said Kevin Strauss, MD, medical director of the Clinic for Special Children in Strasburg, Pennsylvania. “SPR1NT leveraged the advantages conferred by carrier testing and newborn screening programs for SMA, which allowed the first 22 children enrolled to have a confirmed molecular diagnosis between 1 and 26 days of postnatal life, before the onset of dysphagia, respiratory compromise, or overt weakness.”
In this multicenter, open-label, phase 3 trial, presymptomatic patients age 6 weeks or younger who are expected to develop SMA receive onasemnogene abeparvovec-xioi once and are evaluated during 18 or 24 months. The primary outcomes are sitting for 30 or more seconds for infants with two copies of SMN2 and standing unassisted for infants with three copies of SMN2.
As of December 31, 2019, 29 infants had been treated in the efficacy group at a mean age of 20.6 days among infants with two copies of SMN2 and 28.7 days among infants with three copies of SMN2. All patients are alive, and no patient in SPR1NT required ventilation support at last visit. Among 14 patients with two copies of SMN2, all achieved CHOP INTEND scores of 50 or greater, which exceeds the maximal score observed in untreated patients. Eight have achieved sitting, seven of whom achieved it within the World Health Organization sitting age range of 3.8-9.2 months. The other six patients have not yet passed the WHO developmental window. Among 15 patients with three copies of SMN2, four stood independently and three walked independently, all within the WHO developmental windows of 6.9-16.9 months and 8.2-17.6 months, respectively. The other patients have not yet passed the WHO developmental window. No patient in either cohort required a feeding tube, and most remained within the normal weight range. Treatment-emergent adverse events of special interest were reported in 16 patients. The study is ongoing, and patients continue to meet primary endpoints.
“Comparing functional and motor indices between these two groups [i.e., patients with two copies of SMN2 and those with three copies] should contribute to our understanding of how motor neuron loss during fetal development may impact long-term neurological outcomes over the arc of life and could even form a basis for considering antenatal gene therapy for severe forms of SMA,” said Dr. Strauss.
SPR1NT was funded by AveXis. Several of the investigators are employees of AveXis, and others received funding from the company.
Combination therapy may be a possibility
Dr. Darryl C. De Vivo
A benefit of onasemnogene abeparvovec-xioi is that the adeno-associated virus that delivers it does not integrate itself into the genome, said Darryl C. De Vivo, MD, Sidney Carter professor of neurology and professor of pediatrics at Columbia University in New York. “The bad news is that every time the cell divides, the gene therapy goes to one of the two daughter cells, but not to both. ... That means the effectiveness, in theory, would be reduced by 50% with each cell division, possibly affecting the durability of treatment.” The fact that brain and spinal cord neurons are presumed to be fully populated around the time of birth partly mitigates this concern, he added. “There isn’t too much additional cell division going on in neurons after birth at a time when the gene therapy would be administered.”
Furthermore, the cellular distribution of the gene therapy within the nervous system, which is unclear, might affect the therapy’s effect. “These are largely unanswered questions,” said Dr. De Vivo. “The answers to these questions only will come with continued observation of patients who have been treated.”
Considering that nusinersen, the antisense oligonucleotide also approved for SMA, targets SMN2, and the gene therapy replaces SMN1, “there may be some wisdom in thinking about combination therapy,” said Dr. De Vivo. “There’s no doubt that these therapeutic agents are effective,” and continued follow-up will clarify their comparative efficacy, he concluded.
SOURCES: Day JW, et al. AAN 2020. Abstract S27.001. Mendell JR, et al. AAN 2020. Abstract S27.002. Strauss KA, et al. AAN 2020. Abstract S27.003.