Novartis’ Zolgensma (onasemnogene abeparvovec-xioi) and Biogen’s Spinraza (nusinersen) might face a lost market opportunity with a niche group of spinal muscular atrophy (SMA) patients with point mutations. Current prenatal tests might not be able to accurately detect the disease in this subset.

Spinal muscular atrophy treatment

Prenatal testing is becoming more common, providing these treatments stronger uptake potential as presymptomatic treatment would also increase, but this niche group might still not be treated until much later.

New parents are recommended to undergo screening for whether they might be SMA carriers; however, single mothers with no access to the father’s DNA compromise confidence in fetal testing to deliver an accurate risk result. While advances in technology have allowed for noninvasive prenatal testing without the father, the results are seen more as a screening tool rather than a diagnostic, until further advances in accuracy are achieved. Some experts noted that some mothers also opt not to perform prenatal screening and testing either due to costs or perceived risk to the pregnancy.

Spinraza and Zolgensma are involved in ongoing clinical trials — Zolgensma’s 27-patient Phase III SPR1NT (NCT03505099) and Spinraza’s 25-patient Phase II NURTURE (NCT02386553) — in presymptomatic treatment of SMA patients, providing stronger evidence for physicians to recommend using these treatments at that time, experts said.

Analysts have painted an optimistic picture of Zolgensma’s use over Spinraza as screening becomes more commonplace, though this news service previously reported that experts noted Spinraza still has a place in SMA treatment. Zolgensma still carried expert doubts about durability.

Novartis has taken a beating in the news, with US politicians urging the US Food and Drug Administration (FDA) to come down hard on the company for failing to disclose manipulated data used in the approval of Zolgensma, the most expensive drug in US history, with a US$2.1m price tag.

Zolgensma has projected sales of $1.4bn in 2023; Spinraza had sales of $1.72bn in 2018. Novartis and Biogen have market caps of CHF 227.5bn ($230bn) and $44.7bn, respectively.

Novartis and Biogen did not respond for comment.

Some SMA patients might slip through

As most SMA tests detect whether the SMN1 gene is present or absent but not copy number, they identify those patients with homozygous deletions and not those with point mutations, said Dr Herman Hedriana, professor of clinical obstetrics and gynecology, University of California, Davis. About 5% of SMA patients have SMN1 point mutations on one gene and a deletion or conversion in the other, which could lead the test to show that the patient is a carrier rather than a potential symptomatic patient, said a neurologist.

Zolgensma was only recently approved and Spinraza has been approved since 2016, but to fully realize their potential of early treatment, prenatal SMA screening has to be adopted more thoroughly throughout the nation and must be better at capturing typically missed cases, said Dr Alexander Fay, assistant professor of neurology, University of California, San Francisco. Large institutions typically offer screening services, and smaller clinics are increasingly doing so too, he added.

Recent data of Zolgensma’s SPR1NT and Spinraza’s NURTURE trials presented at the annual meetings of American Academy of Neurology (AAN) and Cure SMA in May and June, respectively, have strengthened impressions that these SMA treatments are best used presymptomatically, the neurologist said. These patients were shown to achieve age-appropriate motor milestones, she added.

Given the challenges in testing, missing out on an accurate diagnosis could spell months of lost treatment opportunities, especially in type 1 SMA where disease progression is early and fast, said Dr Darryl De Vivo, professor of neurology, Columbia University, New York. Additionally, there is less certainty on how a treatment like Zolgensma might fare in slightly older patients as pivotal trial data from the 20-patient Phase III trial STR1VE (NCT03306277) covered patients up to six months old while its broad label is approved for patients up to two years of age, he said.
Treating patients by the time symptoms manifest might be too late already, as some motor neurons would have already died off, experts agreed.

Other limitations in screening and testing

While screening and testing become more commonplace, there are still current challenges, said Hedriana. Frequently enough, there are cases of single mothers who do not have access to the father for DNA testing for SMA status, compromising the confidence on whether the fetus might be a carrier or symptomatic, he said.

Prior to the option of cell-free DNA (cfDNA) testing, where fetal cells in the maternal plasma are analyzed, mothers had to opt for amniocentesis or chorionic villus sampling (CVS), Hedriana said. Both tests carry a risk of miscarriage as they are invasive, and while the risk has decreased to about one in 500 births from one in 200 births, some mothers might still opt out, he said.

However, even with cfDNA, there are still limitations: if the mother is a carrier, the test is unable to discern whether the SMA gene abnormality belongs to the mother or the fetus, Hedriana said. Oghuzan Atay, CEO of BillionToOne, a company developing UNITY, a cfDNA tool, said its tool is able to differentiate genetic abnormalities between mother and fetus via molecular counting, achieving higher resolution noninvasive prenatal testing with a sensitivity of more than 98%.

Improvements in cfDNA testing would ease the confirmation of whether a fetus has SMA as the father’s DNA would not be needed, Atay said. Hedriana, who advised on UNITY, agreed that cfDNA tests’ biggest advantage is not needing additional tests from the father, but noted that these tests are typically seen more as a stepping stone to conduct the more diagnostic amniocentesis or CVS should an abnormality be detected. There are still residual accuracy risks associated with cfDNA testing, Hedriana noted.

While increased screening and testing generally help improve uptake — as a prenatal diagnosis would help prepare parents for treatment from the infant’s birth — there might also be the unintended consequence that a prenatal diagnosis could end in a pregnancy termination, Hedriana said. Atay noted that a greater prevalence of noninvasive prenatal testing could result in terminations that might ultimately affect the treatment market. While studies have been done to determine if noninvasive prenatal testing for Down syndrome impacted pregnancy termination (Hill et al. Prenat Diagn. 2017 Dec; 37(13): 1281–1290), none have been conclusive and larger studies are needed, Hedriana said. The studies showed unchanged or decreased rates compared with historical data.

by Shuan Sim in New York
Shuan Sim is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.