LOS ANGELES — An investigational drug significantly boosts the amount of survival motor neuron (SMN) in infants with spinal muscular atrophy (SMA) who are deficient in this protein, initial results of a new study show.

The researchers found that at the highest dose tested, the drug increased SMN by 6.5-fold.

Importantly, all doses explored so far have been well tolerated and none of the study patients lost the ability to swallow or needed permanent ventilation.

The new results are "exciting" because they provide "proof of mechanisms and preliminary clinical data" on the use of the drug, called RG7916 (Hoffman-La Roche), in SMA type 1, one of the most common forms of the disease, study author Giovanni Baranello, MD, PhD, from the Carlo Besta Neurological Institute in Milan, Italy, told Medscape Medical News.

The results will be presented April 24 at the Emerging Science Platform Session here at the American Academy of Neurology (AAN) 2018 Annual Meeting.

SMA is a severe autosomal-recessive disorder characterized by progressive weakness of the lower motor neurons, muscle weakness, and atrophy. The disorder affects mainly proximal muscles, including intercostal muscles, which can lead to serious respiratory complications.

The condition is caused by reduced levels of the SMN protein due to deletions or mutations of the survival of motor neuron 1 (SMN1) gene and alternative splicing of a related SMN2 gene.

SMA affects 1 in approximately 10,000 live births. The disorder typically begins in infancy and leads to reliance on nutritional and ventilation support or death. According to the authors, the published median time to death or permanent ventilation in patients with SMA type 1 with two SMN2 gene copies is 10.5 months. Baranello called the disease "devastating."

Over the years, several types of SMA have been described based on age when clinical features appear. The most common types are acute infantile (SMA type 1), chronic infantile (SMA type 2), chronic juvenile (SMA type 3), and adult onset (SMA type 4).

Liquid Solution

RG7916, formerly called RO7034067, is a centrally and peripherally distributed small molecule that modulates SMN2 pre-messenger RNA (mRNA) splicing to increase SMN protein levels. It is a liquid solution administered orally.

"It acts by modifying the splicing of the SMN2 gene at the mRNA level, thus allowing the inclusion of exon 7 and promoting the production of a full-length functional SMN protein," said Baranello.

The mechanism of action is similar to that of another drug, nusinersen (Spinraza, Ionis Pharmaceuticals/Biogen), already approved by the Food and Drug Administration (FDA) for SMA. Both drugs promote the production of SMN protein by the SMN2 gene. RG7916 is orally administered.

"This may have a double benefit," said Baranello. For example, it could facilitate adherence because the drug doesn't require administration by means of intrathecal injections, so there's no need for sedation or to access a hospital.

But this new oral drug could also be valuable because it's distributed in the body and reaches different organs, he noted. Increasing evidence suggests that SMA is not limited to motor neurons and the central nervous system but could be considered a multiorgan disease, said Baranello.

The FDA has granted orphan drug designation to RG7916 for the treatment of patients with SMA.

The multicenter open-label exploratory study, FIREFISH, includes infants with genetically confirmed SMA type 1 who have two copies of the SMN2 gene. Part 1 of the study enrolled 21 infants aged 1 to 7 months who were given the drug every day for 4 weeks at different doses.

The aim of this study phase was to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of RG7916 at these different dose levels.

The results indicated a dose-dependent increase in SMN protein levels in blood. There was up to a 6.5-fold increase in levels from baseline after 4 weeks of treatment at the highest dose (range, 2.0 - 6.5).

These results are very encouraging, especially in comparing the increased protein levels to those in patients with SMA type 2, said Baranello. He noted that children with type 2, which is less severe than type 1, have about twice as much SMN protein as those with type 1.

The study provides proof of mechanism for oral small molecule SMN2 splicing modifiers, he said.

"The robust increase in SMN protein seen in the current study supports the possibility of having sustained improvement in motor function and in clinical benefits for these infants," said Baranello.

At the time of the analysis, 19 infants were still alive. The two deaths were disease related and not considered due to the investigational drug, the researchers note.

The average study duration for the 19 babies was 4 months but ranged from 1 month to 13.5 months.

No safety problems required infants to be withdrawn from the study.

While follow-up was limited, no study patient has lost the ability to swallow, required tracheostomy, or reached permanent ventilation to date.

The 2-year confirmatory part 2 of the study will enroll 40 infants with SMA type 1 and investigate the clinical benefit of the selected dose, said Baranello.

"This second part of the study has already started and is currently recruiting patients," he said. "Further updates will be provided at scientific conferences during the year."

Other pivotal trials are investigating the drug. The SUNFISH study in adult and pediatric patients with SMA type 2 and type 3 is a placebo-controlled, randomized, ascending-dose study with 36 patients lasting at least 12 weeks. It's investigating the safety and tolerability of RG7916 and determining the dose for the second part of the study.

The second part of SUNFISH will be a double-blind, placebo-controlled, randomized, confirmatory study in patients with SMA type 1 and type 2 for up to 24 months, followed by an open-label extension. The primary objective of the second part of the study is to evaluate the efficacy of RG7916 compared with placebo.

Another study, JEWELFISH, is an open-label exploratory safety and tolerability study that is recruiting patients with type 2 or 3 SMA aged 12 to 60 years, who have participated in previous studies with other SMN2-targeting therapies.

The current study was supported by Hoffman-La Roche, the developer of the drug. Baranello served as scientific consultant for PTC Therapeutics and Sarepta Therapeutics; he is currently principal investigator in the following clinical trials in SMA: BP39055 and BP39056 (Roche); CLMI070X2201 (Novartis); AVXS-101-CL-302 (Avexis); SMA-001 (Catalyst).

American Academy of Neurology (AAN) 2018 Annual Meeting. Emerging Science Abstract 004. To be presented April 24, 2018

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