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LOS ANGELES – An orally administered investigational drug increased protein levels in babies with spinal muscular atrophy (SMA) type 1, according to trial data to be reported here next week.

The new drug, known as RG7916, showed up to 6.5–fold increase of survival motor neuron (SMN) protein levels in blood after 4 weeks of treatment at the highest dose. An early-release abstract from the , slated to begin this weekend, was made available Wednesday.

"The results are exciting because they provide proof of mechanisms and preliminary clinical data on the use of RG7916 in SMA 1, which is a devastating disease leading to death or nutritional and ventilatory support within 2 years of age," said study author Giovanni Baranello, MD, PhD, of the Carlo Besta Neurological Institute in Milan, Italy.

"The robust increase in SMN protein seen in the current study supports the possibility to have sustained and unexpected improvement in motor function and in clinical benefits for these infants," he told 番茄社区app.

SMA, an inherited disease that leads to loss of motor function, is a leading genetic cause of infant and toddler death. On average, SMA type 1 patients with two SMN2 gene copies survive for 10.5 months before they die or need continuous breathing support.

RG7916 appears to be the most advanced in an entirely new class of drug molecule, a "pre-mRNA splicing modifier," acting at the level of gene transcription to boost protein production -- in this case, the SMN protein. Baranello explained that the drug targets SMN2, "a back-up gene which normally produces only about 20% of functioning SMN protein."

The first leg of the study, known as FIREFISH Part 1, involved 21 type 1 SMA babies with two copies of SMN2. The patients were 3 to 7 months old at baseline and received the drug every day for 4 weeks at different dose levels.

Results showed a dose-dependent increase in SMN protein in blood (range 2.0- to 6.5-fold) versus baseline.

At the time of the analysis, 19 babies were alive. The two fatal events reported were disease-related and not considered related to the investigational drug. The average study duration for the 19 babies was 4 months (range 1.0 to 13.5); in that time, no patient lost the ability to swallow, required tracheostomy, or reached permanent ventilation. However, this part of the study was not aimed at assessing clinical outcomes.

"There's been a lot of excitement in recent years about new drugs that can increase SMN expression and in patients with spinal muscular atrophy," observed Charlotte Sumner, MD, of Johns Hopkins Medicine in Baltimore, who was not involved with the study. Last year, the FDA approved the antisense oligonucleotide nusinersen (Spinraza), which is administered through spinal injection. Gene therapy also has shown promising results in SMA patients.

"The reason why this particular approach is so exciting is that it's an orally bioavailable drug," Sumner said. "Unlike [antisense agents] which don't cross the blood brain barrier and therefore have to be given by intraspinal injection, this is a drug that can be taken orally and penetrates the central nervous system as well as everywhere else."

That feature may make levels of the drug easier to monitor in peripheral blood which isn't possible with antisense oligonucleotides, she added.

"Whether this effect in blood will be reflected in the CNS and motor neurons remains to be seen, as well as whether this agent might have even greater effects in other types of SMA involving more copies of SMN2," noted John Kissel, MD, of the Ohio State University in Columbus, who also was not involved with the study.

The exploratory initial phase in FIREFISH is assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of RG7916 at different dose levels. A confirmatory second part will evaluate efficacy as the percentage of treated infants who are able to sit unsupported.

Two other RG7916 trials -- SUNFISH, a trial of patients with type 2 or non-ambulant type 3 SMA, and JEWELFISH, an open-label exploratory safety and tolerability study of type 2 or 3 SMA patients who have participated in previous studies with other SMN2-targeting therapies -- are underway.

Baranello will present updated findings at 5:45 p.m. PT on Tuesday, April 24, 2018, in the Concourse Hall 152/153 at the Los Angeles Convention Center.

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