Rare Disease Report

Isis Pharmaceuticals' New Spinal Muscle Atrophy Data Very Encouraging

OCTOBER 09, 2014
James Radke

At the 19th International World Muscle Society (WMS) Congress in Berlin, Germany , data was presented from ongoing open-label Phase 2 clinical studies of ISIS-SMNRx in infants and children with spinal muscular atrophy (SMA) showing the Isis Pharmaceutical drug to be of benefit to these very sick children.

ISIS-SMNRx is designed to alter the splicing of a closely related gene (SMN2) to increase production of fully functional SMN protein.  SMA is a genetic condition that leads to a deficiency in the motor neuron protein SMN. Symptoms  vary with the type of SMA but tend to be more severe if the onset begins earlier in life.  Generally, the muscles most affected are those near the shoulders, hips, thighs and upper back. Muscles used for breathing and swallowing may also be affected.

The data presented at the WMS is very encouraging for patients with SMA, especially the data from the infant study. Infants with SMA tend to have the most severe form of this condition.

Richard Finkel, M.D., chief, division of neurology, department of pediatrics, Nemours Children's Hospital said:

"I am encouraged with the totality of the data presented today, which show that median event-free ages for SMA infants in both the 6 mg and 12 mg cohorts compare favorably to that observed in a recent natural history study.  These data combined with the safety and tolerability profile observed to date support my enthusiasm to further evaluate ISIS-SMNRx in a Phase 3 study in infants with Type I SMA."

"Often infants with Type I SMA succumb to early death due to progressive weakness of the muscles responsible for breathing and feeding. In the PNCR natural history study, for which I was the lead investigator, in a group of untreated patients similar to those in the Isis Phase 2 study, the median event-free age was 10.5 months, with less than 20% of patients event free at 18 months. In addition to the positive data on event-free survival, substantial and persistent increases in muscle function as measured by the CHOP INTEND and Hammersmith Infant Neurological Examination were also observed in ISIS-SMNRx-treated infants up to 9 months on study.  This is an important finding because in general, infants with Type I SMA decline over time in their motor function as reflected in scores on these tests."

Phase 2 Study in Infants with SMA

A total of 20 infants have been dosed as of September 2, 2014 (4 given  6 mg and  16 given 12 mg).  The preliminary data presented at the Congress included those patients who had completed the dosing protocol as of Sept 2, 2014 (includes all but 4 patients in the 12 mg group).

The study found that in the 6 mg cohort:
  • There have been two events (one accidental death and one permanent ventilation)
  • The median event-free age is 16.3 months (n=6). 
In the 12 mg cohort:
  • The median event-free age is now 11.6 months (n=12). 
  • There have been 4 events (one permanent ventilation and three deaths, all related to respiratory infections; N=16).
  • Muscle Strength: Mean increases from baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) of 11.7 points with 11 of the 12 infants studied showing an increase in CHOP INTEND scores.
As of September 2, 2014, 20 infants have received a total of 67 intrathecal injections. The lumbar puncture procedure in SMA infants has been well tolerated and shown to be feasible.  In all infants dosed, there have been no drug-related serious adverse events. 

Phase 2 Study in Children with SMA

In the ongoing, open-label study in children with SMA, increases in muscle function scores, as measured by the Hammersmith Functional Motor Scale-Expanded (HFMSE), were observed in children treated with multiple doses of ISIS-SMNRx.  In children in the 3 mg, 6 mg and 9 mg cohorts achieved mean increases from baseline of 1.7, 3.2 and 2.3, respectively, eight to 13 months after last dose. 

Increases in two additional functional tests were also observed in the six-minute walk test (6MWT) and the upper limb mobility (ULM) test.  In the 6MWT that was tested in 10 ambulatory children, a mean increase of 24.4 meters was observed 12 to 16 months after the patients' baseline visits.  In the ULM test, a mean increase of 3.1 points was observed 11 to 16 months after the patients' baseline visits.  

As of September 2, 2014, 56 children have been given 183 injection of ISIS-SMNRx,, ranging in doses from 1 mg to 12 mg.  In all children dosed, there have been no drug-related serious adverse events. 

Basil Darras, M.D., professor of neurology, director of clinical neurology at the Boston Children's Hospital and Harvard Medical School said:

"SMA is a heartbreaking disease.  Children with SMA are bright and engaging, but due to progressive muscle weakness, grow weaker over time and suffer a decline in their physical abilities.  Because of the inevitable gradual decline that patients with SMA exhibit, I am encouraged with the consistency of the muscle function scores in these children.  Not only do these children experience increases in muscle function scores, even after a single dose of ISIS-SMNRx, but it now appears that these increases can be sustained for a significant time after dosing."

"The consistency of the increases in muscle function scores across different SMA patient populations, including both children and infants with SMA, and the dose- and time-dependency of these increases is encouraging.   The observation of increases in SMN protein in the spinal cord in tissues analyzed from ISIS-SMNRx-treated infants, suggest that ISIS-SMNRx is acting by the mechanism of action through which it was designed to act."

Webcast at 11:30 a.m.

At 11:30 a.m. EST, October 10, 2014, Isis will conduct a webcast to discuss the SMA data as well as the company’s planned and ongoing pivotal phase 3 studies.  The webcast will be available on the "Investors & Media" section of the Company's website, www.isispharm.com.

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