Isis Pharmaceuticals provides update on Phase 2 clinical studies of ISIS-SMN Rx in children with SMA

Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) today provided an update on its ongoing open-label Phase 2 clinical studies of ISIS-SMN_Rx in infants and children with spinal muscular atrophy (SMA) at the 19^th International World Muscle Society (WMS) Congress in Berlin, Germany. Isis is currently treating infants with SMA with ISIS-SMN_Rx in a Phase 3 study called ENDEAR, and plans to initiate a second Phase 3 study, called CHERISH, in children with SMA later this year.

"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-SMN_Rx in a Phase 3 study in infants with Type I SMA," said Richard Finkel, M.D., chief, division of neurology, department of pediatrics, Nemours Children's Hospital. "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-SMN_Rx-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."

Event-free survival data from Phase 2 study in infants with SMA

In the Phase 2 study in infants with SMA, a total of 20 infants were dosed as of September 2, 2014, four infants in the 6 mg cohort and 16 infants in the 12 mg cohort. As of April 7, 2014, the date of Isis' previous data update, the per protocol efficacy populations (PPEP) (patients who completed the three dose induction regimen in the study) constituted four patients in the 6 mg and seven patients in the 12 mg dose cohorts. As of September 2, 2014, the date for this data update, the PPEP constituted four patients in the 6 mg and 12 patients in the 12 mg dose cohorts.

In the 6 mg cohort:

• No patients have had an event (death or permanent ventilation) since April 2014. As of September 2, 2014, there have been two events (one accidental death and one permanent ventilation) in the 6 mg cohort.
• Isis previously reported a median event-free age of 14 months for the infants in the PPEP on April 7, 2014. The median event-free age on September 2, 2014 for the infants in this group is now 16.3 months.

In the 12 mg cohort:

• Dosing in the 12 mg cohort began five months after the initiation of dosing for the 6 mg cohort. As a result, the patients in the 12 mg cohort have participated in the study for a shorter time than those in the 6 mg cohort. As of April 7, the PPEP in the 12 mg dose cohort contained 7 infants. As of September 2, the PPEP for the 12 mg dose cohort contained 12 infants, which included an additional five infants who had more recently entered the study.
• Isis previously reported a median event-free age of 9.6 months for the infants who constituted the 12 mg PPEP as of April 7, 2014. The median event-free age at September 2, 2014 for these infants is now 13.8 months.
• The median event-free age of the 12 infants in the PPEP as of September 2, 2014 for the 12 mg cohort is 11.6 months. Of these 12 infants, nine are alive without the need for permanent ventilation.
• As of September 2, 2014, there have been four events (one permanent ventilation and three deaths, all related to respiratory infections) in the 16 infants from the 12 mg cohort.

Increases in muscle function scores in this study in infants with SMA

Measures of muscle function are also being assessed in this study. Increases in muscle function scores were observed in infants in both dosing cohorts using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), a motor assessment test that is used to evaluate muscle strength in infants with SMA.

• Increases in CHOP INTEND scores occurred in a majority of infants in the study. Infants in the PPEP from the 6 mg and 12 mg cohorts combined showed mean increases from baseline in CHOP INTEND of 9.3 points with 14 of the 16 infants showing an increase in CHOP INTEND scores.
• Infants from the 12 mg dose cohort PPEP showed mean increases from baseline in CHOP INTEND of 11.7 points with 11 of the 12 infants showing an increase in CHOP INTEND scores.

Developmental milestones are also being examined in this study using the Motor Milestones portion of the Hammersmith Infant Neurological Examination, with 14 out of the 16 infants in the combined PPEP exhibiting improvements in motor milestones.

The safety and tolerability profile of ISIS-SMN_Rx to date supports continued development. As of September 2, 2014, 20 infants have been exposed to doses of either 6 mg or 12 mg of ISIS-SMN_Rx for 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. Most of the adverse events (non-SAEs) have been mild or moderate in severity and not related to drug. There were no changes in the safety profile with repeated doses of ISIS-SMN_Rx.

Clinical data on ISIS-SMN_Rx Mechanism of Action

Today, Isis reported the results from an analysis of spinal cord tissue samples from autopsies showing that ISIS-SMN_Rx is distributed throughout the central nervous system. The results of these analyses also showed greater levels of full length SMN2 mRNA and full length SMN protein in tissues in ISIS-SMN_Rx-treated SMA infants compared to the levels of SMN2 mRNA and full length SMN protein in the tissues analyzed from untreated SMA infants. These analyses were conducted on tissue samples collected in three infants who had received three or more doses of ISIS-SMN_Rx and were compared to tissue samples from four untreated SMA infants and three infants without SMA at a similar age range.

• Analysis of spinal cord tissue showed that ISIS-SMN_Rx concentration in spinal cord tissues was greater than the concentration that resulted in biological activity in animal studies. ISIS-SMN_Rx was found in multiple segments of the spinal cord and brain and in motor neurons.
• Greater level of full-length (containing exon 7) SMN2 mRNA was observed in the spinal cord and brain tissue of ISIS-SMN_Rx-treated SMA infants compared to the level of full-length SMN2 mRNA in the untreated SMA infants.
• In patients treated with ISIS-SMN_Rx, greater amounts of SMN protein were observed in the spinal cord compared to the amount of SMN protein observed in the untreated SMA infants.
• SMN protein was observed in neurons of tissues analyzed in ISIS-SMN_Rx-treated SMA infants in which ISIS-SMN_Rx was present.

"The results on ISIS-SMN_Rx presented today form an encouraging profile of a potential new therapy for patients with SMA," continued Dr. Finkel. "The consistency of observations in event-free survival, CHOP INTEND and development milestones, combined with the clinical data supporting the mechanism of action by which ISIS-SMN_Rx was designed to act, creates strong support to continue evaluation of ISIS-SMN_Rx."

"We are encouraged that we have been able to evaluate both the distribution of ISIS-SMN_Rx in spinal cord tissues and motor neurons, and the levels of full length SMN protein in the spinal cord of ISIS-SMN_Rx-treated infants. We are very fortunate to have access to these tissue samples, and thankful to the families who have allowed us to use them to advance the study of SMA and ISIS-SMN_Rx. Access to these tissues has enabled us to confirm what we observed in our earlier preclinical work; that ISIS-SMN_Rx is broadly distributed throughout the central nervous system of ISIS-SMN_Rx-treated infants. We are also pleased to observe that the levels of ISIS-SMN_Rx in tissues analyzed from ISIS-SMN_Rx-treated infants are greater than the concentrations at which we observed biological activity in our animal studies. We are also encouraged with the greater levels of full-length SMN2 mRNA and commensurate increases in SMN protein we observed in tissues analyzed from ISIS-SMN_Rx-treated SMA infants as compared to the levels of full-length SMN2 mRNA and SMN protein we observed in tissues analyzed from untreated SMA infants," said C. Frank Bennett, Ph.D., senior vice president of research at Isis Pharmaceuticals.

Results from 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-SMN_Rx. As previously reported in April 2014, children in the 3 mg, 6 mg and 9 mg cohorts achieved mean increases from baseline of 1.5, 2.3 and 3.7 points, respectively, nine months following their first dose (six months after last dose). Further evaluation of these children showed that the previously observed mean increases in muscle function scores continued to show increases from baseline for an extended period after their last dose with 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 eight to 13 months after last dose in the six-minute walk test (6MWT) and the upper limb mobility (ULM) test. In the 6MWT, performed with 10 ambulatory children, a mean increase of 24.4 meters was observed 12 to 16 months after the patients' baseline visits, compared to the previously reported increase of 22.7 meters at nine months. In the ULM test, a mean increase of 3.1 points was observed 11 to 16 months after the patients' baseline visits, compared to the previously reported increase of 2.3 points at nine months.

The safety and tolerability profile of ISIS-SMN_Rx continues to support continued development. As of September 2, 2014, 56 children have been exposed to doses ranging from 1 mg to 12 mg of ISIS-SMN_Rx. The majority of these children have received multiple doses of drug and in total 183 doses of ISIS-SMN_Rx have been administered. The lumbar puncture procedure in SMA children has been well tolerated and shown to be feasible. In all children dosed, there have been no drug-related serious adverse events. Most of the adverse events (non-SAEs) have been mild or moderate in severity and not related to drug. There were no changes in the safety profile with repeated doses of ISIS-SMN_Rx.

"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-SMN_Rx, but it now appears that these increases can be sustained for a significant time after dosing," said Basil Darras, M.D., professor of neurology, director of clinical neurology at the Boston Children's Hospital and Harvard Medical School.

"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-SMN_Rx-treated infants, suggest that ISIS-SMN_Rx is acting by the mechanism of action through which it was designed to act," concluded Dr. Bennett.