Clinical Trials

Date: 2016-04-20

Type of information: Presentation of results at a congress

phase: 2,3

Announcement: presentation of results at the American Academy of Neurology annual meeting

Company: Isis Pharmaceuticals (USA - CA), now Ionis Pharmaceuticals (USA - CA)

Product: Spinraza™ -nusinersen - ISIS-SMNRx (antisense oligonucleotide targeted to the SMN2 gene)

Action mechanism:

• antisense oligonucleotide. ISIS-SMNRx is designed to alter the splicing of a closely related gene (SMN2) to increase production of fully functional SMN protein. The FDA granted orphan drug status and fast track designation to ISIS-SMNRx for the treatment of patients with SMA. Isis is currently in collaboration with Biogen Idec to develop and potentially commercialize the investigational compound, ISIS-SMNRx, to treat all types of SMA. Under the terms of the January 2012 agreement, Isis is responsible for global development and Biogen Idec has the option to license the compound until completion of the first successful Phase 2/3 study or the completion of two Phase 2/3 studies.

Disease: spinal muscular atrophy

Therapeutic area: Neuromuscular diseases - Rare diseases - Genetic diseases

Country: Canada, USA

Trial details:

• In the ongoing Phase 2 study, doses of either 6 mg or 12 mg are administered intrathecally on Days 1, 15 and 85.  All infants from the 6 mg dose cohort have completed the three initially scheduled doses and are now eligible to receive a maintenance dose of 12 mg six months after their initial three scheduled doses.  In the 12 mg cohort, 10 infants have received at least one dose of ISIS-SMNRx to date.  Of these 10 infants, nine still remain in the study.  One infant in the 12 mg cohort succumbed to pneumonia early in the treatment portion of study. In both cohorts, ISIS-SMNRx has been well tolerated. (NCT01839656)

Latest news:

• *• On April 20, 2016, Ionis Pharmaceuticals provided an update on its ongoing open-label Phase 2 clinical study of nusinersen in infants with spinal muscular atrophy (SMA) at the American Academy of Neurology (AAN) meeting in Vancouver. The data reported show that there have been no new events, as defined by progression to permanent ventilation or death, in the study since December 2014 with continued increases in event-free survival, muscle function scores as well as achievement of new developmental milestones. Data showing increases in neuromuscular electrophysiology measurements were also reported. The latest analysis also demonstrates that no nusinersen-related safety or tolerability concerns have been identified. Including the nusinersen data, Ionis and its collaborators presented more than 12 oral talks and posters on Ionis' neurological disease programs at the AAN meeting. The Phase 2 open-label study (n=20) was designed to evaluate the safety and tolerability of nusinersen in infants with Type I SMA. Clinical efficacy endpoints include event-free survival, as defined by time to permanent ventilation or death; CHOP-INTEND motor function scores; electrophysiology measurements (compound muscle action potential, or CMAP) and assessments of developmental milestones. An analysis as of January 26, 2016 showed that:
• No new events have occurred since December 2014. The event-free survival observed to date is different from the observed natural history in this patient population with nusinersen-treated infants living longer without the need for permanent ventilation. All infants continuing in the study (n=15) are older than two years of age, with some infants older than three years of age.
• Muscle function scores have increased from baseline with a mean increase of 22.2 points in the CHOP INTEND score at 26 months with no evidence of a therapeutic plateau.
• Infants have achieved new motor milestones since their baseline evaluations, including stable unsupported sitting (n=8), standing with or without support (n=5) and walking (n=2).
• CMAP measurements have increased from baseline, which is different from the observed natural history in this patient population where CMAP measurements decline rapidly before symptom onset, remain low and do not improve over the course of the course of the disease.
• Data from the ENDEAR and CHERISH, the Phase 3 studies in infants with SMA, are expected  in the first half of 2017.
• As of January 26, 2016, the median time in study was 22 months. The lumbar puncture procedure in infants with SMA has been well tolerated and shown to be feasible. There have been no drug-related serious adverse events (SAEs) and the majority of SAEs were related to respiratory infections. Most of the adverse events (non-SAEs) have been mild or moderate in severity. There have been no changes in the safety profile with repeated doses of nusinersen.
• • On June 11, 2015, Isis Pharmaceuticals provided an update on its ongoing open-label Phase 2 clinical study of ISIS-SMNRx in infants with Type I spinal muscular atrophy (SMA). Previously the company reported data from this study on event-free survival, measures of muscle function and assessments of developmental milestones. The data reported here show continued increases in median event-free survival and muscle function scores as well as achievement of developmental milestones. The safety and tolerability profile of ISIS-SMNRx to date continues to support further development. Isis is currently collaborating with Biogen to develop and potentially commercialize ISIS-SMNRx to treat patients with SMA.
• The study was designed to evaluate the safety and tolerability of ISIS-SMNRx in infants with Type I SMA and to explore potential efficacy endpoints to support the Phase 3 program. A total of 20 infants with SMA were dosed with either 6 mg or 12 mg of ISIS-SMNRx. SMA infants 7 months or younger entered the study sequentially, such that the dosing of infants in the 12 mg cohort began five to 15 months after the first infant was dosed in the 6 mg cohort. Nineteen infants completed the three induction doses and are evaluable for efficacy. Clinical efficacy endpoints include event-free survival, as defined by time to permanent ventilation or death; CHOP-INTEND motor function scores; and assessments of developmental milestones. An analysis as of April 17, 2015 showed that since the last analysis as of September 2, 2014 (seven and a half months ago):
• The median event-free age has increased for infants in both dosing cohorts, from 16.3 months to 19.9 months for the four infants in the 6 mg cohort, and from 11.6 months (n=12) to 16.7 months (n=15) for the infants in the12 mg cohort.
• For the seven infants in the 12 mg cohort who were in the original group and reported on at the American Academy of Neurology meeting in 2014, the median event-free age has increased from 9.6 months on April 7, 2014 to 21.4 months on April 17, 2015.
• Two of the four infants in the 6 mg cohort remain enrolled in the study and are now older than 27 months of age. In the 12 mg cohort, 11 of 15 infants (73%) are still event-free and older than 15 months of age.
• Muscle function scores have increased from baseline.
• Infants have achieved motor milestones since their baseline evaluations.
• Only a single event has occurred: One infant in the 12 mg cohort required permanent ventilation. There have been no deaths since the previous analysis. As of April 17, 2015, the median time in study was 13.2 months. The lumbar puncture procedure in infants with SMA has been well tolerated and shown to be feasible. There have been no drug-related serious adverse events (SAEs) and the majority of SAEs were related to respiratory infections. Most of the adverse events (non-SAEs) have been mild or moderate in severity. There were no changes in the safety profile with repeated doses of ISIS-SMNRx.
• • On October 10, 2014, Isis Pharmaceuticals provided an update on its ongoing open-label Phase 2 clinical studies of ISIS-SMNRx in infants and children with spinal muscular atrophy (SMA) at the 19th International World Muscle Society (WMS) Congressin Berlin, Germany. Isis is currently treating infants with SMA with ISIS-SMNRxin a Phase 3 study called ENDEAR, and plans to initiate a second Phase 3 study, called CHERISH, in children with SMA later this year.
• 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 ofSeptember 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 onSeptember 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 ofSeptember 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-SMNRx 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-SMNRx 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-SMNRx.
• Clinical data on ISIS-SMNRx Mechanism of Action:
• Isis also reported the results from an analysis of spinal cord tissue samples from autopsies showing that ISIS-SMNRx 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-SMNRx-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-SMNRx 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-SMNRx concentration in spinal cord tissues was greater than the concentration that resulted in biological activity in animal studies. ISIS-SMNRx 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-SMNRx-treated SMA infants compared to the level of full-length SMN2 mRNA in the untreated SMA infants.
• • In patients treated with ISIS-SMNRx, 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-SMNRx-treated SMA infants in which ISIS-SMNRx was present.
• 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-SMNRx. 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-SMNRx 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-SMNRx. The majority of these children have received multiple doses of drug and in total 183 doses of ISIS-SMNRx 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-SMNRx.
• • On February 21, 2014, Isis Pharmaceuticals has provided an update on its ongoing open label, multiple dose Phase 2 study of ISIS-SMNRx in infants with spinal muscular atrophy (SMA).  To date, all four infants in the 6 mg cohort have been in the study for over six months and are now approximately nine and a half  to 16 months in age with an average age of approximately 12 and a half months.  All four infants are alive and none have required permanent respiratory assistance.

Is general: Yes