Spinal Muscular Atrophy

July 10, 2017

Cytokinetics has announced that data relating to patient baseline characteristics and the reasons for patient screen failure, both from the first cohort of the phase II clinical trial of CK-2127107 in spinal muscular atrophy (SMA), were presented at the Cure SMA 2017 Annual SMA Conference in Orlando, Florida by Stacy Rudnicki, M.D., Director, Clinical Research at Cytokinetics. In collaboration with Astellas Pharma Inc., Cytokinetics is developing CK-2127107 as a potential treatment for people living with SMA and certain other debilitating diseases and conditions associated with skeletal muscle weakness and/or fatigue. Patients enrolled in Cohort 1 of this phase II, hypothesis-generating, double-blind, randomized, placebo-controlled clinical trial were on average 27.7 years of age (SD: 13.81) and had symptom onset 22.2 years prior to enrollment (SD: 12.25) with a confirmed diagnosis 11.6 years before enrollment (SD: 6.25). Of the 39 patients enrolled in Cohort 1, 54% were male; 19 patients were ambulatory (all with SMA Type III), and 20 patients were non-ambulatory (five with Type II and 15 with SMA Type III). With respect to respiratory measurements, patients had on average a forced vital capacity (FVC) of 84% of predicted (min, max: 42, 127), a maximal expiratory pressure (MEP) of 88.7 cm H2O (min, max: 34, 196), and a maximal inspiratory pressure (MIP) of -99.4 cm H2O (min, max: -228, -29). In terms of motor measurements at baseline, ambulatory patients had an average score of 48.8 (min, max: 37, 54) in the Hammersmith Functional Motor Scale Expanded (HFMSE), 39.2 (min, max: 26, 41) in the Revised Upper Limb Module (RULM), 17.7 (min, max: 9, 35) seconds in the timed-up-and-go, and 290.7 (min, max: 138, 426) meters in the six-minute walk. Non-ambulatory patients scored 18.9 (min, max: 10, 50) in the HFMSE, and 28.0 (min, max: 17, 41) in the RULM. The HFMSE ranges from 0 to 66 points, with higher scores indicating a greater degree of function. Screen failures in Cohort 1 were primarily due to a HFMSE score that was either too high in ambulatory patients or too low in non-ambulatory patients. There were no statistically significant differences otherwise in the baseline demographics of enrolled patients compared to screen failures.

April 25, 2016

Marathon Pharmaceuticals released results of a phase III study of deflazacort for Duchenne Muscular Dystrophy (DMD). The pivotal, randomized, double-blind, placebo controlled and active comparator study enrolled 196 DMD patients. Patients were randomized to either deflazacort 0.9mg/kg/day, deflazacort 1.2mg/kg/day, prednisone 0.75mg/kg/day or placebo for 12 weeks. The primary endpoint was change in average muscle strength from baseline to week 12 with deflazacort and prednisone compared to placebo measured by the Medical Research Council Index (MRC). Deflazacort met the primary endpoint at week 12 v. placebo (p=0.0173 and, p=0.0003 for 0.9mg/kg/d and 1.2mg/kg/d doses, respectively v. -0.10 for placebo). After 12 weeks, placebo patients were re-randomized to either of the three active treatments from weeks 12 to 52 and those not randomized to placebo were maintained on their blinded active treatment through 52 weeks. Muscle strength and timed functional tests were included in the analysis. The analyses of non-ambulatory patients were post-hoc and not pre-specified. Muscle strength in non-ambulatory DMD patients, deflazacort at 0.9mg/kg/d and 1.2mg/kg/d, were assessed, with the deflazacort 1.2mg/kg/d arm reaching statistical significance at week 12 v. placebo (p=0.04). The FDA has granted Fast Track status, Orphan Drug designation and Rare Pediatric Disease designation for deflazacort for DMD. Marathon expects to submit an NDA for deflazacort in May 2016 and, if approved by the FDA, deflazacort could be made commercially available in the U.S. in early 2017. 

March 3, 2014

Isis Pharmaceuticals issued interim results of an ongoing phase Ib/IIa, open-label, multiple-dose study of ISIS-SMNRx in children with spinal muscular atrophy (SMA). Children were dosed intrathecally with 3mg, 6mg or 9mg of ISIS-SMNRx. The 3mg and 6mg doses were administered on days 1, 29 and 85. The 9mg dose was administered on days 1 and 85. Muscle function changes were measured using the Hammersmith Functional Motor Scale- Expanded (HFMSE). Subjects in the 3mg, 6 mg and 9mg cohorts achieved mean increases in HFMSE scores of 1.5, 2.3 and 3.7 points, respectively, nine months following the first dose of ISIS-SMNRx. Children in the 9mg cohort achieved mean increases in HFMSE scores of 2.7 and 3.7 points three and nine months after the first dose of ISIS-SMNRx, respectively. Isis plans to give all children who roll over into an extension study a maintenance dose of 12mg of ISISSMN Rx every six months.

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