Muscular Dystrophy

January 15, 2018

Acceleron Pharma announced positive preliminary results for the first two cohorts in Part 1 of the Phase II clinical trial with ACE-083 in patients with facioscapulohumeral dystrophy (FSHD), a rare genetic muscle disorder that results in progressive focal muscle loss and weakness. The company plans to initiate Part 2 of the ACE-083 FSHD Phase II trial during the second quarter of 2018. Part 1 is an open-label, dose-escalation study of ACE-083 designed to evaluate safety as well as changes in total muscle volume in up to 36 patients with FSHD. Preliminary results include data from 23 patients evaluable for magnetic resonance imaging (MRI) among two different cohorts (11 patients with tibialis anterior weakness and 12 patients with biceps brachii weakness). Each patient received ACE-083 (150mg or 200mg) as a unilateral intramuscular injection once every three weeks for 12 weeks. Total muscle volume changes were measured by MRI relative to baseline at three weeks after the last injection of ACE-083. Based on overlap in dosing on a milligram per gram muscle analysis, dose cohorts were pooled for the analyses of each muscle. Strength and function tests are being explored in Part 1 to assist with the design of the randomized, double-blind, placebo-controlled Part 2 of the study.

October 9, 2017

Catabasis Pharmaceuticals reported results of a phase III trial of edasalonexent for Duchenne muscular dystrophy (DMD). The MoveDMD trial was an open-label extension following 24 and 36 weeks of treatment. Across all key assessments of muscle function, improvements were observed in the rate of decline after 24 and 36 weeks of oral 100mg/kg/day edasalonexent treatment compared to the rate of change in the control period for boys prior to receiving edasalonexent treatment. Additionally, supportive changes in measures of muscle health were seen, consistent with positive edasalonexent treatment effects. Muscle enzymes significantly decreased compared to baseline at 12 weeks and later time points (p<0.05) and lower leg muscle MRI T2 rate of change was significantly improved in comparison to progression during the control period (p=0.05). Edasalonexent continued to be well tolerated with no safety signals observed in the trial. Based on the consistency of the MoveDMD results and supportive regulatory input from the FDA, Catabasis plans to initiate a single global phase III trial with edasalonexent in patients with DMD regardless of mutation type in the first half of 2018 with top-line results expected in 2020.

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. 

November 9, 2015

PTC Therapeutics has reported results from the phase III, double-blind, placebo-controlled, 48-week trial of Translarna (ataluren) for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). ACT DMD was a placebo-controlled, multicenter, randomized, double-blind trial involving 228 patients in 53 sites across 18 countries. Patients between the ages of 7 and 16 with nmDMD were randomized to receive either Translarna 40mg/kg per day (n=114) or placebo (n=114) over 48 weeks. The primary endpoint was change from baseline in the six-minute walk test (6MWT). In the overall intent-to-treat study population, the primary endpoint of change from baseline in the 6MWT demonstrated a 15 meter benefit (p=0.213), which was not statistically significant. A highly significant benefit of 47 meters (p=0.007) was demonstrated in the pre-specified patient population of 300-400 meters at baseline as measured by the 6MWT, which is in line with the company’s prior experience in its phase IIb trial and consistent with the evolving understanding of the 6MWT. Importantly, no patients in that group lost ambulation (0/47) versus four patients in the placebo group (4/52). Translarna showed a benefit over placebo across key secondary and tertiary endpoints, including timed function tests (10 meter Run/Walk, 4 Stair Climb, 4 Stair Descend) and the North Star Ambulatory Assessment test. Translarna received marketing authorization from the EMA in 2014 for use in ambulatory nmDMD patients who are 5 years of age and older. PTC intends to submit the results from the ACT DMD study to the EMA and to complete its rolling submission for a NDA to the FDA by the end of 2015.

November 10, 2014

PTC Therapeutics issued results of a phase IIb study of Translarna therapy in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The randomized, double-blind, placebo-controlled, 48-week trial enrolled 173 participants. Participants, males >=five years, were randomized to receive received placebo, Translarna 40mg/kg/day or Translarna 80mg/kg/day given at morning, midday and evening. The data demonstrated from baseline to week 48, nmDMD patients treated with Translarna (40mg/kg/day given in three doses) had a 31.3 meter benefit in six-minute walk distance (6MWD) relative to patients in the placebo group (post hoc p=0.056). Though having achieved the targeted treatment effect, the results did not achieve significance at the p

August 19, 2013

Sarepta Therapeutics released results of a phase IIb trial of eteplirsen for the treatment of Duchenne muscular dystrophy (DMD). The 24-week randomized, double-blind, placebo-controlled study enrolled 12 boys aged seven to 13 with a confirmed genotype amenable to treatment with an exon-51 skipping drug. These patients were randomized to one of three treatment arms including placebo (n=4), eteplirsen 30mg/kg (n=4) and eteplirsen 50mg/kg (n=4), and received eteplirsen or placebo weekly by intravenous infusion. Results showed once-weekly treatment with eteplirsen resulted in a statistically significant increase from baseline in novel dystrophin, the protein lacking in patients with DMD. Eteplirsen-treated patients evaluable on the six-minute walk test demonstrated stabilization in walking ability compared to a placebo/delayed-treatment cohort. After Week 28, all patients were rolled over into a long-term, open-label extension study, which continues to follow patients on clinical and safety measures with data reported through 84 weeks. Eteplirsen was well-tolerated in the study with no clinically significant treatmentrelated adverse events. These data will form the basis of an NDA to the FDA for eteplirsen planned for the first half of 2014.

October 8, 2012

Sarepta Therapeutics released results from a phase IIb trial of eteplirsen for the treatment of Duchenne muscular dystrophy (DMD). This randomized, multi-arm, placebo-controlled study enrolled 12 males aged seven to 13 years old. Subjects received either eteplirsen 30mg/kg or 50mg/kg once weekly for 48 weeks, or for 24 weeks followed by another 24 weeks of placebo. The trial met its efficacy endpoint, increase in novel dystrophin, and achieved a significant clinical benefit on the primary clinical outcome, the six-minute walk test (6MWT) over the placebo/delayed treatment cohort. Data showed a statistically significant increase (p≤0.001) in dystrophin-positive fibers to 47.0% of normal. The placebo/delayed treatment cohort also showed a statistically significant increase in dystrophin-positive fibers to 38.3% of normal (p≤0.009). Patients who received 50mg/kg of eteplirsen demonstrated an increase of 21.0 meters in distance walked from baseline (mean=396.0 meters), while patients who received placebo/delayed-eteplirsen treatment showed a decline of 68.4 meters from baseline (mean=394.5 meters). The drug was well tolerated. There were no treatment-related adverse events.

October 25, 2010

PTC Therapeutics issued positive results from a phase IIb trial of ataluren for the treatment of nonsense mutation Duchenne and Becker muscular dystrophy. This randomized, double-blind, placebo-controlled study enrolled 174 ambulatory males at least five years of age at 37 sites in North America, Europe, Australia and Israel. The subjects received ataluren (10 mg/kg morning, 10 mg/kg midday, 20 mg/kg evening) ataluren (20 mg/kg morning, 20 mg/kg midday, 40 mg/kg evening) or placebo. The primary endpoint was the change in 6-minute walk distance (6MWD) from baseline to 48 weeks. The data showed a 29.7 meter difference in the average change in 6MWD between the low dose ataluren and placebo arms. There was no difference between the high dose ataluren and placebo arms. In addition, at 48 weeks 26% of subjects treated with low dose ataluren arm had progressed compared to 44% of subjects with placebo (p≡0.039). Positive trends were also seen in improved muscle function compared to placebo. Ataluren was generally well tolerated and adverse events were similar across treatment arms.

June 7, 2010

AVI BioPharma released positive results from a phase Ib/II trial of AVI-4658, an RNA-based therapeutic for the treatment of Duchenne muscular dystrophy (DMD). This open label, dose-ranging study (Study 28) enrolled 19 ambulatory subjects between 5 and 15 years of age with DMD who have an error in the gene coding for dystrophin that can be treated by skipping exon 51. The subjects were dosed once per week for 12 weeks by intravenous infusion at one of six doses: 0.5, 1.0, 2.0, 4.0, 10.0 or 20.0 mg/kg. After completion of dosing, they were followed for a further 14 weeks. Data are from eight subjects in the 10 and 20 mg/kg treatment cohorts who completed the 12 weekly doses. Data showed consistent skipping of exon 51 in the dystrophin mRNA, providing evidence of systemic biologic activity of AVI-4658. All eight subjects in the 10 and 20 mg/kg cohorts demonstrated generation of new dystrophin-positive muscle fibers. Three subjects, one in each of the 2.0, 10 and 20 mg/kg cohorts, demonstrated substantial generation of new dystrophin-positive muscle fibers, which increased from 1% to 21%, 1% to 15%, and 3% to 55% of normal, respectively, when comparing pre treatment to post treatment samples. AVI-4658 was generally well tolerated and there has been no evidence of anti-dystrophin antibodies or T and B cell infiltration.

April 21, 2008

BTG issued positive results from a phase II trial of BGC20-0166 for the treatment of obstructive sleep apnea (OSA). This study enrolled thirty nine subjects with mild to severe OSA who received placebo, a single agent or one of two doses of BGC20-0166 daily for a period of twenty eight days. Each subject's apnea-hypopnea index (AHI) was measured in overnight sleep laboratory polysomnograph studies on days fourteen and twenty eight. The primary endpoint was a reduction in the AHI at day twenty eight. The treatment group receiving the high-dose demonstrated a statistically significant reduction in AHI compared to subjects receiving placebo at both day fourteen and twenty eight. AHI was reduced by a mean of 40% in this treatment group, with individual responses ranging between 10% and 85%. Three of ten subjects in the high-dose group were considered complete responders, with a reduction in AHI of 50% or more and an AHI below 10 at day twenty eight. This group also showed reduced AHI in both REM and non-REM sleep stages and independent of sleep position and a trend towards improved oxygen saturation levels relative to placebo. Treatment was well tolerated. Based on the results, BTG plans to continue with the development of BGC20-0166.

Genentech and Biogen released negative results from a phase II/III trial of Rituxan for the treatment of primary-progressive multiple sclerosis. This randomized, double-blind, placebo-controlled study enrolled four hundred and thirty nine subjects in the US and Canada. The subjects received either four treatment courses of Rituxan six months apart or placebo. MRI evaluations were conducted at baseline, weeks six, forty-eight, ninety-six and one hundred and twenty-two. The study did not meet its primary endpoint as measured by the time to confirmed disease progression during the ninety six-week treatment period. The incidence of overall adverse events was comparable between Rituxan and placebo treatment groups. The companies plan to fully analyze the data in order to determine the best path forward.

Santhera reported positive results from a phase II trial of SNT-MC17 for the treatment of Duchenne Muscular Dystrophy (DMD). This double-blind, randomized, controlled study was dubbed DELPHI (Duchenne Efficacy Study In Long-Term Protocol Of High Dose Idebenone). A total of twenty-one pediatric subjects, aged eight to sixteen years, with DMD and cardiac dysfunction were enrolled in Belgium. The subjects received SNT-MC17 450 mg/day or placebo for twelve months. The primary endpoint was the percent change from baseline on the peak systolic radial strain of the left ventricular (LV) inferolateral cardiac wall. In the group treated with SNT-MC17, this was improved by 104%, a significant difference over the placebo group who improved by 29% (p=0.03). In addition, peak systolic longitudinal strain of the LV lateral-mid cardiac region also improved significantly, indicating a beneficial effect of SNT-MC17 on early and systolic myocardial dysfunction in DMD. Secondary endpoints included respiratory function tests. Direct measures of respiratory weakness, including peak expiratory flow, improved in subjects on SNT-MC17. Peak flow expressed as percentage of the predicted value for subjects on SNT-MC17 improved by 2.8% while those on placebo deteriorated by 8.5% (p=0.042). Treatment was determined to be safe and well tolerated. Additional phase II studies are currently underway.

May 14, 2007

Ceregene issued positive interim results from a phase I trial of CERE-110 for the treatment of Alzheimer's disease (AD). This single-site, open-label trial enrolled 6 subjects with mild-to-moderate AD. All subjects underwent stereotactic neurosurgery to deliver CERE-110 into the Nucleus Basalis of Meynert region of the brain. They subsequently underwent cognitive testing and PET scans at baseline, 6 and 12 months. Results suggested a reduction in the rate of cognitive decline. Increases in brain metabolism were observed in several cortical regions at six months (p<0.05) and12 months (p<0.05). Treatment was well tolerated. Based on the results Ceregene plans to initiate a phase II trial in 2008.

Insmed announced positive preliminary results from a phase II trial of iPlex for the treatment of myotonic muscular dystrophy (DM1). Six subjects have completed treatment to date in this open-label trial. These subjects received iplex up to 1 mg/kg/day for six months. Treatment was safe and well tolerated, with no reported adverse events. Improvements in cholesterol and triglycerides, as well as in gastrointestinal function, endurance and cognitive function were observed. In addition, 5 out of 6 subjects showed an improvement in lean muscle mass. The second cohort of subjects is currently being treated at an iPlex dose of 2 mg/kg/day, for six months.

PTC reported positive interim results from a phase II trial of PTC124 for the treatment of Duchenne muscular dystrophy (DMD). This open-label, dose-comparison, single-group-assignment study enrolled pediatric male subjects with nonsense-mutation-mediated DMD. Subjects received one of three doses of PTC124 for 28 days. The primary endpoint was the proportion of subjects with an increase in dystrophin expression in muscle during the treatment duration. Reported results are from the first two cohorts, 26 total subjects, who received the low and medium dose levels. Overall, 67% of subjects treated at the lower dose level and 50% of subjects treated at the medium dose level demonstrated an increase in the expression of dystrophin post-treatment. In addition, statistically significant improvements in concentrations of muscle-derived creatine kinase levels in the blood were observed during PTC124 treatment. Accrual and analysis of the third cohort is currently underway.

April 18, 2005

Neuro3d has announced positive results of a pair of phase II trial of their investigational antipsychotic ocaperidone, for the treatment of schizophrenia. Data from both studies yielded strong evidence of efficacy, with significant improvement in all primary efficacy measures, including both positive (e.g. hallucinations) and negative (e.g. social withdrawal, emotional flatness) symptom severity scores on the PANSS, BPRS and CGI diagnostic scales, vs. placebo. The drug also demonstrated non-inferiority of efficacy vs. an approved antipsychotic, and significant relative superiority in reducing drug-induced weight gain. The first trial, a double-blind, placebo-controlled safety and efficacy study, randomized 127 patients to receive dose ranging regimens of ocaperidone (0.1 mg-0.6 mg) or placebo daily for 8 weeks. The second was an active-controlled approved-therapy comparison study which enrolled 105 subjects, who received ocaperidone or an approved atypical antipsychotic for the treatment daily for 12 weeks. The company announced that these data would form the basis of phase III trials in the near future.

PTC Therapeutics announced results of a phase I study of PTC124, for the treatment of Duchenne muscular dystrophy (DMD) and cystic fibrosis (CF). Results from the study yielded a positive safety profile, with no symptomatic drug-related adverse events at any dose level and minor, reversible laboratory changes noted in some subjects. Preliminary pharmacokinetic data indicated that administration at safe dosing levels was able to produce drug plasma concentrations associated in preclinical studies with activity against the conditions. This open-label study treated healthy volunteers with twice daily PTC124 at multiple dosing levels (up to 50 mg) for 14 days. Based on these results, the company announced that they were working with FDA regulators to finalize the design of upcoming phase II trials.

June 23, 2003

Transgene and the French Muscular Dystrophy Association reported positive results from a phase I trial investigating gene transfer for the treatment of Duchenne and Becker’s muscular dystrophy. The trial involved the administration of a non-viral vector containing the whole sequence of the human dystrophin gene. Results showed that plasmid-dystrophin was found in muscle samples from all subjects. Expression of the dystrophin has been detected in three out of six subjects in the first two cohorts, and in all three subjects in the third cohort. The study enrolled nine subjects and was designed to demonstrate the vector-induced expression of the normal protein and the absence of toxicity and rejection of this protein by patients’ immune systems. Results were reported at the Conference of the American Society of Gene Therapy in Washington, D.C.

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