Clinical Trials

Date: 2017-12-27

Type of information: Publication of results in a medical journal

phase: 2b

Announcement: publication of results in The Journal of Neuromuscular Diseases

Company: Sarepta Therapeutics (USA - MA)

Product: eteplirsen

Action mechanism:

• antisense oligonucleotide. Eteplirsen is designed to address the underlying cause of DMD by enabling the production of a functional dystrophin protein. Eteplirsen uses Sarepta\'s novel phosphorodiamidate morpholino oligomer (PMO)-based chemistry and proprietary exon-skipping technology to skip exon 51 of the dystrophin gene enabling the repair of specific genetic mutations that affect approximately 13 percent of the total DMD population. By skipping exon 51, eteplirsen may restore the gene\'s ability to make a shorter, but still functional, form of dystrophin from messenger RNA, or mRNA. Promoting the synthesis of a truncated dystrophin protein is intended to stabilize or significantly slow the disease process and prolong and improve the quality of life for patients with DMD.

Disease: Duchenne Muscular Dystrophy

Therapeutic area: Genetic diseases - Neuromuscular diseases - Rare diseases

Country: USA

Trial details:

• Study 201 was a randomized, double-blind, placebo-controlled clinical study conducted at Nationwide Children’s Hospital in Columbus, Ohio. Twelve boys aged 7 to 13 years with a confirmed genotype amenable to treatment with an exon-51 skipping drug were randomized to one of three cohorts: 30 mg/kg (n=4), 50 mg/kg (n=4), and placebo/delayed treatment (n=4). Eteplirsen and placebo were administered weekly by intravenous infusion. At Week 25, all patients rolled over to Study 202, a long-term open-label extension study, and placebo-treated patients initiated eteplirsen treatment at 30 mg/kg (n=2) or 50 mg/kg (n=2). The primary efficacy endpoint in Study 201 and Study 202 was the increase in novel dystrophin as assessed by muscle biopsy at Weeks 12 and 24 and at Week 48, respectively. The primary clinical endpoint was the 6MWT, a well-accepted measure of ambulation and clinical function in DMD.
• Long-term follow up in Study 202 continues to evaluate safety and clinical outcomes including the 6MWT. (NCT01396239)

Latest news:

• • On December 27, 2017, Sarepta Therapeutics announced that the pulmonary function results from eteplirsen-treated Duchenne muscular dystrophy (DMD) patients (N=12) in Study 201/202 compared to natural history were published in the December 20, 2017 online edition of The Journal of Neuromuscular Diseases. A statistically significant and clinically meaningful reduction in pulmonary decline as measured by forced vital capacity percent predicted (FVC%p) was observed for eteplirsen-treated patients as compared to natural history data published in the scientific literature.
• In eteplirsen-treated patients, the mean FVC%p decreased from 97.7% to 85.3% over 216 weeks, a decrease of 2.8% per study year. In an age-adjusted mixed-model repeated-measures (MMRM) analysis of FVC%p, an annual decrease of 2.3% was observed for eteplirsen-treated patients compared to an annual decrease of 4.1% observed in a natural history cohort with a similar age range from the United Dystrophinopathy Project (UDP).
• • On November 17, 2015, Sarepta Therapeutics announced that the Annals of Neurology published online positive efficacy and safety results from a Phase IIb long-term open-label extension study of eteplirsen in patients with Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. The study found that at three years of treatment, patients experienced a slower rate of disease progression when compared to untreated matched historical controls and the investigational drug continued to be well-tolerated. This analysis used historical data from the Italian Telethon Network and the Leuven Neuromuscular Reference Group for comparative analysis of 6MWT performance at baseline and Months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use and genotype. At 36 months, eteplirsen-treated patients demonstrated a statistically significant difference of 151 meters in six minute walk test (6MWT), compared to the external cohort. The eteplirsen-treated patients experienced a lower incidence of loss of ambulation (16.7%) compared to natural history control patients (46.2%). (Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, et al. Longitudinal effect of eteplirsen vs. historical control on ambulation in DMD. Annals of Neurology. 2015: Accepted Article, ahead of print. DOI: 10.1002/ana.24555)
• • On October 1, 2015, Sarepta Therapeutics announced additional clinical efficacy and safety data from the Company’s Phase IIb program of eteplirsen in patients with Duchenne muscular dystrophy (DMD). The data demonstrated that eteplirsen provided a statistically significant advantage of 151 meters in the ability of study participants to walk at three years, compared with external controls. Further, the fourth biopsy data confirmed the mechanism of action of eteplirsen, demonstrating exon skipping in all patients and dystrophin production in nearly all patients. Safety data remained consistent with prior results.
• New Long-Term Efficacy Data: Patients who were treated with eteplirsen experienced a statistically significant 151 meter difference in the 6-minute walk test (6MWT) at three years compared with external DMD controls. The 6MWT is a well-accepted measure of ambulation and clinical function in patients with DMD. (p<0.01). Eteplirsen-treated patients had a lower rate of loss of ambulation than external DMD controls over three years. Eteplirsen-treated patients experienced a slower rate of decline through Week 192 than external DMD controls. Pulmonary function remained relatively stable through approximately four years in eteplirsen-treated patients. New results from a fourth biopsy performed on 11 patients demonstrated that exon skipping occurred in 100 percent of patients after 180 weeks of treatment, confirming the mechanism of action of eteplirsen. In addition, biochemical evidence from three quantification methods, analysis of dystrophin positive fibers, dystrophin intensity and Western Blot testing, confirmed that dystrophin was present in most patients following eteplirsen treatment. Fourth Biopsy Results: Confirmed exon skipping in 100% of patients Percent dystrophin-positive fibers increased (p<0.001) in comparison to untreated controls Dystrophin intensity increased (p<0.001) in comparison to untreated controls Western Blot confirmed presence of dystrophin protein in 9 of 11 (82%) of eteplirsen-treated patients at Week 180 vs 1 of 9 (11%) in the DMD control biopsies New Long-Term Safety Data:  New results from Sarepta’s safety database, which includes approximately 100 patients exposed to eteplirsen, showed that the eteplirsen safety profile remained consistent with prior results. Common adverse drug reactions included flushing, erythema, and mild temperature elevation. No pulmonary embolisms, hospitalizations, injection site reactions or thrombocytopenia have been observed.
• Results of Sarepta’s Phase IIb program were included in the New Drug Application (NDA) that Sarepta submitted to the FDA for eteplirsen for the treatment of DMD amenable to exon 51 skipping. The primary clinical endpoint in the NDA was the comparison of the 6MWT ITT analysis of the eteplirsen-treated group compared to an external control with similar inclusion criteria. The FDA granted eteplirsen Priority Review status and assigned a Prescription Drug User Fee Act (PDUFA) action date of February 26, 2016. Previously, the FDA granted Rare Pediatric Disease Designation to eteplirsen, as well Orphan Drug Designation and Fast Track Status.
• • On January 12, 2015, Sarepta Therapeutics announced data through Week 168 from Study 202, a Phase IIb open-label extension study of eteplirsen in patients with Duchenne muscular dystrophy. After more than three years of treatment, results of the 6-minute walk test (6MWT) at 168 weeks showed continued ambulation across all patients evaluable on the test, however all patients showed a decline in distance walked on this measure since the week 144 timepoint. In addition, a continued stability of respiratory muscle function was observed, as assessed by pulmonary function tests. As previously reported, Study 202 met its primary endpoint of increased novel dystrophin as assessed by muscle biopsy at Week 48. At Week 168, the six patients in the modified Intent-to-Treat or mITT population in the 30 and 50 mg/kg eteplirsen cohorts who were able to perform the 6MWT experienced a decline of 76.7 meters, or about 19.5 percent, from baseline in walking ability. A statistically significant treatment benefit of 65.4 meters (p?0.017) was observed compared with the placebo/delayed-treatment cohort (n=4), which initiated treatment at Week 25 following 24 weeks of placebo. This cohort, after experiencing a substantial decline of 68.4 meters from baseline to Week 36, demonstrated a decline of 73 meters in walking ability from Week 36 through Week 168, the period from which meaningful levels of dystrophin were likely produced. These analyses were based on the maximum 6MWT score when the test was performed on two consecutive days. Respiratory muscle function from baseline through Week 168 in the Intent-to-Treat population (n=12), as measured by maximum inspiratory and expiratory pressure (MIP and MEP), continued to show a 11.1 percent mean increase in MIP and a 14.7 percent mean increase in MEP. Analyses of MIP percent predicted (MIP adjusted for weight) and MEP percent predicted (MEP adjusted for age) demonstrated a mean change from 91.7 percent at baseline to 89.5 percent at Week 168 in MIP percent predicted, and a mean change from 79.3 percent at baseline to 74.3 percent at Week 168 in MEP percent predicted. In addition, there was a mean increase in forced vital capacity (FVC), a measure of lung volume, of 11.6 percent. FVC percent predicted (FVC adjusted for age and height) was maintained above a mean of 90 percent at Week 168, with 101.3 percent at Baseline and 91.9 percent at Week 168. Sarepta announced last year that the 168 week results are one of several datasets the FDA has requested be included in, or at the time of, the NDA application. Sarepta’s plan for a mid-year 2015 NDA submission remains unchanged and will continue to be evaluated based on FDA discussions and as additional data become available. Through 168 weeks, eteplirsen was well tolerated and there were no reported clinically significant treatment-related adverse events and no treatment-related serious adverse events. In addition, there were no treatment-related hospitalizations or discontinuations. Patients performed two 6MWT evaluations on consecutive days at time points coinciding with a muscle biopsy procedure at baseline and at Weeks 12, 24 and 48. Two 6MWT evaluations were also performed at Weeks 120, 144, and 168, and will be performed at all future functional assessment visits. All other evaluations were a single 6MWT. The pre-specified primary analysis included the maximum distance walked at those clinic visits where repeated tests were taken. Other analyses of the repeated 6MWT results assessed mean, minimum, and Day 1 (first measure) scores. Results from these additional 6MWT analyses confirm the data observations in the primary analysis.

Analysis of Repeated 6MWT Values†	Baseline 6MWT (meters)	Adjusted Mean 6MWT Change from Baseline (meters) at Week 168	Estimated Treatment Benefit (Eteplirsen Minus Placebo/delayed-Tx)	P-Value
Maximum Score Eteplirsen (n=6)	399.7	-75.8	65.4	0.017
Maximum Score Placebo/delayed-Tx (n=4)	394.5	-141.2
Mean Score Eteplirsen (n=6)	388.6	-72.9	63.0	0.023
Mean Score Placebo/delayed-Tx (n=4)	380.3	-135.9
Minimum Score Eteplirsen (n=6)	377.5	-70.2	60.2	0.034
Minimum Score Placebo/delayed-Tx (n=4)	366.0	-130.4
Day 1 Score Eteplirsen (n=6)	379.7	-64.1	67.3	0.025
Day 1 Score Placebo/delayed-Tx (n=4)	371.5	-131.3

• * All 6MWT analyses are based on a Mixed Model Repeated Measures test.
• † All 6MWT analyses include the mITT population
• Summary of Pulmonary Function Tests: Week 168 Treatment Results

Pulmonary Function Test (PFT)*	Mean Baseline PFT Value	Mean Week 168 Value	%Change from Baseline†
Maximum Inspiratory Pressure	63.1 cm H2O	70.1 cm H2O	+11.1%
Maximum Expiratory Pressure	68.1 cm H2O	77.3 cm H2O	+13.5%
Forced Vital Capacity	1.73 liters	1.93 liters	+11.6%
Forced Vital Capacity % Predicted	101.3%	91.9%	-9.3%
Maximum Inspiratory Pressure %Predicted	91.7%	89.5%	-2.4%
Maximum Expiratory Pressure % Predicted	79.3%	74.3%	-6.3%

• * All PFT analyses include the ITT population (N=12)
• † All Week 168 data were not statistically significantly different from baseline, except for a statistically significant increase & decrease in FVC & FVC % Predicted, respectively (using one-sample t-test).
• Summary of Additional Exploratory Efficacy Endpoints Results through Week 168 for other exploratory efficacy endpoints, including timed function tests (e.g., Gowers’ maneuver, 10 meter run/walk and timed 4-step test) and the North Star Ambulatory Assessment have shown continued declines compared to baseline, though at potentially slower rates as compared to the limited available natural history data. These endpoints are less well characterized in DMD patients than the 6MWT and pulmonary function tests and have more inter- and intra-patient variability, although they may be predictors of decline at various stages of this disease. All patients evaluable on measures of ambulation (modified Intent-to-Treat, or mITT population) are still able to perform these tests including the 10 meter run/walk and 4-step test, with the exception of three patients who are no longer able to perform the Gowers’ maneuver.
  • • On October 8, 2014, Sarepta Therapeutics announced that it will give one oral presentation and two poster presentations on data from its ongoing Phase II and preclinical trials evaluating exon-skipping therapies for the treatment of Duchenne muscular dystrophy (DMD) at the International Congress of the World Muscle Society (WMS), being held fromOctober 7-11, 2014, in Berlin, Germany. The oral presentation will include additional detail about the 144-week, 6-minute walk test (6MWT) and safety data from the Phase IIb study of eteplirsen, as well as other information including 144-week pulmonary function test results and information on individual MIP and MEP results. Details of Sarepta’s presentations at WMS are as follows: Eteplirsen in Duchenne Muscular Dystrophy (DMD): 3 year update on Six-Minute- Walk Test (6MWT) and Safety Presenter: Jerry R. Mendell, M.D., of Nationwide Children’s Hospital
  • • On July 10, 2014, Sarepta Therapeutics announced data through Week 144 from Study 202, a Phase IIb open-label extension study of eteplirsen in patients with Duchenne muscular dystrophy. After nearly three years of follow up, results on the 6-minute walk test (6MWT) showed a decline in walking ability at a rate slower than would be expected based on available DMD natural history data. In addition, a continued stabilization of respiratory muscle function was observed, as assessed by pulmonary function tests. As previously reported, Study 202 met its primary endpoint of increased novel dystrophin as assessed by muscle biopsy at Week 48 and is now in the long-term extension phase in which patients continue to be followed for safety and clinical outcomes. At Week 144, patients in the 30 mg/kg and 50 mg/kg eteplirsen cohorts who were able to perform the 6MWT (modified Intent-to-Treat or mITT population; n=6) experienced a decline of 33.2 meters, or about 8.5 percent, from baseline in walking ability. A statistically significant treatment benefit of 75.1 meters (p?0.004) was observed for the mITT population compared with the placebo/delayed-treatment cohort (n=4), which initiated treatment at Week 25 following 24 weeks of placebo. After experiencing a substantial decline of 68.4 meters from baseline to Week 36, the placebo/delayed-treatment cohort demonstrated a decline of 39.0 meters in walking ability from Week 36 through Week 144, the period from which meaningful levels of dystrophin were likely produced. These analyses were based on the maximum 6MWT score when the test was performed on two consecutive days.
  • Respiratory muscle function from baseline through Week 144 in the Intent-to-Treat population (n=12), as measured by maximum inspiratory and expiratory pressure (MIP and MEP), showed a 14.7 percent mean increase in MIP and a 12.8 percent mean increase in MEP. Analyses of MIP percent predicted (MIP adjusted for weight) and MEP percent predicted (MEP adjusted for age) demonstrated a mean change from 91.7 percent at baseline to 93.9 percent at Week 144 in MIP percent predicted, and a mean change from 79.3 percent at baseline to 75.7 percent at Week 144 in MEP percent predicted. In addition, there was a mean increase in forced vital capacity (FVC), a measure of lung volume, of 11.0 percent. FVC percent predicted (FVC adjusted for age and height) was maintained above a mean of 90 percent at Week 144, with 101.3 percent at baseline and 90.9 percent at Week 144.
  • “We are encouraged to see continued stability on measures of respiratory muscle function in patients treated with eteplirsen for nearly three years, particularly as declines in MIP and MEP are often the first signs of pulmonary dysfunction in DMD,” said Edward Kaye, M.D., senior vice president and chief medical officer of Sarepta Therapeutics. “As we prepare to submit a New Drug Application for eteplirsen including these data, we are also on track to initiate in the coming months several new clinical studies of eteplirsen in a broader patient population to further characterize the drug’s safety and efficacy profile.”
  • Through 144 weeks, eteplirsen was well tolerated and there were no reported clinically significant treatment-related adverse events and no treatment-related serious adverse events. In addition, there were no treatment-related hospitalizations or discontinuations.
  • Summary of 6MWT: Week 144 Treatment Results*

• Analysis of Repeated 6MWT Values†	Baseline 6MWT (meters)	Adjusted Mean 6MWT Change from Baseline (meters) at 144 Weeks	Estimated Treatment Benefit (Eteplirsen Minus Placebo/delayed-Tx)	P-Value
  Maximum Score Eteplirsen (n=6)	399.7	-32.2	75.1	0.004
  Maximum Score Placebo/delayed-Tx (n=4)	394.5	-107.4
  Mean Score Eteplirsen (n=6)	388.6	-27.5	73.1	0.006
  Mean Score Placebo/delayed-Tx (n=4)	380.3	-100.7
  Minimum Score Eteplirsen (n=6)	377.5	-22.9	70.8	0.010
  Minimum Score Placebo/delayed-Tx (n=4)	366.0	-93.8
  Day 1 Score Eteplirsen (n=6)	379.7	-93.8	76.5	0.005
  Day 1 Score Placebo/delayed-Tx (n=4)	371.5	-89.7

  • * All 6MWT analyses are based on a Mixed Model Repeated Measures test.
  • † All 6MWT analyses include the mITT population
  • ‡ The pre-specified primary analysis of the 6MWT results was based on the maximum score.
  • Patients performed two 6MWT evaluations on consecutive days at time points coinciding with a muscle biopsy procedure at baseline and Weeks 12, 24 and 48. Two 6MWT evaluations were also performed at Weeks 120 and 144, and will be performed at all future functional assessment visits. All other evaluations were a single 6MWT. The pre-specified primary analysis included the maximum distance walked at those clinic visits where repeated tests were taken. Other analyses of the repeated 6MWT results assessed mean, minimum, and Day 1 (first measure) scores. Results from these additional 6MWT analyses confirm the data observations in the primary analysis.
  • Summary of Pulmonary Function Tests: Week 144 Treatment Results

  • Pulmonary Function Test (PFT)*			Mean Baseline PFT Value			Mean Week 144 Value			% Change from Baseline†
    Maximum Inspiratory Pressure			63.1 cm H2O			72.4 cm H2O			+14.7%
    Maximum Expiratory Pressure			68.1 cm H2O			76.8 cm H2O			+12.8%
    Forced Vital Capacity			1.73 liters			1.92 liters			11.0%
    Forced Vital Capacity % Predicted			101.3%			90.9%			-10.3%
    Maximum Inspiratory Pressure % Predicted			91.7%			93.9%			+2.4%
    Maximum Expiratory Pressure % Predicted			79.3%			75.7%			-4.5%

  • * All PFT analyses include the ITT population (N=12) † All Week 144 data were not statistically significantly different from baseline, except for a statistically significant increase & decrease in FVC & FVC % Predicted, respectively (using one-sample t-test).
  • Sarepta plans to submit these results along with additional data and analysis as part of a New Drug Application for eteplirsen by year-end.

Is general: Yes