New Medicines

Exondys 51Duchenne muscular dystrophy amenable to exon 51 skipping


Exondys 51
New molecular entity
Sarepta Therapeutics
Sarepta Therapeutics

Development and Regulatory status

Phase III Clinical Trials
Apr 22Sarepta granted Roche an exclusive option to obtain an exclusive license to commercialise certain products, including eteplirsen, outside of the US in Dec 19, as part of a deal to buy ex-US right to gene therapy, SRP-9001. If this option is exercised, Roche will have sole control over and decision-making authority with respect to the commercialisation of such products outside the US. However it appears Roche has yet to exercise its option [47,48].
Nov 19After receiving scientific advice from the EMA, Sarepta announces that once data from ongoing studies are available, it plans to evaluate future engagement with the EMA on potential next steps [45].
Nov 19EMA approves a modified paediatric investigation plan (PIP) for eteplirsen. The PIP is due to complete Mar 22 [44].
May 19A draft evidence report from the Institute for Clinical and Economic Review (ICER) in the US concludes that at its current list price of $892,000 per year, Exondys 51 “would not be cost-effective" [40].
May 19A draft evidence report from the Institute for Clinical and Economic Review (ICER) in the US concludes that at its current list price of $892,000 per year, Exondys 51 “would not be cost-effective" [40].
Feb 19Sarepta plans to seek follow up EMA scientific advice in 2019 to explore a potential approach for EMA approval of eteplirsen. It has initiated key activities in support of the potential launch of eteplirsen in the EU, such as building out commercial infrastructure and scaling-up manufacturing [41].
Jan 19Sarepta are in the process of conducting, starting or planning various EXONDYS 51 clinical trials, including studies that we need to conduct to comply with our post-marketing FDA requirements/commitments to verify and describe clinical benefit of EXONDYS 51 [39].
Jan 19Sarepta has also initiated a market access program (MAP) for eteplirsen in select countries in Europe, North America, South America and Asia where it currently has not been approved. The MAP provides a mechanism through which physicians can prescribe eteplirsen, within their professional responsibility, to patients who meet pre-specified medical and other criteria and can secure funding [39].
Jan 19Has been available in the US since Q1 17 [39].
Sep 18The CHMP has announced that it has re-examined its initial opinion and confirmed its previous recommendation to refuse the granting of a marketing authorisation for eteplirsen [38].
May 18The CHMP has now issued its formal negative opinion, recommending refusal of a EU marketing authorisation for eteplirsen in DMD: its reasons for doing so included the concern over the use of historical controls, and the lack of data to show that the very low amounts of shortened dystrophin produced as a result of the drug brought lasting benefits to the patient. As a result, it concluded that the balance of benefits and risks for the treatment could not be established [36]. Sarepta has confirmed that it will ask for a re-examination, and repeats its request that a Specialist Advisory Group be convened [37].
May 18Sarepta has reported that the CHMP has requested further information, as it currently considers that the application has not yet met the regulatory threshold for conditional approval: this is in part due to the use of external controls as comparators in the studies presented. While it has not indicated that it considers that the drug is ineffective in the indication applied for, a trend vote of the Committee was negative (this is not a formal Negative Opinion). Sarepta will request that a Scientific Advisory Group (SAG) - made up of DMD and neuromuscular specialists, be convened “to provide expert guidance and insight into, among other things, the validity of the external controls used and the importance of slowing pulmonary decline in patients with DMD" [34]. This is not necessarily unusual - the CHMP makes use of a number of specialist advisory groups, both permanent and temporary, to provide advice on specific issues [35].
Dec 16The EMA has validated the Marketing Authorisation Application (MAA) submitted by Sarepta for eteplirsen in the treatment of DMD amenable to exon 51 skipping - this confirms that the EMA has accepted the MAA and starts the review process. Sarepta is asking for conditional approval: a conditional approval is valid for one year, reviewed annually, and commits the MA holder to provide further data to confirm a positive risk to benefit balance for the drug [33].
Sep 16Sarepta is planning to file with the European Medicines Agency at the end of the year and is already in talks with NICE [32].
Sep 16Approved in the US, but the FDA requires a confirmatory clinical trial to demonstrate efficacy. The agency is requiring an additional two-year randomized, dose-ranging controlled trial from the approved dose of 30 mg/kg weekly up to a much higher dosage of 30 mg/kg daily. The injection is approved specifically for DMD patients with a mutation of the dystrophin gene amenable to exon 51 skipping [31].
Jun 16FDA requests data on the key biomarker for efficacy - dystrophin data, as measured by western blot, from biopsies already obtained from the ongoing confirmatory study of eteplirsen (PROMOVI). The Company plans to submit data from thirteen patient biopsy samples, at baseline and Week 48, to the FDA over the coming weeks to facilitate a prompt decision on the NDA by the FDA [30].
Apr 16FDA panel voted 7 to 6 that Sarepta does not provide substantial evidence from adequate and well controlled studies that the drug produced dystrophin at a level that was reasonably likely to produce a clinical benefit [29].
Apr 16FDA panel maintains its negative assessment from January, despite submission of additional data by the company, and reiterated its concern over trial design, statistical analysis and overall effectiveness of the drug [28].
Mar 16Several dozen experts in DMD, including site investigators and advisers working on the drug, circulate a detailed letter explaining why the FDA should support the application for eteplirsen, despite a negative internal assessment from FDA staff [27].
Mar 16FDA advisory committee meeting will now be Apr 25 [26].
Feb 16FDA prolongs its review of eteplirsen, with a decision expected by May 26. The delay gives the agency more time to review some new data Sarepta submitted last month,. However, in documents released ahead of last month´s now-delayed panel meeting, agency staff picked apart Sarepta´s supporting data and questioned whether the drug works at all [25].
Aug 15Granted priority review in US. A decision is expected by Feb 26, 2016 [23].
Jun 15FDA file New Drug Application for eteplirsen for treating Duchenne muscular dystrophy in patients with mutations amenable to exon 51 skipping [22].
May 15The FDA gives Sarepta permission to start a rolling submission for eteplirsen. Sarepta will start filing parts of the submission this week and expects to have everything with FDA by middle 2015. The timeline puts Sarepta in contention to have its DMD drug assessed by an advisory panel alongside competitor, drisapersen [21].
Oct 14The FDA issue a letter stating that it has been consistently requesting an independent assessment of eteplirsen´s effect on dystrophin plus more safety results and history data from Sarepta, and this is not a new request. Commentators note that it seems that the FDA meant to guide Sarepta to submit the additional requested data during a rolling submission process, prior to NDA completion as opposed to following a standard NDA submission, prior to the completion of the review as Sarepta interpreted it following the April minutes [18].
Oct 14At a meeting in September, the FDA asked for imaging and long-term results as well as more safety data. In view of this, Sarepta will have to delay a US filing until mid-2015 or later [17].
Apr 14US FDA New Drug Application will be submitted by the end of 2014 for the approval of eteplirsen for the treatment of Duchenne muscular dystrophy [15].
Nov 13The FDA will not consider early approval for eteplirsen. The Agency has questioned the use of dystrophin as a biomarker due to failed studies of the GSK drug drisapersen for DMD and also questioned the 6-Minute Walk Test results for eteplirsen from the PIIb study, suggesting that the study population should be stable over a 2-year timeframe due to recent natural history data. The FDA believes a placebo-controlled trial would allow interpretable evidence to be collected and other endpoints and/or subpopulations for the next trial of eteplirsen should be considered [13].
Jul 13The company plans to file in the US in 1H 2014 after discussions with the FDA. However, the FDA would not commit to declaring dystrophin an acceptable surrogate endpoint for accelerated approval and has asked for additional information related to the methodology and verification of dystrophin quantification [12].
Apr 13FDA asks for more information on existing data before it decides whether to grant the company´s request for accelerated approval [10].
Mar 13Sarepta is considering filing for accelerated approval in the US with PII data. The decision will be made after a meeting with the FDA at the end of Mar 13 [8].
Jun 12H2: A pivotal NDA-enabling, PIII study of eteplirsen in DMD is planned to begin [3].


RNA interference (corrects dystrophin RNA splicing via exon 51 skipping; enables dystrophin protein expression)
Duchenne muscular dystrophy amenable to exon 51 skipping

Further information


Trial or other data

Dec 19PIII MIS51ON study to evaluate the efficacy and safety of high-dose eteplirsen starts (NCT03992430). The study will be comprised of 2 parts: Part 1 will be conducted to evaluate the safety and tolerability of two doses (high dose level 1 and high dose level 2) of eteplirsen in approximately 8 patients; Part 2 will be conducted for the selection of a high dose (high dose level 1 vs high dose level 2) (dose finding phase), and its comparison with the 30mg/kg dose of eteplirsen (dose comparison phase), in approximately 144 DMD patients with genetically confirmed deletion mutations amenable to treatment by skipping exon 51. 152 boys aged 7 to 13 years will be recruited in Canada. Collection of primary outcome data is due to complete Oct 24 [42].
Nov 19PII trial (NCT03218995) is due to complete collection of primary outcome data in Mar 21 [42].
Nov 19PII extension study to evaluate the ongoing safety and tolerability of additional treatment with eteplirsen administered once weekly by IV infusion in male DMD patients who have successfully completed the 96-week eteplirsen study 4658-102 is enrolling by invitation (NCT03985878). The study, which started in Jun 19, intends to enrol 15 patients [42,43].
Jul 17PII trial to evaluate the safety, tolerability, PK, and efficacy of once-weekly IV infusions of eteplirsen in approximately 12 male patients, ages 6 months to 48 months who had genotypically confirmed DMD with a deletion mutation amenable to exon 51 skipping starts (4658-102; NCT03218995). The open-label trial is enrolling approximately 12 patients in Belgium, France, Germany, Italy and the UK [43].
Oct 15Sarepta Therapeutics announce additional clinical efficacy and safety data from the PIIb program of eteplirsen in pts with DMD. Ptstreated with eteplirsen experienced a statistically significant 151 meter difference in the 6MWT at 3 yrs vs. external DMD controls (p<0.01). Eteplirsen-treated pts also had a lower rate of loss of ambulation and a slower rate of decline vs. external DMD controls over 3 years. Pulmonary function remained relatively stable through approximately 4 yrs in eteplirsen-treated pts. Sarepta’s safety database, which includes ~100 pts, showed that the eteplirsen safety profile is 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 [24].
Nov 14Open label, PIII, non randomised parallel group confirmatory study initiated (4658-301, PROMOVI) of eteplirsen for treatment of Duchenne muscular dystrophy (DMD). The 48 week PROMOVI study aims to evaluate efficacy and safety of eteplirsen in a larger population of boys with DMD (n=160) and to examine functional as well as biochemical endpoints. In PROMOVI, half of the boys (with genotypes amenable to exon 51 skipping) will be treated with 30mg/kg eteplirsen while the other half (with genotypes not amenable to exon 51 skipping) will serve as a control gp. Efficacy and safety parameters will be assessed including dystrophin assessments and the study will be powered to show a benefit on the 6-minute walk test vs. control group. PROMOVI is due to report in August 2016 [19,20].
Jul 14PII data at week 144 of the extension study show a decline in 6-minute walk tests of 33.2 meters, but a significantly improved performance over the boys who were given a placebo in the first 6 months before switching to eteplirsen [16].
Apr 14At 120 weeks, patients in Study 202 in the 30mg/kg and 50mg/kg eteplirsen cohorts who were able to perform the 6MWT (mITT population n=6) experienced a decline of 13.9 metres (<5%) from baseline in walking ability. A statistically significant treatment benefit of 64.9 metres (p ≤0.006) was observed for the mITT population vs the placebo/delayed-treatment cohort (n=4). After experiencing a substantial decline earlier in the study, the placebo/delayed-treatment cohort also demonstrated stabilization in walking ability for more than 1.5 years, from week 36 to week 120, the period from which meaningful levels of dystrophin were likely produced, with a decline of 9.5 metres over this timeframe. These analyses were based on the maximum 6MWT score when the test was performed on two consecutive days [14].
Jun 13Further update from ongoing Study 202. After 84 weeks, patients in the 30 and 50mg/kg dose cohorts who were able to perform the 6MWT (mITT population; n=6) showed a statistically significant treatment benefit of 46.4m (p≤0.045) vs placebo/delayed-treatment cohort (n=4). The eteplirsen-treated patients had <6% decline (20.5m) from baseline in walking ability. The placebo/delayed-treatment demonstrated stabilization with an increase of 3.3m between 36-84 weeks [11].
Apr 13Update from ongoing Study 202. After 74 weeks, patients in the 30 and 50mg/kg dose cohorts who were able to perform the 6MWT (mITT population; n=6) showed a statistically significant treatment benefit of 65.2m (p≤0.004) vs placebo/delayed-treatment cohort (n=4). The eteplirsen-treated patients demonstrated <5% decline (13.4m) from baseline in walking ability. After experiencing a substantial decline earlier in the study, the placebo/delayed-treatment cohort also demonstrated stabilization in walking ability from week 36 through 74, with <10m decline over this timeframe [9].
Dec 12Updated results reported from Study 202, the open-label, extension to the PIIb Study 201. Patients treated with eteplirsen for 62 weeks and evaluable on ambulatory measures (modified Intent-to-Treat population for both the 30mg/kg and 50mg/kg dose cohorts) demonstrated a statistically significant benefit of 62 metres in the 6-minute walk test vs. patients who received placebo for 24 weeks followed by 38 weeks of eteplirsen, using a mixed-model repeated measure statistical test. The mITT consisted of 10 of the enrolled 12 patients; 2 patients who showed signs of rapid disease progression and lost ambulation by week 24 were excluded. The eteplirsen cohort (n=6) continued to show disease stabilization and has shown < 5% decline in walking distance on the 6-minute walk test from baseline. The placebo/delayed-treatment cohort (n=4) also demonstrated stability in walking distance from week 36 through week 62 with a <10m change over this timeframe, the period in which dystrophin was likely produced, with confirmation of significant dystrophin levels at week 48 through analysis of muscle biopsies in these patients. Across both treatment and placebo/delayed treatment cohorts there is evidence of continued stabilization on pulmonary function tests, echocardiogram, muscle strength and clinical laboratory tests over the 62 weeks [7].
Oct 12Results reported from a PIIb extension study. The core study (201), randomised 12 subjects with Duchenne muscular dystrophy to placebo or eteplirsen 30mg/kg or 50mg/kg once weekly for 24 weeks. Treatment continued in the 24 week open-label extension study (202) in those patients on eteplirsen, while those on placebo were randomised to eteplirsen 30mg or 50mg. Patients on either dose of eteplirsen for 48 weeks (n=8) had a statistically significant increase (p≤0.001) in dystrophin-positive fibers to 47% of normal. The placebo/delayed treatment cohort, which had received 24 weeks of eteplirsen also showed a statistically significant increase in dystrophin-positive fibers to 38.3% of normal (p≤0.009). Eteplirsen 50mg/kg over 48 weeks resulted in an 89.4 metre benefit in 6MWT (primary clinical endpoint) vs the placebo /delayed cohort. There was no statistically significant difference between the 30mg/kg eteplirsen and the placebo/delayed treatment groups. There were no treatment-related adverse events and no discontinuations. No clinically significant treatment-related changes were detected on any safety laboratory parameters, including several biomarkers for renal function [6].
Jul 12Results of the PIIb Study 4658-US-201 reported. In the predefined prospective analysis of ITT population on the primary clinical outcome measure, the change in 6MWT distance from baseline, eteplirsen-treated patients who received 50mg/kg weekly for 36 weeks (n=4) demonstrated a decline of 8.7m in distance walked from baseline (mean=396m), while patients who received placebo/delayed-eteplirsen treatment for 36 weeks (n=4) showed a decline of 78m (mean=394.5m), p≤0.019. The benefit was also significant at week 32 (p≤0.045). There was no statistically significant difference between the cohort of patients who received eteplirsen 30mg/kg weekly and the placebo/delayed treatment cohort.T here were no treatment-related adverse events, no discontinuation and no treatment related changes detected on any safety laboratory parameters [5].
Jun 12NCT01540409 is a PII open-label, multiple-dose, efficacy, safety, and tolerability study of eteplirsen given for an additional 80 weeks in the 12 subjects with duchenne muscular dystrophy who participated in Study 4658-US-201. The study started Feb 12 and is due to complete Dec 13 [4].
Apr 12Study 4658-US-201 included 12 boys between 7-13 years of age with appropriate deletions of the dystrophin gene that confirm eligibility for treatment with an exon-51 skipping drug received double-blind IV infusions of placebo (n=4), 30 mg/kg of eteplirsen (n=4), or 50 mg/kg of eteplirsen once weekly for 24 weeks (n=4). Muscle biopsies for evaluation of dystrophin were obtained at baseline for all subjects and after 12 weeks for pts in the 50 mg/kg cohort and after 24 weeks for pts in the 30 mg/kg cohort. Two placebo pts were randomized to the 30 mg/kg cohort and two placebo pts were randomized to the 50 mg/kg cohort. A shorter duration of eteplirsen treatment, 12 weeks, did not show a significant increase in novel dystrophin (0.79% dystrophin-positive fibers as a percentage of normal; p-value NS), despite administration of the drug at a higher dose (50mg/kg once weekly). Eteplirsen administered once weekly at 30mg/kg over 24 weeks resulted in a statistically significant (p ≤ 0.002) increase in novel dystrophin (22.5% dystrophin-positive fibers as a percentage of normal) compared to no increase in the placebo group [2].

Evidence based evaluations