Products

Date: 2018-09-20

Type of information: Negative opinion for the granting of a Market Authorisation in the EU

Product name: Exondys 51®

Compound: eteplirsen

Therapeutic area: Rare diseases - Neuromuscular diseases

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.

Company: Sarepta Therapeutics (USA - MA)

Disease: Duchenne Muscular Dystrophy (DMD) amenable to exon 51 skipping

Latest news:

• • On September 20, 2018, the CHMP confirmed the refusal of the marketing authorisation for Exondys® (eteplirsen) intended for the treatment of Duchenne muscular dystrophy. Sarepta presented the results of two main studies involving 12 boys aged 7 to 13 years with DMD who had a genetic mutation amenable to exon 51 skipping. In the first study, Exondys® was compared with placebo for the first 24 weeks, after which all patients were treated with Exondys®. The main measure of effectiveness was the change in the distance walked during a 6-minute walking test after 24 weeks.
• The second study, an extension of the first one, involved the same patients who were all treated with Exondys® for another 4 years. The company also compared the results of these studies with those from a variety of historical data.
• The CHMP was concerned that the main study, which involved just 12 patients, did not compare Exondys® with placebo beyond 24 weeks, during which there was no meaningful difference between Exondys® and placebo in the 6-minute walking distance. The methods for comparing results of the main studies with historical data were not satisfactory for showing that the medicine was effective. The Committee considered further data were needed to show that the very low amounts of shortened dystrophin produced as a result of Exondys® treatment bring lasting benefits relevant to the patient. Therefore, the CHMP was of the opinion that the balance of benefits and risks of Exondys® in the treatment of DMD could not be established and recommended that the marketing authorisation be refused. The CHMP refusal was confirmed after re-examination. Sarepta will now be seeking follow up Scientific Advice in 2019 in order to explore the approach to bring eteplirsen to Europe.
• • On June 1, 2018, Sarepta Therapeutics announced that the company will request a re-examination of the CHMP's negative opinion, which will result in the assignment of a new rapporteur and co-rapporteur. The company will also request a Scientific Advisory Group (SAG) on DMD be called so that neuromuscular specialists, experienced with working with treatments for these patients, can provide expert guidance and insight into, among other things, the validity of the external controls used and the importance of certain functional endpoints, including for instance, the relevance of meaningful slowing pulmonary decline in patients with this difficult to treat disease. The re-examination process is expected to be completed by year-end 2018.
• •  On May 31, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorisation for Exondys®, intended for the treatment of Duchenne muscular dystrophy. The company presented the results of two main studies involving 12 boys aged 7 to 13 years with DMD who had a genetic mutation amenable to exon 51 skipping. In the first study, Exondys was compared with placebo for the first 24 weeks, after which all patients were treated with Exondys. The main measure of effectiveness was the change in the distance walked during a 6-minute walking test after 24 weeks. The second study, an extension of the first one, involved the same patients who were all treated with Exondys for another 4 years. The company also compared the results of these studies with those from a variety of historical data.
• The CHMP was concerned that the main study, which involved just 12 patients, did not compare Exondys with placebo beyond 24 weeks, during which there was no meaningful difference between Exondys and placebo in the 6-minute walking distance. The methods for comparing results of the main studies with historical data were not satisfactory for showing that the medicine was effective. The Committee considered further data were needed to show that the very low amounts of shortened dystrophin produced as a result of Exondys treatment bring lasting benefits relevant to the patient. Therefore, the CHMP was of the opinion that the balance of benefits and risks of Exondys in the treatment of DMD could not be established.
• • On December 19, 2016,  Sarepta Therapeutics announced that the European Medicines Agency (EMA) validated the previously submitted Marketing Authorization application (MAA) for eteplirsen to treat Duchenne muscular dystrophy amenable to exon 51 skipping. Sarepta is seeking conditional approval of eteplirsen in the EU through the centralized procedure. Validation of the MAA confirms that the submission is accepted and starts the formal review process by the EMA’s Committee for Human Medicinal Products (CHMP).
• • On September 19, 2016, the FDA approved Exondys 51® (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy. Exondys 51® is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD. Exondys 51® was approved under the accelerated approval pathway. This approval is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51®, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.
• Under the accelerated approval provisions, the FDA is requiring Sarepta Therapeutics to conduct a clinical trial to confirm the drug’s clinical benefit. The required study is designed to assess whether Exondys 51® improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug. The most common side effects reported by participants taking Exondys 51® in the clinical trials were balance disorder and vomiting.
• The FDA granted Exondys 51® fast track designation. Sarepta Therapeutics has also received a rare pediatric disease priority review voucher, which comes from a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. This is the seventh rare pediatric disease priority review voucher issued by the FDA since the program began.
• • On April 25, 2016, Sarepta Therapeutics announced that the FDA's Peripheral and Central Nervous System Advisory Committee met to review the new drug application for eteplirsen as a treatment for Duchenne muscular dystrophy amenable to exon 51 skipping. The advisory committee voted 6-7 against the finding of substantial evidence from adequate and well controlled studies that show that eteplirsen induces production of dystrophin to a level that is reasonably likely to predict clinical benefit. The advisory committee voted 3 – 7, with three abstentions, against finding substantial evidence based on the clinical results of the single historically controlled study (Study 201/202) that eteplirsen is effective for treatment of DMD. The Prescription Drug User Fee Act (PDUFA) action date for completion of FDA review of eteplirsen is May 26, 2016. In three additional voting questions, the panel voted 5 to 7, with one abstention, against whether decisions to administer the 6-minute walk test (vs. conclusions that the patient could no longer walk) were sufficiently objective and free of bias and subjective decision-making by patients, their caregivers, and/or health care professionals to allow for a valid comparison between patients in Study 201/202 and an external control group . The panel voted on the impact of the North Star Ambulatory Assessment with one panel member voting that it strengthened the persuasiveness of the findings in Study 201/202, with five voting that it weakened the persuasiveness, and seven voting that it had no effect. The panel also voted on the impact of the other tests of physical performance (e.g., rise time, 10-meter run/walk) on the persuasiveness of the findings in Study 201/202, with the result of one panel member voting that they strengthened the persuasiveness, two voting that they weakened the persuasiveness, and ten voting that they had no effect (FDA Question # 6). The PCNSC Advisory Committee recommendation was based on a review of results from the Phase IIb clinical program for eteplirsen (studies 201 and 202), long-term outcomes (through 168 weeks) from the Study 202 open-label extension study, as well as 4-year clinical effectiveness data based on a comparison of patients in Study 201/202 to a historical control group that was designated as a major amendment to the NDA in January 2016.
• • On March 14, 2016, Sarepta Therapeutics announced that the Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee of the FDA will review Sarepta’s New Drug Application (NDA) for eteplirsen on April 25, 2016.
• • On February 8, 2016, Sarepta Therapeutics announced that the FDA will require additional time to complete its review of the New Drug Application for eteplirsen, for the treatment of Duchenne muscular dystrophy amenable to exon 51 skipping. In a notice received from the FDA, the Prescription Drug User Fee Act (PDUFA) date for eteplirsen has been extended to May 26, 2016. The rescheduled date for the Peripheral and Central Nervous System Advisory Committee meeting has not yet been determined. The FDA notified Sarepta that its January 8, 2016 submission of 4-year clinical effectiveness data, which included additional six minute walk test (6MWT) and loss of ambulation data compared to a historical control, has been designated as a major amendment to the NDA. The FDA stated that the PDUFA goal date has been extended by three months to allow for a full review of the submission. As described in the Sarepta Advisory Committee Briefing Document Addendum, the principal basis for establishing the effectiveness of eteplirsen is a comparison of patients in Study 201/202 to a historical control group. The FDA has previously granted eteplirsen Priority Review status, which is designated for drugs that provide a treatment where no adequate therapy exists. The FDA also granted Rare Pediatric Disease Designation to eteplirsen, as well Orphan Drug Designation and Fast Track Status.
• • On January 20, 2016, Sarepta Therapeutics announced that the FDA Peripheral and Central Nervous System Advisory Committee meeting scheduled for Friday, January 22 has been postponed by the FDA due to an anticipated severe winter snowstorm forecasted to hit the Washington D.C. area. A future meeting date will be announced in the Federal Register. In the event of a change in the February 26, 2016 PDUFA date, the company will provide an update at that time.
• • On December 18, 2015, Sarepta Therapeutics announced that the Peripheral and Central Nervous System Drugs Advisory Committee of the FDA will review Sarepta’s New Drug Application (NDA) for eteplirsen, on January 22, 2016. The Prescription Drug User Fee Act (PDUFA) action date for completion of FDA review of the eteplirsen NDA is February 26, 2016.
• • On August 25, 2015, Sarepta Therapeutics announced that the FDA has filed the New Drug Application for eteplirsen for the treatment of Duchenne muscular dystrophy amenable to exon 51 skipping. The FDA has completed its filing review and has determined that the application is sufficiently complete to permit a substantive review. The Prescription Drug User Fee Act (PDUFA) action date for a decision on the application is February 26, 2015. The FDA has granted eteplirsen Priority Review status, which is designated to drugs that offer benefit over existing therapies, or provide a treatment where no adequate therapy exists.
• • On August  21, 2015, Sarepta Therapeutics announced the FDA has granted Rare Pediatric Disease Designation for eteplirsen.  The Rare Pediatric Disease Designation supplements the Orphan Drug Designation and Fast Track Status previously granted by the FDA for eteplirsen.
• • On June 29, 2015, Sarepta Therapeutics announced the completion of the rolling submission of a New Drug Application to the FDA for eteplirsen on June 26, 2015. The rolling submission of the NDA began on May 20, 2015, after the completion of a pre-NDA meeting with the FDA held on May 19, 2015.
• • On May 19, 2015, Sarepta Therapeutics announced that the Company held a pre-New Drug Application meeting with the FDA regarding eteplirsen, for the treatment of Duchenne muscular dystrophy. Sarepta has agreed with the Agency to initiate a rolling NDA submission and will submit the non-clinical and CMC components of the NDA by the end of this week. As previously announced, Sarepta plans to submit the final component of the NDA by mid-year 2015.
• • On October 27, 2014, Sarepta Therapeutics provided an update on its discussions with the FDA regarding its planned New Drug Application submission for the approval of eteplirsen for the treatment of Duchenne muscular dystrophy. In meeting minutes received last week from a Type B Pre-NDA meeting that took place in September 2014, the FDA provided updated guidance regarding the specific data to be included as part of, or at the time of, Sarepta’s NDA submission. The guidance states that additional data are now required as part of the NDA submission, including the results from an independent assessment of dystrophin images and the 168-week clinical data from study 202. Additionally, the guidance requests more specific data including a minimum duration of safety in new patients exposed to eteplirsen, patient-level natural history data to be obtained by Sarepta from independent academic institutions, and MRI data from a recent study conducted by an independent academic group. The FDA indicated that further discussion with Sarepta “will be necessary to determine what would constitute a complete NDA.” Based on these requests, Sarepta plans to submit an NDA by mid-year 2015, pending any additional requests from further discussions with the FDA.
• • On April 21, 2014, Sarepta Therapeutics announced it plans to submit a New Drug Application to the FDA by the end of 2014 for the approval of eteplirsen for the treatment of Duchenne muscular dystrophy. The plan to submit an NDA for eteplirsen by the end of 2014 is based on a guidance letter from the Agency that proposed a strategy regarding the submission of an NDA for eteplirsen under a potential Accelerated Approval pathway and served as the final meeting minutes for four meetings that took place between November, 2013 and March, 2014. The Agency stated that “with additional data to support the efficacy and safety of eteplirsen for the treatment of DMD, an NDA should be fileable,” and outlined examples of additional data and analysis that, if positive, will be important to enhance the acceptability of an NDA filing by addressing areas of ongoing concern in the existing dataset. Additionally, the Agency provided clear guidance on an open-label, historically controlled confirmatory study of eteplirsen, as well as initial guidance on a placebo-controlled study of one or more follow-on DMD drug candidates, which, like the open-label study, could also be considered an acceptable confirmatory study to verify the clinical benefit of eteplirsen in the event of an accelerated approval.
• Based on the Agency’s guidance, Sarepta plans to initiate several additional clinical studies with eteplirsen later this year in exon-51 amenable genotypes. These studies will include a clinical trial with predefined efficacy endpoints for ambulatory patients between the ages of 7 to 16 years who can walk a minimum distance, and two additional clinical trials that will evaluate safety and biomarkers in DMD patients younger than 7 years and DMD patients who have advanced in their disease progression to a point they cannot walk a minimum distance or have become non-ambulant. Additionally, Sarepta plans to initiate a placebo-controlled study with one or more of its follow-on DMD exon-skipping drug candidates by the end of the year.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE: 2016-12-19

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2016-09-19

UE authorization:

Favourable opinion UE:

Favourable opinion USA:

Orphan status USA: 2007-10-23

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

• • On February 21, 2017, Sarepta Therapeutics announced it has entered into an agreement with Gilead Sciences to sell its Rare Pediatric Disease Priority Review Voucher (PRV). Sarepta received the PRV when Exondys 51® was approved by the FDA for the treatment of patients with Duchenne muscular dystrophy amenable to exon 51 skipping.
• The voucher was awarded by the FDA under a provision that encourages development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. With the passage of the 21st Century Cures Act, this PRV program has been extended through September 30, 2020.
• As part of the agreement, Sarepta will receive an upfront payment of $125 million upon the closing of the transaction, which is subject to customary closing conditions and is expected to occur following expiration of the applicable U.S. antitrust clearance requirements. Credit Suisse served as Sarepta’s advisor on this transaction and conducted an extensive sales process, which included outreach to multiple pharmaceutical and biotech companies.

Is general: Yes