In both October and December 2012, Sarepta Therapeutics announced very encouraging results from a 12-person phase 2b trial of eteplirsen, an exon-skipping compound that is a potential treatment for Duchenne muscular dystrophy.
Eteplirsen targets exon 51 of the dystrophin gene and is designed to treat DMD caused by specific dystrophin mutations.
The results reported in October reflected the first 48 weeks of the trial, and the December results represented 62 weeks of trial data. At both time points, boys treated with a higher dose of eteplirsen for the entire trial period walked significantly farther on a “six-minute walk test” than trial participants who received a placebo for the first 24 weeks of the trial, and then received eteplirsen (called the “placebo/delayed treatment group”).
MDA, which has been funding the development of exon skipping since the 1990s, provided supplemental funding for this trial.
What’s next for eteplirsen? In response to questions from MDA, Sarepta CEO Chris Garabedian discussed the trial results and next steps.
What have you seen so far with eteplirsen in boys with DMD? What evidence is there that eteplirsen is effective?
Garabedian: In our phase 2b extension study, it was demonstrated that treatment with eteplirsen met the primary efficacy endpoint, consisting of an increase in novel [new] dystrophin and, in addition, achieved a significant clinical benefit on the primary clinical outcome, the six-minute walk test (6MWT), over the placebo/delayed treatment group of patients.
Eteplirsen administered once weekly at either 30 milligrams per kilogram [of body weight] or 50 milligrams per kilogram for 48 weeks in eight boys resulted in a statistically significant increase in dystrophin-positive [muscle] fibers to 47 percent of normal.
The four-person placebo/delayed treatment group, which had received 24 weeks of eteplirsen at either 30 milligrams per kilogram or 50 milligrams per kilogram following 24 weeks of placebo, also showed a statistically significant increase in dystrophin-positive fibers to 38.3 percent of normal.
All evaluable boys who received eteplirsen for 48 weeks also experienced a statistically significant 67.3-meter [220.8-foot] benefit on the 6MWT compared to those who received placebo for 24 weeks followed by 24 weeks of eteplirsen in the open-label extension. [Note: Two boys could not be evaluated on the 6MWT because they lost the ability to walk early in the trial.]
Importantly, eteplirsen was well-tolerated with no treatment-related adverse events at up to 50 milligrams per kilogram for 48 weeks.
We understand that your next step is a meeting with the U.S. Food and Drug Administration (FDA). When do you expect that to take place? What will occur at that meeting?
Garabedian: We plan to meet with the FDA to review the data from the phase 2b study in the first quarter of next year . The purpose of the meeting will be to discuss the 48-week data and next steps for the clinical program, including the appropriate path toward potential approval. Based on those discussions, we will work toward the fastest path to make eteplirsen available to patients in the future.
You probably can't predict exactly what the FDA will ask Sarepta to do before eteplirsen can be approved for DMD, but, if you had to guess, what do you think the agency is going to require, and why?
Garabedian: It is very hard to anticipate what the FDA will require for eteplirsen approval. There are a variety of registration paths available, such as accelerated approval [see below] and the traditional phase 3 study pathway.
An important regulatory advance for rare diseases, "PDUFA V" [Prescription Drug User Fee Act, fifth authorization], was signed into law this year. PDUFA V promotes accelerated access for patients to new therapies and accelerated development of promising therapies. [See MDA Urges Legislators to Speed Up Approval of Rare Disease Drugs.]
There is language encouraging the FDA to use flexibility in disease areas of high unmet medical need like DMD. However, we need to meet with the FDA to understand how this language will apply in a real-world setting, such as with a drug like eteplirsen for DMD. We look forward to meeting with the FDA to discuss the most appropriate of these options.
If a phase 3 trial is required, how long do you think it would take to recruit for such a trial and complete it? How many participants are likely to be needed? When would we expect approval under this scenario, assuming a positive result?
Garabedian: We plan to discuss additional clinical studies of eteplirsen with the FDA when we meet with them. The details of our trial design, including inclusion criteria, endpoints, duration, size and other aspects of the study will depend on the outcome of our discussions with the FDA.
Once we have the FDA's input, Sarepta will determine the best clinical development path forward and will have a better idea of the timing for study initiation and enrollment.
If a phase 3 trial is required, how would an individual patient go about trying to be a part of that trial?
Garabedian: We will keep the patient community informed as we make progress on the design and planning of any additional clinical studies through organizations such as MDA. We also will have updates on our website as well as on ClinicalTrials.gov that will include any clinical trial information and the contact information for clinical trial sites as they open for enrollment. If a patient or family would also like to receive Sarepta updates via email, please send an email to email@example.com and ask to be included on our distribution list.
Is it possible that approval could be obtained without a phase 3 trial? If so, what (if any) other studies might be needed? What is the difference between a phase 3 study and a "confirmatory" study? What do you think the time frame might be for approval and for availability of eteplirsen under this scenario?
Garabedian: There is a regulatory framework in place, called accelerated approval, which allows for the approval of an investigational drug based on a surrogate endpoint [a measurement that can "stand in" for an accepted measurement of disease progression] in early-phase studies if the condition is serious or life-threatening. A confirmatory study is then needed to further evaluate and confirm the efficacy and safety of a drug that is granted accelerated approval. [The Accelerated Approval pathway] allows other patients to access the drug while the company continues to study the drug in a set of patients enrolled in the confirmatory trial. [See FDA Accelerated Approval Program.]
A phase 3 study is designed to also further evaluate and confirm the efficacy seen in a phase 2 study of an investigational drug.
The main difference with a phase 3 study [compared to a confirmatory study] is that only patients who are enrolled in the study will be able to access the drug.
Until we discuss possible trial designs with the FDA, it is difficult to know how long a phase 3 study may take, although we would anticipate a study would be approximately 48 weeks in duration, as has been standard in DMD.
Apart from FDA approval, what other hurdles must be faced before patients can obtain eteplirsen? For instance, when can Sarepta manufacture enough of the drug to satisfy demand?
Garabedian: Manufacturing is an area Sarepta is devoting a significant amount of time and resources to right now. We are currently working to scale up manufacturing of eteplirsen to support future clinical development and to meet patient needs. We have a plan in place to meet this challenge, but we must be thorough and methodical to ensure we are successful.
Are you going to try to get this drug approved outside of the U.S.? What steps do you need to take to make this happen?
Garabedian: We plan to include European physicians and patients in the future clinical studies of the next exon-skipping drugs that we are developing — for exons 44, 50 and 53, and any additional exons we initiate development on with our PMO technology.
For eteplirsen, we are not able to provide access through any mechanism, including clinical studies, due to current intellectual property constraints. We are open to discussing sustainable paths to seek approval and access to eteplirsen for DMD patients in the European Union, and we hope to be able to find a path for approval and access in the future.
What, if anything, can the DMD community in the United States do to ensure that eteplirsen is available as soon as is safely possible?
Garabedian: It is our role at Sarepta, as the sponsor of the eteplirsen program, to gather the appropriate preclinical and clinical data and to analyze that data for discussions with the regulatory authorities. We will be discussing the data in terms of the overall mean [average] effect, the various patient populations and the patient subgroups.
As patients and caregivers, you have a powerful voice in educating about the disease and its impact. We would recommend that parents connect with existing organizations, such as MDA, that are supportive of the interests of all patients and who are undertaking important initiatives to efficiently and responsibly meet patients' needs. We believe by pooling your support and resources behind these types of established initiatives, you will be able to effect the most change.
What could potentially prevent this drug from being approved?
Garabedian: There are a number of factors the FDA looks at to evaluate the safety and efficacy of a new investigational therapy. We will be meeting with the FDA to discuss the eteplirsen 48-week data set in the context of these evidentiary standards.
What is your plan to address other deletions with your exon-skipping technology? Which ones will go first, and what is the sequence? How will you address more rare exons?
Garabedian: Our goal is to pursue exon-skipping therapeutics for all DMD patients who can benefit from our technology, including those with rare deletions. As we presented, we are actively conducting research on additional exon-skipping compounds that target exon 45, exon 50 and the recently announced EU grant for exon 53. [See DMD: Sarepta Expands Exon-Skipping Program.]
We are in the process of establishing additional partnerships and collaborations to address other exons and to move the entire platform forward. Through these collaborations we will move clinical development forward with these compounds with the hope of demonstrating that the clinical benefit we have seen with eteplirsen can be reproduced across other exon-skipping targets.