We are all acutely aware of the need for an effective treatment for Duchenne. Finding a way for children and young men affected by Duchenne to lead longer, healthier lives is at the heart of all of our efforts as families’ fight this devastating disease.
This week PPMD received an open letter from Sarepta Therapeutics, the company developing the investigational compound eteplirsen, providing an update to patients, parents and families on the company’s clinical program and progress. After reading the letter, I had the opportunity to interview Chris Garabedian, CEO of Sarepta, about the company’s progress and future plans.
Chris, thank you for taking the time to speak with us. It has obviously been a very busy time at Sarepta, and many members of the Duchenne community have been following your progress with eteplirsen very closely in recent weeks. Will you give us an update on what is happening with the company, and what we should be on the lookout for in the months ahead?
Certainly Sharon, and thank you and PPMD for this opportunity. It’s true that we at Sarepta have been very busy and the eteplirsen program has gotten much more attention over the past several weeks, especially since we released our interim 36-week data set from our Phase IIb trial in mid-July.
We had previously shown that 24 weeks of eteplirsen treatment was effective at helping patients with DMD produce increased levels of dystrophin. The theory behind eteplirsen treatment is that if we can produce meaningful levels of a functional dystrophin in the muscle, over time this will lead to a clinical benefit for patients. The interim analysis at 36 weeks is an early indication that the level of dystrophin we saw at 24 weeks may be translating to a favorable clinical impact in slowing the progression of the disease.
When we analyzed the data at 36 weeks, we saw the first signs of a clinical benefit in the 6MWT begin to emerge, and that is what has generated so much interest. Exciting as this is, however, it is important to recognize that these data are based on interim results. Like you, we will be eagerly awaiting the 48-week results in October to determine how this benefit holds up.
It’s safe to say, though, that even as we await the 48-week results, the clinical signal that emerged at 36 weeks has only reinforced our sense of urgency around all of the critical steps ahead of us – from completing the 48-week analysis in our ongoing Phase IIb study, to developing our regulatory and clinical trial strategy to pursue product approval, and to scaling up production of eteplirsen to meet the demands of a pivotal study and, ultimately, commercial approval and broader patient access. We know that our execution in the months ahead will be critical to our long-term success in bringing eteplirsen forward.
You just mentioned several things that need to happen in the coming months; completing the Phase IIb 48 week data analysis, finalizing your regulatory strategy, manufacturing scale-up. Could you tell us a bit more about each?
Sure. Let’s start with the trial, because everything else really flows from that. Again I would stress that the results we saw at 36 weeks were an interim analysis and not originally planned, but this interim analysis provided important information about the potential clinical utility of eteplirsen. The true indication of the potential safety and efficacy profile of eteplirsen will come at 48 weeks, when we will have a much more robust set of data to analyze on all patients, including new biopsy data on dystrophin production, as well as a more complete picture of the clinical impact of eteplirsen over time. The additional safety data through 48 weeks will also be important to demonstrate that eteplirsen shows the potential to be administered continuously, an important criteria for a disease that will require lifelong treatment. These data will be a critically important part of our discussions with FDA about the path forward, so we must be highly rigorous and methodical in understanding the data and how to build the most compelling case possible for eventual approval.
Once we have fully analyzed those data and released them to the public in October, we will request a meeting with the U.S. Food and Drug Administration (FDA) to gain their perspective about what we will need to demonstrate to submit a data package for evaluation and hopefully approval. At this point, the outcome of those discussions is impossible to guess. Our operating assumption and what we are preparing for as a company is that we will be asked to conduct at least one confirmatory study in a larger patient population than we have studied before. But how that trial is designed, or what the criteria will be for participation, will all depend on our discussions with the FDA near the end of this year.
The third track of activity, which is just as important as the first two, is manufacturing. As you have heard me say, eteplirsen is a truly novel RNA-based therapy that is highly complicated to produce. In fact, there is no commercially available product of this kind on the market today. It has been critical for Sarepta to work with the world’s leading experts on the manufacturing of these kinds of materials, and we have put together a team with the required expertise.
To this point, we have focused a significant amount of our manufacturing efforts to supply eteplirsen for the ongoing 12-patient clinical trial. Shifting production from the current small scale for this clinical study to a level that would support our confirmatory pivotal trial will require a substantial investment of time, money, and expertise. We have a plan in place to ramp up manufacturing, but it is also important to stress that it will be many months before we have enough supply to support our confirmatory pivotal trial.
As you know, there has been an increased attention paid in recent weeks to the question of how patients might gain access to eteplirsen outside of the current trial. I know your letter this week indicated that you do not have a supply to offer patients at the present time, even on a compassionate use basis; what is the company’s view of when you might be able to offer eteplirsen more broadly?
First of all, I want to stress unequivocally that we share the same sense of urgency as the patient community about how we will address this difficult issue, and over what timeframe. The question of access to treatment is one we get every day from many parents and families around the globe.
The reality is that there is no excess drug supply to pull off the shelf that would allow us to make eteplirsen available on a compassionate use basis. Every vial of the drug that we are manufacturing at the present scale is dedicated to the ongoing clinical trial. At this time, we simply cannot produce enough eteplirsen to meet needs outside of this trial until after we have substantially scaled up our production from current levels, which as I mentioned previously we are currently working on in collaboration with a number of highly experienced partners. We also need to understand from our discussions later this year with the FDA what our future study requirements will be.
It is perhaps important to stress here, too, that we will work very closely with regulators as we work through our scale-up process. One key factor that makes this kind of manufacturing challenging and time-consuming is the need to demonstrate that the drug material made at the larger scale has the same characteristics as that produced at the smaller scale. This is critically important when evaluating the potential safety and efficacy of any drug, and it involves a substantial effort and extensive procedures to demonstrate. Unfortunately, there are no shortcuts that will make this scale-up any faster.
And what about patients with mutations other than those that require skipping exon 51? What can we expect from Sarepta in the future for these patients?
We are absolutely aware and appreciate that this is of the utmost concern for all families whose children have other genetic mutations that may be amenable to a different exon skipping therapy beyond exon 51. We are working as quickly as possible to address this in collaboration with academic and medical experts in the field.
Currently we have research programs on additional exon-skipping compounds that target exon 45 and exon 50, in collaboration with the Children's National Medical Center, the Carolinas Medical Center, and the NIH.
We are optimizing our investigational compounds to move into preclinical, or animal, studies for both of these programs. Based on the results of the preclinical data, we will move to evaluating the exon 45 and 50 skipping drugs in human clinical studies. We’re working toward a goal of completing the work necessary to submit an investigational new drug, or IND, application to begin human clinical trials in late 2013, and to initiate enrollment in these trials in 2014. We will rely upon the PPMD Duchenne Connect Registry and other sources when the time comes to recruit for these trials.
Ultimately, our goal is to develop innovative RNA-based treatments that may help boys and young men who have any of the genetic mutations associated with DMD that are amenable to exon skipping, including those that are less common than exons 51, 45 and 50. I want to assure the DMD community that we are committed to finding the most expeditious and effective path forward to bring these investigational new therapies to all patients who could benefit from our exon-skipping technology.
As this program advances, what can patients and their families do to help?
I think all of us who have had an opportunity to work with the DMD community are incredibly motivated by the patients and families we talk to every day. From the numerous calls and emails we receive to the many one-on-one meetings we have had together, I have a deep appreciation and direct personal experience on the important role that the DMD community plays in providing your unique perspective and guidance to Sarepta and everyone involved in advancing DMD research. It is only by working together that we will be able to develop innovative treatment options for all DMD patients and their families.
As we continue to advance our DMD program, the opportunity for the patient community to make an impact will continue to evolve and grow. You have our commitment that we will regularly and transparently update the community on our progress. I invite DMD parents, patients, and advocates to stay in close touch with us and be ready to help us in our efforts to become successful in providing eteplirsen and follow-on exon-skipping drugs to the DMD community.
Note: If you’d like to receive news alerts and updates from Sarepta Therapeutics, you can send an email to firstname.lastname@example.org with your contact information (name, address, email), and you will be added to the company’s contact list.
Sharon Hesterlee, Ph.D.
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