Dystrophin as a surrogate endpoint

Posted by: Christine McSherry on April 18, 2013

Sarepta recently revealed that the Division of Neurology Products requested a coherent and comprehensive summary to support dystrophin as a surrogate, in order for the agency to decide on the suitability of the eteplirsen dataset to be reviewed under the Accelerated Approval pathway. This disclosure sparked much debate so I thought it might be helpful to share what we said to the FDA in our recent meetings about this issue.


The first thing I did when I realized that accelerated approval might be a viable pathway to get this life saving treatment to those with Duchenne faster was to look up the actual regulation.

Subpart H–Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses


My interpretation of this is that a drug can be approved on an accelerated basis if the surrogate endpoint is reasonably likely to predict clinical benefit – it doesn’t say – a surrogate endpoint should be directly correlated with clinical endpoints – so I want to discuss why I think dystrophin is reasonably likely to predict a clinical benefit in Dcuhenne and how we described this to the FDA in our recent meetings.
2001 – Jett was diagnosed with Duchenne muscular dystrophy, they told me had his muscles did not contain an important protein, dystrophin, therefore, he had Duchenne.  If Jett had a small amount of this protein, or a varying amount of dystrophin, he would likely have Becker muscular dystrophy.  The difference between Duchenne and Becker become increasingly clear that day.  If Jett had Becker, there was a chance of survival. If Jett had Duchenne, there was most certainly no chance of survival past the age of 19.  In that moment, I prayed that he had Becker, a truncated – but somewhat potentially functional dystrophin, as time would tell, Jett has Duchenne.


2013 – Sarepta Therapeutics provides data to the FDA that demonstrates dystrophin, a truncated – but seemingly functional dystrophin – appears to be created in the muscles of the boys in their trial.  48 weeks into the trial, the biopsy results were released.  A truncated dystrophin was being made.  The 6MW demonstrated stability.  74 weeks into the trial, now at an age where patients with Duchenne are generally beginning to show a decline in ambulation (and very specifically these boys who had low baseline walk test scores), these patients, the 6 patients that were not in the placebo arm – were showing stability. What is even more striking is that the 4 placebo patients who declined initially seem to have stabilized after receiving eteplirsen. From my experience of having a child with Duchenne and all of the conferences that I have been to – when a boy has such a steep decline in ambulation it is almost unheard of to see a stabilization for over a year, by this time they are likely in wheelchairs. This seems like a very profound effect and in stark contrast to the natural progression of Duchenne.


Does this mean that they were showing a functional clinical benefit?  Using Becker as a biological model and how its natural progression differs so vastly than a Duchenne model it would appear that a truncated dystrophin can be functionally active and provide a clinical benefit.


This would reason that some dystrophin is better than no dystrophin.  A point that I recently raised in my last FDA meeting with the Dr. Janet Woodcock,  Dr. Bob Temple and Dr. Russell Katz.  It was my sense that this concept was well received by these regulatory officials at the FDA.  There was discussion that the dystrophin protein needed to be biologically active in order to change the slope of Duchenne disease progression. Recently at the Cold Springs Harbor conference, we saw slides stained for the presence of dystrophinglycan complex (presented in a similar way of the dystrophin fibers) of some of the boys who participated in the eteplirsen clinical trial. These slides clearly showed the presence of the dytrophinglycan complex and that the complex was actually in the sarcolemma. I was quite encouraged that to see that dystrophin binds with other proteins it is supposed to and is in the proper place in the cell and not just floating around in the cytoplasm somewhere. I suspect that if the dystrophin was not functional it would not be able to form the complex. I have seen many boys in this clinical trial gain skills that they lost before taking eteplirsen. I have lived through Jett progressing and there is no doubt in my mind that the slope has changed.


So in my mind – we have a working biological model, Becker muscular dystrophy. Sarepta’s trial suggests some translation from making a truncated dystrophin to the degree of stabilized ambulation at 74 weeks providing a functional model. And supportive evidence that the dystrophin which is produced is engaging with other proteins to form a complex in the appropriate place in the cell gives demonstrates the histological model.


Is it possible that my prayers are coming true?  Could exon skipping, eteplirsen, turn Jett’s deadly Duchenne into a Becker muscular dystrophy?  I would speculate that much would depend on how much functional muscle he has left…I would further speculate that because his heart is still beating, he is still breathing – he is still enjoying his life, and because he doesn’t expect to “gain” the ability to walk again – that yes, the chance to have a Becker type dystrophy is acceptable to him (as he has verbalized)  and just maybe some of my prayers are being answered, again, all speculative.


The one thing that is clear to me that the dystrophin produced in this trial is likely functional but more importantly that dystrophin is reasonably likely to predict clinical benefit in Duchenne patients and should serve as a surrogate endpoint for accelerated approval.

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