Some companies have all the luck. Some have all the pain. In this case, Summit Therapeutics’s collapse today on news that its utrophin modulator ezutromid showed no benefit in Duchenne muscular dystrophy (DMD) at 48 weeks came in sharp contrast to the lift seen last week for its partner Sarepta, which has moved on to gene therapy to address the degenerative condition.
It was good fortune for Sarepta that it had three success stories in its gene therapy trial to talk about last week, or else it could have been at risk of being pulled down on the ezutromid news. Summit, meanwhile, has pivoted back to its anti-infective pipeline, and will need to work out how to stretch its £28m ($36m) cash pile to key catalysts for its Clostridium difficile treatment ridinilazole.
On further review
Summit shares fell 80% in London trading today – a far cry from the lift they got in September 2016 when the group signed ezutromid European rights to the DMD leader, Sarepta, as that company went on a business development rampage following US approval of Exondys 51.
Summit then saw further progress with 24-week data from a phase II trial showing that ezutromid reduced muscle damage in patients as measured by the production of developmental myosin, a sign that by increasing utrophin production the disease process could be slowed (DMD-day for investors, January 26, 2018).
The hope was that utrophin could be a functional replacement for dystrophin, the muscle-building protein complex that is absent or greatly diminished in DMD patients because of gene mutations. Furthermore, ezutromid was seen as something that could be used broadly in DMD patients, as opposed to the exon-skipping approach of Sarepta's approved DMD therapy, Exondys 51, which focuses on a specific mutation to improve dystrophin production.
At 48 weeks, however, the data with ezutromid were not so promising, and Summit said today that the trial had missed its primary and secondary endpoints.
The primaries were improvements in muscle mass in the calf and thigh as measured by magnetic resonance imaging, and ezutromid plasma concentrations. The secondary endpoints were measures of utrophin and developmental myosin production, the latter of which was touted at 24 weeks. Very little detail was provided about the data.
The approval of Exondys 51 was controversial because that project showed only the barest amount of dystrophin production in some patients. However, the US FDA’s posture since has been less generous, with the former new drugs office chief John Jenkins having clearly stated that Exondys is not a good model; presumably the ezutromid trial investigators looked at the data and saw no hope of getting through the agency in the post-Exondys world.
Before you try gene therapy, try ...
In any case, the investment case for Sarepta has shifted somewhat away from its oligonucleotides and small-molecule modulators to the gene therapy AAVrh74.MHCK7.micro-dystrophin, which caused the company's shares to surge 37% last week (Sarepta investors party like it’s 2015, June 19, 2018).
The appeal of gene therapy is of course as a once-and-done treatment that could be applied to DMD patients broadly, rather than having a piecemeal approach of specific drugs for specific mutations – at a cost, of course. As a small-molecule agent that did not rely on exon-skipping, ezutromid had the potential to become a cheap alternative, or at least something patients could try first before progressing to gene therapy.
That did not come to pass. Still, there is some reason to believe that DMD specialists could come up with some treatments that will work without needing to test the financial tolerance of patients and payers as gene therapy will. Sarepta’s lead pipeline candidates for now are golodirsen and casimersen, which focus on mutations at exons 53 and 45; Wave Life Sciences hopes to put an exon-51 skipping agent into competition with Exondys.
And, of course, do not forget the big pharmas Roche and Pfizer, which have the myostatin inhibitors RG-6206 and domagrozumab respectively in phase III – these do not appear to be mutation specific.
For the sake of stretched payer finances, not to mention families who will be expected to share the cost, it should be hoped that less-expensive alternatives can make gene therapy the exception, not the rule. Ezutromid will not be the answer, but the sector looks like it will keep on trying.