$SRPT $FGEN @douglas_ingram Evolving DMD science will quickly force companies to make hard decisions, so I wanted to lay out some of the issues in a twit longer.

$SRPT (the first of the two companies I believe will ultimately be a part of the combination therapy for muscular dystrophy) is currently on track to have 6 different types of therapy in the clinic:
1) First generation exon skippers--delivered into cells by PMOs.
2) Second generation exon skippers--delivered into cells by PPMOs.
3) Ezutromid (via Summit partnership)--daily pill hoped to generate production of Utrophin, which might act similarly to dystrophin.
4) Gene therapy--microdystrophin gene delivered by virus--program partnered with Children's Hospital
5) Gene therapy--also mycrodystrophin--program with Genethon.
6) Gene therapy--gene for galgt2, which might act similarly to dystrophin

SRPT faces hard strategic decisions. The six therapies must compete for company money, resources, and trial patients--and ultimately they cannot all co-exist in the marketplace. PPMO, if safe, will render PMO completely obsolete. However, any of the gene therapies has the capacity to render PPMO, PMO, and Ezutromid obsolete. How, then, does SRPT prioritize its strategy?

The greatest threat to SRPT making the proper decision is emotional: The company has concentrated for years on exon skipping. It will be very hard for @douglas_ingram to shut down years of work, even if the gene therapies quickly and conclusively make exon skipping obsolete. The time for that decision may come very soon. The first microdystrophin gene therapy is expected to begin its trial in October. It will infuse one patient (only one infusion is required) every two weeks. Each patient will be biopsied at 12 weeks. Therefore, 18 weeks from the start of the trial (approximately late February, 2018), SRPT will have biopsies from 3 patients. Jerry Mendell, who is running the trial, has, in more than one public forum, indicated he expects to know at that point if the therapy works.

So let's be clear: Mendell hopes that by as early as late February, 2018, SRPT will have a pretty good idea of whether their microdystrophin gene therapy will make all of their other programs and partnerships obsolete. Of note: in mice, that gene therapy restored 100% of function in the diaphragm and nearly 100% in skeletal muscle. That's light-years ahead of anything exon-skipping can do, or anything that is expected from ezutromid. If that happens, will @douglas_ingram continue to run trials for therapies that will be obsolete before they could ever be approved?

Now, there is more to curing MD than merely restoring dystrophin. Nearly everything that goes wrong in the body (cancer, heart disease, lung disease, etc) causes fibrosis which makes it worse. Muscular dystrophy is no exception. As disordered fibers build up in the boys' legs, they lose their last muscle function. Therefore, gene therapy will work best on the young (the microdystrophin trial has two cohorts, one for those under age-3, and another for 3-7), whose muscles have not already seen too much fibrosis. For older kids, gene therapy will help, but the restoration of waning function will require a second therapy which treats fibrosis. $FGEN is the only company working on such a therapy. Fibrogen's FG-3019 (Pamrevlumab) has already shown effectiveness in both IPF and pancreatic cancer in reducing fibrosis. It is currently conducting a DMD trial in non-ambulatory boys as well. If it proves effective (and I believe it will), Fibrogen will need to be paired with a SRPT therapy (likely Microdystrophin), and the together the two therapies will provide hope for DMD sufferers of every age.

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