Sarepta Snaps Up Gene Therapy Approaches to DMD

Sarepta may have launched its first therapy for Duchenne muscular dystrophy in the US, but it is facing potential competition from a plethora of late-stage DMD therapies; it is backing research that could lead to new gene therapies able to treat most affected patients, rather than a subgroup of individuals with a particular gene mutation.

Sarepta Therapeutics Inc. has licensed rights to two gene therapy research programs underway at the Nationwide Children’s Hospital, Columbus, Ohio, adding new projects to its growing Duchenne muscular dystrophy pipeline to complement its recently launched lead DMD product Exondys 51 (eteplirsen).

Marketing a range of therapies for a specific disease or condition is a well-established strategy for pharmaceutical companies, particularly in a disease like DMD that is mediated by a number of different genetic mutations. “Given the complexities of Duchenne muscular dystrophy, we know that it is going to require multiple treatment approaches,” said Sarepta’s CEO Ed Kaye.

Of course, it’s even better to develop a new therapy that has the potential to be used in most patients with the condition, and that’s the promise of the two new gene therapy approaches to DMD that are the subject of the agreements between Sarepta and the Nationwide Children’s Hospital in Columbus, Ohio. In the first collaboration, hospital researcher Dr Paul Martin has developed a “surrogate gene” therapy approach aimed at upregulating the production of the muscle protein urotrophin, that can deputize for, or replace, the abnormal muscle protein dystrophin in DMD patients.

The approach uses the Galgt2 gene that encodes GalNAc transferase, an enzyme usually only found in neuromuscular junctions that upregulates urotrophin. Making it available throughout muscle fibers using a gene therapy approach could be beneficial in DMD patients. Sarepta expects this approach to enter the clinic this year. (Also see "J.P. Morgan Notebook Day 2: Bristol Humbled By Competition, Sanofi’s Sarilumab Ready For Review, Justifying Spinraza’s Price And More" - Scrip, 11 Jan, 2017.)

In its second deal with the Hospital, the Cambridge, Mass.-based biotech has entered into a research agreement involving the micro-dystrophin gene therapy program being developed at Nationwide by investigators Jerry Mendell and Louise Rodino-Klapac. Sarepta has taken an exclusive option to license the program. The research is being supported by the Parent Project Muscular Dystrophy (PPMD) that is providing $2.2m in funding, and other foundations and charities, and a Phase I/IIa trial is expected to start in late 2017.

The trial will involve the direct intramuscular injection of a recombinant adeno-associated virus containing a micro-dystrophin gene into a foot or small leg muscle. The large size of the dystrophin gene has hampered its use in gene therapy in the past, leading to the development of shortened genes that still express functional protein; some micro-dystrophin versions have not worked, and the identification of a functioning micro-dystrophin gene is thought key to this research avenue.

Trying to find a therapy or cure for DMD is a highly active research area for the pharmaceutical industry, with numerous approaches and types of compounds being evaluated, including monoclonal antibodies, exon-skipping antisense compounds and glucocorticoid receptor binders. Informa Pharma Intelligence’s database Biomedtracker lists more than a dozen projects in late-stage clinical studies, as shown below:

Selected Projects in Clinical Development for DMD

Source: Biomedtracker.

Project	Lead Company	Target	Phase of Development
deflazacort	Marathon Pharmaceuticals LLC	glucocorticoid receptor	NDA filed
Cabaletta (trehalose)	BioBlast Pharma ltd	mTOR/mTORC	III
Catena (idebenone)	Santhera Pharmaceuticals AG	free radicals	III
SRP-4045	Sarepta Therapeutics Inc.	dystrophin gene	III
SRP-4053	Sarepta Therapeutics Inc.	dystrophin gene	III
Translarna (ataluren)	PTC Therapeutics Inc.	RNA translation	III
tideglusib (AMO-02)	AMO Pharma Ltd.	glycogen synthase kinase 3	II
Ezutromid	Summit Therapeutics PLC	utrophin	II
pamrevlumab (FG-3019)	FibroGen Inc.	connective tissue growth factor	II
HT-100 (halofungine)	Akashi Therapeutics Inc.	collagen	II
NS-065 antisense	Nippon Shinyaku Co. Ltd.	dystrophin gene	II
PF-06252616	Pfizer Inc.	myostatin	II
Vasomera (PB1046)	PhaseBio Pharmaceuticals Inc.	vasoactive intestinal peptide receptor	II
vamorolone (VBP15)	ReveraGen BioPharma Inc.	glucocorticoid receptor	II

Combinations As Well

Last October, Sarepta entered into a collaboration with Summit Therapeutics plc to have commercialization rights to Summit’s utrophin modulator ezutromid in Europe, Turkey and the Commonwealth of Independent States (CIS), thus setting up the possibility that Sarepta and Summit could combine their two approaches to the treatment of DMD (Also see "Sarepta’s $852m Summit Collaboration Could Enable DMD Drug Combinations" - Scrip, 5 Oct, 2016.).