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The Path We’re On: Many Challenges, but Ultimately a Drug

The Challenges of Drug Development

The U.S. Food and Drug Administration’s (FDA) gold standard is that marketing approval requires sponsors of candidate therapeutics to provide “substantial evidence” that the drug or biologic is safe and effective. As we’ve seen subsequent to the recent marketing approvals of Exondys 51 and Spinraza, convincing payers that an expensive rare disease drug is effective is not an inconsequential hurdle. Programs for myotonic dystrophy (DM) need to proceed with both the regulators and the payers in mind.

Yet the odds of success for newly-launched drug development programs are poor—even candidate therapies reaching phase 2 trials have success rates as low as 18% (Nat Rev Drug Discov 10, 328–29, 2011).  

The Only Path Forward

In the face of the challenges facing drug development, the only strategy to achieve safe and effective therapies for DM is to encourage the launch of multiple early-stage drug discovery and development programs and insist upon a substantial level of effect of the candidate therapeutic at each stage of development.

MDF regularly meets with pharmaceutical and biotechnology companies (ten companies in just the last few months) to receive program updates and to make the case that DM is “tractable” and thus attractive as a target for therapy development. As more precompetitive space tools (registries, biomarkers, early stage endpoints, registration endpoints) are put into place for DM, the “selling” our disease to industry becomes easier.

First Steps for Small Molecule Drugs

Academic-corporate partnerships are very effective in early stage drug development programs—the academics bring mechanistic knowledge and experience with cell lines and animal models that can provide indications of target engagement, modulation and initial proof of concept. The companies bring to the table substantial resources (e.g., compound libraries, funds for subsequent clinical trials) and experience (e.g., assay design, construction of target product profiles) that are essential if a program is to move beyond publications.

Pfizer just reported out the development and initial use of a novel flow cytometry-based high throughput assay to identify small molecules that up-regulate MBNL1.  This effort, involving corporate and academic investigators, developed a cell-based reporter assay and identified positive controls for MBNL1 up-regulation from a library of established epigenetic modulators. The team then adapted the assay to a 384-well format and screened the Pfizer Chemogenomics Library (2,753 compounds) and an FDA-approved drug set. After evaluating screening hits, two compounds (vorinostat and ISOX) emerged and were validated as increasing MBNL and partially rescuing splicing defects in DM1 patient fibroblasts. 

Vorinostat and ISOX are generic HDAC inhibitors—while unlikely drug candidates themselves, their identification in this early stage discovery program validates the screening approach and supports pursuit of other pathways that regulation MBNL1 seen in the Pfizer Chemogenomics Library screen. 

More Shots on Goal

Traditional small molecule discovery and development efforts by the Pfizer team and their colleagues using the screen developed and targets identified here represent an important step toward a novel therapy for DM. This program complements other known DM programs. Informed efforts such as these, backed by resources and an emerging path toward drug approval, give us the best opportunity for marketed therapies for DM. The long and arduous path to a drug can only be seen through to completion by encouraging many targeted, high-caliber programs to commit to and stay the course for DM.


A Flow Cytometry-Based Screen Identifies MBNL1 Modulators that Rescue Splicing Defects in Myotonic Dystrophy Type I.
Zhang F, Bodycombe NE, Haskell KM, Sun YL, Wang ET, Morris CA, Jones LH, Wood LD, Pletcher MT.
Hum Mol Genet. 2017 May 23. doi: 10.1093/hmg/ddx190. [Epub ahead of print]





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