The PRMT5 Edge: Every Uncertainty Presents an Opportunity

THE COWEN INSIGHT

First-gen SAM and substrate competitive PRMT5 inhibitors had disappointing efficacy and toxicity. Newer MTA cooperative inhibitors are more promising, offering broader therapeutic windows, selectivity to tumor cells, and brain penetration.

THE NEW WAVE OF (MTA) COOPERATIVE INHIBITORS

Protein arginine methyltransferase 5 (PRMT5) is an epigenetic regulator with an increasingly recognized role in the progression of multiple cancers. As an emerging target in drug development, PRMT5 is still very much an early story in the clinical pipeline. First-generation SAM competitive inhibitors and substrate competitive PRMT5 inhibitors suffered from limited efficacy and dose-limiting toxicities in early clinical trials.

Thankfully, a new wave of methylthioadenosine (MTA) cooperative inhibitors that target MTAPnull tumors with enhanced selectivity and potentially differentiated profiles leads us to be cautiously optimistic for the class. This class can unlock a slew of new opportunities in cancers that need new therapeutic modalities. The next 6-18 months will shepherd in a much clearer outlook on whether this potential will be realized.

KEY DIFFERENTIATORS: IMPROVED THERAPEUTIC WINDOWS & BRAIN PENETRANCE

We believe the future of this class of drugs will hinge on differentiated mechanisms, improved therapeutic windows, and unique properties such as brain penetrance. Combinations with other agents have also demonstrated encouraging evidence of synergy, including with KRAS inhibitors.

Depending on how broadly effective these PRMT5 inhibitors turn out to be, it is possible for multiple candidates to occupy somewhat non-overlapping treatment niches such as NSCLC, GBM, GI tumors, and other solid cancers.

WHAT TO WATCH

1. Given disappointing efficacy & toxicity, there is less reason to be optimistic about SAM competitive inhibitors compared to MTA cooperative inhibitors, which have shown signs of offering broader therapeutic windows, selectivity to tumor cells, and brain penetration.
2. The next 6-8 months will be crucial in determining the potential of this new wave of MRA Inhibitors.
3. Of the various drugs in development, broad application is limited, while multiple candidates target specific tumors such as NSCLC, GBM, GI tumors, and other solid cancers.

In our full report, we provide an overview of the biology of PRMT5, its emerging role as an oncogene in multiple cancers, the major differentiating features of various inhibitors in clinical development, including new MTA cooperative drugs, key preclinical and clinical data to date, and the overall competitive landscape.

We also highlight key upcoming catalysts that we believe will provide greater visibility on the prospects of this space. Our research includes a propriety analysis of available scientific and medical literature, one-on-one meetings with management, and consultant interviews with physicians who have served on the PRMT5 clinical trials.