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Repare Therapeutics Inc. (NASDAQ:RPTX) uses the so-called synthetic lethality approach for precision drug development. There are pairs of genes called synthetic lethal gene pairs, and these cause apoptosis or cell death when both are inactivated. So, for example, ATM and ATR are a pair of SL genes, and when both are inactive, that results in cell death. In cancer cells, however, ATM is inactive but ATR is active, so the cells do not die.
Synthetic lethality is nothing new. A number of existing drugs use a form of SL. These include PARP inhibitors like Lynparza and Zejula. Here the inactivated gene is BRCA, while the target protein is PARP. These are approved drugs from big pharma, and they sell in billions of dollars.
What Repare is trying to do is to make this process more comprehensive. They have a huge library of such pairs of genes, and using a technology similar to CRISPR, their plan is to identify such synthetically lethal pairs, and then use small molecule drugs to target one gene from the pair. This is tumor-agnostic; no matter what type of cancer you have, if you have that particular genetic mutation, Repare’s small molecule drug can work on you.
This is a big idea, and big pharma has shown some interest. However, their phase 1 trial wasn’t as big a success as their theory makes it out to be. Here’s an excerpt from Evaluate reporting on partial data from AACR last year for lead candidate camonsertib or RP-3500:
Similarly failing to hit expectations was Repare, which claimed a meaningful clinical benefit with its ATR inhibitor RP-3500 in almost half of the 69 evaluable patients with cancers with synthetic lethal genomic alterations including CDK12, Brca and ATM mutations.
However, actual efficacy here amounted to just 12 partial responses, mostly seen in Brca1-mutated cancers. Though the data were early this 17% ORR fell well short of Stifel’s expectations of 36%, which would have been in line with Bayer’s rival ATR inhibitor BAY 1895344.
Moreover, the Bayer ORR figure comes specifically from 11 patients with ATM aberrations, where Repare’s RP-3500 could only manage an 8% ORR among 37 subjects. Given the activity signs in Brca mutants Stifel suggested the possibility of combining RP-3500 with Parp inhibition, but investors did not buy it: compared with Wednesday the stock is today off 20%.
The actual data is here. If you compare that data with the complete data announced this year – here – you can see that there has been some improvements, including one CR in an ovarian cancer patient. As management noted:
We see promising monotherapy data across tumor types, particularly in advanced ovarian cancer where 90% of patients had failed previous treatment with PARP inhibitors and platin based therapy. We are especially pleased with the 25% overall response observed, the clinical benefit rate of 75% and a median PFS of 35 weeks in this heavily pre-treated patient population with a growing unmet need. These findings, together with anticipated initial data of RP-3500 in combination with PARP inhibitors or gemcitabine expected in the second half of this year, will help us refine our development strategy for this potential best-in-class drug.
This is monotherapy; the company is now running a number of combo trials with various PARP inhibitors like niraparib and olaparib to see how RP-3500 works in tandem with these established drugs.
Financials
RPTX has a market cap of $621mn and a cash balance of $311mn. R&D expenses were $26.5 million for the three months ended March 31, 2022 and general and administrative expenses were $8.8 million. This gives them a very long cash runway, however, this is a phase 1 stage company, and as it moves to later stages, expenses will rise considerably.
Roche has a $1.3bn deal with Repare, with $125mn in upfront payment, for co-development and opt-in rights to camonsertib. In 2020, Bristol Myers Squibb paid $50mn upfront to a still nascent Repare for a share of the pipeline for a total deal valued at $3bn.
Bottom Line
Repare is doing very interesting science, but the market has a lot of reasons to be wary of the entire gene editing space. Yes, I will add this to a watchlist somewhere, but until I see a lot more clinical validation, I am going to stay away.
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