Repare Therapeutics: Fighting Cancer With Synthetic Lethality

Synthetic lethality provides a new opportunity in oncology drug development. First described by Calvin Bridges in 1922, synthetic lethality arises when deficiencies in a pair of genes occur simultaneously to result in cell death, but if that deficiency exists in only one gene, the cell will survive.

The company we are profiling today is a clinical-stage precision oncology company focused on synthetic lethality – Repare Therapeutics Inc. (RPTX).

The lead drug candidate is RP-3500, an oral inhibitor of ataxia telangiectasia and Rad3 related (ATR) kinase, a protein that helps repair damage to DNA. There is synthetic lethality relationship between ATR inhibition and ATM deficiency. ATM is one of the DNA repair genes. If the activity of ATR in cancer cells is blocked, then they would not be able to repair themselves and they will cease to grow.

A phase I/II trial of orally-administered RP-3500 alone or in combination with Pfizer’s Talazoparib (Talzenna), a PARP inhibitor, in patients with advanced solid tumors with ATR inhibitor-sensitizing mutations is ongoing.

Initial results are expected to be reported from the monotherapy arm of the trial in the second half of 2021.

Another clinical compound that merits mention is RP-6306, a PKMYT1 inhibitor, synthetic lethal in CCNE1 amplified, FBXW7 loss and tumors with other specific alterations.

A phase I clinical trial of RP-6306 in patients with recurrent tumors characterized by specific genomic alterations was initiated in May of this year. After completion of the phase I trial, the company intends to advance RP-6306, both as monotherapy and in combination with chemotherapies and other treatment modalities, into proof-of-concept studies in 2022.

The 4 approved PARP inhibitors namely AstraZeneca’s Lynparza, GlaxoSmithKline’s Zejula, Clovis Oncology’s Rubraca and Pfizer’s Talzenna are based on the concept of synthetic lethality.

The oncology medicine industry is thriving and profitable. According to a study published in the journal Nature, oncology therapeutics account for about 41% of the current blockbusters.

Targeting DNA damage repair using synthetic lethal strategies is a massive opportunity to build on the success of PARP inhibitors, according to Maria Koehler, Chief Medical Officer of Repare.

Collaboration:

The company has an exclusive, worldwide research collaboration with Bristol Myers Squibb (BMY) that was signed last May. Bristol Myers Squibb leverages Repare’s proprietary SNIPRx synthetic lethal discovery platform to identify multiple oncology drug candidates.

As part of the deal, Repare received $65 million upfront payment and is eligible to receive up to approximately $3 billion in milestone payments in addition to royalties.

Cash position:

Repare’s cash, restricted cash and marketable securities totaled $319.1 million as of March 31, 2021.

Canada-based Repare Therapeutics went public on the Nasdaq Global Select Market on June 19, 2020 under the ticker symbol “RPTX.”, offering its shares at a price of $20.00 each.

RPTX has traded in a range of $21.45 to $46.44 in the last 1 year. The stock closed Monday’s (Jun.21, 2021) trading at $34.61, up 1.73%.

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