Investors Up the Ante for Drugs Striking Cancer via DNA Repair

A colossal deal struck last month between Germany’s Merck KGaA and UK-based Artios Pharma is one of several highlighting soaring interest in cancer drugs that target the DNA repair systems of our cells.

The deal, potentially worth €5.7B, granted Merck optional rights to co-develop a class of cancer treatments called DNA damage response (DDR) inhibitor drugs. Merck took this gamble on drugs that haven’t yet reached clinical testing, demonstrating hitherto unseen levels of support for the emerging DDR inhibitor field.

Artios’ CEO Niall Martin — who was instrumental in developing the blockbuster DDR inhibitor drug Lynparza — told me the collaboration represents a great validation for the DNA damage response field.

Its multi-billion-dollar potential underscores the possible, future value which multinational pharma companies see in the field and its ability to revolutionize targeted treatment of cancer and deliver on the promise of precision medicine,” he said.

Drugs targeting DNA repair have been heralded as a game-changer for multiple cancers, promising more precisely targeted treatments, better tolerance, and improved survival for patients.

DDR inhibitors exploit the imperfect DNA repair machinery found in many cancer cells, which makes them rely on certain repair pathways to survive and proliferate. Blocking these pathways leads to DNA damage building up and ultimately cancer cell death, while the healthy cells that retain alternative DDR pathways survive.

Artios’ deal is among several recently struck in this expanding therapeutic field, which has the potential to become a key part of the standard of care for many cancers. These deals focus on ways to overcome the biggest challenges of the DNA repair field. For example, the ability of some tumors to become resistant to PARP inhibitors, which are a class of DDR inhibitors.

Earlier this month, the Hungarian startup Turbine nailed €5.7M in a pre-Series A round. The company uses computational simulations and artificial intelligence to discover drugs that can overcome resistance to PARP inhibitors.

The announcements from Artios and Turbine come after a number of deals seen throughout 2020 in the DNA repair space. In April, Merck’s venture capital arm M Ventures led a €10M seed round raised by the Swiss startup FoRx Therapeutics, which aims to target a wider range of cancers than can be reached by conventional DDR blockers.

In North America, US giant Bristol Myers Squibb struck a deal in May worth over €2.5B with the Canadian firm Repare Therapeutics to identify new targets for blocking tumor DNA repair. The month after, the big pharma GSK announced a €140M collaboration with the US company IDEAYA on three programs against new targets in the same field.

“The DDR class is an expanding therapeutic field with the potential to be a fundamental part of the standard of care in many cancer subtypes, alone or in combination with immunotherapy, chemotherapy, or radiotherapy,” said Andree Blaukat, Head of Merck’s translational innovation platform in oncology and immuno-oncology. 

Several DDR agents have entered the pipeline since AstraZeneca’s PARP inhibitor Lynparza was first approved in 2014 for ovarian cancer. Newer targets include two enzymes known as ATM and DNA-PK as well as the ATR protein. 

Merck is currently pushing ahead with an ATR inhibitor called berzosertib as an intravenous treatment for several solid tumors. Artios’ existing pipeline — which wasn’t included in the Merck deal — includes an ATR inhibitor and a first-in class drug for the emerging DDR target Pol theta. Both of the candidates are expected to enter the clinic this year. 

Meanwhile, French biotech Onxeo aims to smash tumor resistance to PARP inhibitors with its first-in-class drug AsiDNA, which acts as a DDR decoy rather than a direct blocker. The aim is to use it in combination with chemotherapy and PARP inhibitors. According to interim results from a phase Ib trial in November, the drug combination showed signs of controlling tumors where other treatments had failed. 

All of these DDR developments are taking place amid big clinical trial disruption caused by the Covid-19 pandemic, said Ruth Plummer, director of the Sir Bobby Robson Cancer Trials Centre in the UK.

The huge impact on the field from the Covid-19 pandemic is that worldwide trials recruitment has slowed, and even stopped in a number of centers, such that the timelines for all studies to complete has lengthened,” she told me.

In addition, many universities have had to stop laboratory science work, and many of the DDR inhibitors in development have come out of key academia and industry partnerships, so again there will have been a slowing to movements in the field.

Nonetheless, Klaus Edvardsen, Senior Vice President and Global Head Oncology Development at Merck, remains confident that the industry can ride out the storm.

Our most important objective remains ensuring the safety and wellbeing of the patients participating in our clinical trials, and continuity in treatment and care of these patients,” he told me.

“Overall, we have mitigated the impact of Covid-19 on our DDR research and development activities and are committed to our timelines, which remain on track.”

Image from Elena Resko

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