A €1.1B deal struck this week between Novartis and the UK-based company Artios Pharma forges a new path for cancer drugs that target the DNA repair systems of our cells.
As part of the deal — which consists of €17M upfront and up to €1.1B in undisclosed milestone payments — Novartis and Artios Pharma will collaborate to discover up to three target proteins involved in the repair of DNA. The team will specifically be looking for targets of DNA damage response (DDR) inhibitors, a class of cancer drugs that block DNA repair.
The goal of Novartis is to block these DDR targets to prevent resistance against targeted radioligand therapies — which break the DNA of tumor cells with radiation — by disrupting the repair of the damaged DNA.
“This collaboration expands the reach of our discovery platform, leveraging our DDR expertise and target knowledge to enhance the potential of radioligand therapies,” stated Artios’ CEO Niall Martin.
Drugs targeting DNA repair have been heralded as a game-changer for multiple cancers compared to traditional therapies, promising more precisely targeted treatments, better tolerance, and improved survival for patients. They exploit the imperfect DNA repair machinery found in many cancer cells, which makes them heavily rely on specific remaining repair pathways to survive and reproduce. Blocking these pathways leads to DNA damage building up and ultimately cancer cell death, while the healthy cells that retain alternative DDR pathways survive.
One of the most prominent DDR inhibitors is Lynparza, a blockbuster drug approved since 2014 that blocks a protein called PARP. Lynparza was developed in its early stages by the firm KuDOS Pharmaceuticals, which was led by Artios’ current CEO until its acquisition by AstraZeneca in 2005.
Targets of newer DDR blockers in development include two enzymes known as ATM and DNA-PK as well as the ATR protein. Merck KGaA is currently pushing ahead several ATR inhibitors in phase I. Artios’ existing pipeline — which isn’t part of the Novartis 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 clinical trials this year.
Discovering new DDR targets is the main push of many recent deals in the field. In January this year, for instance, a colossal collaboration worth up to €5.7B was struck between Artios and Merck KGaA to explore new DDR targets. Such an enormous potential windfall for Artios demonstrated hitherto unseen levels of support for the emerging DDR inhibitor 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,” said Martin.
Other efforts to uncover new DDR targets include a €10M seed round raised last year by the Swiss startup FoRx Therapeutics along with big pharma collaborations in North America including Bristol Myers Squibb with the Canadian firm Repare Therapeutics, and GSK with the US company IDEAYA.
“The DDR class is an expanding therapeutic field with 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.
Another big push in the DDR field focuses on stopping tumors from becoming resistant to common DDR inhibitors such as PARP inhibitors. In January, 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.
Meanwhile, the French biotech Onxeo aims to smash tumor resistance to PARP inhibitors with a drug that misdirects the tumor cell’s DNA repair machinery rather than directly blocking it. According to interim results from a phase Ib trial in November, the drug combined with chemotherapy 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 movement forwards 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,” Edvardsen 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.”
This is an updated version of an article published on 19/01/2021
Cover image from Elena Resko