Cancer treatment can be painfully limited. The gold standard chemotherapy works by killing cancer cells, but it also destroys some healthy cells.
Fortunately, Rakovina Therapeutics Inc (TSX-V:RKV) is working to revolutionize how cancer is treated by developing new treatments based on novel DNA-damage response (DDR) technologies.
DDR defects can allow cancer to develop, but those tumors become heavily reliant on alternate DNA repair systems providing opportunities to develop targeted therapies.
In a nutshell, Rakovina’s DNA-damage response inhibitor (DDRi) agents target these alternate systems to kill cancer cells, while sparing normal cells in a process known as “synthetic lethality.” Put another way, Rakovina is developing precision medicines that selectively target and kill cancer cells.
The first-generation DDRis are called PARP inhibitors, and they have become important in the treatment of breast, ovarian and prostate cancer. In short, PARP helps damaged cells to repair themselves. Therefore, as a cancer treatment PARP inhibitors stop PARP from doing its repair work in cancer cells, allowing the cancer cells to die.
“Over the past several decades, we’ve made progress in treating many cancers. Unfortunately, tumors eventually become resistant to treatment, so continued innovation is crucial. The first cancer treatments – chemotherapy and radiation – are designed to kill cancer cells through DNA damage,” Rakovina Therapeutics executive chairman Jeffrey Bacha told Proactive.
“It’s new knowledge about the mechanisms of DNA damage and DNA damage response that Rakovina Therapeutics is exploiting. This offers opportunities to overcome treatment resistance and develop new, safer treatment paradigms that are personalized to patients.”
Bacha has 25 years of street cred in the pharma industry both on the research and corporate side. He is the inventor on several issued and pending patents. He is also the founder and CEO of Edison Oncology which has a portfolio of promising late-stage assets.
Bacha started out in a research lab with a biophysics degree from the University of California but has since put his MBA degree to use on the business side.
“I spent time in a research lab, but we all figured out quickly that it would be safer if I was behind a desk,” he quipped.
The dream team
In 2020, Bacha sold Edison Oncology’s kt-2000 series to establish Rakovina. He roped in DNA damage and repair expert Dr Mads Daugaard as a co-founder and chief scientific officer at Rakovina.
The hallmark of the Bacha-Daugaard team is its great ability to brainstorm esoteric ideas, flesh them out and then advance them to the point of creating a breakthrough transformation.
“While talking about DNA damage, we brainstormed the possibility of taking kt-2000, adding other assets and creating a new company that would focus on DNA damage response and work within Mads’ lab at the University of British Columbia (UBC) to establish a lead optimization engine,” said Bacha.
Prior to starting Edison Oncology, Bacha co-founded Kintara Therapeutics, which was formerly known as DelMar Pharmaceuticals.
“I met Jeff in 2012, through DelMar,” said Daugaard, who has helped the world decode repair systems in cancer.
Mads Daugaard, co-founder and chief scientific officer at Rakovina
Daugaard's research has been published in Nature and Cell scientific journals and he is an expert on drugs targeting DNA integrity and a type of DNA repair called homologous recombination. He received the Robert J Arceci Innovation Award from the St. Baldrick’s Foundation in 2019 and the Prostate Cancer Canada Rising Star Award in 2014.
“It’s the quality of science that is driving our progress. The team assembled around Rakovina from the scientific leadership to the boardroom has done this before,” said Bacha.
Blockbuster kt-3000
Rakovina’s kt-3000 series is designed to defeat treatment resistance by simultaneously inhibiting two different DNA repair mechanisms, one of them being Poly-ADP ribose polymerase (PARP) inhibitor activity.
Rakovina’s kt-3000 type molecule is bifunctional, able to inhibit PARP and also inhibit another enzyme called histone deacetylases (HDACs) at the same time.
“That combination of inhibition has a potent effect on cells that tend to replicate fast — or a lot — like cancer cells,” said Daugaard. “Therefore, it’s a molecule that could potentially really help patients.”
The million-dollar question: Does Rakovina have a blockbuster dual-function DDRi that can overcome resistance to PARP inhibition?
Daugaard has a short answer: “Yes, I think we do.”
Rakovina is targeting an investigational new drug (IND) application for its lead candidate in early 2024. “We are currently working to selecting the final clinical candidate from a series of promising leads,” said Daugaard.
kt-3000 in Ewing sarcoma
Rakovina recently shared positive research results at the American Association of Cancer Research meeting, in Orlando. Rakovina showed its kt-3000 lead candidate exhibited potent activity against both PARP and HDAC and the ability to overcome treatment resistance when compared to a Food and Drug Administration (FDA) approved PARP inhibitor.
The Vancouver company has received funding from the NRC-IRAP for kt-3000 as a treatment for Ewing sarcoma, a rare bone and soft tissue cancer that occurs in children and young adults.
Rakovina was also invited to join the C$1.3 million Ewing sarcoma research program funded by St. Baldrick’s Foundation. Professor Daugaard is a principal researcher in the project with Professor Paul Sorensen at the University of British Columbia.
Significantly, studies in mice have shown that the lead compound reduced lung metastases in mice inoculated with Ewing sarcoma tumor cells.
Daugaard noted that Ewing sarcomas were “very, very sensitive to kt-3000 type molecules.”
“It has potential in healing treatment-resistant tumors, particularly in the recurrent disease setting for Ewing sarcoma and major cancers such as breast and ovarian cancer that are resistant to FDA-approved PARP inhibitors,” said Daugaard.
“There are limited treatment options for Ewing sarcoma patients, especially in cases where the tumor has recurred after initial chemotherapy and radiation — the five-year survival is abysmal. We believe we can do something there,” said Bacha.
Other than Ewing's sarcoma, Rakovina believes the drug will help patients with adult tumors, including in the $6 billion ovarian cancer market.
“That's our end goal. By focusing initially on a rare childhood tumor, we see opportunities for fast tracking the review and accelerating approval through the FDA,” said Bacha.
“The US has a voucher which is an incentive for drug developers focusing on rare childhood cancers that are small markets. But when you get approval, you win a voucher which is like a golden ticket.”
The voucher entitles the holder to ask the FDA for priority review of a drug application. That could shorten the review process to six months from the standard 10 months. Retrophin Inc sold a priority-review voucher to French drug maker Sanofi SA for $245 million.
“It lets you apply the voucher to your next drug development program, and you go to the front of the line for the FDA review,” said Bacha.
The kt-2000 advantage
Meanwhile, Rakovina’s kt-2000 series of compounds are similar to approved PARP inhibitors.
“We are aiming to improve the way it can penetrate the central nervous system and move across the blood brain barrier,” said Daugaard.
“There are limitations in the approved PARP inhibitors, so they function poorly in brain cancers, and cancers that have metastasized to that environment. That's what we are trying to overcome with kt-2000.”
PARP inhibitors are the first DDR blockbusters with multiple FDA-approved products likely to exceed $1 billion in yearly sales, according to Rakovina.
Dual activity kt-4000
Meanwhile, Rakovina’s kt-4000 lead candidates release a potent methylation agent causing damage to a tumor cell’s DNA, while also inhibiting DNA-damage repair mechanisms leading to cancer cell death.
“kt-4000 has dual activity compounds, but instead of inhibiting each stack, in addition to PARP enzymes, kt-4000 has a DNA alkylating function. It creates DNA damage at the same time as it is inhibiting PARP,” said Daugaard.
“That's a different way to improve the effect of PARP inhibitors that we predict will have a huge impact on cancers.”
Multiple shots on goal
Rakovina hopes to catch Wall Street’s eye with its deep oncology pipeline.
“When we were putting the company together, we ensured that Rakovina would have a deep pipeline with multiple opportunities, partly to overcome the risk of drug development,” said Bacha.
“So, we have multiple shots on goal, but we're also seeing that the existing FDA-approved PARP inhibitors aimed at types of ovarian, breast, prostate and pancreatic cancer have limitations.”
When Bacha deliberated on what assets to bring into Rakovina, his team probed the limitations from different angles.
“Each of our programs come at those limitations from a different angle so we're building on the success of important therapies, while targeting ways to improve the patient outcomes by overcoming those limitations,” said Bacha.
Rakovina is on track to hit near-term milestones as it moves a lead molecule into formal pre-IND studies and starts human clinical trials with its kt-3000 lead molecule.
Finding blockbuster drugs that could work in oncology from scratch is a high-stakes effort which could spell massive financial returns for Rakovina. With fierce competition for good assets, Big Pharma is likely to jump at the chance to partner up with the Canadian company.
Contact the author Uttara Choudhury at uttara@proactiveinvestors.com
Follow her on Twitter: @UttaraProactive