Turning Point Therapeutics is ‘Cycling’ Toward a Precise Cure for Cancer
Dr. Athena Countouriotis’ office, located in the sunny confines of San Diego, is covered with pictures from her kids. A pediatric oncologist by training, she is a tour-de-force in the pharmaceutical and biotechnology industries, while simultaneously filling the computer screen with an undeniable warmth.
After experiencing the early loss of her grandfather to lung cancer, the path to medicine seemed like a natural progression.
“I wanted to be a doctor when I was five. And I never changed the course of my path,” Countouriotis said.
Countouriotis is the CEO and president of Turning Point Therapeutics, a San Diego-based precision oncology company focused on the creation of tyrosine kinase inhibitors (TKIs) to target specific mutated cancers. Turning Point, which went public two years ago, is now worth 5.9 billion – exponentially growing from its initial value of 560 million in 2019.
Their lead drug candidate, Repotrectinib, is currently in Phase I/II clinical studies to target non-small cell lung cancer (NSCLC) in patients with a ROS1 or NTRK metastatic mutation. Several other TKIs, including TPX-0022 and TPX-0046, are similarly in development as promising therapeutic candidates for MET and RET metastatic mutations in solid tumors.
Today, lung cancers are the leading cause of cancer-related death worldwide, with NSCLCs comprising most cases. These NSCLCs form a diverse group of malignancies, with potential activating mutations in EGFR, ROS1, TRK, ALK, MET, and RET receptor tyrosine kinases.
Across various forms of cancer, receptor tyrosine kinases are a major group of master signaling proteins. When altered, these proteins can be responsible for the unchecked cell proliferation characteristic of metastatic tumors.
Kinases generally work by incorporating ATP molecules into their ATP binding pockets – visually similar to a Pac-Man opening his mouth to consume his lunch. By blocking the ATP binding pocket (or, sealing off Pac-Man’s mouth), the kinase can be inhibited to stop cancer growth. This mechanism was the genesis for first-generation TKIs.
However, cancers quickly evolved to circumvent these first-generation TKIs. Mutations in the structure of the kinase’s ATP binding pocket can cause steric hindrance, subsequently blocking the TKI from entering the binding pocket and interfering with the kinase.
“The company (TPTX) was founded by a husband and wife – the wife was a chemist by training. She had developed some of the first and second-generation ALK inhibitors that are currently on the market,” Countouriotis said. “If you went back and looked at the initial way that this company was described, it really was looking at the unique chemistry that would be able to overcome treatment resistance. That’s what was lacking with these other drugs. Unfortunately, over time, the tumors mutated, the patients were no longer going to respond to those drugs, and she wanted to be able to develop something that could accommodate them.”
Turning Point’s specialization is the synthesis and optimization of next-generation tyrosine kinase inhibitors, in the form of carefully designed macrocycles. Macrocycles are cyclic rings representing a large class of promising drug molecules. Turning Point’s Repotrectinib is a small, compact 3D macrocycle devised to potently and selectively inhibit certain mutated kinases, including ROS1, TRK and ALK.
“The way that our molecules were designed, was specifically to be able to avoid that steric interference,” Countouriotis said. “The second component is for them to be incredibly potent, and selective. Selectivity is important with kinase inhibitors, because you want to make sure that the patient does not have as much off-target toxicity if they don’t have to.”
In recent studies, Repotrectinib demonstrated a 91-93% objective response rate in patients with ROS1 positive NSCLCs without former exposure to TKIs, with a 40-67% objective response rate in patients with prior TKI exposure. Interestingly, the molecule has also demonstrated activity in the central nervous system, suggesting potential penetrative abilities that other bulkier molecules may not have.
With these promising results, the drug was designated as an FDA Breakthrough Therapy in 2020. For Countouriotis and the rest of the Turning Point team, this represented a highly exciting moment.
“We were the first tyrosine kinase inhibitor to get Breakthrough Therapy designation in a space where there is already one tyrosine kinase inhibitor approved. It gives us potentially a faster path, and definitely more conversations that we can have now, with the FDA. That’s the biggest benefit of getting it,” she said.
Acquired resistance, however, is still something to keep in mind.
“Inevitably, the tumor will mutate. We always say that there will be some likely resistance coming off of Repotrectinib,” Countouriotis said. “So, we evaluate patients coming in at baseline, and then at the end of their second cycle (after two months of treatment). We look at their blood samples to see if they have any emerging resistant mutations. The idea would be, based on that information, would we ever build a backup molecule or another molecule to help overcome that resistance?”
Likewise, the team has discussed the possibility of combination therapy with multiple next-generation TKIs – of which the first study will begin in the middle of this year. Here, the team is looking to concurrently inhibit several downstream kinase pathways to more fully address the issue of resistance.
While Turning Point is known for its macrocyclic approach to the precise targeting of cancers, Countouriotis acknowledges the enormous growth the company has experienced in the past few years – and the potential for expansion into complementary areas.
“Before we took the company public, just two years ago, we had one drug, and the valuation of the company was significantly lower than where it is now. We’re about to bring our fourth drug candidate to the clinic,” Countouriotis said. “I think as we grow, though, we’re looking at opportunities for our Discovery Group, to continue to focus there.”
For Countouriotis and the team at Turning Point, this cross-disciplinary synergy between discovery, translation, and implementation is a key part of the company’s driving values. Cancer therapeutics is a competitive space, but space with a monumentally unfulfilled medical need, nonetheless.
“There is nothing that brings me more pride than the conversations I’ve had over the years with patients who have actually benefitted from these drugs,” Countouriotis said. “All we’re doing it for, I hope, is to benefit patients.”
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