Mr. Kim Oishi reports

RAKOVINA THERAPEUTICS AND VARIATIONAL AI ADVANCE BRAIN-PENETRANT ATR PROGRAM TOWARD DEVELOPMENT CANDIDATE SELECTION

Rakovina Therapeutics Inc. has made significant preclinical progress in its kt-5000AI program, a collaboration with Vancouver-based Variational AI Inc. focused on the discovery and development of novel, brain-penetrant inhibitors of ataxia telangiectasia and Rad3-related protein kinase (ATR).

Rakovina has advanced the program from target specification through lead generation and five cycles of iterative lead optimization in approximately two years, using Variational AI's Enki generative AI (artificial intelligence) platform together with focused experimental validation.

The program has progressed from target specification to an advanced lead-optimization stage in approximately two years, with 122 compounds synthesized program-wide and direct external discovery expenditure of approximately $1-million (U.S.). By comparison, a conventional program to the same stage would typically synthesize 600 to 1,700 compounds over roughly 4.5 years at a modelled direct external cost of $7.6-million (U.S.), demonstrating the potential for AI-enabled drug discovery to compress timelines and concentrate capital on experiments designed to generate decision-enabling data.

"ATR is one of the best-validated targets in the DNA damage response. Eight ATR inhibitors have entered the clinic, and none of them reaches the brain at levels that could support treating CNS [central nervous system] tumours or brain metastases," said Dr. Mads Daugaard, president and chief scientific officer of Rakovina Therapeutics. "That is not an accident of chemistry; the hinge-binding features that make these molecules potent are the same features that keep them out of the brain. Patients with glioblastoma, medulloblastoma and brain metastases from breast, lung and melanoma have no access to this class of medicine, and radiation, the standard of care for these tumours, is exactly the setting where ATR inhibition should add the most. Brain penetration was therefore the defining requirement of the kt-5000AI program from day one. We now have multiple compounds demonstrating the potency, selectivity, metabolic stability and CNS-oriented properties required to pursue a differentiated, brain-penetrant ATR program. Our work with Variational AI has demonstrated that generative AI can help us explore novel chemical space while optimizing the properties that matter most."

"Enki compressed hit-finding/ID and hit-to-lead into a single generative AI design cycle: 35 compounds made, four IP-clear lead series and a brain-penetrant compound in the first round," said Handol Kim, co-founder and chief executive officer of Variational AI. "From there, with each design-make-test-analyze (DMTA) cycle, the program's own experimental results were fed back into the Enki model, so every round of optimization started from better molecules than the last. The lead optimization campaign ran five cycles with only 87 compounds synthesized to reach subnanomolar potency, efflux ratios near unity and a 10-fold gain in metabolic stability. Typical lead optimization campaigns require tens to over 100 DMTA cycles generating thousands of compounds that do not work."

"For a company like Rakovina, AI is how we take cost and time out of drug discovery, and that is a strategic advantage, not an accounting exercise," said Kim Oishi, chief executive officer of Rakovina Therapeutics. "Instead of synthesizing and testing more than a thousand compounds over four or five years, Enki designed molecules that already satisfied the full target product profile, so we made 122 and spent about $1-million (U.S.) of direct external capital to reach candidate ready in roughly two years. Our cost per compound is in line with conventional rates; the saving comes from making far fewer molecules and from getting decision-enabling data in weeks rather than months. That is what allows an emerging biotechnology company to advance a program and to keep more of the value with our shareholders."

Building a differentiated ATR asset around brain penetration

ATR is a central regulator of the DNA damage response and an important vulnerability in tumours characterized by elevated replication stress and DNA-repair defects. While several ATR inhibitors have entered clinical development, none has been shown to reach the brain at levels that would support the treatment of CNS tumours. Rakovina and Variational AI established CNS penetration as a core design requirement from the outset of the kt-5000AI campaign.

The initial campaign produced multiple novel lead series. In pharmacokinetic studies in mice, a first-generation compound reached levels in brain tissue equivalent to those in plasma. Subsequent optimization has focused on transferring this CNS-penetrant property into increasingly potent and developable chemical series.

Multiple indicators of a developable drug profile

The kt-5000AI program has progressed through successive design-make-test-analyze cycles, with resulting compounds demonstrating:

• Potent ATR inhibition: multiple optimized compounds reaching single-digit nanomolar and subnanomolar potency in a qualified biochemical assay;
• Strong selectivity: substantial selectivity over other PIKK-family members such as ATM, DNA-PK, PI3Kalpha and mTOR;
• Improved metabolic stability: intrinsic clearance substantially improved through lead optimization;
• Favourable permeability and efflux: apparent permeability consistent with CNS drug-discovery objectives and efflux ratios approaching unity;
• CNS exposure: brain penetration established in first-generation compounds within the program's novel chemical space; studies to characterize CNS exposure in the optimized series are continuing;
• In vivo anti-tumour activity: an earlier kt-5000AI compound demonstrated tumour-growth control comparable with the clinical-stage ATR inhibitor ceralasertib in a prostate cancer xenograft model while maintaining favourable tolerability observations.

These findings build upon data previously presented by Rakovina and its collaborators at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics 2025, the Society for Neuro-Oncology 2025 annual meeting, and the 2026 AACR (American Association for Cancer Research) annual meeting.

Advancing toward development -- candidate selection

The kt-5000AI program remains in preclinical development, with lead optimization continuing through the end of 2026.

Planned work includes:

• Selection of lead and backup compounds;
• Expanded pharmacokinetic characterization;
• Formulation and solubility studies;
• Safety and metabolic profiling;
• Scale-up;
• Other studies required to support IND-enabling development.

The current results represent preclinical drug-discovery and development progress and do not establish clinical efficacy or safety in humans. kt-5000AI has not entered clinical trials, and a final development candidate has not yet been formally nominated.

Rakovina believes the combination of potent and selective ATR inhibition, CNS-oriented drug properties, demonstrated preclinical activity, and multiple optimized chemical series provides a strong foundation for continued development and potential pharmaceutical partnering.

Joint webinar

Rakovina will host a joint webinar with Variational AI on Nov. 5, at 9:30 a.m. PST to discuss the kt-5000AI collaboration and the program's progress to date, including the results described in the case study. The webinar will feature Dr. Daugaard, president and chief scientific officer of Rakovina Therapeutics, and Mr. Kim, co-founder and chief executive officer of Variational AI.

About the kt-5000AI program

Rakovina's kt-5000AI program is focused on the discovery and preclinical development of next-generation ATR inhibitors for cancers associated with DNA damage response vulnerabilities, including tumours affecting the CNS.

The program is being advanced with Variational AI using the Enki generative AI platform. The collaboration combines AI-enabled molecular design, experimental validation and iterative lead optimization to identify novel compounds with optimized potency, selectivity, pharmacokinetic and CNS-penetrant properties. Rakovina retains control over compound selection and development strategy.

About Rakovina Therapeutics Inc.

Rakovina Therapeutics is a biopharmaceutical research company focused on the development of innovative cancer treatments. Rakovina's work is based on unique technologies for targeting the DNA damage response powered by artificial intelligence (AI) using validated, proprietary platforms. By using AI, Rakovina can review and optimize drug candidates at a much greater pace than ever before.

The company has established a pipeline of distinctive DNA damage response inhibitors with the goal of advancing one or more drug candidates into human clinical trials in collaboration with pharmaceutical partners.

We seek Safe Harbor.