The next generation of PARP inhibitors

Tilikum is a new biotechnology company, co-founded by Dr Alan Barge and Professor Mike Cohen, to develop the next generation of PARP inhibitors – drugs which specifically target genetically-defined subsets of common cancers.

PARP inhibitors treat cancers that have a failure in their ability to repair damage to their DNA. The best known of these kinds of cancer are those associated with the mutation of one of the BRCA genes. Patients with BRCA mutation have a very high (up to 50%) risk of developing a range of cancers, most commonly breast, ovarian, prostate and pancreatic cancer. Many women with BRCA mutations have their breasts and ovaries removed prophylactically.

PARP inhibitors, specifically kill tumours with DNA-repair failure, and have transformed the treatment of these cancers, dramatically prolonging survival without severe side effects, and have become the standard of care worldwide. The current market is estimated to be around $4.5B worldwide, growing to $8.5B by 2026.

Despite their huge clinical and commercial success, the current generation of PARP inhibitors have significant limitations. Many patients develop resistance to the drugs, and their tumours progress rapidly. The mechanisms for this are being understood at a molecular level. The biggest limitation of their use is the fact that they only work if a tumour already has a failure of DNA repair, so they are limited to small subsets of patients.

Tilikum is developing a genuinely novel new generation of PARP inhibitor, which targets PARP in a completely different way. By causing a conformational change in the structure of PARP, it ‘locks’ it onto DNA, preventing the DNA from being replicated, and is able to kill not just genetically-deficient cancer cells but others that are replicating rapidly. This will enable Tilikum to target other very aggressive subsets of cancer that are not treatable with the current generation of drugs. This has the potential to more than double the addressable population and size of the market.

Alan and Mike have assembled an impressive team of scientists to develop this unique drug and take it into clinical trials in the next two years. They are seeking to raise a Seed round of $14M to enable them to complete the chemistry, profile the drug in pre-clinical models and fresh human tumours and develop a tool for selecting patients likely to benefit the most from this treatment.

Extending the scope of PARP inhibitors

PARP inhibitors have become a foundation treatment for patients with tumours associated with Homologous Recombination Deficiency (HRD), a failure of DNA repair. The most common type of HRD is mutation of the BRCA genes, which is usually an autosomal dominantly-inherited loss-of-function. Other mutations of DNA-repair proteins, either germ-line (inherited) or somatic (tumour-only), are associated with malignancy and are amenable to treatment with a PARP inhibitor.

There are currently four approved PARP inhibitors. Olaparib (Lynparza® AstraZeneca), niraparib (Zejula® GSK), rucaparib (Rubraca®, Clovis) and talazoparib (Talzenna® Pfizer). Olaparib has the broadest label, being approved for nine indications across breast, ovarian, pancreatic and prostate cancers. The current market for the four approved compounds is estimated to be in excess of $4.5B, and is forecast to rise to $8.5B by 2026.

Despite the transformational clinical efficacy of 1st-generation PARP inhibitors, there are significant limitations to their applicability. Although generally well tolerated, the drugs all cause a degree of bone marrow suppression. Although only a significant issue in a minority (~15%) of patients when used alone, this becomes very problematic when the drugs are combined with chemotherapy and precludes their use in combination.

The other significant challenge is the development of resistance, either de-novo or secondarily. A good deal of work has explored the mechanisms of resistance. The most common mechanism, occurring in 45-50% of treated patients, is a second ‘reversion’ mutation of BRCA1 or 2. This is a secondary ‘gain-of-function’ mutation that causes some reinstatement of primary DNA repair function to the BRCA gene. This negates the synthetic lethality produced by PARP 1-inhibition, rendering the tumour resistant.

The third and most obvious limitation to the application of PARP inhibitors is their dependence on ‘synthetic-lethality’ as their sole mechanism of action, and thereby, their limitation to use in tumours with DNA repair failure.

Tilikum’s PARP ‘locking’ approach

Tilikum has set out to address the current limitations of 1st and 2nd-generation PARP inhibitors, which simply inactivate PARP 1. TLK-001 has a unique profile, mechanistically ‘locking’ PARP 1 onto single-stranded DNA. This prevents DNA replication and kills the cell. This unique mechanism allows TLK-001 to target tumours that, despite having intact DNA-repair mechanisms, are nonetheless dependent on PARP 1 Only Tilikum’s drug has these properties, and it is the only PARP inhibitor capable of killing cells that do not have DNA repair failure. Tilikum can prospectively identify these tumours with a biomarker and select those patients most likely to benefit.

TLK001 binds to PARP-1 in a unique way, enabling it to kill tumour cells

The Tilikum Team

Tilikum has been founded by Dr Alan Barge and Professor Mike Cohen. Alan is a medical oncologist who trained in the UK and US. He has worked in Pharma for over 25 years, and was formerly Head of Oncology at AstraZeneca, where he led the acquisition and early development of Olaparib (Lynparza®). Mike is Professor of Chemical Physiology and Biochemistry at Oregon Health Sciences University (OHSU) in Portland, Oregon. Mike has worked on PARP and related biochemistry for a number of years and has been deeply involved in researching new methodologies for targeting these proteins with new drugs.

Summary

Tilikum is developing a series of unique ‘DNA-locking’ PARP inhibitors, which are fundamentally differentiated from first and second-generation compounds. The ability to ‘lock’ PARP-1 onto single-stranded DNA confers fundamentally important pharmacology and therapeutic efficacy by:

Being active in tumours with reversion mutations of BRCA 1&2 that are resistant to 1st generation compounds

Being active in cells without DNA repair-failure with rapid replication (High Replicative Stress (HRS)

Being at least as active as first and second-generation inhibitors in patients with BRCA-mutant and other HR-deficient tumours Tilikum will profile its lead compound in a series of pre-clinical in-vitro and in-vivo tumour models.

Tilikum will undertake clinical Phase 1A and B studies in defined populations of patients with High-Replicative Stress (HRS) tumours to determine the efficacy of the compound as monotherapy.

Tilikum will position TLK001 in settings such as gastric and endometrial cancer, in subsets of patients with aggressive, highly replicative tumours, which are beyond the scope and licensed indications of the currently approved 1st-generation PARP inhibitors, and the potential reach of the second-generation compounds currently in development.