By John Vandermosten, CFA

TSX:RKV.V

Rakovina Therapeutics Inc. (TSX:RKV.V) is a preclinical oncology company founded in 2020 to build upon the success of targeted therapies and address several of their shortcomings. The executives at the company have worked together on other oncology projects and now are preparing to successfully advance this new endeavor. With executive leadership from Jeffry Bacha and laboratory experience from Dr. Mads Daugaard, the company plans to develop a new generation of PARP inhibitors designed to address the key drawbacks of the class. The next generation of PARP inhibitors may better address brain metastases, employ multiple mechanisms to improve patient survival and expand the field of oncology beyond current approaches.

PARP

PARP or poly-ADP ribose polymerase, is a family of enzymes that are involved in multiple cellular processes including transcription, replication and DNA repair. DNA can be damaged by radiation, oxidative stress, chemotherapy, exposure to genotoxic agents and other events leading to breaks in the DNA helix backbone. The breaks prevent the DNA from replicating, thereby leading to cell death. In response, cellular systems have developed multiple mechanisms to repair DNA strand breaks or lesions in the DNA including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR) and non-homologous end joining (NHEJ). PARP is one of the key DNA repair proteins that detects and fixes single strand breaks (SSB), mainly via BER. In normal cells, PARP guides DNA repair returning cells to normal functioning status. However, in the case of cancer cells, the ability of PARP and other pathways to repair DNA allows cancer cells to survive and proliferate in spite of underlying mutations that have allowed tumor formation. The PARP enzyme has been observed to be upregulated in several cancer types including triple negative breast (TNBC), ovarian and colorectal cancer.

PARP Inhibitors

PARP inhibitors (PARPi) have been able to prevent the DNA repair process that allows cancer cell survival by blocking the activity of PARP. The PARPi class selectively brings about synthetic lethality in cancer cells with HR deficiencies; the deficiencies are often mutations in the breast cancer gene 1 (BRCA1) and BRCA2. Cells that lack functional BRCA1 and BRCA2 are substantially more likely to be sensitive to PARPi as these cells lack an effective alternate mechanism to repair DNA damage. PARPis inhibit PARP enzymes resulting in persistent SSBs which devolve into double strand breaks (DSB) during the DNA replication phase of the cell cycle, ultimately leading to cancer cell death. PARPi can work in two ways, either increasing tumor sensitivity to DNA damaging chemotherapy and radiation or by inducing synthetic lethality in cells with defective HR.

The term synthetic lethality refers to the occurrence of two enzymatic abnormalities that are non-lethal in isolation but that become lethal when they co-exist. PARP inhibition in the context of some types of mutated or deficient DNA repair mechanisms2 can induce synthetic lethality by blocking DNA repair of damaged tumor cells, leading to cell death. Normal cells with proficient DNA repair capacity are not damaged and will therefore survive with reduced toxic side-effects. Synthetic lethality between BRCA deficiency and PARP inhibition is a leading example.

PARPi have been successful in improving progression free survival (PFS) in BRCA-deficient breast, ovarian and prostate cancer. In various clinical studies, PARPi increased median PFS by 3 to 15 months and median overall survival (mOS) was extended from two to six months. In some combination therapy trials PFS was extended by 18 to 37 months.3

Approved PARPi

Four PARP inhibitors have been approved by the FDA for use in ovarian, fallopian tube, prostate, pancreatic and breast cancer. Sales for the group were approximately $2.5 billion in 2020 with AstraZeneca’s Lynparza dominating the field not only in revenues but also in number of indications approved. Growth is expected to remain brisk with the four approved products anticipated to achieve a 25% compound annual growth rate (CAGR) over the next five years.4 We summarize details and forecasted growth of the PARP inhibitors below.

Shortcomings and Unmet Clinical Need

Since the first PARP inhibitor was approved in 2014, this group of products has made impressive strides in improving overall survival and progression free survival for ovarian and other cancers, especially those with BRCA mutations. However, several limitations have emerged which can impact PARPi effectiveness. Two of the principal shortcomings are poor ability of the molecule to cross the blood brain barrier (BBB) and development of tumor resistance to these agents.

Despite PARPi working well in vitro in combination with chemotherapy against many solid tumors with mutated DNA damage repair pathways, PARPi do not easily cross into the central nervous system (CNS).6 Breast cancer patients with BRCA mutations and brain metastases have a poor therapeutic outcome with PARP inhibitors. In addition, the expansion of the use of PARPi into glioblastoma multiforme (GBM) in combination with temozolomide has been stalled by the PARPi limited distribution across the BBB.7

There are several mechanisms of PARPi resistance that rely on restoration of DNA repair pathways and restabilization of replication forks that lead to resistance to these inhibitors. Cancer cells are adept at exploiting unique survival pathways that can help them overcome treatment stresses. To address the resistance, combination or dual action therapies have been considered to attack multiple mechanisms simultaneously in order to block the development of clinical resistance.

PARPi and Beyond

PARP inhibitors have provided a substantial benefit to cancer patients with certain DNA repair gene mutations, especially in ovarian, breast and prostate cancer. However, the approved drugs in the class have several shortcomings that create opportunities for next generation compounds. To address these limitations, Rakovina is developing these solutions to drug resistant cancers. With the guidance of Dr. Mads Daugaard, Rakovina’s President and Chief Scientific Officer, the company has initiated preclinical studies to develop the new drug candidates. These include drug discovery and development programs designated kt-2000, kt-3000 and kt-4000, each of which may augment previous success in the PARPi universe.

kt-2000

With the PARPi’s limitation of crossing the blood brain barrier and into central nervous system, Rakovina and Dr. Daugaard have developed a next-generation PARPi designated kt-2000. The molecule has been modified to cross the BBB and reach tumor metastases in the brain. The design chemically modifies the surface of the molecule to improve its ability to cross the BBB threshold. If successful, kt-2000 holds promise to expand the utility of PARPi into cancers with brain metastases.

kt-3000

In some cases, PARPi is insufficient to halt the progress of tumor growth and cancer cells develop resistance as alternate DNA repair pathways are utilized. This occurs through drug target related resistance, restoration of HR and the restoration of replication fork stability. kt-3000 is a dual-specificity small molecule able to bind and inhibit both PARP and histone-deacetylase (HDAC) enzymes simultaneously.

To halt or delay cancer’s drug resistance, PARPi may be combined with HDAC inhibitors (HDACi). HDACs are important for enabling HR repair of DNA. HDACi may therefore decrease the activity of DNA repair pathways and sensitize cancer cells to PARPi thereby reinstating synthetic lethality.

HDAC inhibitors inhibit deacetylation of proteins, particularly those involved in cell proliferation, differentiation and apoptosis. HDACi has shown potential to sensitize cells to the effects of PARPi.9 HDACi has also been shown to help trap PARP1 at DSB sites,10 which supports synthetic lethality.

kt-4000

The third program in Rakovina’s arsenal is kt-4000 which combines a PARPi with DNA-alkylation. Alkylating agents add an alkyl group to the guanine base of DNA preventing the strands of the double helix from linking. This creates single strand DNA lesions that translate into lethal double strand DNA breaks during the DNA replication phase of the cell cycle. As a result, the tumor cell cannot divide, which triggers cell death. The combination with a PARPi further blocks DNA repair providing therapeutic synergy with the alkylating agent.

Rakovina is using alkylating agent chemistry structurally inspired by temozolomide. The dual action molecule will incur damage to the DNA with its alkylating portion while at the same time blocking DNA repair via PARP inhibition. While there have been concerns about side effects for both of these compounds, using them together may allow lower doses of each to be used thereby improving the side effect profile.

Building on Success

Four PARP inhibitors have been approved to treat multiple cancer indications in the last decade including ovarian, fallopian, breast, prostate and pancreatic cancer. This class of medicine demonstrates improved PFS and OS in DNA damage repair deficient cancers. Rakovina Therapeutics plans to build upon these foundations with the development of the next generation of products in the evolving field of DNA damage repair inhibition. The company sees opportunities in the same areas where predecessors have already been successful. The five oncology indications where PARPis have been approved represents approximately 600,000 cases in the US every year and after adjusting for the proportion of cancers with the relevant mutation, this is equivalent to an addressable market of near 116,000 individuals per year. There are other cancers with BRCA mutations where PARPis have not yet been approved but may be appropriate such as gastrointestinal, lymphoma, osteosarcoma, skin (non-melanoma) thyroid and small cell lung cancer. While Rakovina is still in its early stages of development, its astute recognition of the unmet need in DNA damage response and the current limitations of PARPi provides an opening for new entries into the class and the potential for addressing new indications. We see the possibility of Rakovina advancing the vanguard in second and third generation PARP inhibitors.

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1. Source: Rakovina Therapeutics 3Q:21 Corporate Presentation

2. This includes BRCA mutated or homologous recombination-deficient tumor cells.

3. Min, A.; Im, S. PARP Inhibitors as Therapeutics: Beyond Modulation of PARylation. Cancers (Basel). 2020 Feb; 12(2): 394. Published online 2020 Feb 8. doi: 10.3390/cancers12020394

4. Based on consensus analyst forecasts compiled by Evaluate Pharma, Ltd. Data accessed September 2021.

5. Source: Analyst compilation of data and Evaluate Pharma, Ltd. Accessed September 2021.

6. Parrish, K. et al. Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system. Mol Cancer Ther. 2015 December. Rucaparib had a significantly lower accumulation in the brain and levels were undetectable 360 minutes after injection into a mouse model. Limited distribution of rucaparib into brain tumors may account for the lack of efficacy of rucaparib in the orthotopic models.

7. Gupta, S. et al. PARP Inhibitors for Sensitization of Alkylation Chemotherapy in Glioblastoma: Impact of Blood-Brain Barrier and Molecular Heterogeneity. Front Oncol. 2018; 8: 670. Published online 2019 Jan 22. doi: 10.3389/fonc.2018.00670

8. Source: Rakovina Therapeutics 3Q:21 Corporate Presentation

9. Ha, K. et al. Histone deacetylase inhibitor treatment induces 'BRCAness' and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. Oncotarget, July 30, 2014.

10. Robert, C. et al. Histone deacetylase inhibitors decrease NHEJ both by acetylation of repair factors and trapping of PARP1 at DNA double-strand breaks in chromatin. Leuk Res. 2016 Jun;45:14-23. doi: 10.1016/j.leukres.2016.03.007. Epub 2016 Mar 30.

11. Source: Rakovina Therapeutics 3Q:21 Corporate Presentation

12. Source: Rakovina Therapeutics 3Q:21 Corporate Presentation