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Rise of PARP Inhibitors: Clovis Oncology vs Tesaro

PARP inhibitors are a new class of drugs found to suppress the progression of certain cancers such as ovarian, in recurrent platinum-sensitive patients. Due to their initial success in treatment, research and development in the field has taken off and several new drugs have entered the market this year. Given their implications in the field of oncology, PARP inhibitors pose an unique investment opportunity.

Understanding PARP Inhibitors

Cells in the body are constantly damaged by external and internal sources. Genetic material that make up the cells are the most vital to the cell because they contain information to keep the cell alive. Chemicals in the cells, radiation outside the cells, errors in replication, and countless other sources constantly damage the genetic material. Damage can be classified as a double or single strand break. Double strand breaks, which are less frequent but more severe, are processed by major tumor suppressor genes such as BRCA. On the other hand, single strand breaks are much less severe and can be repaired by proteins such as PARP(poly-ADP-ribose polymerase). When a single-stranded nick is detected, the PARP proteins correct the damaged nick , preventing these errors from aggregating.

Drugs known as PARP inhibitors work by disrupting the function of the PARP proteins. This prevents the cell from repairing itself from the single strand nicks. This would seem counter intuitive, as accumulating errors in the genetic material is detrimental to the cell and causes cancer but a deeper understanding on the mechanisms of cancer shed light on the success of this class of drugs. Many patients who develop cancer have errors in the genes coding proper homologous recombination such as the BRCA gene. This prevents the cell from correcting double strand breaks, leading to formation of errors in the genetic material, deregulating the cells internal mechanics and increasing the chance of the formation of cancerous cells. Once a cancerous cell is formed, it undergoes uncontrolled cell division, continues to accumulate more errors and becomes progressively more aggressive. This cycle repeats till the cancer eventually leads to the death of the patient.

Cancer cells replicate extremely quickly. Each time they replicate their genetic material undergoes severe amount of stress and damage and needs to be repaired so that the cell can continue to replicate. PARP aids in the correction of single strand breaks. When PARP is inhibited, the rapidly dividing, error prone, cancerous cells cannot correct these single strand nicks. Since single strand nicks occur so rapidly that the cancerous cell cannot survive the sheer amount of errors they accumulate. Since there is a remarkably higher rate of division in cancerous cells, they are extremely sensitive to PARP inhibition in comparison to normal somatic cells.

Competitive PARP inhibitor Space

Due to the remarkable results seen with PARP inhibitors in the space of ovarian cancer and the promise seen with breast, pancreatic and prostate cancer, investors are extremely excited and companies are aggressively pursuing this field. In 2016, Pfizer acquired Medivation for $14B in part to acquire the rights to the PARP inhibitor, talazoparib. Currently there are three companies with approved drugs for second-line defense against ovarian cancer: Clovis Oncology’s Rucaparib, Tesaro’s Niraparib (Zeluja™), and AstraZeneca’s Olaparib (Lynparza™). All three of these drugs have been shown to improve the progression free survival (PFS) in ovarian cancer and are also in trials for their indication in breast, pancreatic and prost