On March 13 2017 Astex Pharmaceuticals ("Astex"), a pharmaceutical company dedicated to the discovery and development of novel small molecule therapeutics for oncology and diseases of the central nervous system, reported that its long-standing pharmaceutical collaborator, Novartis, has received US Food and Drug Administration (FDA) marketing approval for Kisqali (ribociclib, formerly known as LEE011) plus an aromatase inhibitor as a first-line treatment in post-menopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced (metastatic) breast cancer (Press release, Astex Pharmaceuticals, MAR 13, 2017, View Source [SID1234518119]).

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Astex is eligible to receive a milestone payment in respect of this FDA marketing approval and on approval of additional regulatory filings in Europe and Japan, as well as royalty payments on annual sales of Kisqali, under the drug discovery alliance entered into between Astex and Novartis in 2005. The partnership was struck to discover cell cycle inhibitors which represented a novel class of compounds that target the mechanisms of cell division in order to prevent or interfere with cancer growth.

Under the collaboration, Astex scientists, based at the company’s research laboratories in Cambridge UK, were responsible for solving the crystal structure of the key cancer target protein CDK4. This was an important scientific breakthrough that no other group had previously been able to achieve, leading to a peer-reviewed publication in PNAS[1]. Working with the Novartis team at the Novartis Institutes for BioMedical Research (NIBR), Cambridge, Mass., USA, Astex then applied its structure-based drug discovery technology, part of its Pyramid platform, in the collaboration that led to the discovery of LEE011, (now known as Kisqali) which was then taken forward by Novartis into clinical trials. In total, a team of some 25 Astex scientists were involved in this research program.

Kisqali (ribociclib) is a selective cyclin-dependent kinase inhibitor, a class of drug that helps slow the progression of cancer by inhibiting two proteins (CDK4 & CDK6) which, when over-activated, can enable cancer cells to grow and divide quickly.

Novartis received the approval under the FDA Breakthrough Therapy Designation and Priority Review programs, based on data from a first-line Phase III trial that met its primary endpoint at interim analysis, due to its superior efficacy compared to letrozole alone. The combination of Kisqali plus letrozole reduced the risk of disease progression or death by 44% over letrozole alone. There was a sustained separation of the progression free survival curves evident as early as 8 weeks and more than 53% of patients with measurable disease who took Kisqali plus letrozole saw their tumour size shrink by at least 30%. The combination also showed significant clinical benefit in all patient subgroups regardless of disease burden or tumour location[2].

Harren Jhoti, President and CEO of Astex, UK, said, "We’re committed to the fight against cancer and so we are absolutely delighted that Novartis has received this first approval of a cancer drug arising from our productive collaboration. This milestone further validates the power of our Pyramid platform and the excellence of our science. It’s a moment to celebrate when such ground-breaking scientific work results in a new treatment option for women with advanced breast cancer."

Astex was formed in 1999 in Cambridge, UK, and was a pioneer in the development of fragment-based drug discovery technology. Backed by leading venture capital firms, including Abingworth, it has established multiple partnerships with major pharmaceutical companies including AstraZeneca, Janssen (Johnson & Johnson) and GSK as well as Novartis to use the Company’s drug discovery platform, Pyramid, to identify novel small molecule drugs addressing key disease targets. Today it is a wholly-owned subsidiary of Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan, with a focus on cancer and diseases of the central nervous system. It employs about 200 staff at its research headquarters in Cambridge UK and its clinical development headquarters in Pleasanton, California, USA.

On March 13, 2017 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported the presentation of secondary endpoint results from the Phase 3 ENGOT-OV16/NOVA trial of niraparib at the 2017 Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, March 12 to 15, 2017 by Dr. Sven Mahner, M.D., Director, Department of Gynecology and Obstetrics, University of Munich (Press release, TESARO, MAR 13, 2017, View Source [SID1234518109]).

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"The results of several secondary endpoints from the ENGOT-OV16/NOVA trial, including chemotherapy-free interval (CFI), time to second subsequent therapy (TSST), and progression-free survival 2 (PFS-2), demonstrate the positive and durable treatment effect of niraparib in a broad population of patients with ovarian cancer, regardless of germline BRCA mutation status," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "An assessment of progression-free survival in patients who have progressed on treatment received after completing the NOVA study treatment (PFS-2) compared to their first progression while on the NOVA study (PFS) indicates that niraparib does not decrease the benefit of subsequent treatment."

Niraparib is the only PARP inhibitor that has shown a clinically meaningful increase in progression-free survival (PFS) in women with recurrent ovarian cancer, regardless of BRCA mutation or biomarker status, in a randomized, prospectively designed Phase 3 clinical trial.

Secondary Endpoint Results:
Niraparib Significantly Improved Chemotherapy-free Interval (CFI)
Among patients who were germline BRCA mutation (gBRCAmut) carriers, the niraparib arm successfully achieved statistical significance over the control arm for the secondary endpoint of CFI, with a hazard ratio of 0.26 (95% CI, 0.166-0.409). The median CFI for patients treated with niraparib was 22.8 months, compared to 9.4 months for control (p<0.0001).

Among patients without germline BRCA mutations (non-gBRCAmut), the niraparib arm successfully achieved statistical significance over the control arm for the secondary endpoint of CFI, with a hazard ratio of 0.50 (95% CI, 0.370-0.666). The median CFI for patients treated with niraparib was 12.7 months, compared to 8.6 months for control (p<0.0001).

Niraparib Significantly Improved Time to First Subsequent Treatment (TFST)
Among patients who were germline BRCA mutation carriers, the niraparib arm successfully achieved statistical significance over the control arm for the secondary endpoint of TFST, with a hazard ratio of 0.31 (95% CI, 0.205-0.481). The median TFST for patients treated with niraparib was 21.0 months, compared to 8.4 months for control (p<0.0001).

Among patients without germline BRCA mutations, the niraparib arm successfully achieved statistical significance over the control arm for the secondary endpoint of TFST, with a hazard ratio of 0.55 (95% CI, 0.412-0.721). The median TFST for patients treated with niraparib was 11.8 months, compared to 7.2 months for control (p<0.0001).

Niraparib Had No Impact on the Efficacy of Next-Line Therapy
For a pooled group of patients who have progressed on subsequent therapy (including patients with germline BRCA mutations and without germline BRCA mutations), each patient’s initial progression-free survival interval was subtracted from the progression-free survival 2 interval, which showed no reduction in benefit of niraparib treatment on the effectiveness of subsequent chemotherapy, with a hazard ratio of 1.02 (95% CI, 0.765-1.349). In the NOVA study, a HR of 1.0 demonstrates that the impact of niraparib on efficacy of the subsequent therapy was clinically indistinguishable from the impact of placebo control on the efficacy of the subsequent therapy.

Progression-free Surivival-2 and Overall Survival are Immature, but Favor Niraparib
PFS-2 data were statistically significant and favored niraparib over control for patients in both the gBRCAmut cohort (HR 0.48; 95% CI, 0.242-0.687) and non-gBRCAmut cohort (HR 0.69; 95% CI, 0.494-0.964). Given the relatively long PFS patients experienced on niraparib, PFS-2 was immature, with only 30% of events captured for patients in the gBRCAmut cohort and only 50% of events captured for patients in the non-gBRCAmut cohort. Data for overall survival were also immature (HR 0.73; 95% CI, 0.480 to 1.125; p=0.1545), as fewer than 20% of events had occurred at the time of analysis.

Phase 3 ENGOT-OV16/NOVA Trial Results
The ENGOT-OV16/NOVA trial is an international Phase 3, double-blind, placebo-controlled study that enrolled 553 patients with recurrent ovarian cancer who had achieved either a partial or complete response (PR or CR) to their most recent platinum-based chemotherapy. Niraparib significantly increased PFS in patients with and without germline BRCA mutations as compared to control, and the magnitude of benefit was similar for patients entering the trial with a PR or a CR. Results also showed that treatment with niraparib reduced the risk of disease progression or death by 73% in patients with germline BRCA mutations (HR 0.27) and by 55% in patients without germline BRCA mutations (HR 0.45). Niraparib is the only PARP inhibitor that has shown a clinically meaningful increase in progression-free survival (PFS) in women with recurrent ovarian cancer, regardless of BRCA mutation or biomarker status, in a randomized, prospectively designed Phase 3 clinical trial.

The most common grade 3/4 adverse reactions to niraparib in the NOVA trial included thrombocytopenia (29%), anemia (25%), neutropenia (20%), and hypertension (9%). The majority of hematologic adverse events were managed via dose modification. Discontinuation of therapy due to thrombocytopenia, neutropenia and anemia occurred in 3.3%, 1.9% and 1.4% of patients, respectively.

About Niraparib
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in three pivotal trials. In pre-clinical studies, niraparib was found to concentrate in the tumor relative to plasma, delivering selective, greater than 90% durable PARP inhibition and a persistent anti-tumor effect.

TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development program for niraparib includes a Phase 3 trial in patients who have received first-line treatment for ovarian cancer (the PRIMA trial), a registrational Phase 2 trial in patients who have received multiple lines of treatment for ovarian cancer (the QUADRA trial), and a Phase 3 trial for the treatment of patients with germline BRCA-mutated, metastatic breast cancer (the BRAVO trial). Several combination studies are also underway, including trials of niraparib plus pembrolizumab and niraparib plus bevacizumab. Janssen Biotech has licensed rights to develop and commercialize niraparib specifically for patients with prostate cancer worldwide, except in Japan.

The niraparib New Drug Application (NDA) has been accepted for priority review by the U.S. Food and Drug Administration (FDA) and is supported by data from the ENGOT-OV16/NOVA trial, a double-blind, placebo-controlled, international Phase 3 study that enrolled 553 patients, either with or without a germline BRCA mutation, with recurrent ovarian cancer following complete or partial response to their most recent platinum-based chemotherapy. The full results of the ENGOT-OV16/NOVA trial were presented in detail at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen on October 8, 2016 by Dr. Mansoor Raza Mirza, M.D., Medical Director of the Nordic Society of Gynecologic Oncology (NSGO) and principal investigator. These data were simultaneously published in the New England Journal of Medicine.

Regulatory applications are under review for niraparib in the U.S. and Europe and TESARO expects to launch niraparib in the U.S. in the first half of 2017 and in Europe by year-end 2017, pending regulatory approvals. Niraparib is an investigational agent and, as such, has not been approved by the FDA, European Medicines Agency (EMA), or any other regulatory agencies.

About Ovarian Cancer
Approximately 22,000 women are diagnosed each year with ovarian cancer in the United States, and more than 65,000 women are diagnosed annually in Europe. Ovarian cancer is the fifth most frequent cause of cancer death among women. Despite high response rates to platinum-based chemotherapy in the second-line advanced treatment setting, approximately 85% of patients will experience recurrence within two years. Without an active treatment following chemotherapy, the majority of women who have responded to platinum-based chemotherapy undergo "watchful waiting" — a period without any anti-cancer treatment during which a patient and their healthcare provider will monitor signs of the disease returning. If approved, niraparib may address the difficult "watchful waiting" periods experienced by patients with recurrent ovarian cancer in between cycles of platinum-based chemotherapy.