Chugai Announces 2018 Full Year Results and Forecasts for 2019

On January 31, 2019 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported its financial results for the fiscal year ended December 31, 2018 and forecasts for the fiscal year ending December 31, 2019 (Press release, Chugai, JAN 31, 2019, View Source [SID1234533002]).

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In 2018, both revenues and profits increased driven by: contribution from new products including the hemophilia A treatment Hemlibra and the immune checkpoint inhibitor Tecentriq; steady growth of mainstay products in Japan and overseas; and an increase in royalties and other operating income primarily due to one-time income from the transfer of long-term listed products and out-licensing of an investigational drug for diabetes. Revenues, operating profit and net income achieved record-high for two consecutive years. Reflecting the favorable results and based on our dividend policy, year-end dividends for the fiscal year 2018 are planned to be ¥55 per share, which is higher by ¥10 as increased regular dividend and ¥14 as special dividends than the forecast at the beginning of the fiscal year. As a result, total dividends for the fiscal year will be ¥86 per share, and the Core dividend payout ratio is 48.7%.

For the fiscal year 2019, Chugai expects growth in both revenues and profits owing to increases in overseas sales with a steady growth in Alecensa export to Roche and the continued growth in sales quantity of Actemra, and increases in royalties mainly for Hemlibra, while domestic sales are expected to decrease due to the negative impact from competition including generic competition and the NHI drug price revisions. Chugai expects total estimated dividends of ¥96. Accordingly, the forecast for the Core dividend payout ratio is 48.5%.

Domestic sales excluding Tamiflu were almost steady at ¥389.2 billion (+0.2%). Contribution from new products including the hemophilia A treatment Hemlibra created by Chugai and the immune checkpoint inhibitor Tecentriq, and the steady growth of mainstay products in bone and joint diseases area have offset the negative impact of the NHI drug price revisions. However, overall domestic sales slightly decreased to ¥399.9 billion (-1.3%) because Tamiflu sales for government stockpiles decreased remarkably.
Oncology: Sales were almost flat compared with the previous year. Sales of Tecentriq that was launched in April totaled ¥9.1 billion and sales of the mainstay product ALK inhibitor Alecensa reported steady growth. However, sales of Herceptin and Rituxan decreased mainly due to the NHI drug price revisions in April.
Bone and joint diseases: Sales increased due to the robust sales of mainstay products such as the anti-rheumatic agent Actemra and the osteoporosis agent Edirol.
Renal diseases: Sales declined mainly due to decreases in sales of the secondary hyperparathyroidism treatment Oxarol and the renal anemia agent Mircera, primarily as a result of the NHI drug price revisions in April.
Others: Sales recorded a double-digit decline due primarily to the long-term listed products transferred to Taiyo Pharma Co., Ltd., despite sales of ¥3.0 billion for Hemlibra launched in May experienced favorable market penetration.
Overseas sales increased to ¥127.9 billion (+36.1%) due to increases in exports of Alecensa and Actemra to Roche.
Royalties and other operating income increased remarkably to ¥51.9 billion (+48.7%) due to one-time income primarily from the transfer of long-term listed products to Taiyo Pharma Co., Ltd. and out-licensing of an investigational drug for diabetes OWL833 to Eli Lilly and Company.

Cost of sales ratio to revenues improved mainly due to a change in product mix and increases in royalties and other operating income. As a result, Core gross profit totaled ¥317.9 billion (+13.0%), achieving a double-digit growth.
Core operating expenses amounted to ¥187.6 billion (+5.3%) with a single-digit growth rate, contrary to Core gross profit. The increase in Core operating expenses was mainly driven by R&D expenses. As a result, Core operating profit totaled ¥130.3 billion (+26.3%). Core operating profit ratio to revenues was 22.5%, improved by 3.2 percentage points from the previous year.
Forecast for the fiscal year ending December 31, 2019
[Revenues]
Domestic sales are forecasted to decrease to ¥389.1 billion (-2.7%) compared to the previous year. The negative impact from competition including generic competition and the NHI drug price revisions will exceed the sales growth in new products including Hemlibra and Tecentriq.
Overseas sales are expected to increase to ¥138.9 billion (+8.6%), reflecting the steady growth in Alecensa export to Roche and the continued growth in sales quantity of Actemra.
Royalties and other operating income is expected to increase to ¥64.5 billion (+24.3%). Royalty and profit-sharing income is forecasted to rise to ¥53.5 billion (+122.0%) because of increases in royalties from Roche mainly for Hemlibra. Other operating income is expected to decrease to ¥11.0 billion (-60.6%) mainly because one-time income was recorded in the previous year from the transfer of long-listed products.
[Core operating profit]
Core gross profit is expected to rise to ¥340.0 billion (+7.0%) mainly due to the increase in revenues.
Core operating expenses are expected to amount to ¥197.0 billion (+5.0%). Particularly, R&D expenses are expected to increase to ¥102.0 billion (+8.3%).
As a result, Core operating profit is expected to be ¥143.0 billion (+9.7%).
About Core results
Chugai discloses its results on a Core basis from 2013 in conjunction with its decision to apply IFRS. Core results are the results after adjusting non-Core items to IFRS results, and are consistent with the Core concept disclosed by Roche. Core results are used by Chugai as an internal performance indicator, for explaining the underlying business performance both internally and externally, and as the basis for payment-by-results such as a return to shareholders

MorphoSys Announces Settlement in Patent Lawsuit with Janssen and Genmab

On January 31, 2019 MorphoSys AG (FSE: MOR; Prime Standard Segment, MDAX & TecDAX; NASDAQ: MOR) reported that in its lawsuit against Janssen Biotech and Genmab A/S, the parties have settled the dispute (Press release, MorphoSys, JAN 31, 2019, View Source [SID1234533001]). As a result of this, the parties to the dispute have agreed to drop the mutual claims related to this litigation.

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On April 4, 2016 MorphoSys had filed a lawsuit in the United States (U.S.) District Court of Delaware against Janssen Biotech, and Genmab, A/S for patent infringement of U.S. Patent Number 8,263,746. In 2017, a second and a third patent with US Patent Numbers 9,200,061 and 9,758,590 were added to the lawsuit. MorphoSys had sought redress for alleged infringement by Janssen’s and Genmab’s daratumumab, a CD38-directed monoclonal antibody for the treatment of multiple myeloma. MorphoSys is dismissing those claims and will not appeal from the previously-announced court order dated January 25, 2019. Janssen and Genmab are dismissing their counterclaims

Cancer vaccine firm Oxford Vacmedix holds first meeting of Scientific Advisory Council

On January 31, 2019 Oxford Vacmedix UK Limited (OVM), the UK-based biopharma company focused on the development of cancer vaccines, reported the first meeting of its Scientific Advisory Council (Press release, Oxford Vacmedix, JAN 31, 2019, View Source [SID1234532980]). World-class experts gathered to guide the research and preclinical development programmes of the company and to give input on the planned Phase 1 clinical trials of the lead development candidates; OVM-100 in cervical cancer and OVM-200 for the treatment of solid tumours.

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The Scientific Advisory Council met in Oxford on 17th January 2019 with the participation of:

Professor Sir Andrew McMichael, Emeritus Professor, former Professor of Molecular Medicine, and previously Director of the Weatherall Institute of Molecular Medicine at the University of Oxford. He was a pioneer in T cell research and has particular expertise in the field of T cell responses to viral infections and in vaccine development.
Professor Xu Xiao-Ning is a leading immunologist who was previously at the Institute of Molecular Medicine at the University of Oxford and then head of Novartis Vaccines in China. He is currently Chair of Human Immunology at Imperial College, London.
Dr Nicola Burgess-Brown, Head of the Structural Genomics Consortium (SGC) at Oxford and Principal Investigator in Biotechnology, responsible for the world class biotech research on soluble proteins, membrane proteins and epigenetics targets being led from the Oxford site.
Dr Wang-Jun Lee, Chairman and CEO of the Myongji Medical Foundation and Dr Baek-Seung Lee, Chief Technology Officer of Cancer ROP, the lead Series A investor in OVM also attended. The meeting focused on the manufacturing and preclinical development of the cancer vaccines and also the promising proof of concept research ongoing to test the potential synergies between the vaccines and immuno-oncology (IO) agents.

Spun out from the University of Oxford, OVM is commercialising the research led by Dr Shisong Jiang and developed in Oxford University’s Department of Oncology. The technology uses the novel, proprietary platform of recombinant overlapping peptides to design and develop therapeutic cancer vaccines and diagnostics with the potential for increased efficacy, lower costs, simpler regulatory pathways and synergy when used in combination with other IO agents.

Shisong Jiang, CSO and Founder of OVM, said:

"We are very pleased to have the input from such an experienced Scientific Advisory Council and to have the Advisors input to the research and development of our cancer vaccines. The expertise and experience brought by our new Advisors will be key to OVM’s cancer vaccines being progressed to important clinical milestones both to benefit patients and in the development of the company. We look forward to working with the Council to guide the development of our immunotherapy vaccines".

FDA Expands Lilly’s ALIMTA® (pemetrexed) Label with Combination of KEYTRUDA® (pembrolizumab) and Platinum Chemotherapy for the First-Line Treatment of Metastatic Nonsquamous Non-Small Cell Lung Cancer

On January 31, 2019 Eli Lilly and Company (NYSE: LLY) reported that the U.S. Food and Drug Administration (FDA) has granted approval for a new indication for ALIMTA (pemetrexed for injection) in combination with KEYTRUDA (pembrolizumab), developed and marketed by Merck (known as MSD outside the U.S. and Canada), and platinum chemotherapy for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations (Press release, Eli Lilly, JAN 31, 2019, View Source [SID1234533000]). This indication is approved based on data from Merck’s Phase 3 KEYNOTE-189 trial, which enrolled patients regardless of PD-L1 expression and had dual primary endpoints of overall survival (OS) and progression-free survival (PFS).

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ALIMTA in combination with pembrolizumab and carboplatin was first approved in June 2018 under the FDA’s accelerated approval process for the first-line treatment of patients with metastatic nonsquamous NSCLC, based on tumor response rates and PFS data from the Phase 2 study KEYNOTE-021 (Cohort G1). In accordance with the accelerated approval process, continued approval was contingent upon verification and description of clinical benefit, which has now been demonstrated in the KEYNOTE-189 trial and has resulted in the FDA converting the accelerated approval to full (regular) approval.

"KEYNOTE-189 demonstrated an exceptional effect of the ALIMTA-pembrolizumab-platinum chemotherapy combination in the first-line setting, offering significantly improved survival in patients with metastatic nonsquamous non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations," said Anne White, president, Lilly Oncology. "This new indication reinforces Lilly’s continued commitment to providing practice-changing treatment options that can make a meaningful difference for people living with lung cancer."

ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed. See additional Important Safety Information below.

KEYNOTE-189 Trial Results
On August 20, 2018, Merck’s pembrolizumab was approved by the FDA for this indication, based on data from the KEYNOTE-189 study, which demonstrated that treatment with ALIMTA in combination with pembrolizumab plus platinum-based chemotherapy resulted in significantly longer OS and PFS than ALIMTA plus platinum chemotherapy with placebo.

Efficacy Results

Endpoint

ALIMTA

Pembrolizumab

Platinum Chemotherapy

n=410

ALIMTA

Placebo

Platinum Chemotherapy

n=206

OS

Number (%) of patients with event

127 (31%)

108 (52%)

Median in months (95% CI)

NR

(NR, NR)

11.3

(8.7, 15.1)

Hazard ratio* (95% CI)

0.49 (0.38, 0.64)

p-Value†

<0.0001

PFS

Number (%) of patients with event

244 (60%)

166 (81%)

Median in months (95% CI)

8.8 (7.6, 9.2)

4.9 (4.7, 5.5)

Hazard ratio* (95% CI)

0.52 (0.43, 0.64)

p-Value†

<0.0001

ORR

Overall response rate‡ (95% CI)

48% (43, 53)

19% (14, 25)

Complete response

0.5%

0.5%

Partial response

47%

18%

p-Value§

<0.0001

Duration of Response

Median in months (range)

11.2 (1.1+, 18.0+)

7.8 (2.1+, 16.4+)

*Based on the stratified Cox proportional hazard model

† Based on stratified log-rank test

‡ Response: Best objective response as confirmed complete response or partial response

§ Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy and smoking status

NR = not reached

In the KEYNOTE-189 study, safety was evaluated in 405 patients who received ALIMTA in combination with pembrolizumab and platinum chemotherapy and 202 patients who received placebo, ALIMTA and platinum chemotherapy. ALIMTA was discontinued for adverse reactions in 23 percent of patients in the ALIMTA-pembrolizumab-platinum chemotherapy arm. The most common adverse reactions resulting in discontinuation of ALIMTA in this arm were acute kidney injury (3%) and pneumonitis (2%). Adverse reactions leading to the interruption of ALIMTA occurred in 49 percent of patients in the ALIMTA-pembrolizumab-platinum chemotherapy arm; the most common adverse reactions or laboratory abnormalities leading to interruption of ALIMTA in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%). Adverse reactions of any grade occurring in ≥20 percent of patients receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%) and pyrexia (20%).

KEYNOTE-189 Trial Design
Conducted by Merck, the KEYNOTE-189 trial (ClinicalTrials.gov, NCT02578680), a randomized, double-blind, placebo-controlled, Phase 3 study, evaluated ALIMTA in combination with pembrolizumab and cisplatin or carboplatin compared with ALIMTA in combination with placebo and cisplatin or carboplatin, in 616 untreated patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression. Patients had no sensitizing EGFR or ALK genomic tumor aberrations, and had not previously received systemic therapy for advanced disease. This was a treat-to-progression protocol, with both ALIMTA and pembrolizumab being used until progression or unacceptable toxicity (or 35 cycles for pembrolizumab)1, and had dual primary endpoints of OS and PFS [assessed by blinded independent central review (BICR) per RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)]; secondary endpoints include overall response rate (ORR) and duration of response (DOR). Patients were randomized 2:1 to one of two treatment groups, as follows:

ALIMTA (500 mg/m2) (with vitamin supplementation) plus pembrolizumab (200 mg fixed dose every three weeks) plus cisplatin (75 mg/m2) or carboplatin AUC 5 mg/mL/min on day one every three weeks (Q3W) for four cycles, followed by ALIMTA (500 mg/m2) plus pembrolizumab 200 mg Q3W; or
ALIMTA (500 mg/m2) (with vitamin supplementation) plus saline placebo plus cisplatin (75 mg/m2) or carboplatin AUC 5 mg/mL/min on day one every three weeks (Q3W) for four cycles, followed by ALIMTA (500 mg/m2) plus placebo Q3W.
Patients on the control arm who experienced disease progression, verified by central independent review, were permitted to undergo treatment assignment unblinding and crossover to receive open-label pembrolizumab. The KEYNOTE-189 study was conducted in collaboration with Lilly.

About Lung Cancer
Lung cancer is the leading cause of cancer death in the U.S. and most other countries, killing nearly 1.7 million people worldwide each year.2 In the U.S., lung cancer is responsible for approximately 25 percent of all cancer deaths, more than those from breast, colon and prostate cancers combined.3 Stage IV non-small cell lung cancer (NSCLC) is a very difficult-to-treat cancer and the prognosis is poor for metastatic NSCLC.4 NSCLC is much more common than other types of lung cancer and accounts for about 80 to 85 percent of all lung cancer cases.5 For those people afflicted with NSCLC, about 70 percent have nonsquamous cell carcinoma, while about 30 percent have squamous cell carcinoma.5

About ALIMTA (pemetrexed for injection)
ALIMTA is indicated in combination with pembrolizumab and platinum chemotherapy for the initial treatment of patients with metastatic nonsquamous non-small cell lung cancer, with no EGFR or ALK genomic tumor aberrations. For all FDA-approved indications for ALIMTA, please see full Prescribing Information.

IMPORTANT SAFETY INFORMATION FOR ALIMTA (pemetrexed for injection)

CONTRAINDICATION

ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed.
WARNINGS AND PRECAUTIONS

Myelosuppression and Increased Risk of Myelosuppression Without Vitamin Supplementation

ALIMTA can cause severe myelosuppression resulting in a requirement for transfusions and which may lead to neutropenic infection. The risk of myelosuppression is increased in patients who do not receive vitamin supplementation.
Prior to treatment with ALIMTA, patients must be instructed to initiate supplementation with oral folic acid. Intramuscular injections of vitamin B12 are also required prior to ALIMTA treatment. Folic acid and vitamin B12 supplementation should be continued during treatment and for 21 days after the last dose of ALIMTA as they may reduce the severity of treatment-related hematologic and gastrointestinal toxicities. Obtain a complete blood count at the beginning of each cycle. Do not administer ALIMTA until the ANC is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3. Permanently reduce ALIMTA in patients with an ANC of less than 500 cells/mm3 or platelet count of less than 50,000 cells/mm3 in previous cycles.
In Studies JMDB and JMCH, among patients who received vitamin supplementation, incidence of Grade 3-4 neutropenia was 15% and 23%, the incidence of Grade 3-4 anemia was 6% and 4%, and incidence of Grade 3-4 thrombocytopenia was 4% and 5%, respectively. In Study JMCH, 18% of patients in the ALIMTA arm required red blood cell transfusions compared to 7% of patients in the cisplatin arm. In Studies JMEN, PARAMOUNT, and JMEI, where all patients received vitamin supplementation, incidence of Grade 3-4 neutropenia ranged from 3% to 5%, and incidence of Grade 3-4 anemia ranged from 3% to 5%.
Renal Failure

ALIMTA can cause severe, and sometimes fatal, renal toxicity. Determine creatinine clearance before each dose and periodically monitor renal function during treatment with ALIMTA.
The incidences of renal failure in clinical studies in which patients received ALIMTA with cisplatin were 2.1% in Study JMDB and 2.2% in Study JMCH. The incidence of renal failure in clinical studies in which patients received ALIMTA as a single agent ranged from 0.4% to 0.6% (Studies JMEN, PARAMOUNT, and JMEI).
Withhold ALIMTA in patients with a creatinine clearance of less than 45 mL/min.
Bullous and Exfoliative Skin Toxicity

Serious and sometimes fatal, bullous, blistering, and exfoliative skin toxicity, including cases suggestive of Stevens-Johnson Syndrome/toxic epidermal necrolysis, can occur with ALIMTA. Permanently discontinue ALIMTA for severe and life-threatening bullous, blistering, or exfoliating skin toxicity.
Interstitial Pneumonitis

Serious interstitial pneumonitis, including fatal cases, can occur with ALIMTA treatment. Withhold ALIMTA for acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, or fever pending diagnostic evaluation. If pneumonitis is confirmed, permanently discontinue ALIMTA.
Radiation Recall

Radiation recall can occur with ALIMTA in patients who have received radiation weeks to years previously. Monitor patients for inflammation or blistering in areas of previous radiation treatment. Permanently discontinue ALIMTA for signs of radiation recall.
Increased Risk of Toxicity With Ibuprofen in Patients With Renal Impairment

Exposure to ALIMTA is increased in patients with mild to moderate renal impairment who take concomitant ibuprofen, increasing the risks of adverse reactions of ALIMTA. In patients with creatinine clearances between 45 mL/min and 79 mL/min, avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA. If concomitant ibuprofen use cannot be avoided, monitor patients more frequently for ALIMTA adverse reactions, including myelosuppression, renal, and gastrointestinal toxicity.
Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses lower than the recommended human dose of 500 mg/m2. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ALIMTA and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with ALIMTA and for 3 months after the final dose.
DRUG INTERACTIONS

Ibuprofen increases exposure (AUC) of pemetrexed. In patients with creatinine clearance between 45 mL/min and 79 mL/min:
Avoid administration of ibuprofen for 2 days before, the day of, and 2 days following administration of ALIMTA.
Monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity, if concomitant administration of ibuprofen cannot be avoided.
ADVERSE REACTIONS

Severe adverse reactions (Grade 3-4) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were fatigue (12% vs 6%); diarrhea (5% vs 3%); dyspnea (3.7% vs 5%); vomiting (3.7% vs 3%); nausea (3.5% vs 3.5%); rash (2% vs 2.5%); decreased appetite (1.5% vs 0.5%); constipation (1% vs 0.5%); and pyrexia (0.2% vs 0%).
Common adverse reactions (all grades) occurring in ≥20% of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) receiving ALIMTA in combination with pembrolizumab and platinum chemotherapy (carboplatin or cisplatin) versus ALIMTA with platinum chemotherapy + placebo for initial treatment (KEYNOTE-189), respectively, were nausea (56% vs 52%); fatigue (56% vs 58%); constipation (35% vs 32%); diarrhea (31% vs 21%); decreased appetite (28% vs 30%); rash (25% vs 17%); vomiting (24% vs 23%); cough (21% vs 28%); dyspnea (21% vs 26%); and pyrexia (20% vs 15%).
USE IN SPECIFIC PATIENT POPULATIONS

Lactation: There is no information regarding the presence of pemetrexed or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from ALIMTA, advise women not to breastfeed during treatment with ALIMTA and for one week after the last dose.
Males of Reproductive Potential: ALIMTA may impair fertility in males of reproductive potential. It is not known whether these effects on fertility are reversible.
Pediatric Use: The safety and effectiveness of ALIMTA in pediatric patients have not been established. Adverse reactions observed in pediatric patients studied were similar to those observed in adults.
Patients with Renal Impairment: ALIMTA is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function. No dose is recommended for patients with creatinine clearance less than 45 mL/min.
Geriatric: The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials.
PM_HCP_ISI_NSCLC1L_Combo_30JAN2019

For safety and dosing guidelines for ALIMTA, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the full Prescribing Information and Patient Prescribing Information.

Repare Therapeutics Announces a Strategic Partnership Agreement with ONO Pharmaceutical Co., Ltd. for Repare’s Pol? Inhibitor Program in Japan and Selected Territories in Asia

On January 31, 2019 Repare Therapeutics, Inc., a privately held precision oncology company pioneering synthetic lethality to develop novel therapeutics that target specific vulnerabilities of tumors in clearly defined patient populations, reported that it has entered into an exclusive strategic research, development and commercialization partnership with ONO Pharmaceutical Co., Ltd., for Repare’s small molecule Polθ inhibitor program in Japan, South Korea, Taiwan, Hong Kong, Macau and ASEAN countries, excluding mainland China (Press release, Repare Therapeutics, JAN 31, 2019, View Source [SID1234532999]). Repare retains all rights to develop and commercialize the products outside the ONO territory, including the US, Canada and EU.

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"We’re excited to have ONO as a discovery and development partner," said Lloyd M. Segal, President and CEO of Repare. "This relationship will support our drive to and through the clinic in this important new area of precision oncology therapeutic development."

"ONO identified Repare Therapeutics as the partner of choice for bringing in a potential first-in-class and best-in-class Polθ inhibitor to our portfolio," said Gyo Sagara, President, Representative Director and CEO of ONO. "We are excited to work with Repare for the benefit of cancer patients."

Under the terms of the agreement, ONO will provide an up-front payment and research service payments potentially totaling US $15M, plus additional cost-sharing through IND. Beyond IND, significant clinical, regulatory and commercial milestones are also included in the agreement, with a potential total of US $160M. ONO will also pay to Repare high single-digit to low double-digit tiered royalties based on net sales of the product. Repare retains all rights to develop and commercialize the products outside the ONO territory, including the US, Canada and the EU.

Polθ inhibitor opportunity

DNA Polymerase θ (Polθ) is a unique, multifunctional DNA polymerase essential to repairing DNA breaks, especially in homologous recombination deficient (HRD) cells. HRD, including deficiency in the BRCA1 and BRCA2 genes, is a clinically important feature across a variety of important tumor types, including breast, ovarian, prostate and pancreatic cancers. Polθ gene expression is low in normal cells but elevated across a broad range of tumor types, including those with HRD. Currently, HRD tumors may be treated with Poly(ADP-ribose) Polymerase (PARP) inhibitors, which represent a rapidly growing, multi-billion dollar global market. A significant fraction of patients does not initially respond to PARP inhibitor treatment, and the vast majority of treated patients eventually develop PARP inhibitor resistance. A Polθ inhibitor has potential as both a mono-therapy across multiple tumor types and in combination with PARP inhibitors, where its distinct mechanism of action may help address both forms of PARP resistance. Additional clinical populations may also be attractive for combination treatment with a Polθ inhibitor, including possible combinations with chemotherapy, radiotherapy and Immuno-Oncology agents