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Lynparza approved in the EU for BRCA-mutated metastatic pancreatic cancer

On July 8, 2020 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported that Lynparza (olaparib) has been approved in the European Union (EU) for patients with germline BRCA-mutated (gBRCAm) metastatic pancreatic cancer (Press release, AstraZeneca, JUL 8, 2020, View Source [SID1234561741]).

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Pancreatic cancer is a rare, life-threatening disease with the lowest survival rate among the most common cancers.1 Approximately 5-7% of patients with metastatic pancreatic cancer have a germline BRCA mutation.2

The approval by the European Commission was based on results from the Phase III POLO trial, which were published in The New England Journal of Medicine. It follows the recommendation for approval by the Committee for Medicinal Products for Human Use of the European Medicines Agency.

Hedy L. Kindler, Co-Principal Investigator of the POLO trial and Professor of Medicine, University of Chicago Medicine, said: "Today’s approval opens the door to a new era of biomarker-led care for patients with metastatic pancreatic cancer in the EU, which has the highest incidence of any region globally. Lynparza now provides clinicians with a targeted, well-tolerated treatment option for patients with germline BRCA-mutated metastatic pancreatic cancer."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: "Patients with metastatic pancreatic cancer historically have faced poor outcomes due to the aggressive nature of the disease and few treatment advances have been made over the last few decades. In the POLO trial, Lynparza nearly doubled median progression-free survival versus placebo after 1st-line chemotherapy for patients with germline BRCA-mutated metastatic pancreatic cancer. This approval underscores the importance of testing all patients for germline BRCA mutations at the time of diagnosis, as it will help inform personalised treatment options for patients in the EU."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "MSD and AstraZeneca are committed to advancing research into the treatment of patients with challenging types of cancer, including those with metastatic pancreatic cancer. Lynparza is now the only approved PARP inhibitor in biomarker-selected patients with metastatic pancreatic cancer. We look forward to making this targeted treatment option available for patients across the EU as quickly as possible."

The POLO trial demonstrated that Lynparza nearly doubled the time patients with gBRCAm metastatic pancreatic cancer lived without disease progression or death to a median of 7.4 months versus 3.8 months on placebo. The safety and tolerability profile of Lynparza in the trial was consistent with previous trials.

Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with germline BRCA1/2 mutations who have metastatic adenocarcinoma of the pancreas and have not progressed after a minimum of 16 weeks of platinum treatment within a 1st-line chemotherapy regimen.

Lynparza is approved in the US and several other countries as a 1st-line maintenance treatment for patients with gBRCAm metastatic pancreatic cancer based on the Phase III POLO trial, with ongoing regulatory reviews in other regions.

Pancreatic cancer

Pancreatic cancer is a deadly cancer with a high unmet medical need. Globally, pancreatic cancer is the 11th-most commonly occurring cancer and the seventh leading cause of cancer death.3,4 There were approximately 460,000 new cases worldwide in 2018.1 As there are often no symptoms, or symptoms may be non-specific in the early stages, it is most commonly diagnosed at an incurable stage.5,6

Around 80% of pancreatic cancer patients are diagnosed when the disease has metastasised, at which point average survival is less than a year.7 Despite advances, few improvements have been made in diagnosis and treatment in the past few decades.8 Current treatment is surgery (for which approximately only 10-20% of patients are eligible), chemotherapy and radiotherapy, highlighting a critical unmet medical need for more effective treatment options.9

POLO

POLO is a randomised, double-blinded, placebo-controlled, multi-centre Phase III trial of Lynparza tablets (300mg twice daily) as maintenance monotherapy versus placebo. The trial randomised 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed on 1st-line platinum-based chemotherapy. Patients were randomised (3:2) to receive Lynparza or placebo until disease progression. The primary endpoint was progression-free survival and key secondary endpoints included overall survival, time to second disease progression, overall response rate and health-related quality of life.

BRCA mutations

BRCA1 and BRCA2 (breast cancer susceptibility genes 1/2) are human genes that produce proteins responsible for repairing damaged DNA and play an important role in maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair, such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US as a 1st-line maintenance treatment with bevacizumab for patients with homologous recombination deficiency positive advanced ovarian cancer. Lynparza is approved in the US, Japan, and a number of other countries for gBRCAm, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. It is also approved in the US and several other countries for the treatment of gBRCAm metastatic pancreatic cancer. Lynparza is approved in the US for homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer. Regulatory reviews are underway in several regions for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 30,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

Carina Biotech welcomes new CEO, Dr Deborah Rathjen

On July 8, 2020 Carina Biotech’s board and management team reported that are delighted to welcome Dr Deborah Rathjen as our new CEO (Press release, Carina Biotech, JUL 8, 2020, View Source [SID1234561740]). Deborah’s appointment coincides with Carina completing the first commercial transaction of its CAR-T therapy technology, and signals a new stage in the company’s development with a much stronger focus on market development and commercialisation.

Our founding CEO and Managing Director, Dr Justin Coombs, initiated this change, recognising the importance of bringing strong strategic commercial expertise into the company so that he can focus on driving Carina’s outstanding scientific progress. Deborah and Justin will work closely together to ensure our technological and commercial strategies are closely aligned and integrated.

Deborah brings a wealth of experience in leading private and listed biotech companies, investment and commercial deals, both in Australia and internationally. This experience, combined with her immunology research background, positions Deborah as the ideal CEO to develop Carina’s corporate strategy, secure new capital and position the company for very attractive commercial partnerships and deals.

In the first instance, Deborah is taking a half-time position as Carina CEO, while also continuing her existing part-time role as Executive Chair of a US biotech company in the neuroscience field. Justin’s position as Head, IP and Technology Development will also be a half-time position from August, when he will take on the additional role as half-time CEO of CureCell Ltd, the not-for-profit organisation that was previously CTM CRC. CureCell is working with the Seattle Children’s Research Institute (USA) to establish Cureworks Australia to bring potentially life-saving CAR-T clinical trials for childhood cancers to Australia.

Ascendis Pharma A/S Announces Pricing of Public Offering of ADSs

On July 8, 2020 Ascendis Pharma A/S (Nasdaq:ASND), a biopharmaceutical company that utilizes its innovative TransCon technologies to address unmet medical needs, reported the pricing of its underwritten public offering of 4,225,352 American Depositary Shares ("ADSs"), each of which represents one ordinary share of Ascendis, at a price to the public of $142.00 per ADS (Press release, Ascendis Pharma, JUL 8, 2020, View Source [SID1234561721]). All of the ADSs are being offered by Ascendis. The offering is expected to close on or about July 10, 2020 subject to customary closing conditions. In addition, Ascendis has granted the underwriters a 30-day option to purchase up to an additional 633,802 ADSs at the public offering price, less the underwriting commissions.

Ascendis estimates net proceeds from the offering to be approximately $569.2 million (assuming no exercise of the underwriters’ option to purchase additional ADSs), after deducting the underwriting commissions and estimated offering expenses. Ascendis intends to use the net proceeds of the offering to support the clinical development, regulatory approval and commercial preparations for TransCon hGH, to fund clinical development of its other endocrinology rare disease programs, including TransCon PTH and TransCon CNP, to identify and progress development of new product candidates, including in the therapeutic area of oncology, and for working capital and general corporate purposes.

J.P. Morgan Securities LLC, Morgan Stanley & Co. LLC, Evercore Group L.L.C. and SVB Leerink LLC are acting as joint book-running managers for the offering. Credit Suisse Securities (USA) LLC, Cantor Fitzgerald & Co. and Canaccord Genuity LLC are acting as co-lead managers for the offering and Oppenheimer & Co. Inc., Wedbush Securities Inc. and Kempen & Co are acting as co-managers for the offering.

A shelf registration statement relating to these securities was filed with the U.S. Securities and Exchange Commission ("SEC") on May 30, 2018 and automatically became effective upon filing. This offering is being made solely by means of a prospectus. A copy of the final prospectus supplement and the accompanying prospectus relating to this offering, when available, may be obtained by contacting J.P. Morgan Securities LLC, Attention: Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, or by telephone at (866) 803-9204, or by email at [email protected]; Morgan Stanley & Co. LLC, Attention: Prospectus Department, 180 Varick Street, 2nd Floor, New York, NY 10014; Evercore Group L.L.C., Attention: Equity Capital Markets, 55 East 52nd Street, 35th Floor, New York, NY 10055, or by telephone at (888) 474-0200, or by email at [email protected]; or SVB Leerink LLC, Attention: Syndicate Department, One Federal Street, 37th Floor, Boston, MA, 02110, or by telephone at (800) 808-7525, ext. 6218, or by email at [email protected].

Luminary Therapeutics And Case Western Reserve University Enter Formal Collaboration

On July 7, 2021 Luminary Therapeutics (Luminary Tx) and Case Western Reserve University reported that they have entered into a formal collaboration agreement that includes an option for Luminary to exclusively license a novel BAFF target for use in CAR-T (chimeric antigen receptor T cells) constructs (Press release, Luminary Therapeutics, JUL 7, 2020, View Source [SID1234577965]).

The BAFF target was discovered by Reshmi Parameswaran, PhD, an assistant professor at the Case Western Reserve School of Medicine and a faculty member in the Division of Hematology and Oncology, Department of Medicine, and the Seidman Cancer Center at University Hospitals (UH) in Cleveland.

Luminary intends to conduct IND-enabling non-clinical studies to support two clinical trials with its novel and proprietary non-viral autologous BAFF CAR-T (LMY-920) to treat Mantle Cell Lymphoma and Sjogren’s Syndrome. This BAFF target is unique in that it binds to three distinct receptors (BAFF, BCMA, and TACI). Additionally, this BAFF target avoids early B-Cells while targeting more mature B-Cells that express one of three antigens.

"This next generation BAFF CAR offers the promise of treating B-Cell malignancies without total loss of a patient’s healthy B-Cells as well as offering the promise of a reduction in antigen escape during the treatment regimen," said Beau Webber, Luminary Tx’s chief scientific officer.

"Our rationale for choosing to collaborate with Luminary Tx is due to their non-viral approach for clinical development with our BAFF target," said Michael Haag, Case Western Reserve’s executive director of Technology Management. "We believe that Luminary’s experience and flexibility can move this asset into the clinic faster than other therapeutic companies."

Luminary has an aggressive clinical development plan to initiate two Phase I clinical trials. Jeff Liter, Luminary Tx’s CEO, noted that, "Our development plan focuses on non-viral CAR-T platforms that can speed our time to the clinic well ahead of other virus-based approaches."

In addition to scientific expertise and intellectual property, Luminary is excited to work with CWRU and UH because of the expertise and infrastructure available in the Cellular Therapy Laboratory, an on-site state-of-the-art GMP cell manufacturing facility capable of generating CAR-T cells in an expedited fashion and at reduced cost. UH is also a home to several cell therapy clinical trials led by experienced oncologists at the UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center and the region’s only freestanding cancer hospital.

Astex Pharmaceuticals, Taiho Oncology, and Otsuka Pharmaceutical announce FDA and Health Canada approval of INQOVI® (decitabine and cedazuridine) tablets

On July 7, 2020 Astex Pharmaceuticals, Inc.; Taiho Oncology, Inc.; and Otsuka Pharmaceutical Co., Ltd. reported that the U.S. Food and Drug Administration (FDA) and Health Canada have approved INQOVI (decitabine and cedazuridine) tablets. The three companies are all part of the Otsuka group of companies (Press release, Astex Pharmaceuticals, JUL 7, 2020, View Source [SID1234562739]).

INQOVI is the first and only orally administered hypomethylating agent for the treatment for adults with intermediate and high-risk myelodysplastic syndromes (MDS) including chronic myelomonocytic leukemia (CMML),1 two blood malignancies.

Approval was based on data from the ASCERTAIN phase 3 study and supporting phase 1 and 2 clinical studies. The ASCERTAIN phase 3 study evaluated the five-day, decitabine exposure equivalence between oral INQOVI and intravenous decitabine. The safety and efficacy of INQOVI was also assessed in the clinical studies.

The review and approval of INQOVI was conducted under the ORBIS initiative from the FDA Oncology Center of Excellence (OCE) with simultaneous submission and regulatory review in the U.S., Canada, and Australia. The FDA also reviewed the NDA under Priority Review status. INQOVI is not currently approved in Australia. INQOVI was formerly named ASTX727, its experimental compound code.

"Intravenous or subcutaneous administered hypomethylating agents have been the cornerstone for the treatment of patients with MDS and CMML since the mid-2000s," said Guillermo Garcia-Manero, MD, Professor and Chief of Section of Myelodysplastic Syndromes, Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, Texas, and Principal Investigator of the ASCERTAIN clinical study. "The FDA’s approval of INQOVI builds on the proven therapeutic utility of hypomethylating agents in these diseases and offers a new orally administered option that offers patients an alternative to five consecutive days of IV infusions every month during a treatment period that can extend to several months."

"Until now, patients with intermediate and high-risk MDS and CMML have not had an approved, orally administered hypomethylating agent option for treatment of their disease," said Mohammad Azab, MD, president and chief medical officer of Astex Pharmaceuticals, Inc. "The INQOVI clinical program was designed to deliver an oral alternative to IV decitabine based on comparative decitabine exposure data in the clinical trials, and to assess INQOVI’s safety and efficacy profile. As part of the ORBIS project initiative of FDA and Health Canada we were able to share and address information requests simultaneously with both agencies resulting in a more efficient review and completion of assessment in a timely manner. The outcome is expedited availability of this important oral alternative to patients in both countries" added Dr. Azab. "We greatly appreciate the FDA’s priority review and Health Canada’s review of the INQOVI NDA / NDS under Project ORBIS and the approval of a new therapeutic option for patients with these diseases."

INQOVI is an orally administered, fixed-dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine,2 an inhibitor of cytidine deaminase.3 By inhibiting cytidine deaminase in the gut and the liver, INQOVI is designed to allow for oral delivery of decitabine over five days in a given cycle to achieve comparable systemic exposure to IV decitabine (geometric mean ratio of the 5-day cumulative decitabine area-under-the-curve following 5 consecutive once daily doses of INQOVI compared to that of intravenous decitabine was 99% (90% CI: 93, 106).1 The phase 1 and phase 2 clinical study results have been published in Lancet Haematology4 and Blood,5 respectively. The phase 3 ASCERTAIN study data was presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting in Orlando, Florida, in December 2019 by Dr. Garcia-Manero.6

Astex’s parent company, Otsuka Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd. previously announced that, subject to regulatory approvals, commercialization of oral INQOVI in the U.S. and Canada will be conducted by Taiho Oncology, Inc. and Taiho Pharma Canada, Inc. respectively.

"Our partnership with Astex is a demonstration of the commitment that Taiho Oncology has to bringing new therapeutic options to patients with cancer," said Tim Whitten, president and chief executive officer of Taiho Oncology, Inc. "The approval of INQOVI makes the possibility of at-home hypomethylating agent treatment of intermediate and high-risk MDS and CMML a reality, enabling patients to take their medication from the convenience and comfort of their home. This is especially significant during the COVID-19 pandemic, allowing patients to potentially reduce the number of office visits needed for current IV treatment administration. We look forward to working with all healthcare professionals to help deliver the first new oral HMA treatment alternative for patients with intermediate and high-risk MDS and CMML in nearly fifteen years."

About INQOVI (See View Source)

INQOVI is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.1

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Myelosuppression: Fatal and serious myelosuppression can occur with INQOVI. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%.

Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1%.

Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors, and anti‑infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended.

Embryo-Fetal Toxicity: INQOVI can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise patients to use effective contraception during treatment with INQOVI and for 6 months (females) or 3 months (males) after last dose.

ADVERSE REACTIONS

Serious adverse reactions in > 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.

The most common adverse reactions (≥ 20%) were fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The most common Grade 3 or 4 laboratory abnormalities (>50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased.

USE IN SPECIFIC POPULATIONS

Lactation: Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for at least 2 weeks after the last dose.

Renal Impairment: No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min).

About Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic progenitor cells, and associated with cytopenias affecting one or more of the three lineages. U.S. incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought to be under-diagnosed.7,8 The prevalence has been estimated to be from 60,000 to 170,000 in the U.S.9 MDS may evolve into acute myeloid leukemia (AML) in one-third of patients.10 The prognosis for MDS patients is poor; patients die from complications associated with cytopenias (infections and bleeding) or from transformation to AML.

CMML is a clonal hematopoietic malignancy characterized by accumulation of abnormal monocytes in the bone marrow and in blood. The incidence of CMML in the U.S. is approximately 1,100 new cases per year,11 and CMML may transform into AML in 15% to 30% of patients.12 The hypomethylating agents decitabine and azacitidine are effective treatment modalities and are FDA-approved for the treatment of intermediate and high-risk MDS and CMML. These agents are administered by IV infusion, or by large-volume subcutaneous injections.