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]).

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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.

On July 7, 2020 Evive Biotech, a global biologics company developing novel biological therapies, reported that its pivotal Phase III study (NCT03252431) for F-627 (efbemalenograstim alpha) to treat chemotherapy-induced neutropenia (CIN) in breast cancer patients has met its primary and secondary endpoints, demonstrating strong and lasting benefit (Press release, Evive Biotech, JUL 7, 2020, View Source [SID1234561798]).

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F-627 increases the production of white blood cells (neutrophils) which are a key part of the immune system’s ability to fight infection. A low concentration of these cells is a common side-effect of chemotherapy, and boosting their levels strengthens the immune system, meaning that patients are less likely to succumb to infections during treatment with chemotherapy.

"F-627 has now shown positive results in its pivotal Phase III trial. We are excited that this trial has met its efficacy and safety endpoints as we believe that it has the potential to positively impact cancer treatment," said Dr. William Daley, Evive’s Chief Medical Officer. "F-627 has proven that it is at least as efficacious and safe as NEULASTA, which is the current standard of care. This successful trial result reinforces F-627’s potential to be a strong first line treatment, and an alternative for patients contraindicated or refractory to current treatment options. F-627’s fusion protein structure presents a unique alternative as it reduces the possibility of allergic reactions caused by PEGylation used in pegfilgrastim. It was also very encouraging to see that the treatment was well tolerated, with infection rates for those treated with F-627 lower than in the control arm of the trial which was more pronounced in certain patient subgroups."

"The successful completion of our global Phase III trial for F-627 is a validation of Evive’s platform, and the entire team’s commitment, dedication and belief in this product," said Jacky Liu, CEO of Evive. "This moment is a key milestone for us as a business as we move towards submitting F-627’s BLA application to the FDA — one of the first Asian biologics companies to advance a novel biologic product from pre-clinical studies to BLA submission. As we begin the next stage of our journey, exploring commercialization partnerships to make this product available to patients worldwide, I would like to thank the Evive team, trial clinics and doctors who have worked so tirelessly to develop this critical and potentially life-saving treatment."

The global pivotal Phase III trial was a multi-center, randomized, single dose, double-blind, active-controlled study comparing the efficacy and safety of Evive’s F-627 (dimeric recombinant human granulocyte colony stimulating factor-fc fusion protein) and Neulasta (pegylated recombinant methionyl human granulocyte colony stimulating factor) in the prophylactic treatment of chemotherapy-induced neutropenia in women with breast cancer receiving myelotoxic TC chemotherapy treatment (docetaxel + cyclophosphamide).

This trial was conducted under a Special Protocol Assessment (SPA) in agreement with the Food and Drug Administration (FDA) of the United States Federal Government and will be submitted as part of the Biologic License Application (BLA) filing to the FDA, and the Market Authorization Application (MAA) filing to the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). F-627’s global development program also includes successfully completed placebo-controlled and Neupogen-controlled Phase III trials that met all primary and secondary endpoints. In total, the program involved 10 trials and over 1,200 subjects.

As Evive progresses its BLA submission with the FDA and equivalent submissions around the world, it is exploring commercialization partnerships for F-627 in the US, Europe, Japan and China, as well as Rest of World countries to ensure the broadest access for patients around the globe.

Notes for Editors

Chemotherapy-induced Neutropenia (CIN)

CIN occurs commonly during current cancer treatments involving cytotoxic chemotherapy. Market research indicates that CIN affects more than eight million people every year with around one million people affected in the United States alone. The global CIN market is estimated to be at US$6.0 billion with about >85% of patients still on first-generation of rhG-CSFs, and less than 15% of patients using second-generation rhG-CSFs, the pegylated rhG-CSF.

About F-627

F-627 (efbemalenograstim alpha) is under development for the treatment of CIN in cancer patients after chemotherapy. F-627 is a recombinant fusion protein containing G-CSF at the amino terminal and human IgG2-Fc fragment at the carboxyl terminal. F-627 is expressed in Chinese Hamster Ovary (CHO) cells. F-627 exists as a dimer with two molecules of rhG-CSF covalently linked through disulfide bonds formed between the Fc fragment of the molecule. G-CSF is a growth factor acting on the neutrophilic lineage in the hematopoietic system. G-CSF binds specifically to G-CSF receptors (G-CSFR) on precursor cells in bone marrow and mature neutrophils. G-CSF stimulates survival, proliferation, differentiation, function of neutrophil precursors and mature neutrophils.

On July 7, 2020 Pacira BioSciences, Inc. (Nasdaq: PCRX) reported the pricing of $350.0 million aggregate principal amount of convertible senior notes due 2025 (the "notes") in a private placement to qualified institutional buyers pursuant to Rule 144A under the Securities Act of 1933, as amended (the "Securities Act") (Press release, Pacira Pharmaceuticals, JUL 7, 2020, View Source [SID1234561756]). The offering size was increased from the previously announced offering size of $300.0 million aggregate principal amount of notes. Pacira also granted the initial purchasers of the notes a 30-day option to purchase up to an additional $52.5 million aggregate principal amount of notes. The sale of the notes to the initial purchasers is expected to settle on July 10, 2020, subject to customary closing conditions.

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Pacira estimates that the net proceeds from the offering will be approximately $339.0 million (or approximately $389.9 million if the initial purchasers fully exercise their option to purchase additional notes), after deducting the initial purchasers’ discounts and commissions and estimated offering expenses. Pacira expects to use approximately $211.1 million of the net proceeds to repurchase $185.0 million aggregate principal amount of its outstanding 2.375% Convertible Senior Notes due 2022 (the "2022 Notes") concurrently with the note offering in privately negotiated transactions effected through one of the initial purchasers of the notes or its affiliate, as Pacira’s agent. Pacira intends to use the remainder of the net proceeds from the offering for general corporate purposes, including working capital, research and development expenditures and the license or acquisition of complementary products and/or technologies. Holders of the 2022 Notes that are repurchased in the concurrent repurchases described above may purchase shares of Pacira’s common stock in the open market to unwind any hedge positions they may have with respect to the 2022 Notes. These activities may affect the trading price of Pacira common stock and the initial conversion price of the notes.

The notes will be general unsecured senior obligations of Pacira and will mature on August 1, 2025, unless earlier repurchased, redeemed or converted in accordance with their terms. The notes will bear interest at a fixed rate of 0.750% per year, payable semi-annually in arrears on February 1 and August 1 of each year, beginning on February 1, 2021.

Prior to the close of business on the business day immediately preceding February 3, 2025, the notes are convertible at the option of the holders only under certain conditions. On or after February 3, 2025, until the close of business on the second scheduled trading day immediately preceding the maturity date, holders may convert their notes at their option, irrespective of these conditions. Pacira will settle conversions of the notes by paying or delivering, as the case may be, cash, shares of its common stock, or a combination of cash and shares of its common stock, at its election.

The conversion rate will initially be 13.9324 shares of common stock per $1,000 principal amount of notes, subject to adjustment in certain circumstances. This represents an initial conversion price of approximately $71.78 per share, representing a conversion premium of approximately 32.5% over the closing price of $54.17 per share of Pacira common stock on July 7, 2020.

On or after August 1, 2023, Pacira may redeem for cash all or part of the notes under certain circumstances at a redemption price equal to the principal amount of the notes to be redeemed, plus accrued and unpaid interest, if any. In addition, calling any note for redemption will constitute a make-whole fundamental change (as defined in the indenture governing the notes) with respect to that note, in which case the conversion rate applicable to the conversion of that note, if it is converted in connection with the redemption, will be increased in certain circumstances.

The offering of the notes is being made to qualified institutional buyers pursuant to Rule 144A under the Securities Act. The offer and sale of the notes and the shares of Pacira common stock, if any, issuable upon conversion of the notes have not been and will not be registered under the Securities Act or any state securities laws, and, unless so registered, the notes and such shares may not be offered or sold in the United States or to U.S. persons except pursuant to an exemption from, or in a transaction not subject to, the registration requirements of the Securities Act and applicable state securities laws.

On July 7, 2020 Biogen Inc. (Nasdaq:BIIB) reported it will report second quarter 2020 financial results Wednesday, July 22, 2020, before the financial markets open (Press release, Biogen, JUL 7, 2020, View Source [SID1234561755]).

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Following the release of the financials, the Company will host a live webcast with Biogen management at 8:00 a.m. ET. To access the live webcast, please go to the investors section of Biogen’s website at View Source Following the live webcast, an archived version of the call will be available on the website.

On July 7, 2020 Myriad Genetics, Inc. (NASDAQ: MYGN), a leader in molecular diagnostics and precision medicine, reported two recent publications validating the polygenic risk score (PRS) component of Myriad’s breast cancer risk stratification tool riskScore (Press release, Myriad Genetics, JUL 7, 2020, View Source [SID1234561739]). The publications clinically validate both the ability of the PRS component of riskScore to predict breast cancer risk in asymptomatic women and modify risk estimations for patients identified with pathogenic mutations.

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"Historically we’ve considered breast cancer risk most significant for women diagnosed with pathogenic mutations in hereditary cancer genes. These studies demonstrate clearly that other genetic factors evaluated through Myriad’s riskScore test can dramatically alter breast cancer risk both independent of, and in combination with, gene mutations," said Nicole Lambert, president of Myriad International, Oncology and Women’s Health. "This information can dramatically change patient clinical management and Myriad is currently working diligently to provide access to this important information for all women."

The first study published in JCO Precision Oncology described the PRS component of riskScore in over 150,000 women. It showed that independent of other hereditary breast cancer gene mutations (e.g., BRCA1), Myriad’s polygenic risk score can add great value and precision to breast cancer risk estimates. The PRS was highly associated with breast cancer risk with an odds ratio of 1.47 (95% confidence interval 1.45 to 1.49) per unit standard deviation in the PRS. This translated to women in the top PRS percentile having a three-fold higher risk of breast cancer than an average risk patient.

The second study published in the Journal of the American Medical Association Network Open demonstrates the ability of Myriad’s polygenic risk score to improve breast cancer risk stratification in women diagnosed with pathogenic mutations in common breast cancer genes. The study evaluated over 150,000 patients and approximately 10,000 patients who were carriers of pathogenic mutations in the BRCA1, BRCA2, CHEK2, ATM and PALB2 genes who were tested at Myriad. The study demonstrated that patients with high penetrant genes such as BRCA1 and BRCA2 did not warrant changes in clinical management; however, breast cancer risks in patients with moderate penetrant genes such as CHEK2, ATM, and PALB2 could vary significantly, warranting different clinical management considerations. For example, patients with a PALB2 mutation historically have been assessed to have an approximately 50 percent lifetime risk for breast cancer. However, after incorporating the data from Myriad’s 86 single nucleotide polymporphism (SNP) riskScore test, patient risks varied between 26 percent to 79 percent (see Graph 1 below).

"These are some of the largest polygenic risk score studies ever published. Patient medical management can vary dramatically depending on where patients with and without pathogenic mutations fall within the risk spectrum," said Thomas P. Slavin M.D., senior vice president for Medical Affairs in Oncology at Myriad Genetic Laboratories. "This information will help empower patients and clinicians to make more informed decisions based upon the most precise breast cancer risk estimates availiable."

About riskScore
riskScore is a new clinically validated personalized medicine tool that enhances Myriad’s myRisk Hereditary Cancer test. riskScore helps to further predict a women’s lifetime risk of developing breast cancer using clinical risk factors and genetic-markers throughout the genome. The test incorporates data from more than 80 single nucleotide polymorphisms identified through 20 years of genome wide association studies in breast cancer and was prospectively validated in our laboratory to predict breast cancer risk in women of European descent. This data is then combined with a best-in-class family and personal history algorithm, the Tyrer-Cuzick model, to provide every patient with individualized breast cancer risk.