On August 22, 2022 The Medical Device Innovation Consortium (MDIC) reported that launched its Somatic Reference Samples (SRS) Initiative with a pilot project to improve the validation and regulatory review process for cancer diagnostics based on next generation sequencing (NGS) (Press release, PerkinElmer, AUG 22, 2022, View Source [SID1234618542]).

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MDIC will lead a collaboration with the U.S. Food and Drug Administration (FDA), the National Institute of Standards and Technology (NIST), National Institutes of Health (NIH) and industry stakeholders to manufacture, validate, and distribute SRSs to simplify and support validation of NGS-based cancer diagnostics. The initiative also includes the goal to create a publicly available global genomic data resource library of datasets with the potential to be used by sponsors and regulators.

"NGS is a powerful technology enabling breakthroughs in diagnostics and ultimately therapeutics. These diagnostic tests need to be validated for accurate clinical use, and reference samples are essential to the validation process. But well-characterized and widely accepted reference materials do not exist for NGS-based diagnostics, complicating the development and validation process," said Andrew Fish, President and CEO, MDIC. "Through the MDIC SRS Initiative, we are developing reference samples and data sets that can be used globally by test developers and regulators to bring more consistency to NGS-based cancer diagnostic development, increasing the confidence and accuracy of these tests, which will ultimately lead to more accuracy in diagnosis and treatment for patients."

"There is a need for appropriately consented, highly characterized, and broadly available reference materials that may improve the accuracy, reliability, and transparency of NGS-based oncology tests and support the generation of validation data for use in regulatory submissions. The reference samples and datasets being created by the MDIC Somatic Reference Samples Initiative can help fulfill this need," said Wendy Rubinstein, MD, PhD, Director, Personalized Medicine, Center for Devices and Radiological Health, U.S. Food and Drug Administration.

Horizon Discovery, a PerkinElmer company, is conducting the development and manufacture of these reference samples. The goal of this pilot project is to individually engineer 10 gene variants clinically associated with cancer into a highly characterized human cell line – GM24385 (PGP/GIAB) – using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology resulting in ten edited human cell lines, each containing one gene variant clinically associated with one or more specific cancers. The cell lines, containing confirmed sequences, will be combined and available in FFPE format. The fully characterized reference samples will be commercially available to the end users from Horizon and the characterization data will be accessible through public databases, including precisionFDA, an FDA-sponsored site for data information, sequencing, and bioinformatics.

NIST’s involvement in this work is to foster understanding.* "As our collaboration validates the MDIC SRS samples, we will also learn and build best practices to improve the efficiency and sustainability of reference sample validation and dataset generation in general. This project is a major step in the development and optimization of new sequencing technologies and the translation of DNA sequencing to clinical applications for diagnosing and treating cancer," said Justin Zook, PhD, Co-Leader, Biomarker and Genomic Sciences Group, National Institute of Standards and Technology.

MDIC’s SRS project began as a working group in 2018, representing more than forty stakeholders with a mission to address the gap in reference material for NGS-based diagnostic tests. The initial output of this working group, MDIC’s SRS Landscape Analysis, published in 2019, was a comprehensive catalog of existing clinically relevant cancer variants and available reference samples. Based on the unmet needs discovered through the SRS Landscape Analysis, the SRS Initiative has prioritized a subset of ten variants to be engineered into reference samples for the pilot project. In addition to the utility of these samples in development, validation, and regulatory review, these samples potentially have value in reimbursement decisions, post-market monitoring and informing the path forward for addition SRS.

The work in the SRS Initiative is funded in part by the Gordon and Betty Moore Foundation (Grant GBMF), the National Philanthropic Trust, Illumina, and Quidel.

* Affiliation with a commercial product does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose.

On August 22, 2022 Novo Nordisk reported that initiated a share repurchase programme in accordance with Article 5 of Regulation No 596/2014 of the European Parliament and Council of 16 April 2014 (MAR) and the Commission Delegated Regulation (EU) 2016/1052 of 8 March 2016 (the "Safe Harbour Rules") (Press release, Novo Nordisk, AUG 22, 2022, View Source [SID1234618541]). This programme is part of the overall share repurchase programme of up to DKK 24 billion to be executed during a 12-month period beginning 2 February 2022.

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Under the programme initiated 3 August 2022, Novo Nordisk will repurchase B shares for an amount up to DKK 4.4 billion in the period from 4 August 2022 to 31 October 2022.

Since the announcement 15 August 2022, the following transactions have been made:

The details for each transaction made under the share repurchase programme are published on novonordisk.com.

With the transactions stated above, Novo Nordisk owns a total of 18,703,211 B shares of DKK 0.20 as treasury shares, corresponding to 0.8% of the share capital. The total amount of A and B shares in the company is 2,280,000,000 including treasury shares.

Novo Nordisk expects to repurchase B shares for an amount up to DKK 24 billion during a 12-month period beginning 2 February 2022. As of 19 August 2022, Novo Nordisk has since 2 February 2022 repurchased a total of 16,992,432 B shares at an average share price of DKK 767.29 per B share equal to a transaction value of DKK 13,038,186,830.

On August 22, 2022 Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, reported that the first patient has been dosed in IMproveMF, a Phase 1 study evaluating imetelstat, a first-in-class telomerase inhibitor, in combination with ruxolitinib in patients with frontline myelofibrosis (MF) (Press release, Geron, AUG 22, 2022, View Source [SID1234618540]).

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"We designed the Phase 1 IMproveMF study based on preclinical data that showed the sequential treatment of ruxolitinib followed by imetelstat had a selective inhibitory effect on malignant MF stem cells, while sparing normal hematopoietic stem cells. This disease-modifying potential of imetelstat to affect the malignant clones driving disease progression differentiates it from any other drug currently approved or in development for myelofibrosis treatment," said Faye Feller, MD, Executive Vice President, Chief Medical Officer of Geron. "Given these preclinical data, we want to explore the potential for disease modification with imetelstat in the earlier, frontline disease setting. In parallel, our separate IMpactMF Phase 3 trial is ongoing in MF patients who are relapsed/refractory to JAK inhibitors. This Phase 3 trial is designed to confirm the results from the IMbark Phase 2 study where single-agent imetelstat treatment resulted in multiple clinically meaningful benefits, including symptom response and potential improvement in overall survival."

"Upon diagnosis, intermediate-2 and high-risk myelofibrosis patients typically receive ruxolitinib as the primary therapy, which reduces enlarged spleens and alleviates symptoms, but does not change the course of the disease. As a non-JAK inhibitor treatment option with a potentially novel mechanism of action, imetelstat could provide an additive benefit of disease modification when combined with ruxolitinib," said John Mascarenhas, MD, Professor of Medicine at the Icahn School of Medicine at Mount Sinai and a principal investigator on the IMproveMF study. "The dosing of the first patient is an important step in identifying a potential safe and efficacious dose and schedule of imetelstat and ruxolitinib in frontline MF."

IMproveMF is a single arm, open label, two-part Phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of imetelstat in combination with ruxolitinib as a frontline treatment in patients with Intermediate-2 or High-risk MF (frontline MF). In both parts, patients will receive ruxolitinib followed by imetelstat, a dosing schedule that showed synergistic and additive effects of the two drugs in preclinical experiments. Part 1 will enroll up to 20 frontline MF patients who, at the time of enrollment, have received an optimized dose of ruxolitinib, to which imetelstat treatment will be added at increasing dose levels based on safety and tolerability. The primary purpose of Part 1 is to identify a safe dose for treating frontline MF patients with a combination of imetelstat and ruxolitinib. If a safe dose is identified in Part 1, participants in Part 2 will be JAK inhibitor naïve and will receive treatment with ruxolitinib after screening and enrollment at a starting dose based on standard-of-care or local prescribing information. Treatment with single-agent ruxolitinib will continue for at least 12 weeks, including four consecutive weeks at a stable dose prior to the addition of imetelstat. Part 2 is designed to confirm the safety profile of imetelstat in combination with ruxolitinib and to evaluate for preliminary clinical activity of the combination. Geron expects to present preliminary results from this study by the end of 2023.

The study is enrolling patients and is being conducted at three trial sites in the U.S., two of which are currently open for patient screening. For more information, please visit ClinicalTrials.gov (Identifier NCT05371964).

About Imetelstat

Imetelstat is a novel, first-in-class telomerase inhibitor exclusively owned by Geron and being developed in hematologic malignancies. Data from Phase 2 clinical trials provide strong evidence that imetelstat targets telomerase to inhibit the uncontrolled proliferation of malignant stem and progenitor cells in myeloid hematologic malignancies resulting in malignant cell apoptosis and potential disease-modifying activity. Imetelstat has been granted Fast Track designation by the United States Food and Drug Administration for both the treatment of patients with non-del(5q) lower risk MDS who are refractory or resistant to an erythropoiesis stimulating agent and for patients with Intermediate-2 or High-risk MF whose disease has relapsed after or is refractory to janus associated kinase (JAK) inhibitor treatment.

On August 22, 2022 Fennec Pharmaceuticals Inc. (NASDAQ:FENC; TSX: FRX), a specialty pharmaceutical company, reported it has completed the first closing of US$5 million of senior secured promissory notes under our previously announced investment agreement with Petrichor Healthcare Capital Management (Press release, Fennec Pharmaceuticals, AUG 22, 2022, View Source [SID1234618539]). Under the terms of the investment agreement, an additional $20 million is to be funded upon the potential U.S. Food and Drug Administration (FDA) approval of PEDMARKTM by September 30, 2022 and satisfaction of other closing conditions. Further, Fennec upon mutual agreement with Petrichor may draw up to $20 million of additional financing under the investment agreement.

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In connection with the first closing, the Company repaid in full its secured indebtedness with Bridge Bank.

Further information surrounding the investment agreement will be set forth in the Current Report on Form 8-K to be filed by the Company with the SEC on or about August 22, 2022. The offer and sale of the notes and the shares of common stock issuable upon conversion of the notes, if any, have not been registered under the Securities Act of 1933, as amended, or the securities laws of any other jurisdiction, and the notes and such shares may not be offered or sold absent registration with the U.S. Securities and Exchange Commission (the "SEC") or an applicable exemption from registration requirements, or in a transaction not subject to, such registration requirements. We are relying upon the exemption set forth in Section 602.1 of the TSX Company Manual, which provides that the TSX will not apply its standards to certain transactions involving eligible interlisted issuers on a recognized exchange, such as Nasdaq.

No regulatory authority has either approved or disapproved the contents of this press release. This press release is neither an offer to sell nor a solicitation of an offer to buy the notes or the shares of common stock issuable upon conversion of the notes, if any, nor shall there be any sale of these securities in any state or jurisdiction in which such an offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or jurisdiction.

About PEDMARK

Cisplatin and other platinum compounds are essential chemotherapeutic agents for many pediatric malignancies. Unfortunately, platinum-based therapies cause ototoxicity, or hearing loss, which is permanent, irreversible and particularly harmful to the survivors of pediatric cancer.

In the U.S. and Europe, it is estimated that, annually, over 10,000 children may receive platinum-based chemotherapy. The incidence of ototoxicity depends upon the dose and duration of chemotherapy, and many of these children require lifelong hearing aids. There is currently no established preventive agent for this hearing loss and only expensive, technically difficult and sub-optimal cochlear (inner ear) implants have been shown to provide some benefit. Infants and young children that suffer ototoxicity at critical stages of development lack speech language development and literacy, and older children and adolescents lack social-emotional development and educational achievement.

PEDMARK has been studied by cooperative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity, The Clinical Oncology Group Protocol ACCL0431 and SIOPEL 6. Both studies have been completed. The COG ACCL0431 protocol enrolled childhood cancers typically treated with intensive cisplatin therapy for localized and disseminated disease, including newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, and medulloblastoma. SIOPEL 6 enrolled only hepatoblastoma patients with localized tumors.

The U.S. Food and Drug Administration (FDA) has accepted for filing the Company’s resubmitted New Drug Application (NDA) for PEDMARKTM (a unique formulation of sodium thiosulfate (STS)) for the prevention of platinum-induced ototoxicity in pediatric patients with localized, non-metastatic, solid tumors. The PDUFA target action date for the NDA is September 23, 2022. The Marketing Authorization Application (MAA) for sodium thiosulfate (tradename PEDMARQSI) is currently under evaluation by the European Medicines Agency (EMA). PEDMARK has received Breakthrough Therapy and Fast Track Designation by the FDA in March 2018.

On August 22, 2022 Astex Pharmaceuticals, Inc. (Astex) reported that the European Medicines Agency (EMA) has accepted the Marketing Authorisation Application (MAA) for the oral fixed-dose combination of decitabine and cedazuridine (ASTX727) for the initial treatment of adults with acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy (Press release, Astex Pharmaceuticals, AUG 22, 2022, View Source [SID1234618537]).

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The current standard of care for AML is hospital-administered intravenous (IV) chemotherapy infusions or, for those patients not eligible for chemotherapy, parenterally administered hypomethylating agents, with treatment cycles typically extending for a week or more1. Fatigue can significantly restrict daily activities and reduce health-related quality of life2. If approved, oral decitabine and cedazuridine would be the first and only oral hypomethylating agent licensed in the European Economic Area (EEA) for the initial treatment of adults with AML who are ineligible for intensive chemotherapy, offering a potentially more convenient administration regimen.

The MAA is supported by results from the Phase 3 ASCERTAIN clinical trial investigating the pharmacokinetic (PK) exposure equivalence of the novel oral fixed-dose combination versus IV decitabine3.

The ASCERTAIN study met its primary endpoint, with the orally administered decitabine and cedazuridine fixed-dose combination showing exposure equivalence to a standard 5-day regimen of IV decitabine using a two-cycle cross-over study design. Safety findings for the fixed-dose combination of decitabine and cedazuridine were generally consistent with those anticipated for IV decitabine3.

In December 2021, the oral decitabine and cedazuridine fixed-dose combination was granted orphan drug designation by the European Commission which entitles companies to ten years of market exclusivity once the product is approved in the EU4. This status signifies that the oral decitabine and cedazuridine fixed-dose combination is considered to be a medicine that may potentially benefit those affected by this rare, life-threatening condition. In April 2022, the EMA agreed to a Paediatric Investigation Plan (PIP) in the EU for the oral decitabine and cedazuridine fixed-dose combination, representing an important milestone for the prospect of furthering clinical studies in children with AML. If granted, a paediatric extension would add a further two years of market exclusivity.

About decitabine and cedazuridine fixed-dose combination (ASTX727)
ASTX727 is an orally administered, fixed dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine5, an inhibitor of cytidine deaminase6. By inhibiting cytidine deaminase in the gut and the liver, the fixed dose combination is designed to allow for oral delivery of decitabine over five days in a given cycle to achieve comparable systemic exposure to IV decitabine administered over five days.

The oral decitabine and cedazuridine fixed-dose combination has been evaluated in a Phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study, and a Phase 3 exposure equivalence study in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) – the ASCERTAIN study. The ASCERTAIN study was expanded to include AML patients who were not candidates for standard induction chemotherapy. The Phase 1 and Phase 2 clinical study results have been published in Lancet Haematology7 and Blood8 respectively, and the Phase 3 results have been presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 20199, the International Congress on Myelodysplastic Syndromes in September 202110, and the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress in June 20223.

Indications
Oral decitabine and cedazuridine fixed-dose combination is approved under the brand name INQOVI in the U.S. and Canada for the 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 groups11,12.

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%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of INQOVI dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

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 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 (55%), constipation (44%), hemorrhage (43%), myalgia (42%), mucositis (41%), arthralgia (40%), nausea (40%), dyspnea (38%), diarrhea (37%), rash (33%), dizziness (33%), febrile neutropenia (33%), edema (30%), headache (30%), cough (28%), decreased appetite (24%), upper respiratory tract infection (23%), pneumonia (21%), and transaminase increased (21%). The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased (81%), platelet count decreased (76%), neutrophil count decreased (71%), and hemoglobin decreased (55%).

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 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).

Please see full Prescribing Information.

Commercialization of INQOVI in the U.S. and Canada is conducted by Taiho Oncology, Inc. and Taiho Pharma Canada, Inc., respectively.

OTHER APPROVALS
INQOVI is also approved in Australia for the treatment of adult patients with MDS intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups, and patients with CMML13

About acute myeloid leukemia (AML)
AML is the most common form of acute leukemia in adults14. The median age at diagnosis is approximately 70 years1. Within Europe, the incidence of AML is increasing; this may be attributed to the aging population: AML incidence in Europe has risen from 3.48 in 1976 to 5.06 patients per 100,000 population in 20131. Across Europe and all age groups, AML is notably more common in males than it is in females1. The outlook for patients diagnosed with AML has improved over time due to improved care and treatment, however between the years of 2000 and 2007, five-year survival for patients was just 17%1.

About Otsuka
Otsuka Pharmaceutical is a global healthcare company with the corporate philosophy: "Otsuka-people creating new products for better health worldwide." Otsuka researches, develops, manufactures and markets innovative products, focusing on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health. In pharmaceuticals, Otsuka is a leader in the challenging area of mental health and also has research programs in several under-addressed diseases including tuberculosis, a significant global public health issue.

The Otsuka group of companies employed 47,000 people worldwide with consolidated sales of approximately €11.6 billion and a spend of €1.8 billion on research and development in 2021.

Otsuka, the Otsuka logo, Astex, the Astex logo, and INQOVI are registered trademarks of Otsuka Holdings Co., Ltd. or its subsidiaries.