On August 16, 2021 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has obtained manufacturing and marketing approval for the EZH2 inhibitor "Tazverik Tablets 200 mg" (tazemetostat hydrobromide) in Japan with the indication of relapsed or refractory EZH2 gene mutation-positive follicular lymphoma (only when standard treatment is not applicable) (Press release, Eisai, AUG 16, 2021, View Source [SID1234586585]).

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This approval is based on the results of a multicenter, open-label, single-arm clinical phase II trial (Study 206)1 in Japan conducted by Eisai and other studies2 conducted by Epizyme, Inc. (Headquarters: Massachusetts, United States) outside Japan. Study 206 enrolled patients with EZH2 gene mutation-positive, primarily follicular lymphoma, who had relapsed or were refractory. The primary endpoint of this study was objective response rate (ORR), and secondary endpoints included safety. This study achieved the primary endpoint target and exceeded a prespecified tumor response threshold with statistical significance: ORR in patients with EZH2 mutation-positive relapsed or refractory follicular lymphoma (n=17) was 76.5% (90% confidence interval (CI): 53.9-91.5) as measured by independent review. Treatment-emergent adverse events (incidence of 25% or more) observed in this study were dysgeusia (52.9%), nasopharyngitis (35.3%), lymphopenia (29.4%) and blood creatine phosphokinase increased (29.4%). Eisai will conduct a post-marketing special use results survey (all-case surveillance) in all patients who are administered "Tazverik" until a pre-determined number of patients has been reached in accordance with an approval condition imposed by the MHLW.

Created by utilizing Epizyme’s proprietary product platform, "Tazverik" is a first-in-class small molecule inhibitor of the epigenetic enzyme EZH2. It is one of the histone methyltransferases in the epigenetics-related protein group, and is thought to regulate the expression of cancer-related genes and suppress the growth of cancer cells by specifically targeting EZH2, which contributes to the cancer growth process.3 Eisai is responsible for the development and commercialization of this agent in Japan, while Epizyme, Inc. is responsible for all regions outside of Japan. In the United States, "Tazverik" received accelerated approval for the indication of epithelioid sarcoma in January 2020, and follicular lymphoma in June 2020 (Notes to editors 1).

Follicular lymphoma is a low-grade B-cell lymphoma that accounts for 10-20% of non-Hodgkin’s lymphomas. Follicular lymphoma is generally indolent and sensitive to chemotherapy. However, development of a new treatment strategy is required for follicular lymphoma which still remains difficult to cure, as recurrence often occurs repeatedly. 7-27% of follicular lymphomas are reported to have gain-of-function mutations in the EZH2 gene,4,5 and it is estimated that there are approximately 600 to 2,400 patients with follicular lymphoma with EZH2 gene mutations in Japan. A companion diagnostic test for EZH2 gene mutations, "cobas EZH2 Mutation Test" by Roche Diagnostics K.K. (Headquarters: Tokyo) was approved in May 2021.
　

Eisai aims to make continuous efforts to meet the diversified needs of and increase the benefits provided to patients with cancer, their families, and healthcare professionals, by delivering "Tazverik" as a new treatment option for EZH2 gene mutation-positive follicular lymphoma.　

1. About "Tazverik Tablets 200 mg" (tazemetostat hydrobromide, Development Code: E7438, Epizyme, Inc.’s Development Code: EPZ-6438)

"Tazverik" is a first-in-class, oral small molecule inhibitor that targets EZH2. Eisai and Epizyme, Inc. have conducted joint research and development with utilizing Epizyme, Inc.’s proprietary product platform, based on the alliance agreement concluded in March 2011 targeting EZH2 for research, development, and sales. This agent selectively inhibits EZH2 in a competitive matter with S-adenosylmethionine (a methyl group donor) to suppress methylation of H3K27. Due to the alteration in the alliance agreement between the two companies in March 2015, Eisai is responsible for development and commercialization of this agent in Japan, while Epizyme, Inc. is responsible for all regions outside Japan.

At the Kawashima Industrial Park located in Gifu Prefecture, Japan, the production site for this agent in Japan, Eisai has successfully developed the innovative pharmaceutical manufacturing technology so-called "Continuous Manufacturing", and has applied it to production. Continuous Manufacturing contributes to quality improvement and stable supply of pharmaceutical products by integrating manufacturing automation and real-time quality monitoring technology. In addition, Continuous Manufacturing is a technology that is attracting attention as a new pharmaceutical manufacturing method that can achieve high production efficiency with space saving and energy saving, and has a low environmental load. Eisai was one of the first to adopt Continuous Manufacturing system (CTS-MiGRA) and applied this technology to the production of this agent.

The accelerated approval was granted for this agent in January 2020 in the United States with the indication of "adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection". Also, in June of the same year, the accelerated approval was granted for this agent with the indication of "adult relapsed / refractory follicular lymphoma who had at least 2 regimens of prior treatment and whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test", and of "adult relapsed / refractory follicular lymphoma for which there are no satisfactory alternative treatment options".

2. About epigenetics

Epigenetics is a branch of science that studies the mechanism for the acquired activation/inactivation of gene function and seeks to determine how gene function is inherited through cell division, irrespective of DNA base sequence alteration. Examples of modification that lead to the regulation of gene expression include methylation of DNA and modifications of histone (methylation, acetylation, phosphorylation, etc.).

3. About EZH2

EZH2 is one of the histone methyltransferases within a larger class of epigenetics-related proteins, and specifically catalyzes the methylation of histone H3 at lysine 27 (H3K27), thus controlling expression of various genes. It is indicated that an increase in methylation of H3K27 caused by EZH2 gain-of-function mutation, overexpression, or the dysfunction of EZH2 suppressive factors plays an important role in carcinogenesis.

1 Shinya Rai, et al. Phase 2 Study of Tazemetostat in Japanese patients with Relapsed or Refractory EZH2 mutation-positive B-cell Non-Hodgkin’s Lymphoma. AACR (Free AACR Whitepaper) Meet. 2021, CT176.

2 Franck Morschhauser, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. The Lancet Oncology. 2020 Nov; 21(11):1433-1442.

3 Sarah K. Knutson, Satoshi Kawano, Yukinori Minoshima, et al. Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma. Molecular Cancer Therapeutics. 2014 Apr; 13(4):842–854.

4 Csaba Bödör, et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood, 2013 Oct; 122(18), 3165-3168.

5 Ryan D. Morin, et al. Somatic mutation of EZH2 (Y641) in Follicular and Diffuse Large B-cell Lymphomas of Germinal Center Origin. Nat Genet. 2010 February; 42(2): 181–185.

On August 16, 2021 Carrick Therapeutics, an oncology-focused biopharmaceutical company discovering and developing highly differentiated therapies, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designations to samuraciclib in combination with fulvestrant for CDK4/6i resistant HR+, HER2- advanced breast cancer and samuraciclib in combination with chemotherapy for the treatment of locally advanced or metastatic triple negative breast cancer (TNBC) (Press release, Carrick Therapeutics, AUG 16, 2021, View Source [SID1234586624]).

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"The FDA’s decision to grant Fast Track designations for both samuraciclib combinations underscores the urgent need for innovative therapies that can significantly improve HR+, HER2- advanced breast cancer and locally advanced or metastatic TNBC patient outcomes," said Tim Pearson, Chief Executive Officer of Carrick Therapeutics. "This is a meaningful milestone for our development in samuraciclib as we work to advance innovative combination treatment approaches for patients who have few treatment options available today."

The FDA’s Fast Track program is designed to facilitate and expedite the development of investigational treatments that demonstrate a potential to address unmet medical needs in serious or life-threatening conditions. Programs with Fast Track designation can benefit from early and frequent communication with the FDA in addition to a rolling submission of the marketing application.

Samuraciclib in combination with fulvestrant is currently being evaluated in a Phase 2a study for CDK4/6i resistant HR+, HER2- metastatic breast cancer and the Company expects to present the new data from the ongoing study at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 in September. Meanwhile, samuraciclib in combination with chemotherapy for the treatment of treatment of TNBC is currently undergoing IND-enabling studies.

About Fast Track Designation
Fast Track is a process designed to facilitate the development, and expedite the review of, drugs to treat serious conditions that address an unmet medical need, by providing a therapy where none exists or providing a therapy which may be potentially better and shows some advantage over available therapy. Fast Track designation includes opportunities for more frequent meetings with the FDA to discuss trial design, development plans, data needed to support drug approval, submission of a New Drug Application (NDA) on a rolling basis, and eligibility for accelerated approval and priority review, if relevant criteria are met.

Visit the FDA’s website for more information on Fast Track Designation.

About Samuraciclib (CT7001)
Samuraciclib is the most advanced oral CDK7 inhibitor in clinical development. Inhibiting CDK7 is a promising therapeutic strategy in cancer as CDK7 regulates the transcription of cancer-causing genes, promotes uncontrolled cell cycle progression and resistance to anti-hormone therapy. Samuraciclib has demonstrated a favorable safety profile and encouraging efficacy in early clinical studies. Samuraciclib has been granted Fast Track designations from the U.S. Food and Drug Administration (FDA) for use in combination with fulvestrant for the treatment of CDK4/6i resistant HR+, HER2- advanced breast cancer and samuraciclib in combination with chemotherapy for the treatment of locally advanced or metastatic triple negative breast cancer (TNBC).

On August 16, 2021 Centessa Pharmaceuticals plc (Nasdaq: CNTA), a clinical-stage company leveraging its innovative asset-centric business model to discover, develop and ultimately deliver impactful medicines to patients, reported financial results for the quarter ended June 30, 2021, and provided a review of recent accomplishments and anticipated upcoming milestones (Press release, Centessa Pharmaceuticals, AUG 16, 2021, View Source [SID1234586641]).

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"Centessa has made significant progress since launch and completion of our $250 million Series A financing in January," said Saurabh Saha, M.D., Ph.D., Chief Executive Officer of Centessa. "The successful execution of our upsized initial public offering in the second quarter has substantially enhanced our resources and will support the advancement of our broad portfolio of assets across our 10 subsidiary companies. This added capital, together with the appointment of exceptional industry leaders in key functional areas across the organization, positions us for continued success. We look forward to sharing our progress, including a planned Phase 2a data update from ApcinteX in the coming weeks."

Business Updates

$379.5 Million Initial Public Offering (IPO) Successfully Completed: In the second quarter, Centessa closed its initial public offering of 16,500,000 American Depositary Shares (ADSs). In addition, the underwriters fully exercised their option to purchase an additional 2,475,000 ADSs at the IPO price of $20.00 per ADS, less underwriting discounts and commissions. The gross proceeds to Centessa from its IPO, before deducting underwriting discounts, commissions and other estimated offering expenses, totaled an aggregate of $379.5 million.

Leadership Team Strengthened by Appointment of Key Industry Executives: In May, Centessa announced the leadership appointments of Antoine Yver, M.D., M.Sc., Chief Medical Officer; Tia Bush, Chief Quality Officer; David Chao, Ph.D., Chief Administrative Officer; and Thomas Templeman, Ph.D., Chief Technology Officer. In addition, Marella Thorell was promoted to Chief Accounting Officer, and Carol Stuckley joined the Board of Directors, serving as Chairperson of the Audit Committee. Each of these leaders provides significant expertise in their respective functions and will help drive execution across the Company’s portfolio of programs.
Program Updates and Upcoming Milestones in the Second Half of 2021

Topline Phase 2a data from ApcinteX’s 24-week repeat dose study evaluating SerpinPC in hemophilia A (HA) and hemophilia B (HB) patients
SerpinPC, a first-in-class coagulation rebalancing agent, is a specific inhibitor of activated protein C (APC) being evaluated as a monthly subcutaneous therapeutic for HA and HB patients that has the potential to significantly reduce bleeding rates.
The Phase 2a has completed dosing and the Company anticipates sharing topline results in the third quarter of 2021.
All subjects who have completed the 24-week repeat dose portion of the study have elected to roll-over into a long-term open-label extension study.
Start-up activities have begun for the ACTION Study, Palladio Biosciences’ global Phase 3 registrational study of lixivaptan in autosomal dominant polycystic kidney disease (ADPKD)
Lixivaptan, a vasopressin V2 receptor antagonist, is being investigated as a potential best-in-class therapy in patients with ADPKD.
The Company anticipates dosing the first patient in the registrational ACTION Study in the first quarter of 2022.
The Company expects to report ongoing safety data from the initial subjects in the open-label ALERT Study of patients who previously discontinued JYNARQUE (tolvaptan) due to liver toxicity in the fourth quarter of 2021.
Phase 1 data from Z Factor’s study evaluating ZF874 for the treatment of alpha-1-antitrypsin deficiency (AATD)
ZF874, a small molecule folding corrector of the Z variant of alpha-1-antitrypsin, is designed to increase serum levels of alpha-1-antitrypsin and reduce liver polymer burden to treat or prevent associated lung and liver disease manifestations associated with AATD.
The Company anticipates providing an update from an ongoing 28-day repeat dose Phase 1 study in subjects with PiXZ genotype by the end of 2021.

Phase 2 trial initiation with Pega-One’s imgatuzumab in advanced cutaneous squamous cell carcinoma (CSCC)
Imgatuzumab, a non-fucosylated epidermal growth factor receptor (EGFR) targeting monoclonal antibody (mAb), is being investigated as a next-generation EGFR agent with enhanced Antibody-Dependent Cellular Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP) properties to potentially address CSCC.
The Company expects to initiate an open label, single arm, Phase 2 trial of imgatuzumab in advanced CSCC by the end of 2021.
Second Quarter 2021 Financial Results

Cash Position: Cash and cash equivalents were $613.8 million as of June 30, 2021, compared to $7.2 million for the Centessa Predecessor Group (comprised of Z Factor Limited, LockBody Therapeutics Ltd, and Morphogen-IX Limited, three of the Centessa Subsidiaries acquired in January 2021) as of December 31, 2020. The increase in cash resulted from $344.1 million in net proceeds from the Company’s initial public offering completed in June 2021, and the full exercise of the underwriters’ option to purchase additional shares, $241.6 million in net proceeds from the Company’s Series A financing completed in January 2021, and cash contributed upon the acquisition of the additional Centessa Subsidiaries, net of cash used during the period. Based on the current, non-risk-adjusted operating plan, the Company expects the cash and cash equivalents as of June 30, 2021, to fund its operations until the end of 2023.

Research & Development (R&D) Expenses: R&D expenses for the Company for the three months ended June 30, 2021, were $18.1 million, compared to $1.9 million for the Centessa Predecessor Group during the three months ended June 30, 2020. The $16.2 million increase is primarily attributable to the growth in the portfolio of product candidates under development following the acquisition of the Centessa Subsidiaries in January 2021, as well as increased spending in the Centessa Predecessor Group.

General & Administrative (G&A) Expenses: G&A expenses for the Company for the three months ended June 30, 2021. were $11.8 million, compared to $0.3 million for the Centessa Predecessor Group during the three months ended June 30, 2020. The $11.5 million increase is primarily attributable to public company costs, the operating costs of Centessa Pharmaceuticals plc and Centessa Pharmaceutical Inc. including professional fees, personnel costs and share-based compensation expense, and the increase in operating costs resulting from the acquired Centessa Subsidiaries.

Change in Fair Value of Contingent Value Rights (CVR): The Company recognized a charge of $11.3 million for the three months ended June 30, 2021, compared to $0.0 million for the three months ended June 30, 2020. The CVR, issued at the time of the acquisition, represents future payments (that will be satisfied through the issuance of Centessa shares) that are contingent upon the dosing of the first patient in a registrational Phase 3 study of Palladio Biosciences’ lixivaptan. The fair value is based on the cumulative probability of achieving this milestone, which increased during the period resulting in the charge.

Net Loss: Net Loss attributable to common stockholders for the quarter ended June 30, 2021, was $41.5 million, or $0.65 per share, compared to a net loss of $2.2 million for the Centessa Predecessor Group for the quarter ended June 30, 2020.

On August 16, 2021 Gracell Biotechnologies Inc. (NASDAQ: GRCL) ("Gracell"), a global clinical-stage biopharmaceutical company dedicated to developing highly efficacious and affordable cell therapies for the treatment of cancer, reported an exclusive license agreement with FutureGen Biopharm ("FutureGen"), an innovative biopharmaceutical company, to develop engineered immune cell therapies targeting Claudin 18.2 ("CLDN18.2") in solid tumors (Press release, Gracell Biotechnologies, AUG 16, 2021, View Source [SID1234586657]).

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The collaboration aims to leverage Gracell’s extensive experience in immune cell therapy in synergy with FutureGen’s fully human CLDN18.2 antibodies to develop, manufacture and commercialize novel immune cell therapies for the treatment of patients with CLDN18.2 positive cancers.

CLDN18.2 is a tumor-specific marker that is overexpressed in a variety of tumor tissues, including in gastric or gastroesophageal junction cancers, pancreatic cancers and esophageal cancers, but rarely expressed in normal human tissues. This feature supports the therapeutic potential of CLDN18.2 as a key target for immune cell therapies. In particular, gastric cancer (around 70%[1] CLDN18.2 expression) is among the most frequently diagnosed malignancies worldwide and the second leading cause of cancer-related death. An estimated 1,033,701 new cases and 782,685 deaths occurred in 2018[2], representing a highly unmet medical need in treating gastric cancer.

"Gracell has been making significant progress in developing innovative CAR-T therapies for solid tumors as well as hematological malignancies," Dr. William (Wei) Cao, Founder, Chairman and Chief Executive Officer of Gracell said. "This partnership with FutureGen marks another key milestone in our persistent efforts for treating solid tumors. Moving forward, we expect to explore more strategic alliances to identify additional targets that maximize the value of our highly differentiated technology platforms and eventually benefit cancer patients worldwide."

"Gracell has been optimizing its proprietary Enhanced CAR technology to improve CAR-T cell persistence and efficacy in solid tumors. The preliminary clinical investigator-initiated trial data of our first generation Enhanced CAR-T for solid tumors has shown tolerability and preliminary efficacy. These initial results have been accepted to be published soon in Cellular & Molecular Immunology," said Dr. Lianjun Shen, Senior Vice President, Head of Research and Development at Gracell. "We are very excited to partner with FutureGen to develop next generation immune cell therapies against CLDN18.2-expressing malignancies, and hope to unlock significant potential of our next generation Enhanced CAR-T therapies for solid tumors, one of our founding missions."

Dr. Zhaoyu Jin, the Founder and Chief Executive Officer of FutureGen said, "The specific CLDN18.2 antibody has been developed through our innovative STEP and CAP technology platforms. The fine-tuned affinity of antibody for CAR-T application may eliminate CLDN18.2 positive tumor cells more specifically with better safety profile. We are very excited to collaborate with Gracell, a lead company in the cell and gene therapy industry, to leverage their innovative Enhanced CAR-T technology platform and experience in the field and our proprietary cutting-edge technologies to develop advanced treatments across solid tumors."

Under the terms of the agreement, FutureGen will receive an upfront payment and will be eligible to receive additional payments based on the achievement of non-clinical validation, clinical development and commercialization milestones, as well as low single-digit royalties.

About CLDN18.2

CLDN18.2, a small transmembrane protein with four transmembrane domains and two extracellular loops, is overexpressed in a significant proportion of gastric cancers and esophageal adenocarcinomas. The restricted expression makes it a promising target for the treatment of gastric or gastroesophageal junction cancers, pancreatic cancers, etc. Overall, CLDN18.2 is prevalently expressed in the cancer tissues of approximately 70% of gastric cancer patients and approximately 60% of pancreatic cancer patients. CLDN18.2-specific antibodies developed to target CLDN18.2 have exhibited anti-tumor activity in preclinical studies.[3]

About Enhanced CAR

Enhanced CAR is Gracell’s proprietary technology that further strengthens the functionality of CAR-T cells, for example by overcoming the immunosuppressive tumor micro-environment (TME) and/or increasing cytokine signaling. Gracell utilizes gene editing technologies to edit some check point inhibitor(s) or/and cytokine(s) or cytokine receptor(s) on CAR-T cells to release potential suppression from tumor cells and other suppressive immune cells in tumor tissue to enhance CAR-T cells’ functionality. Our second generation Enhanced CAR technology can be implemented to many other targets in several types of solid tumors.

On August 16, 2021 Novo Nordisk reported that it 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 16, 2021, View Source [SID1234586625]). This programme is part of the overall share repurchase programme of up to DKK 18 billion to be executed during a 12-month period beginning 3 February 2021.

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Under the programme initiated 4 August 2021, Novo Nordisk will repurchase B shares for an amount up to DKK 3.3 billion in the period from 5 August 2021 to 1 November 2021.

Since the announcement of the programme, the following transactions have been made:

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

Transactions related to Novo Nordisk’s incentive programmes have resulted in a net transfer from Novo Nordisk of 32,026 B shares in the period from 5 August 2021 to 13 August 2021. The shares in these transactions were not part of the Safe Harbour repurchase programme.

With the transactions stated above, Novo Nordisk owns a total of 18,096,886 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 2,310,000,000 including treasury shares.

Novo Nordisk expects to repurchase B shares for an amount up to DKK 18 billion during a 12- month period beginning 3 February 2021. As of 13 August 2021, Novo Nordisk has since 3 February 2021 repurchased a total of 19,290,414 B shares at an average share price of DKK 479.66 per B share equal to a transaction value of DKK 9,252,771,246.