On December 23, 2022 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) and Nippon Shinyaku Co., Ltd. (TOKYO: 4516) reported that Chugai obtained regulatory approval today from the Ministry of Health, Labour and Welfare (MHLW) for an anti-cancer agent/humanized anti-CD20 monoclonal antibody Gazyva Intravenous Infusion 1000 mg [generic name: obinutuzumab (genetical recombination)] for an additional indication of CD20-positive chronic lymphocytic leukemia (including small lymphocytic lymphoma) (Press release, Chugai, DEC 23, 2022, View Source [SID1234625551]).

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"We are very pleased that this line extension enables us to offer the combination treatment as a new treatment option for patients with chronic lymphocytic leukemia (CLL)," said Chugai’s President and CEO, Dr. Osamu Okuda. "CLL has a long disease course. We will continue to provide information on efficacy and safety of Gazyva for the benefit of patients with CLL ."

"We are very pleased that Gazyva has become a new option for the treatment of chronic lymphocytic leukemia (CLL), and to be able to meet medical needs," said Nippon Shinyaku’s President, Toru Nakai. "We hope for Gazyva to become a contribution for treating patients with CLL, and will continue to promote information provision activities for the proper use of Gazyva."

The approval is based on data including the phase III ELEVATE-TN study, conducted by AstraZeneca, which evaluated the efficacy and safety of Gazyva and acalabrutinib (Bruton’s tyrosine kinase (BTK) inhibitor, product name Calquence) in patients with untreated CLL. The study showed that the combination of Gazyva and acalabrutinib significantly improved progression free survival compared to the combination of Gazyva and chlorambucil (hazard ratio: 0.10, 95% confidence interval: 0.06-0.17, p value < 0.0001). Major adverse reactions were neutropenia, headache, diarrhea, contusion, fatigue, nausea, thrombocytopenia, rash, arthralgia, petechiae, dizziness and anemia.

About ELEVATE-TN study
ELEVATE-TN (ACE-CL-007, NCT02475681) study is a randomized, multicenter, open-label Phase III trial evaluating the safety and efficacy of acalabrutinib in combination with obinutuzumab or acalabrutinib alone versus chlorambucil (unapproved) in combination with obinutuzumab in previously untreated patients with CLL. In the study, 535 patients are randomized 1:1:1 to following groups: chlorambucil plus obinutuzumab, acalabrutinib plus obinutuzumab, and acalabrutinib monotherapy.

The primary endpoint is IRC-assessed progression-free survival (PFS) with acalabrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab. The secondary endpoint is IRC-assessed PFS with acalabrutinib monotherapy versus chlorambucil plus obinutuzumab. Other secondary endpoints are overall response rate, time to next treatment, safety and overall survival etc.1)

Approval Information *Newly added description

Indications:
CD20-positive chronic lymphocytic leukemia (including small lymphocytic lymphoma)

Dosage and administrations:
When used in combination with acalabrutinib, the usual adult dose of obinutuzumab (genetical recombination) is 100 mg infused intravenously on Day 1 of Cycle 1 concomitant with acalabrutinib, 900 mg on Day 2, and 1000 mg on Days 8 and 15, and then 1000 mg on Day 1 of Cycle 2 and subsequent cycles. One cycle is 28 days, and administration is repeated for up to 6 cycles.

Precautions concerning dosage and administrations (Excerpt version):
Start administration of GAZYVA after administering acalabrutinib for 28 days.

About Gazyva (obinutuzumab)
Gazyva is a glycoengineered type II anti-CD20 monoclonal antibody designed to bind to CD20, a protein expressed on certain B cells, but not on stem cells or plasma cells. Gazyva is designed to attack and destroy targeted B cells both directly and together with the body’s immune system. Chugai and Nippon Shinyaku jointly develop and market the product in Japan.

About chronic lymphocytic leukemia (CLL)
In CLL, blood stem cells in the bone marrow become excessive abnormal lymphocytes and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows there is less room for healthy white blood cells, red blood cells, and platelets.2) This could result in anemia, infection, and bleeding. Small lymphocytic lymphoma is the same type of cancer as CLL. When lymphocytes are not located in the peripheral blood or bone marrow, the disease is called small lymphocytic lymphoma.3) CLL/ small lymphocytic lymphoma is a rare type of lymphoma accounting for less than one case in 100,000 population annually in Japan.4) B-cell receptor signaling through BTK is one of the essential growth pathways for CLL.

On December 22, 2022 (the "Effective Date"), Akebia Therapeutics, Inc. (the "Company"), Keryx Biopharmaceuticals, Inc., a wholly-owned subsidiary of the Company ("Keryx"), and Averoa SAS ("Averoa") entered into a License Agreement (the "License Agreement") pursuant to which the Company granted to Averoa an exclusive license to develop and commercialize ferric citrate (the "Licensed Product") in the European Economic Area, Turkey, Switzerland and the United Kingdom (the "Territory") (Filing, 8-K, Akebia, DEC 22, 2022, View Source [SID1234625633]).

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Under the License Agreement, the Company is entitled to receive tiered, escalating royalties ranging from a mid-single digit percentage to a low double-digit percentage of Averoa’s annual net sales of the Licensed Product in the Territory, including certain minimum royalty amounts in certain years, and subject to reduction in certain circumstances. The royalties will expire on a country-by-country basis upon the latest to occur of (a) 10 years following the date of first commercial sale of the Licensed Product in such country; (b) expiration of the last valid claim of Company patent rights and joint patent rights in such country; and (c) the date of expiration of the data, regulatory, or marketing exclusivity period conferred by the applicable regulatory authority in such country with respect to the Licensed Product.

The Company and Averoa will establish a joint steering committee to oversee the development, manufacturing and commercialization of the Licensed Product in the Territory.

The License Agreement expires on the date of expiration of all royalty obligations due thereunder with respect to the Licensed Product on a country-by-country basis in the Territory, unless earlier terminated in accordance with the agreement. Either party may, subject to a cure period, terminate the License Agreement in the event of the other party’s uncured material breach. Averoa has the right to terminate the License Agreement for convenience upon 12 months’ prior written notice delivered on or after the date that is 12 months after the Effective Date. In addition, Averoa has the right to terminate the License Agreement upon 30 days’ notice if the European Medicines Agency (EMA) rejects Averoa’s marketing authorization application ("MAA") for the Licensed Product and the parties in good faith agree that submitting a new MAA to the EMA will not result in approval. The License Agreement includes customary terms relating to, among others, indemnification, confidentiality, remedies, and representations and warranties.

The License Agreement provides that the Company and Averoa will enter into a supply agreement pursuant to which the Company will supply the Licensed Product to Averoa for commercial use in the Territory. The Company will have the right to terminate the Supply Agreement for convenience upon 24 months’ notice, which may be provided on or after January 1, 2024.

The foregoing description of the License Agreement does not purport to be complete and is qualified in its entirety by reference to the License Agreement, a copy of which the Company expects to file as an exhibit to its Annual Report on Form 10-K for the year ending December 31, 2022.

BioVectra Termination Agreement

On December 22, 2022, Keryx and BioVectra Inc. ("BioVectra"), entered into a termination and settlement agreement (the "Termination Agreement"). Pursuant to the Termination Agreement, Keryx and BioVectra agreed, among other things, to terminate, effective immediately, any and all existing agreements entered into between the parties in connection with the manufacture and supply, by BioVectra to the Company, of ferric citrate drug substance (the "Product") for the Company’s proprietary product, Auryxia, including but not limited to that certain Manufacture and Supply Agreement, dated May 26, 2017, as amended by the Amendment to Manufacture and Supply Agreement, dated December 11, 2017 (the "Manufacture and Supply Agreement"), and that certain Amended and Restated Product Manufacture and Supply and Facility Construction Agreement, dated September 4, 2020 (the "Supply and Facility Construction Agreement") (such agreements, collectively, the "BioVectra Agreements"). The parties agreed to terminate the BioVectra Agreements for business reasons.

Under the terms of the Termination Agreement, the Company has agreed to pay to BioVectra a total of $32,500,000, consisting of (i) an upfront payment of $17,500,000 and (ii) six quarterly payments of $2,500,000 starting in April 2024, in consideration for the termination of the BioVectra Agreements and all obligations thereunder, and the covenants and agreements set forth in the Termination Agreement, including the settlement and release of all disputes and claims and the return of certain materials and documents as provided therein. In addition, each of the Company and BioVectra have released one another from all existing and future claims and liabilities arising from the BioVectra Agreements, subject to certain customary exceptions.

The Manufacture and Supply Agreement and the Supply and Facility Construction Agreement provided that the Company would purchase minimum quantities of the Product annually at predetermined prices. In addition, the Manufacture and Supply Agreement and the Supply and Facility Construction Agreement required the Company to reimburse BioVectra for certain costs in connection with construction of a new facility for the manufacture and supply of the Product. The foregoing summary of the BioVectra Agreements do not purport to be complete, and are subject to and are qualified in their entirety by the terms of each of (i) the Manufacture and Supply Agreement (incorporated by reference to Exhibit 10.61 to the Company’s Annual Report on Form 10-K (001-36352), filed on March 26, 2019) and (ii) the Supply and Facility Construction Agreement (incorporated by reference to Exhibit 10.1 to the Company’s Current Report on Form 8-K (001-36352), filed on September 11, 2020).

The foregoing description of the Termination Agreement does not purport to be complete and is qualified in its entirety by reference to the Termination Agreement, a copy of which the Company expects to file as an exhibit to its Annual Report on Form 10-K for the year ending December 31, 2022.

On December 22, 2022, Aldeyra Therapeutics, Inc. ("Aldeyra" or the "Company") entered into the Second Amendment (the "Second Amendment") to Loan and Security Agreement, which is effective as of December 31, 2022 (the "Effective Date") and amended that certain Loan and Security Agreement, dated as of March 25, 2019, by and among the Company, Helio Vision, LLC, the several banks and other financial institutions or entities from time to time parties thereto (the "Lenders") and Hercules Capital, Inc., in its capacity as administrative agent and collateral agent for itself and the Lenders (the "Original Loan Agreement" and as previously amended and as amended by the Second Amendment, the "Loan Agreement") (Filing, 8-K, Aldeyra Therapeutics, DEC 22, 2022, View Source [SID1234625608]).

The Second Amendment makes certain changes to the Loan Agreement, including, among other things, (i) extending the expiration of the period in which interest-only payments on borrowings under the Loan Agreement are made from May 1, 2023 to May 1, 2024; (ii) extending the Term Loan Maturity Date (as defined in the Loan Agreement) from October 1, 2023 to October 1, 2024; (iii) extending the availability of the fourth term loan tranche commitment of $20 million from May 1, 2023 to May 1, 2024; and (iv) amending the Prepayment Charge (as defined in the Loan Agreement) to equal 0.75% of the amount prepaid during the 12-month period following the Effective Date, and 0% thereafter. In addition, a supplemental end of term charge of $292,500 shall be due on the earlier of (A) Term Loan Maturity Date, as amended, or (B) repayment of the outstanding Advances. The existing end of term charge of $1,042,500 remains due on the earlier of (A) October 1, 2023 or (B) repayment of the outstanding Advances. The ability to draw the fourth term loan tranche commitment remains conditioned on approval by the Lenders’ investment committee.

The foregoing summary of the Original Loan Agreement and the Second Amendment does not purport to be complete and is qualified in its entirety by the complete text of the Original Loan Agreement and the Second Amendment, which are filed as Exhibit 10.1 and 10.2, respectively, to this Current Report on Form 8-K and are incorporated herein by reference.

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On December 22, 2022 Rigel Pharmaceuticals, Inc. (Nasdaq: RIGL), reported that REZLIDHIA (olutasidenib) capsules are available in the U.S. by prescription for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test (Press release, Rigel, DEC 22, 2022, View Source [SID1234625552]). REZLIDHIA is an oral, small molecule, inhibitor of mutated IDH1 designed to bind to and inhibit mIDH1 to reduce 2-hydroxyglutarate levels and restore normal cellular differentiation of myeloid cells. REZLIDHIA was approved by the U.S. Food and Drug Administration (FDA) on December 1, 2022.

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"We are pleased to launch REZLIDHIA today in the U.S. and are ready to provide access to patients," said Raul Rodriguez, Rigel’s president and CEO. "REZLIDHIA is Rigel’s second commercial product and is a new and promising oral treatment option for mIDH1 R/R AML patients who typically experience poor clinical outcomes. With durable efficacy data, promising overall survival, and a well characterized safety profile, we are excited to bring REZLIDHIA to patients in need."

The recommended dosage of REZLIDHIA is 150 mg taken orally twice daily. Based on the recommended dosage, the wholesale acquisition cost (WAC) of REZLIDHIA in the U.S. is $32,200 per month. REZLIDHIA is supplied as follows:

NDC Number

Product

Package

WAC

71332-005-01

Oral capsule 150 mg

Bottle – 30 capsules each

$16,100

To assist with access to REZLIDHIA, RIGEL ONECARE, a comprehensive patient support center, can help patients and physicians as they navigate through insurance coverage requirements and provide financial assistance when needed and if eligible, along with other support programs. Patients will be assigned a Nurse Navigator to assess the patient’s individual case.

To learn more, visit www.REZLIDHIA.com or contact RIGEL ONECARE at 833-RIGELOC (833-744-3562).

In August 2022, Rigel and Forma Therapeutics, Inc. announced they entered an exclusive, worldwide license agreement to develop, manufacture and commercialize REZLIDHIA. Under the terms of the agreement, Rigel is responsible for the launch and commercialization of REZLIDHIA in the U.S., and intends to work with potential partners to further develop and commercialize the product outside the U.S.

About AML
Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood and bone marrow that affects myeloid cells, which normally develop into various types of mature blood cells. AML occurs primarily in adults and accounts for about 1 percent of all adult cancers. The American Cancer Society estimates that in the United States alone, there will be about 20,050 new cases, most in adults, in 2022.1

Relapsed AML affects about half of all patients who, following treatment and remission, experience a return of leukemia cells in the bone marrow.2 Refractory AML, which affects between 10 and 40 percent of newly diagnosed patients, occurs when a patient fails to achieve remission even after intensive treatment.3 Quality of life declines for patients with each successive line of treatment for AML, and well-tolerated treatments in relapsed or refractory disease remain an unmet need.

About REZLIDHIA
INDICATION
REZLIDHIA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.

IMPORTANT SAFETY INFORMATION

WARNING: DIFFERENTIATION SYNDROME
Differentiation syndrome, which can be fatal, can occur with REZLIDHIA treatment. Symptoms may include dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, hypotension, fever, and weight gain. If differentiation syndrome is suspected, withhold REZLIDHIA and initiate treatment with corticosteroids and hemodynamic monitoring until symptom resolution.

WARNINGS AND PRECAUTIONS
Differentiation Syndrome
REZLIDHIA can cause differentiation syndrome. In the clinical trial of REZLIDHIA in patients with relapsed or refractory AML, differentiation syndrome occurred in 16% of patients, with grade 3 or 4 differentiation syndrome occurring in 8% of patients treated, and fatalities in 1% of patients. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal. Symptoms of differentiation syndrome in patients treated with REZLIDHIA included leukocytosis, dyspnea, pulmonary infiltrates/pleuropericardial effusion, kidney injury, fever, edema, pyrexia, and weight gain. Of the 25 patients who experienced differentiation syndrome, 19 (76%) recovered after treatment or after dose interruption of REZLIDHIA. Differentiation syndrome occurred as early as 1 day and up to 18 months after REZLIDHIA initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, temporarily withhold REZLIDHIA and initiate systemic corticosteroids (e.g., dexamethasone 10 mg IV every 12 hours) for a minimum of 3 days and until resolution of signs and symptoms. If concomitant leukocytosis is observed, initiate treatment with hydroxyurea, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms. Differentiation syndrome may recur with premature discontinuation of corticosteroids and/or hydroxyurea treatment. Institute supportive measures and hemodynamic monitoring until improvement; withhold dose of REZLIDHIA and consider dose reduction based on recurrence.

Hepatotoxicity
REZLIDHIA can cause hepatotoxicity, presenting as increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased blood alkaline phosphatase, and/or elevated bilirubin. Of 153 patients with relapsed or refractory AML who received REZLIDHIA, hepatotoxicity occurred in 23% of patients; 13% experienced grade 3 or 4 hepatotoxicity. One patient treated with REZLIDHIA in combination with azacitidine in the clinical trial, a combination for which REZLIDHIA is not indicated, died from complications of drug-induced liver injury. The median time to onset of hepatotoxicity in patients with relapsed or refractory AML treated with REZLIDHIA was 1.2 months (range: 1 day to 17.5 months) after REZLIDHIA initiation, and the median time to resolution was 12 days (range: 1 day to 17 months). The most common hepatotoxicities were elevations of ALT, AST, blood alkaline phosphatase, and blood bilirubin.

Monitor patients frequently for clinical symptoms of hepatic dysfunction such as fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Obtain baseline liver function tests prior to initiation of REZLIDHIA, at least once weekly for the first two months, once every other week for the third month, once in the fourth month, and once every other month for the duration of therapy. If hepatic dysfunction occurs, withhold, reduce, or permanently discontinue REZLIDHIA based on recurrence/severity.

ADVERSE REACTIONS
The most common (≥20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, alanine aminotransferase increased, potassium decreased, sodium decreased, alkaline phosphatase increased, nausea, creatinine increased, fatigue/malaise, arthralgia, constipation, lymphocytes increased, bilirubin increased, leukocytosis, uric acid increased, dyspnea, pyrexia, rash, lipase increased, mucositis, diarrhea and transaminitis.

DRUG INTERACTIONS

Avoid concomitant use of REZLIDHIA with strong or moderate CYP3A inducers.
Avoid concomitant use of REZLIDHIA with sensitive CYP3A substrates unless otherwise instructed in the substrates prescribing information. If concomitant use is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
LACTATION
Advise women not to breastfeed during treatment with REZLIDHIA and for 2 weeks after the last dose.

GERIATRIC USE
No overall differences in effectiveness were observed between patients 65 years and older and younger patients. Compared to patients younger than 65 years of age, an increase in incidence of hepatotoxicity and hypertension was observed in patients ≥65 years of age.

HEPATIC IMPAIRMENT
In patients with mild or moderate hepatic impairment, closely monitor for increased probability of differentiation syndrome.

Click here for Full Prescribing Information, including Boxed WARNING.

To report side effects of prescription drugs to the FDA, visit www.fda.gov/medwatch or call 1-800-FDA-1088 (800-332-1088).

REZLIDHIA is a trademark and RIGEL ONECARE is a registered trademark of Rigel Pharmaceuticals, Inc.

RIGEL ONECARE is a patient support center sponsored by Rigel Pharmaceuticals, Inc.

On December 22, 2022 InSitu Biologics, Inc. reported that it has entered into an agreement with the Mayo Foundation for Medical Education and Research to further develop its prolonged-release drug delivery technology for anti-cancer therapeutics (Press release, InSitu Biologics, DEC 22, 2022, View Source [SID1234625566]).

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InSitu Biologics has developed an industry-leading platform technology for loading large doses of a variety of medications into a localized delivery matrix. Once injected, medication elutes from the multi-phase matrix over an extended period. The collaboration with Mayo is both a research and commercial endeavor, and will accelerate InSitu Biologics’ work in adapting this technology for anti-cancer therapeutics. This partnership will encompass traditional cancer medications as well as newly developed novel agents.

"We are extremely excited to begin work with this group of amazing physicians and scientists. Their cutting-edge expertise and deep clinical experience will be invaluable as we extend our platform to address significant unmet needs in controlled-release drug delivery for cancer patients," said Kevin Bassett, CEO of InSitu Biologics.

"Combining Mayo’s world-class expertise with InSitu Biologics’ unique technology should yield novel and effective treatment solutions for cancer patients. We look forward to having the Mayo team join us on this important journey to advance and improve therapeutic options in the cancer field," said Dr. Mark Ereth, Chief Medical Officer of InSitu Biologics.