On April 3, 2023 Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, "Eisai") reported that it has entered into an agreement with the National Cancer Center to collaborate on investigator-initiated clinical research for the EZH2 inhibitor tazemetostat hydrobromide (generic name, product name "Tazverik Tablets 200 mg", "tazemetostat") based on "Patient-Proposed Healthcare Services" system (Press release, Eisai, APR 2, 2023, View Source [SID1234629724]). This clinical research will be conducted by the National Cancer Center Hospital.

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The "Patient-Proposed Healthcare Services" system is a system under which medical treatment using unapproved drugs not covered by insurance is applied for to the government based on the patient’s request, and is conducted as a clinical trial to confirm safety and efficacy. Under the terms of the agreement, Eisai will provide tazemetostat free of charge to the National Cancer Center Hospital as the drug to be used in "A clinical trial of Tazemetostat for pediatric and AYA* patients with malignant tumors which have no standard of care or and which is refractory to standard of care: Patients-Proposed Healthcare Service" to be conducted by the hospital under this program.

Researched and developed by Eisai and Epizyme, Inc.,** an Ipsen (Headquarters: France) company, tazemetostat is a first-in-class, oral 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.1 Eisai holds the rights for development and commercialization of tazemetostat in Japan, where it was approved for the indication of "relapsed or refractory EZH2 gene mutation-positive follicular lymphoma (only when standard treatment is not applicable)" in 2021, and manufactures and distributes the product.

Eisai positions oncology as a key franchise area and aims to create innovative drugs that act towards curing cancer. Eisai is committed to expanding the potential clinical benefits of tazemetostat for cancer treatment, as it seeks to contribute to addressing the diverse needs of, and increasing the benefits provided to, patients with cancer, their families and healthcare professionals.

On March 31, 2023 Genor Biopharma (Stock code: 6998.HK) reported its 2022 annual financial results, business progress and other highlights in the past year (Press release, Genor Biopharma, MAR 31, 2023, View Source [SID1234629910]).

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Dr. GUO Feng, Chairman of the Board and Chief Executive Officer, Genor Biopharma, said: "2022 was a year full of changes and challenges. It was also a year for the positive development of Genor Biopharma and the firm implementation of the strategy of ‘Focus, Optimization, Acceleration and Enrich’. The company has achieved a number of important milestones at a speed better than the industry average, and lays a solid foundation for steady growth in 2023."

Focus and Optimization, Acceleration 2022

GB491 (Lerociclib) – a CDK4/6 inhibitor was developed for breast cancer patients with better safety and excellent efficacy

GB491 (Lerociclib) is a novel, potent, selective oral bioavailable CDK4/6 inhibitor co-developed by the Group and G1 Therapeutics, a US-based company, for use in combination with endocrine therapy in advanced breast cancer. Patient enrollment in Phase III trials for both the first line and the second line was completed quickly via adaptive and seamless experiment design, scientific reference and data bridging, a seamless registration strategy, and excellent execution.

At present, NMPA has officially accepted the new drug application for GB491 (Lerociclib) in combination with Fluvestran as the treatment of HR+/HER2- locally advanced or metastatic breast cancer patients with disease progression following previous endocrine therapy. And GB491 (Lerociclib) has completed patient enrolment for the first line Phase III clinical trial.

Based on data from the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2020 Conference, GB491 (Lerociclib) has demonstrated excellent safety and tolerability profile, enabling uninterrupted daily dosing and better long-term benefits, and could potentially be a BIC CDK4/6 drug candidate.

GB261 (CD20/CD3, BsAb) – potential best-in-class (BIC) CD20/CD3

GB261 (CD20/CD3, BsAb) is the first T-cell engager with ultra-low affinity to bind CD3 and has Fc-enabled functions (ADCC and CDC). GB261 (CD20/CD3, BsAb) significantly inhibits rituximab-resistant cancer cell proliferation in both in vitro assays and in vivo models; meanwhile with T-cell activation, GB261 (CD20/CD3, BsAb) induces less cytokine release compared with compounds in the same class. Thus, GB261 (CD20/CD3, BsAb) is a highly potent bi-specific therapeutic antibody for B-cell malignancies. It has potential to be a better and safer T-cell engager with competitive advantages over other CD3/CD20 agents.

GB261 (CD20/CD3, BsAb) has opened more than a dozen clinical centres in Australia and China. Efficacy has been observed in the first-in-human (FIH) clinical trial in Australia in the dose-climbing low-dose group with preliminary clinical Proof of Concept (POC) data, which was consistent with the molecular design mechanism of GB261 (CD20/CD3, BsAb), indicating a good safety, pharmacokinetic profile and clinical antitumor activities. The high-dose group currently is in dose escalation.

In China, GB261 (CD20/CD3, BsAb) obtained an implied license for Phase I/II clinical trials from the NMPA on May 23, 2023 for the treatment of patients with recurrent or refractory B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). On September 8, 2022, GB261 (CD20/CD3, BsAb) Phase I/II clinical trials achieved the first patient dosing in China.

GB263T (EGFR/cMET/cMETT, TsAb) – the world’s first EGFR/cMET/cMET tri-specific antibody

GB263T (EGFR/cMET/cMET, TsAb) is targeting EGFR and two different epitopes of cMET, and has been designed with the goal of improving safety and efficacy. Thus, GB263T is a highly differentiated tri-specific antibody that exhibits multiple mechanisms of action to inhibit primary and secondary EGFR mutations and cMET signaling pathway simultaneously.

Preclinical studies showed that GB263T (EGFR/cMET/cMET, TsAb) potently blocked ligand-induced phosphorylation of EGFR and cMET, and demonstrated better dual inhibition of EGFR and cMET signaling pathways compared to the JNJ-372 analogue. GB263T (EGFR/cMET/cMET, TsAb) effectively induced enhanced internalization of EGFR and cMET, and downregulated the expression levels of both EGFR and cMet proteins. The in vivo anti-cancer efficacy of GB263T (EGFR/cMET/cMET, TsAb) was demonstrated in several different tumor models, such as those with EGFR exon 20 insertion, EGFR exon 19 deletion, including C797S mutation, and various cMET alteration models. In all models studied, GB263T (EGFR/cMET/cMET, TsAb) demonstrated significant and dose-dependent tumor inhibition. In addition, GB263T (EGFR/cMET/cMET, TsAb) did not show any major toxicities in monkeys, even at a high dose given for four weeks in a GLP tox study.

Bellberry HREC approval for the FIH clinical trial of GB263T (EGFR/cMET/cMET, TsAb) was obtained in Australia on March 28, 2022 for the treatment of patients with advanced non-small cell lung cancer (NSCLC), with the first patient dosed on May 18.

In China, the Phase I/II clinical trials application for GB263T (EGFR/cMET/cMET, TsAb) was approved by the National Medical Products Administration (NMPA) on June 2, 2022, with the first patient dosed on October 14, 2022 in China for the treatment of patients with advanced NSCLC. The high-dose group currently is in dose escalation.

GB492 (IMSA101) – potential best-in-class STING agonist

GB492 (IMSA101) is the major mediator of innate immune sensing of cancerous cells, which the Group exclusively licensed from ImmuneSensor Therapeutic in June 2020.

STING agonist, as an immune stimulatory therapy, may further increase the response of immune checkpoint inhibitors for patients. Multiple studies have shown that STING agonists can activate cGAS-STING signaling and significantly enhance the efficacy of the cancer immunity cycle when used in combination with other immune checkpoint inhibitors (ICI). It may become a potential FIC therapy.

In Phase I/II clinical trials of GB492 (IMSA101) as a monotherapy or in combination with GB226 (Aibining艾比寧, Geptanolimab) in patients with advanced/treatment-refractory malignancies, monotherapy clinical trials were finished and a dose escalation up to 400ug was completed in January 2022

In January 2022, approval was obtained from the CDE to directly conduct a dose-escalating study of GB492 (IMSA101) in combination with PD-1 in patients with advanced malignancy, based on the available data on the 400ug dose group in the monotherapy study in China and all data of the monotherapy dose-escalation study in the United States. In this clinical trial, an innovative FIH trial design was employed to combine the dose escalations when GB492 (IMSA101) was administered alone and when it was administered with GB226 (Aibining艾比寧, Geptanolimab). It is the first STING agonist combination therapy that has obtained clinical trial approval in China.

Deep cultivation and cooperation, value enrichment

Focusing on the potential global first-in-class (FIC)/best-in-class (BIC) innovation pipeline, Genor Biopharma has developed and is executing a comprehensive strategy to optimize and enrich the existing product portfolio and conduct molecular research with the greatest potential to produce clinical and commercially viable drugs. It aims to address unmet medical needs in China and around the world. As of December 31, 2022, five FIC/BIC bi-specific/multi-specific antibody projects were carried out and nearly 10 differentiated innovation projects involving different molecular forms were in the early stage of research and development.

Independent innovation and strategic cooperation have developed simultaneously. In May 2022, Genor Biopharma entered into a cooperative development agreement with Abogen Biosciences Co., Ltd. ("Abogen") to jointly develop globally innovative mRNA products and related pharmaceuticals. GH Biopharma’s antibody development platform will be integrated with Abogen’s mRNA technology platform to enable them to jointly research and develop mRNA drugs for tumor treatment. It is progressing smoothly. One of the collaborative projects is in the pre-pcc stage. Currently, the Group is exploring opportunities to conduct cooperative development projects with various innovative technology platforms. It is actively expanding external cooperation in early research and development, commercialization and other levels, in order to continuously expand global innovation.

On February 23, 2022, the NMPA granted marketing approval for Jiayoujian 佳佑健 (GB242, Infliximab) which is used for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriasis, adult ulcerative colitis, adult and pediatric (aged above 6 years old) Crohn’s disease and fistulizing Crohn’s disease. Genor Biopharma commercialized its first product. Up to now, Jiayoujian 佳佑健 (GB242, Infliximab) is available for online procurement in 22 provinces and cities across the country, and has achieved sales of approximately RMB 11.9 million.

Efficient operation, win in 2023

In the face of the complex international situation and uncertainties brought about by the COVID-19 pandemic, Genor Biopharma has clarified its development priorities and adopted a variety of effective measures to continuously optimize its organizational structure, operation management and daily business. In 2023, it will promote key projects with higher operational efficiency to achieve its strategic goals.

Specifically, Genor Biopharma will continue to focus on promoting key projects and exploration of FIC potential in multi-dimensions to achieve an effective balance between efficiency and cost based on the in-depth understanding of target molecular biology, cell biology and immunological mechanisms. Cooperative R&D and open innovation, Genor Biopharma is actively exploring cooperation projects between its platform for early discovery of highly differential T-cell Engager / bi-specific/multi-specific antibodies in immune-oncology / BsADC and different innovative technology platforms to further promote global innovation through cooperation.

In terms of clinical pipeline advancement, Genor Biopharma expects to achieve the approval of the new drug application for GB491 (Lerociclib cyclin-dependent kinase 4/6 inhibitor) in combination with Fluvestran as the treatment of HR+/HER2- locally advanced or metastatic breast cancer patients with disease progression following previous endocrine therapy; and to submit an NDA application to the NMPA depending on the results of the Phase III clinical trials of GB491 (Lerociclib) in 1L HR+/HER2- breast cancer. It remains committed to addressing the large group of breast cancer patients in China and around the world with a safe, effective and well-tolerated novel therapy in the next 18 months.

As for bi-specific and tri-specific antibody drug candidates, Genor Biopharma will continue to accelerate the development of clinical trials in Australia and China. GB261 (CD20/CD3, BsAb) is scheduled to complete its phase I/II clinical trials within the next 12 to 18 months and proceed to the pivotal registration trial. The clinical trial of GB263T (EGFR/cMET/cMET, TsAb) will continue to progress rapidly, with preliminary clinical data to validate POC planned within the next 12 months. Meanwhile, Genor Biopharma will actively expand external partnerships in its clinical programs.

FINANCIAL HIGHLIGHTS

Total revenue was RMB15.9 million for the Reporting Period, primarily generated by (i) drug sales of Jiayoujian 佳佑健 (GB242, Infliximab Biosimilar), and (ii) providing research and manufacturing services to our customers under fee-for-service contracts.
Research and development expenses were RMB583.9 million for the Reporting Period, as compared with RMB612.7 million for the year ended 31 December 2021. The spending was mainly attributable to (i) our new drugs development fee and ongoing clinical trials expenses and (ii) our employee salary and related benefit costs. The decrease was mainly due to the decrease in employee benefits expenses.
Total comprehensive loss was RMB731.8 million for the Reporting Period, as compared with RMB865.8 million for the year ended 31 December 2021. The decrease was primarily due to (i) decrease in expenses and (ii) total revenue generated for the Reporting Period.
By the end of December 2022, the cash balance was RMB1.59 billion. Enough to support the company’s stable operation in the next 4-5 years.

On March 31, 2023, Gritstone bio, Inc. (the "Company") entered into a First Amendment to Loan and Security Agreement (the "Loan Amendment") with Silicon Valley Bank, a division of First-Citizens Bank & Trust Company (successor by purchase to the Federal Deposit Insurance Corporation as Receiver for Silicon Valley Bridge Bank, N.A. (as successor to Silicon Valley Bank)) ("SVB"), Hercules Capital, Inc. ("Hercules Capital") Hercules Capital Funding Trust 2022-1 (together with Hercules Capital ("Hercules")), each as Lenders, and Hercules Capital, in its capacity as administrative agent and collateral agent for itself and the financial institutions or entities from time to time party to the Loan Agreement (as defined below), which amends that certain Loan and Security Agreement (as amended, restated, or modified from time to time, the "Loan Agreement"), dated as of July 19, 2022, between the Company, SVB, Hercules and the other financial institutions or entities from time to time party thereto to defer the events triggering certain minimum Qualified Cash (as such term is defined in the Loan Agreement) covenants set forth therein (Filing, Gritstone Bio, MAR 31, 2023, View Source [SID1234629856]).

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The foregoing description of the Loan Amendment does not purport to be complete and is qualified in its entirety by the full text of the Loan Amendment, a copy of which is filed as Exhibit 10.1 hereto and is incorporated herein by reference.

On March 31, 2023, (the "Closing Date"), Cerus Corporation (the "Company") reported to have entered into (i) an Amended and Restated Credit, Security and Guaranty Agreement (Term Loan) (the "Term Loan Credit Agreement"), by and among the Company, the lenders party thereto from time to time and MidCap Financial Trust, as agent and a lender, which amended and restated the Company’s existing Credit, Security and Guaranty Agreement (Term Loan), dated as of March 29, 2019, as amended (the "Existing Term Loan Credit Agreement") and (ii) an Amended and Restated Credit, Security and Guaranty Agreement (Revolving Loan) (the "Revolving Loan Credit Agreement," and together with the Term Loan Credit Agreement, the "Credit Agreements"), by and among the Company, the lenders party thereto from time to time and MidCap Funding IV Trust, as agent and a lender, which amended and restated the Company’s existing Credit, Security and Guaranty Agreement (Revolving Loan), dated as of March 29, 2019, as amended (the "Existing Revolving Loan Credit Agreement") (Filing, 8-K, Cerus, MAR 31, 2023, View Source [SID1234629828]).

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The Term Loan Credit Agreement provides a secured term loan facility in an aggregate principal amount of up to $75.0 million. The Company borrowed the first advance of $40.0 million ("Tranche 1") and the second advance of $15.0 million ("Tranche 2") on the Closing Date to refinance the term loans under the Existing Term Loan Credit Agreement. Under the terms of the Term Loan Credit Agreement, (i) the third advance of $10.0 million ("Tranche 3") will be available to the Company through July 1, 2024, subject to the Company’s satisfaction of certain conditions described in the Term Loan Credit Agreement, and (ii) the fourth advance of $10.0 million ("Tranche 4"), will be available to the Company from July 1, 2024 through July 1, 2025, subject to the Company’s satisfaction of certain other conditions described in the Term Loan Credit Agreement. The proceeds from Tranche 3 and Tranche 4 are expected to be used for working capital and general corporate purposes.

Tranche 1 and Tranche 2 and, if borrowed, Tranche 3 and Tranche 4, each bear interest at a floating rate equal to the sum of the Term SOFR rate (subject to a floor of 1.00%) plus 6.50%. Interest on each term loan advance is due and payable monthly in arrears. Interest only payments are due for the first 36 months, and the remaining payments are due over the remaining 24 months. The interest only payment period can be extended for 12 months upon achievement of a specified trailing twelve month net revenue target. Prepayments of the term loans under the Term Loan Credit Agreement, in whole or in part, will be subject to early termination fees which decline each year until the fourth anniversary, at which time there is no early termination fee. The Company also must pay an annual administrative fee equal to a fractional percentage of the amount outstanding pursuant to the Term Loan Credit Agreement, and upon the final payment must also pay an exit fee of a percentage of the amount borrowed pursuant to the Term Loan Credit Agreement (the "Exit Fee"). The Company is required to pay a pro rata portion of the Exit Fee in connection with any prepayment.

The Revolving Loan Credit Agreement provides a secured revolving credit facility in an initial aggregate principal amount of up to $20.0 million. The Company may request an increase in the total commitments under the Revolving Loan Credit Agreement by up to an additional $15.0 million, subject to agent and lender approval and the satisfaction of certain conditions. Availability of the revolving credit facility under the Revolving Loan Credit Agreement will be based upon a borrowing base formula and periodic borrowing base certifications valuing certain of the Company’s accounts receivable and inventory, as reduced by certain reserves, if any. As of the Closing Date, there was $18.0 million outstanding under the Revolving Loan Credit Agreement. The proceeds of any loans under the Revolving Loan Credit Agreement may be used for working capital and general corporate purposes.

Loans under the Revolving Loan Credit Agreement accrue interest at a floating rate equal to the Term SOFR rate (subject to a floor of 1.00%) plus 3.75%. Accrued interest on the revolving loans will be paid monthly and revolving loans may be borrowed, repaid and re-borrowed until March 1, 2028, when all outstanding amounts must be repaid. Termination or permanent reductions of the revolving loan commitment under the Revolving Loan Credit Agreement will be subject to termination fees which decline each year until the fourth anniversary, at which time there is no early termination fee.

In connection with the Revolving Loan Credit Agreement, the Company is required to pay customary fees, including an origination fee equal to a fractional percentage of the original commitment amount at closing (and an equivalent origination fee with respect to any increased commitments at the time of the applicable increase), a monthly unused line fee based upon the average daily unused allowable borrowing base of the revolving credit facility and a monthly collateral management fee based upon the average daily used portion of the revolving credit facility. The Company is also required to maintain a minimum drawn balance under the revolving line or pay interest on the minimum drawn balance.

The Company’s obligations under the Credit Agreements are secured by a security interest on substantially all of its assets, with some exclusions.

The Credit Agreements contain customary affirmative covenants and customary negative covenants limiting the Company’s ability and the ability of the Company’s subsidiaries, if any, to, among other things, dispose of assets, undergo a change in control, merge or consolidate, make acquisitions, incur debt, incur liens, pay dividends, repurchase stock and make investments, in each case subject to certain exceptions. The Company must also comply with a financial covenant relating to trailing twelve month minimum net revenue requirements, tested on a quarterly basis.

The Credit Agreements also contain customary events of default relating to, among other things, payment defaults, breaches of covenants, a material adverse change, listing of the Company’s common stock, bankruptcy and insolvency, cross defaults with certain material indebtedness and certain material contracts, judgments, and inaccuracies of representations and warranties. Upon an event of default, agent and the lenders may declare all or a portion of the Company’s outstanding obligations to be immediately due and payable and exercise other rights and remedies provided for under the agreement. During the existence of an event of default, interest on the obligations could be increased.

The foregoing description of the terms of the Credit Agreements does not purport to be complete and is qualified in its entirety by reference to the full text of the Credit Agreements, copies of which will be filed with the Securities and Exchange Commission as exhibits to the Company’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2023.

On March 31, 2023 Fennec Pharmaceuticals Inc. (NASDAQ: FENC; TSX: FRX), a commercial stage specialty pharmaceutical company, reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion and recommended granting a Marketing Authorization for Pedmarqsi (sodium thiosulfate) – known as PEDMARK in the U.S. – for the prevention of ototoxicity (hearing loss) induced by cisplatin chemotherapy in patients 1 month to <18 years of age with localized, non-metastatic, solid tumors (Press release, Fennec Pharmaceuticals, MAR 31, 2023, View Source [SID1234629795]). When formally approved by the European Commission, Pedmarqsi will be the first and only treatment approved in the European Union (EU) to address this area of significant unmet medical need.

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"Children treated with cisplatin for solid tumours carry a very high risk of losing their hearing permanently," said Penelope "Peppy" R. Brock, M.D., Ph.D, of Great Ormond Street Hospital in London and International Chair of the SIOPEL 6 trial. "As cure rates increase into the high nineties for several cancers, the need to resolve these permanently disabling side effects becomes more and more pressing. I am delighted that finally we have something to offer to counter this life impacting side effect and can give children the opportunity to live healthy, happy and fully integrated lives after overcoming cancer."

"There are currently no approved treatments in Europe to mitigate the risk of permanent and irreversible bilateral hearing loss which occurs in approximately 60 percent of children treated with cisplatin and can be as high as 90 percent.i The CHMP positive opinion brings European patients and their families closer to having a preventive treatment option to prevent the devastating consequences of hearing loss following the use of cisplatin chemotherapy, an indispensable treatment of choice in many pediatric cancer cases," said Rosty Raykov, chief executive officer of Fennec Pharmaceuticals. "With approximately five thousand children eligible for treatment with a platinum-based chemotherapy each year in Europe, we are excited by the potential this therapy can offer to the pediatric oncology community."

The CHMP adopted its positive opinion on safety and efficacy data from two pivotal open-label, randomized Phase 3 trials (SIOPEL 6 and Clinical Oncology Group [COG] Protocol ACCL0431), which compared Pedmarqsi plus cisplatin-based regimen to cisplatin-based regimens alone for the reduction of cisplatin-induced hearing loss in pediatric patients. In both studies, the incidence of hearing loss was consistently and significantly lower in the Pedmarqsi plus cisplatin arm compared with the cisplatin alone arm 28.6% vs. 56.4% (p = 0.004) and 35.1% vs. 67.3% (p = 0.001) with hearing loss in COG ACCLO431 and SIOPEL6, respectively. The most common adverse reactions (≥25% with difference between arms of >5% compared to cisplatin alone) in SIOPEL6 were vomiting, infection, nausea, decreased hemoglobin, and hypernatremia. The most common adverse reaction (≥25% with difference between arms of >5% compared to cisplatin alone) in COG ACCL0431 was hypokalemia.

The CHMP’s recommendation will now be reviewed by the European Commission, ratification of the CHMP recommendation is expected by early June 2023. PEDMARK was approved by the U.S. Food and Drug Administration (FDA) in September 2022.

About Cisplatin-Induced Ototoxicity

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

The incidence of ototoxicity depends upon the dose and duration of chemotherapy, and many of these children require lifelong hearing aids or cochlear implants, which can be helpful for some, but do not reverse the hearing loss and can be costly over time.iii Infants and young children that are affected by ototoxicity at critical stages of development lack speech and language development and literacy, and older children and adolescents often lack social-emotional development and educational achievement.iv

PEDMARK (sodium thiosulfate injection)

PEDMARK is the first and only U.S. Food and Drug Administration (FDA) approved therapy indicated to reduce the risk of ototoxicity associated with cisplatin treatment in pediatric patients with localized, non-metastatic, solid tumors. It is a unique formulation of sodium thiosulfate in single-dose, ready-to-use vials for intravenous use in pediatric patients.7 PEDMARK is also the only therapeutic agent with proven efficacy and safety data with an established dosing paradigm, across two open-label, randomized Phase 3 clinical studies, the Clinical Oncology Group (COG) Protocol ACCL0431 and SIOPEL 6.

In the U.S. and Europe, it is estimated that, annually, more than 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 co-operative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity, COG 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, medulloblastoma, and other solid tumors. SIOPEL 6 enrolled only hepatoblastoma patients with localized tumors.

Indications and Usage

PEDMARK (sodium thiosulfate injection) is indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumors.

Limitations of Use

The safety and efficacy of PEDMARK have not been established when administered following cisplatin infusions longer than 6 hours. PEDMARK may not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred.

Important Safety Information

PEDMARK is contraindicated in patients with history of a severe hypersensitivity to sodium thiosulfate or any of its components.

Hypersensitivity reactions occurred in 8% to 13% of patients in clinical trials. Monitor patients for hypersensitivity reactions. Immediately discontinue PEDMARK and institute appropriate care if a hypersensitivity reaction occurs. Administer antihistamines or glucocorticoids (if appropriate) before each subsequent administration of PEDMARK. PEDMARK may contain sodium sulfite; patients with sulfite sensitivity may have hypersensitivity reactions, including anaphylactic symptoms and life-threatening or severe asthma episodes. Sulfite sensitivity is seen more frequently in people with asthma.

PEDMARK is not indicated for use in pediatric patients less than 1 month of age due to the increased risk of hypernatremia or in pediatric patients with metastatic cancers.

Hypernatremia occurred in 12% to 26% of patients in clinical trials, including a single Grade 3 case. Hypokalemia occurred in 15% to 27% of patients in clinical trials, with Grade 3 or 4 occurring in 9% to 27% of patients. Monitor serum sodium and potassium levels at baseline and as clinically indicated. Withhold PEDMARK in patients with baseline serum sodium greater than 145 mmol/L.

Monitor for signs and symptoms of hypernatremia and hypokalemia more closely if the glomerular filtration rate (GFR) falls below 60 mL/min/1.73m2.

Administer antiemetics prior to each PEDMARK administration. Provide additional antiemetics and supportive care as appropriate.

The most common adverse reactions (≥25% with difference between arms of >5% compared to cisplatin alone) in SIOPEL 6 were vomiting, nausea, decreased hemoglobin, and hypernatremia. The most common adverse reaction (≥25% with difference between arms of >5% compared to cisplatin alone) in COG ACCL0431 was hypokalemia.

Please see full Prescribing Information for PEDMARK at: www.PEDMARK.com.