Thiotepa

2025年5月12日，CASI制药公司（以下简称“CASI”或“公司”）今日宣布，已与董事长兼首席执行官何为无博士全资控股的开曼实体Kaixin Pharmaceuticals Inc. (“Kaixin Pharmaceuticals”) 及公司在中国的两家全资子公司（“目标公司”）达成最终《股权及资产转让协议》。根据协议约定，公司将向Kaixin Pharmaceuticals转让目标公司100%股权（“目标股权”），以及BI-1206（大中华地区）、CID-103（亚洲，日本除外）和塞替派（中国内地，不含港澳台地区）相关产品（“目标管线产品”）的全部许可权、经销权、供货协议及附属权益。总交易对价2000万美元，其中包括承担公司不超过2000万美元的债务（“本次交易”）。 本次交易完成须满足若干惯例交割条件，包括解除因公司未决法律纠纷导致的目标股权司法冻结。根据交易安排，公司和Kaixin Pharmaceuticals计划与相关许可方签署权益转让协议，以完成目标管线产品相关权益的转让，预计将与目标股权交割同步完成。 公司董事会依据其设立的独立董事委员会（“特别委员会”）的一致建议，批准了《股权及资产转让协议》及本次交易。特别委员会在财务顾问及法律顾问的协助下完成了协议条款磋商。 交易完成后，公司将保留CID-103（日本及非亚洲地区）、EVOMELA®、FOLOTYN®、CNCT19及CB-5339的相关权益，并将加速推进CID-103用于器官移植排斥反应及自身免疫疾病的临床开发。此举标志着公司战略重心向CID-103创新疗法的全面聚焦。 The Benchmark Company, LLC担任特别委员会财务顾问，Skadden, Arps, Slate, Meagher & Flom LLP担任特别委员会美国法律顾问，中伦律师事务所担任公司中国法律顾问。 环球律师事务所担任Kaixin Pharmaceuticals中国法律顾问。

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Shorla Oncology (‘Shorla’), a U.S.-Ireland specialty pharmaceutical company, announced today that the U.S. Food and Drug Administration has granted approval for 100 mg/10mL multi-dose vial of TEPYLUTE, a ready-to-dilute formulation of thiotepa to treat breast and ovarian cancer, that eliminates the need for reconstitution and may reduce preparation time and errors offering more scheduling flexibility for their patients. Shorla Oncology Announces FDA Approval of TEPYLUTE® 100mg, First and Only Ready-to-Dilute Multi-Dose Vial of Thiotepa to Treat Breast and Ovarian Cancer and Commercial Launch of TEPYLUTE 15mg and 100mg Vials in the U.S. “We are pleased to offer another viable treatment option for patients with breast and ovarian cancer,” said Sharon Cunningham, Chief Executive Officer and Co-Founder of Shorla Oncology. “Once opened, our 100mg vial of TEPYLUTE is stable for 14 days when properly stored, giving providers the flexibility they need when preparing and administering this very important treatment. TEPYLUTE is a ready to dilute formulation of a well-established, standard of care oncology drug thiotepa that has been manufactured as freeze-dried powder since the 1950s. “This is a huge win for providers because TEPYLUTE avoids the need for complicated and time-consuming reconstitution,” said Orlaith Ryan, Chief Technical Officer and Co-Founder of Shorla Oncology. We are excited to bring TEPYLUTE to the US Market. It provides consistent dosing accuracy and allows for “just in time” preparation, which benefits everyone, especially patients.” said Rayna Herman, Chief Commercial Officer, Shorla Oncology. The American Cancer Society estimates that more than 300,000 women will be diagnosed with breast cancer in the U.S in 2025.2 About 20,890 women will be diagnosed with ovarian cancer in the U.S. in 2025.3 About Shorla Oncology Shorla Oncology is a privately- held, U.S. and Ireland- based commercial stage specialty pharmaceutical company established by Sharon Cunningham and Orlaith Ryan. The company has an advanced pipeline of innovative oncology drugs for orphan and pediatric cancers. Shorla is focused on indications where existing treatments are limited, in shortage or the drug applications are inadequate for the target population. The company’s growing portfolio brings accessible, affordable and life-saving treatments to patients, delivering a major contribution to patient care. Shorla currently markets three products, Nelarabine for the treatment of T-cell leukemia, JYLAMVO™ for the treatment of acute lymphoblastic leukemia and other indications and IMKELDI for the treatment of Chronic Myeloid Leukemia, Gastrointestinal Stromal Tumors (GISTs) and other indications. For further information, please visit www.shorlaoncology.com. TEPYLUTE® (thiotepa) Injection for Intravenous Use INDICATION TEPYLUTE is an alkylating drug indicated for the treatment of adenocarcinoma of the breast or ovary. IMPORTANT SAFETY INFORMATION WARNING: SEVERE MYELOSUPPRESSION and CARCINOGENICITY • TEPYLUTE may cause severe marrow suppression, and high doses may cause marrow ablation with resulting infection or bleeding. Monitor hematologic laboratory parameters. • TEPYLUTE should be considered potentially carcinogenic in humans. CONTRAINDICATIONS TEPYLUTE is contraindicated in patients with severe hypersensitivity to thiotepa and in concomitant use with live or attenuated vaccines. WARNINGS AND PRECAUTIONS Myelosuppression : For patients receiving TEPYLUTE for treatment of adenocarcinoma of the breast or adenocarcinoma of the ovary, if the bone marrow has been compromised by prior irradiation or chemotherapy, or is recovering from chemotherapy, the risk of severe myelosuppression with TEPYLUTE may be increased. Perform periodic complete blood counts during the course of treatment with TEPYLUTE. Provide supportive care for infections, bleeding, and symptomatic anemia. Inform patients of the possibility of developing low blood cell counts and the need for hematopoietic progenitor cell infusion. Instruct patients to immediately report to their healthcare provider if bleeding or fever occurs. Hypersensitivity: Clinically significant hypersensitivity reactions, including anaphylaxis, have occurred following administration of thiotepa. If anaphylactic or other clinically significant allergic reaction occurs, discontinue treatment with TEPYLUTE, initiate appropriate therapy, and monitor until signs and symptoms resolve. Counsel patients on the signs and symptoms of hypersensitivity and to seek immediate emergency assistance if they develop any of these signs and symptoms. Cutaneous Toxicity: TEPYLUTE and/or its active metabolites may be excreted in part via skin in patients receiving high-dose therapy. Treatment with TEPYLUTE may cause skin discoloration, pruritus, blistering, desquamation, and peeling that may be more severe in the groin, axillae, skin folds, in the neck area, and under dressings. Instruct patients to shower or bathe with water at least twice daily through 48 hours after administration of TEPYLUTE. Change the occlusive dressing and clean the covered skin at least twice daily through 48 hours after administration of TEPYLUTE. Change bed sheets daily during treatment. Skin reactions associated with accidental exposure to TEPYLUTE may occur. Wash the skin thoroughly with soap and water in case the TEPYLUTE solution contacts the skin. Flush mucous membranes in case of TEPYLUTE contact with mucous membranes. Concomitant Use of Live and Attenuated Vaccines: Do not administer live or attenuated viral or bacterial vaccines to a patient treated with TEPYLUTE until the immunosuppressive effects have resolved. Hepatic Veno-Occlusive Disease: Monitor by physical examination, serum transaminases, and bilirubin, and provide supportive care to patients who develop hepatic veno-occlusive disease. Central Nervous System Toxicity: Fatal encephalopathy has occurred in patients treated with high doses of thiotepa. Other central nervous system toxicities, such as headache, apathy, psychomotor retardation, disorientation, confusion, amnesia, hallucinations, drowsiness, somnolence, seizures, coma, inappropriate behavior, and forgetfulness have been reported to occur in a dose-dependent manner during or shortly after administration of high-dose thiotepa. Do not exceed the recommended dose of TEPYLUTE. If severe or life-threatening central nervous system toxicity occurs, discontinue administration of TEPYLUTE and provide supportive care. Carcinogenicity: Like many alkylating agents, thiotepa has been reported to be carcinogenic when administered to laboratory animals. Carcinogenicity is shown most clearly in studies using mice, but there is some evidence of carcinogenicity in man. There is an increased risk of secondary malignancy with the use of TEPYLUTE. Inform patients that TEPYLUTE can increase the risk of secondary malignancy. Polyethylene glycol (PEG) 400 toxicity : TEPYLUTE contains a high concentration of PEG 400. Based on findings in animals, administration of high amounts of PEG 400 may cause damage to the kidneys and liver at dosages higher than recommended. When prescribing TEPYLUTE, take into consideration the PEG 400 load from concomitant medications. Embryo-Fetal Toxicity: Based on the mechanism of action and findings in animals, TEPYLUTE can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of TEPYLUTE in pregnant women. Thiotepa given by the intraperitoneal (IP) route was teratogenic in mice at doses ≥1 mg/kg (3.2 mg/m 2 ), approximately 8-fold less than the maximum recommended human therapeutic dose (0.8 mg/kg, 27 mg/m 2 ), based on body-surface area. Thiotepa given by the IP route was teratogenic in rats at doses ≥3 mg/kg (21 mg/m 2 ), approximately equal to the maximum recommended human therapeutic dose, based on body-surface area. Thiotepa was lethal to rabbit fetuses at a dose of 3 mg/kg (41 mg/m 2 ), approximately two times the maximum recommended human therapeutic dose based on body-surface area. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use highly effective contraception during TEPYLUTE treatment and for 6 months after therapy/the last dose. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant. Advise males with female partners of reproductive potential to use effective contraception during TEPYLUTE treatment and for 1 year after therapy/the last dose. ADVERSE REACTIONS The most common adverse reactions (incidence greater than 10%) are neutropenia, anemia, thrombocytopenia, elevated alanine aminotransferase, elevated aspartate aminotransferase (AST), elevated bilirubin, mucositis, cytomegalovirus infection, hemorrhage, diarrhea, hematuria, and rash. The clinically significant adverse reactions include myelosuppression, infection, hypersensitivity, cutaneous toxicity, hepatic veno-occlusive disease, central nervous system toxicity, and carcinogenicity. DRUG INTERACTIONS Effect of Cytochrome CYP3A Inhibitors and Inducers: In vitro studies suggest that thiotepa is metabolized by CYP3A4 and CYP2B6 to its active metabolite triethylene phosphoramide (TEPA). Avoid coadministration of strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) and strong CYP3A4 inducers (e.g., rifampin, phenytoin) with thiotepa due to the potential effects on efficacy and toxicity. Consider alternative medications with no or minimal potential to inhibit or induce CYP3A4. If concomitant use of strong CYP3A4 modulators cannot be avoided, closely monitor for adverse drug reactions. Effect of TEPYLUTE on Cytochrome CYP2B6 Substrates: In vitro studies suggest that thiotepa inhibits CYP2B6. Thiotepa may increase the exposure of drugs that are substrates of CYP2B6 in patients; however, the clinical relevance of this in vitro interaction is unknown. The administration of thiotepa with cyclophosphamide in patients reduces the conversion of cyclophosphamide to the active metabolite, 4‑hydroxycyclophosphamide; the effect appears sequence-dependent with a greater reduction in the conversion to 4-hydroxycyclophosphamide when thiotepa is administered 1.5 hours before the intravenous administration of cyclophosphamide compared to administration of thiotepa after intravenous cyclophosphamide. The reduction in 4-hydroxycyclophosphamide levels may potentially reduce the efficacy of cyclophosphamide treatment. USE IN SPECIFIC POPULATIONS Pregnancy: TEPYLUTE can cause fetal harm when administered to a pregnant woman based on findings from animals and the drug’s mechanism of action. Limited available data on thiotepa use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of thiotepa to pregnant mice and rats during organogenesis produced teratogenic effects (neural tube defects and malformations of the skeletal system of the fetus) at doses approximately 0.125 and 1 times, respectively, the maximum recommended human daily dose on a mg/m2 basis. Thiotepa was lethal to rabbit fetuses at approximately 2 times the maximum recommended human therapeutic dose based on body-surface area. Consider the benefits and risks of TEPYLUTE for the mother and possible risks to the fetus when prescribing TEPYLUTE to a pregnant woman. Lactation: There is no information regarding the presence of thiotepa in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions, including the potential for tumorigenicity shown for thiotepa in animal studies, advise patients not to breastfeed during TEPYLUTE treatment and for 1 week after therapy/the last dose. Females and Males of Reproductive Potential: TEPYLUTE can cause fetal harm when administered to a pregnant woman. Pregnancy Testing - Verify the pregnancy status of females of reproductive potential before initiating TEPYLUTE therapy. Contraception for Females - Advise females of reproductive potential to avoid pregnancy during TEPYLUTE treatment and for 6 months after therapy/the last dose. Advise females to immediately report pregnancy. Contraception for Males - TEPYLUTE may damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Males with female sexual partners of reproductive potential should use effective contraception during TEPYLUTE treatment and for 1 year after therapy/the last dose. Infertility - Based on nonclinical findings, male and female fertility may be compromised by treatment with TEPYLUTE. Advise patients that TEPYLUTE can produce infertility. Inform male patients about the possibility of sperm conservation before the start of therapy. Pediatric Use: Safety and effectiveness of TEPYLUTE in neonates have not been established. Safety and effectiveness of TEPYLUTE for the treatment of adenocarcinoma of the breast and adenocarcinoma of the ovary in pediatric patients have not been established. Geriatric Use: Clinical studies of thiotepa for treatment of adenocarcinoma of the breast and adenocarcinoma of the ovary did not include sufficient numbers of subjects aged 65 years and over to determine whether elderly subjects respond differently from younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreasing hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment: In patients with moderate (creatinine clearance [CLcr] of 30 mL/min to 59 mL/min) renal impairment, decreased renal excretion may result in increased plasma levels of thiotepa and TEPA. This may result in increased toxicity. Monitor patients with moderate to severe (CLcr <30 mL/min) renal impairment for signs and symptoms of toxicity following treatment with TEPYLUTE for an extended period of time. Hepatic Impairment: Thiotepa is extensively metabolized in the liver. Patients with moderate (bilirubin levels greater than 1.5 times to 3 times the upper limit of normal and any AST) hepatic impairment may have increased plasma levels of thiotepa. This may result in toxicity. Monitor patients with moderate to severe (bilirubin levels greater than 3 times the upper limit of normal and any AST) hepatic impairment for signs and symptoms of toxicity following treatment with TEPYLUTE for an extended period of time. To report suspected adverse reactions, contact Shorla Oncology at 1-844-668-3940 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. For Print: Please see the accompanying full Prescribing Information, including Boxed Warning. For Digital: Please click here for full Prescribing Information, including Boxed Warning. All trademarks are the property of Shorla Oncology. ©SHORLA ONCOLOGY® 2025. PRO-TEP-1377-v1 04/2025