On September 27, 2022 Seagen Inc. (Nasdaq: SGEN), a world leader and pioneer in antibody-drug conjugate (ADC) therapies, and Zai Lab Limited (Nasdaq: ZLAB; HKEX: 9688), a patient-focused, innovative, commercial-stage global biopharmaceutical company, reported an exclusive collaboration and license agreement for the development and commercialization of TIVDAK (tisotumab vedotin-tftv) in mainland China, Hong Kong, Macau, and Taiwan (Press release, Seagen, SEP 27, 2022, View Source [SID1234621455]). TIVDAK is the first and only ADC approved in the U.S. for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.
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Under the terms of the agreement, Seagen will receive an upfront payment of $30 million, as well as development, regulatory, and commercial milestone payments, and tiered royalties on net sales of TIVDAK in the Zai Lab territory. Based on the existing TIVDAK co-development and co-commercialization collaboration between Seagen and Genmab (Nasdaq: GMAB), all upfront, milestone payments, and royalties will be shared 50/50 with Genmab.
In 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval for TIVDAK for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. As verification and description of clinical benefit in the U.S., and to support further global regulatory applications, a confirmatory phase 3 open-label, randomized, global clinical trial, innovaTV 301, is ongoing.
"This agreement enables us to leverage Zai Lab’s strong expertise in developing and commercializing innovative medicines in the licensed territory," said Natasha Hernday, EVP Corporate Development and Alliance Management, Seagen. "We are delighted to collaborate with Zai Lab, including on the phase 3 innovaTV 301 trial, an important component of expanding the availability of TIVDAK to recurrent or metastatic cervical cancer patients around the world. TIVDAK is also under evaluation and development in early trials for first-line cervical cancer and certain other solid tumors."
"Zai Lab has a significant presence treating women’s cancers in China, and TIVDAK is an important addition to our oncology commercial portfolio. Treatments for cervical cancer remain a significant unmet need in China with approximately 110,000 new cases annually 1, and currently there are few effective therapeutic options available," said William Liang, Chief Commercial Officer, President of Greater China at Zai Lab. "We look forward to this collaboration with Seagen to make TIVDAK available for patients in China as we expand our oncology portfolio."
"Following progression on first-line standard of care therapy, there are limited treatment options, and chemotherapy has low objective response rates with poor outcomes," said Dr. Lingying Wu, Director of the Department of Gynecologic Oncology, National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. "This represents one of the biggest challenges faced by gynecologic oncologists with significant unmet needs for new therapies. We believe TIVDAK could become an important treatment option for patients with cervical cancer in China, as it demonstrated clinically meaningful, durable responses with a tolerable safety profile."
About Cervical Cancer in China
Cervical cancer remains one of the leading causes of cancer death in women in China and globally. An estimated 110,000 new cases of cervical cancer occur annually in China1. Treatment options are limited for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TIVDAK is currently not approved in this region and is well positioned to provide a new option for previously treated advanced cervical cancer patients who currently have limited treatment options and poor outcomes.
About TIVDAK (tisotumab vedotin-tftv)
TIVDAK (tisotumab vedotin-tftv) is an ADC composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Seagen’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Nonclinical data suggests that the anticancer activity of TIVDAK is due to the binding of the ADC to TF expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, TIVDAK also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.
Please see Important Safety Information below.2
TIVDAK (tisotumab vedotin-tftv) for injection, for intravenous use, 40 mg Important Safety Information
BOXED WARNING: OCULAR TOXICITY
TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity.
Warnings and Precautions
Ocular Adverse Reactions occurred in 60% of patients with cervical cancer treated with TIVDAK. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose.
In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse, including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.
Refer patients to an eye care provider for an ophthalmic exam including visual acuity and slit lamp exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction.
Peripheral neuropathy (PN) occurred in 42% of cervical cancer patients treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain- Barré syndrome.
Monitor patients for signs and symptoms of neuropathy. For new or worsening PN, withhold, dose reduce, or permanently discontinue TIVDAK based on the severity of PN.
Hemorrhage occurred in 62% of cervical cancer patients treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.
Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or CNS hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK.
Pneumonitis: Severe, life-threatening, or fatal pneumonitis can occur in patients treated with antibody-drug conjugates containing vedotin, including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.
Monitor patients for pulmonary symptoms indicative of pneumonitis. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations.
Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis.
Embryo-fetal toxicity: TIVDAK can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.
Adverse Reactions
Serious adverse reactions occurred in 43% of patients; the most common (≥3%) were ileus (6%), hemorrhage (5%), pneumonia (4%), PN, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock, pneumonitis, sudden death, and multisystem organ failure (each 1%).
Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).
In the innovaTV 204 study, the most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).
Drug interactions
Strong CYP3A4 Inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for TIVDAK adverse reactions.
Use in Specific Populations
Moderate or Severe Hepatic Impairment: MMAE exposure and adverse reactions are increased. Avoid use.
Lactation: Advise lactating women not to breastfeed during TIVDAK treatment and for at least 3 weeks after the last dose.
Please see full prescribing information, including BOXED WARNING for TIVDAK here.
About the Seagen and Genmab Collaboration
TIVDAK (tisotumab vedotin) is being co-developed and co-commercialized by Genmab and Seagen under an agreement in which the companies, with respect to certain major markets, including China, share costs and profits for the product on a 50/50 basis, including upfront payments, future milestones and royalties received under the collaboration and licensing agreement with Zai Lab.