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FDA approves mirvetuximab soravtansine for ovarian, fallopian tube, or primary peritoneal cancer

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The US Food and Drug Administration (FDA) granted an accelerated approval for mirvetuximab soravtansine-gynx (ELAHERE™) for the treatment of adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens, on November 14, 2022. FDA also approved a companion diagnostic, VENTANA FOLR1 (FOLR1-2.1) RxDx Assay, developed by Roche.

Mirvetuximab soravtansine, developed by ImmunoGen as a treatment for epithelial malignancies such as ovarian adenocarcinoma, is an antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα). The cytotoxic warhead, the tubulin-targeting maytansinoid drug DM4, is conjugated to the humanized IgG1ҡ antibody via a cleavable disulfide linker. The ADC has been granted Orphan Drug designations for ovarian cancer in the US and EU, and FDA’s Fast Track designation for a specific subset of ovarian cancer patients with medium to high FRα-positive platinum-resistant lesions who received between one and three prior systemic treatments, and for whom single-agent chemotherapy is appropriate as the next line of therapy.

FDA’s approval was based on positive results of the Phase 3 SORAYA study (NCT04296890), which evaluated the efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant advanced high-grade epithelial ovarian, primary peritoneal or fallopian tube cancer, whose tumors express a high-level of FRα. A total of 106 platinum-resistant ovarian cancer patients with high FRα expression previously treated with at least one, but less than three prior systemic treatments, at least one of which included bevacizumab, received mirvetuximab soravtansine (6 mg/kg adjusted ideal body weight) administered on day 1 of every 3-week cycle. Results from the SORAYA trial were presented at the Society of Gynecologic Oncology (SGO) annual meeting held in March 2022. Additional efficacy analyses based on a 120-day cut-off date showing tumor reduction in 71.4% of patients, an objective response rate of 32.4% as assessed by the investigator, and a preliminary median OS of 13.8 months were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting held June 3-7, 2022. A retrospective safety analysis based on 464 patients with FRα positive, recurrent ovarian cancer pooled across three studies (a Phase 1 first-in-human trial and the Phase 3 FORWARD I and SORAYA trials) demonstrating a differentiated and consistent safety profile was also presented at the 2022 ASCO meeting.

Mirvetuximab soravtansine was also evaluated in the randomized Phase 3 FORWARD I trial (NCT02631876), which enrolled 366 patients with platinum-resistant ovarian cancer, randomized 2:1 to receive either the ADC or the physician’s choice of pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel. Improved patient-reported outcomes associated with mirvetuximab compared with chemotherapy were presented at the European Society for Medical Oncology (ESMO) in held in Paris, France in September 2022. In addition, ImmunoGen continues to enroll patients in the randomized, open-label Phase 3 MIRASOL study (NCT04209855), which is evaluating mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. Top-line data from the confirmatory MIRASOL study are expected to be announced in early 2023. If positive, the results may support a full approval by FDA.

Interested in more information about approved antibody therapeutics? Explore our searchable table of antibody therapeutic products for details.

 

European Commission approves Beyfortus® (nirsevimab) for the prevention of RSV disease

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The European Commission (EC) has approved AstraZeneca and Sanofi’s Beyfortus® (nirsevimab) for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants during their first RSV season. Nirsevimab is human IgG1ҡ antibody targeting RSV. The Fc domain was engineered using AstraZeneca’s proprietary YTE half-life extension technology. Developed by AstraZeneca and Sanofi, nirsevimab is designed to offer newborns and infants direct protection against RSV and help prevent RSV-related lower respiratory tract infections.

Nirsevimab received regulatory designations to facilitate development, including a Promising Innovative Medicine designation from the UK Medicines and Healthcare Products Regulatory Agency; Breakthrough Therapy designation from China’s NMPA; Breakthrough Therapy designation from FDA; and PRIME designation from EMA. In addition, it was named “a medicine for prioritized development” under the Project for Drug Selection to Promote New Drug Development in Pediatrics by Japan’s Agency for Medical Research and Development. The approval by the EC was based on results of the Phase 3 MELODY (NCT03979313), Phase 2/3 MEDLEY (NCT03959488), and Phase 2b (NCT02878330) clinical trials.

The Phase 2b trial is a randomized, placebo-controlled trial designed to measure the efficacy of nirsevimab in preventing medically attended RSV-related lower respiratory tract infections through 150 days post-dose. The study was conducted on healthy preterm infants (29–35 weeks’ gestation) who were randomized (2:1) to receive a single intramuscular injection of nirsevimab (50 mg) or placebo. The primary endpoint of the study was met, with a reduction of the incidence of medically attended RSV-related lower respiratory tract infections by 70.1% (95% CI: 52.3, 81.2) compared to placebo.

MELODY is a randomized, placebo-controlled Phase 3 trial evaluating the safety and efficacy of nirsevimab for the prevention of medically attended lower respiratory tract infections in healthy late preterm and term infants (i.e., born at 35 weeks’ gestation or later). Participants (n=1490) up to 1 y of age were randomized (2:1) to receive a single intramuscular injection of nirsevimab (50 mg if <5 kg or 100 mg if >5 kg body weight) or placebo. The primary endpoint of this study was met, with a reduction in the incidence of medically attended lower respiratory tract infections caused by RSV of 74.5% (95% CI 49.6, 87.1; P<0.001) compared to placebo.

The randomized, double-blind, palivizumab-controlled Phase 2/3 MEDLEY study evaluated the safety and pharmacokinetics of nirsevimab compared to palivizumab in preterm infants and infants with congenital heart disease and/or chronic lung disease of prematurity eligible to receive palivizumab entering their first RSV season. Participants (n=925) up to 1 year of age entering their first RSV season were randomized to receive a single intramuscular injection of nirsevimab or palivizumab (50 mg if <5 kg or 100 mg if >5 kg body weight). Safety was assessed by monitoring the occurrence of treatment-emergent adverse events or treatment-emergent serious adverse events through 360 days post-dose. Serum levels of nirsevimab following dosing (on day 151) in this trial were comparable with those observed in the MELODY study, suggesting a similar protection in this population to that in the healthy term and late preterm infants.

Interested in more information about approved antibody therapeutics? Explore our searchable table of antibody therapeutic products for details.

Call for Papers: Collection on Bispecific and Multispecific Antibodies

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Antibodies and antibody-derived bispecifics are one of the most successful therapeutic classes due to their excellent target specificity and tunable drug-like properties. The ability to tailor antibody functions using modern engineering approaches has ushered in a new wave of bi- and multi-specific antibody therapeutics that unlock novel target classes, biology, and mechanisms of action for the treatment of human diseases. In this collection of reviews, we invite The Antibody Society members, mAbs readers, and the broader scientific community to contribute review articles focused on bispecific and multispecific antibody-based molecules. The reviews should narrate the current state of the art in bi- and multi-specific antibody therapeutics, challenges and opportunities, and speculate on new vistas for the field.

mAbs will waive publication charges for up to 8 of the best review articles selected from pre-submission inquiries, which should include the authors, title, abstract, and general outline of the intended review article.

The deadline for pre-submission enquiries is January 31, 2023.

We are particularly interested in reviews in the following topics:

•         Overview of bispecific and multispecific antibody platforms (includes but not limited to Fc engineering, heavy and light chain pairing methodologies, high throughput production methods, geometrical and valency considerations etc.).

•         Reviews on multispecific antibodies (beyond bispecifics i.e., more than two binding epitopes) and their applications.

•         Reviews on bispecifics and multispecific antibodies beyond oncology (i.e., neurology, infectious disease, ophthalmology, rare diseases etc.).

•         Reviews on various cell engagers (T cells, NK cells, macrophages etc.), overview of their design strategies, formats, applications and considerations for safety and tolerability in multiple disease areas.

•         Bispecific/Biparatopic and multispecific/multiparatopic targeting beyond antibodies (Antibody drug conjugates, antibody cytokine fusions, CAR-T/NK/M therapies, ProTACs etc) in various therapeutic areas.

•         Clinical development experience with bispecific and multispecific molecules with a focus on any or all of these areas: safety and tolerability, immunogenicity, biomarkers and/or bioanalytical assay development.

•         Reviews on tissue targeting via bispecific and multispecific antibodies, important considerations for safety, tolerability and preclinical and clinical development.

•         Focused review on developability of bispecific and multispecific molecules, CMC and manufacturing considerations. Bispecifics design and challenges in cell line development, upstream and downstream process development, analytical method development, product quality control strategy, process design and scale up, material demand and commercial manufacturing, regulatory guidance, etc.

Although these topics are especially of interest, we welcome well-written reviews in related areas as well. We intend to waive publication charges for up to 8 of the best review articles selected from pre-submission inquiries, which should consist of the title, abstract and general outline of the intended review article.

The deadline for submission of the completed review articles is August 15, 2023.

Please send pre-submission inquiries to Editor-in-Chief Dr. Janice Reichert (reichert.biotechconsulting@gmail.com), and Assistant Editors Drs. Nimish Gera (ngera@mythictx.com), Li Zhou (li.zhou@abbvie.com) and Jonathan Sockolosky (jonathan@curie.bio). Please feel free to contact us if you have any questions.

For examples of other mAbs Collections, please visit the journal website.

FDA approves teclistamab (Tecvayli) for relapsed or refractory multiple myeloma

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On October 25, 2022, the Food and Drug Administration granted accelerated approval to teclistamab-cqyv (Tecvayli, Janssen Biotech, Inc.) for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Teclistamab (TECVAYLI) is a T-cell redirecting IgG4λ bispecific antibody recognizing BCMA on target cells and CD3e on T cells. Generated from Ligand’s transgenic mouse (OmniAb) and Genmab’s DuoBody technology, the Fc was engineered with the stabilizing S228P mutation and L234A/L235A mutations to minimize its effector functions. Teclistamab was granted Orphan Drug designations for the treatment of MM in both the US and EU, and received the Breakthrough Therapy designation for the treatment of relapsed or refractory MM (RRMM) by the FDA, and a PRIority MEdicines (PRIME) designation by the EMA for treatment of adult patients with RRMM who previously received ≥3 prior lines of therapy. TECVAYLI (teclistamab) was granted conditional marketing authorization in the EU as monotherapy for the treatment of adult RRMM patients who previously received ≥3 prior lines of therapy in August 2022.

The authorizations for marketing were based on the results from the multicohort, open-label, Phase 1 and Phase 2 MajesTEC-1 studies (NCT03145181, NCT04557098, respectively), evaluating the safety and efficacy of teclistamab in adults with RRMM. The ongoing first-in-human dose escalation and dose expansion clinical study (NCT03145181) is assessing the efficacy of teclistamab in patients with RRMM, with the antibody administered IV (range: 0.3−19.2 μg/kg [once every 2 weeks] or 19.2−720 μg/kg [once per week]) or subcutaneously (range: 80−3000 μg/kg [once per week]) in different cohorts, with step-up dosing for 38.4 μg/kg or higher doses. Based on the dose escalation data, in the Phase 2 portion of the study patients received a weekly subcutaneous dose of teclistamab (1.5 mg/kg), after receiving step-up doses of 0.06 mg/kg and 0.3 mg/kg. Results of the MajesTEC-1 study showed that teclistamab induced durable responses that deepened over time in patients with triple-class exposed RRMM (n=165), with an overall response rate of 63%, including a complete response in 39.4% of the patients. The median duration of response and duration of progression-free survival were 18.4 months (95% confidence interval [CI], 14.9 to not estimable) and 11.3 months (95% CI, 8.8 to 17.1), respectively. Adverse events were consistent with this patient population and toxicities consistent with T-cell redirection were mostly Grade 1/2.

Interested in more information about approved antibody therapeutics? Explore our searchable table of antibody therapeutic products for details.

Tremelimumab combination with Imfinzi (durvalumab) approved by FDA for liver cancer

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On October 24, 2022, AstraZeneca announced that Imjudo (tremelimumab) in combination with Imfinzi (durvalumab) has been approved in the US for the treatment of adult patients with unresectable hepatocellular carcinoma (HCC), the most common type of liver cancer. Tremelimumab (CP-675,206), originally developed by Pfizer using Abgenix’s XenoMouseÔ technology, is a human IgG2ҡ antibody targeting CTLA-4. In 2011, MedImmune (now AstraZeneca) gained tremelimumab’s global development rights, while Pfizer retained the rights for use in certain combination therapies. Tremelimumab blocks the activity of the immune checkpoint CTLA-4, contributing to T-cell activation, fostering antitumor immune responses and cancer cell death. Tremelimumab and anti-PD-L1 durvalumab (Imfinzi) were granted Orphan Drug designation in the US for the treatment of hepatocellular carcinoma (HCC), and tremelimumab was also granted Orphan Drug designation for HCC in the EU. On October 24, 2022[JR1] , FDA approved the combination of tremelimumab with Imfinzi for unresectable advanced liver cancer based on the results of the Phase 3 HIMALAYA trial. Marketing applications for this combination for liver cancer is under review by regulatory authorities in other countries and regions. Moreover, based on the results of the POSEIDON trial, marketing applications for the combination of tremelimumab with Imfinzi and chemotherapy for first-line metastatic NSCLC are also under review.

HIMALAYA (NCT03298451) is a randomized, open-label, global Phase 3 trial evaluating the safety and efficacy of durvalumab monotherapy and the combination of durvalumab and tremelimumab versus sorafenib, a standard-of-care multi-kinase inhibitor, as first-line treatment in patients with unresectable HCC who had not received prior systemic therapy and were not eligible for localized treatment. The combination of durvalumab and tremelimumab, called the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab), comprises a single priming dose of 300 mg of tremelimumab added to 1500 mg of durvalumab followed by durvalumab every four weeks.[1] Patients were randomized to STRIDE (n=393), durvalumab (n=389), or sorafenib (n=389). The primary outcome measure was overall survival. Results of the HIMALAYA trial were presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium held January 20-22, 2022 in San Francisco. At data cutoff, the primary objective was met: OS was significantly improved for STRIDE vs sorafenib (hazard ratio [HR], 0.78; 96% confidence interval [CI], 0.65–0.92; p=0.0035. 3). In addition, the ORRs were higher for STRIDE and durvalumab (20.1% and 17.0%, respectively) than for sorafenib (5.1%).

Interested in more information about approved antibody therapeutics? Explore our searchable table of antibody therapeutic products for details.