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Ordspono™ (odronextamab) approved in the European Union

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On August 26, 2024, Regeneron announced that the European Commission approved Ordspono™ (odronextamab) to treat adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) or R/R diffuse large B-cell lymphoma (DLBCL), after two or more lines of systemic therapy. This marks the first regulatory approval of Ordspono in the world for these patients.

Odronextamab (REGN1979) is a hinge-stabilized, bispecific human IgG4k antibody targeting CD20 and CD3 with an Fc that was modified to reduce Fc receptor binding. The antibody was derived from Regeneron’s VelocImmune® technology and Veloci-Bi® platform and is being developed for the treatment of RR B-cell NHL. In 2020, Regeneron granted Zai Lab rights to develop and exclusively commercialize odronextamab in oncology in mainland China, Hong Kong, Taiwan, and Macau. Odronextamab received Fast Track designation from FDA and Orphan Drug designations by the FDA and EMA for the treatment of patients with FL and DLBCL, which are subtypes of NHL.

The approval in the European Union is based on results from the Phase 1 ELM-1 (NCT02290951)  and pivotal Phase 2 ELM-2 (NCT03888105) trials, which demonstrated robust, durable response rates in adults with R/R FL or R/R DLBCL

  • Results from ELM-1 (N=60) in R/R DLBCL patients who had progressed after CAR-T therapy, as assessed by an independent review committee (IRC) showed 48% objective response rate (ORR), with 32% achieving a complete response (CR). Among responders (n=29), the median duration of response (DoR) was 15 months (95% CI: 3 months to not estimable (NE)).
  • Results from ELM-2 (N=127) in R/R DLBCL patients who were CAR-T therapy naive, as assessed by an IRC showed 52% ORR, with 31% achieving a CR. Among complete responders the median DoR was 18 months (95% CI: 10 months to NE).
  • In R/R FL, results from ELM-2 (N=128) as assessed by an IRC showed an objective response rate (ORR) of 80%, with 73% achieving a CR. Among complete responders, the median DoR was 25 months (95% confidence interval [CI]: 20 months to NE).

Regeneron submitted biologics license applications (BLAs) for odronextamab for RR FL and DLBCL to FDA. In March 2024, Regeneron announced that the FDA issued complete response letters for the Biologics License Applications for odronextamab. The company noted that FDA’s only approvability issue is related to the enrollment status of the confirmatory trials.

FDA approves IMDELLTRA™ (tarlatamab-dlle) for extensive-stage small cell lung cancer

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On May 16, 2024, the U.S. Food and Drug Administration (FDA) granted an accelerated approval for IMDELLTRA™ (tarlatamab-dlle) for the treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) with disease progression on or after platinum-based chemotherapy. The approval was based on surrogate endpoints, including response rate and duration of response observed in clinical studies, and continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

IMDELLTRA is bispecific T cell engager (BiTE®, (scFv)2-scFc)) antibody that targets DLL3 on tumor cells and CD3 on the patient’s T cells and has mutations in the Fc (N297G; R292C, V302C) to extend the half-life of the molecules.

FDA’s accelerated approval of IMDELLTRA is based on results from the Phase 2 DeLLphi-301 clinical trial (NCT05060016) that evaluated IMDELLTRA in patients with SCLC who had failed two or more prior lines of treatment, and who had received the 10 mg every two weeks dosing (Q2W) regimen. As reported in the New England Journal of Medicine, results from the study found that IMDELLTRA at the 10 mg Q2W dose demonstrated an objective response rate of 40% and median progression-free survival of 4.9 months. treatment-related adverse events that caused patients discontinuation of tarlatamab treatment occurred in a low percentage (3%) of patients.

IMDELLTRA is currently being evaluated in two Phase 3 studies of SCLC. The Phase 3 DeLLphi-304 study (NCT05740566) is evaluating tarlatamab compared with standard of care in subjects with relapsed SCLC after platinum-based first-line chemotherapy. The Phase 3 DeLLphi-306 study (NCT06117774) is evaluating tarlatamab in subjects with limited-stage SCLC who have not progressed following concurrent chemoradiation therapy. A third Phase 3 study, DeLLphi-305 (NCT06211036), evaluating tarlatamab in combination with durvalumab vs durvalumab alone in subjects with ES-SCLC following platinum, etoposide and durvalumab was not yet recruiting patients as of the last update posted on May 10, 2024.

Details for all approved antibody therapeutics are found in our searchable online table.

TEVIMBRA (tislelizumab-jsgr) granted first FDA approval for esophageal squamous cell carcinoma

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On March 13, 2024, the U.S. Food and Drug Administration (FDA) approved TEVIMBRA (tislelizumab-jsgr) as monotherapy for the treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor. TEVIMBRA, a humanized IgG4 antibody engineered with modifications that stabilize the hinge region and abrogate binding to Fc receptors, was approved as an orphan drug for this indication.

FDA’s approval is based on the Phase 3 RATIONALE 302 trial (NCT03430843), which met its primary endpoint in the intention-to-treat (ITT) population, with a median overall survival (OS) in the TEVIMBRA arm or 8.6 months (95% CI: 7.5, 10.4) compared to 6.3 months (95% CI: 5.3, 7.0) in the chemotherapy arm (p=0.0001; hazard ratio [HR]=0.70 [95% CI: 0.57, 0.85]). The results showed a statistically significant and clinically meaningful survival benefit for TEVIMBRA compared with chemotherapy and the safety profile of TEVIMBRA was favorable over chemotherapy.

In 2019, China’s National Medical Products Administration granted the first global approval of tislelizumab. In 2023, the product received approval by the European Commission for advanced or metastatic ESCC after prior chemotherapy, and it received a positive opinion by the Committee for Medicinal Products for Human Use of the European Medicines Agency in February 2024 as a treatment for non-small cell lung cancer across three indications.

Biologics license applications for tislelizumab as first-line treatment for patients with unresectable, recurrent, locally advanced, or metastatic ESCC and patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma are currently undergoing FDA review. The target action dates for these applications are in July and December 2024, respectively.

Details for all approved antibody therapeutics and those in regulatory review can be found in our searchable table.

Crovalimab approved in China

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On February 8, 2024, Chugai Pharmaceutical Co., Ltd. announced that crovalimab (Chinese product name : 派圣凯®) was approved in the People’s Republic of China for treatment of adults and adolescents with paroxysmal nocturnal hemoglobinuria (PNH) not been previously treated with complement inhibitors. The regulatory application was filed by a China affiliate of F. Hoffmann-La Roche Ltd. because Roche is responsible for the development of crovalimab outside Japan and Taiwan. China is the first country in the world to approve crovalimab. Marketing applications for crovalimab have been submitted to regulatory agencies in the US, EU, and Japan.

Crovalimab (SKY59, RG6107, RO7112689) is a complement C5 inhibiting, humanized IgG1k antibody without effector functions that was engineered (M428L/N434A) to have enhanced affinity to FcRn at an acidic pH to extend its plasma half-life. Based on Chugai’s Recycling Antibody® technology, crovalimab is engineered to bind its antigen repeatedly, enabling sustained complement inhibition at a low dose administered subcutaneously (SC) every 4 weeks. Moreover, crovalimab binds a different epitope of C5 compared to existing antibody drugs, suggesting that it represents an alternative option for patients with PNH with a specific C5 gene mutation.

Crovalimab was granted Breakthrough Therapy for PNH by NMPA and the marketing application for crovalimab, which included data from the China-specific Phase 3 COMMODORE 3 study (NCT04654468), was accepted by NMPA under Priority Review.

COMMODORE 3 was a multicenter single-arm trial studying crovalimab in C5 inhibitor-naive patients with PNH in China. Patients (n=51) received crovalimab according to a weight-based dosing schedule, including loading (intravenous (IV) dose on Days 1 and 4, weekly SC doses starting from Day 2) and SC maintenance doses (every 4 weeks starting from Week 5); treatment continued after 24 weeks in patients with clinical benefit. The co-primary efficacy endpoints of hemolysis control and transfusion avoidance (TA) were met. The mean proportion of participants with hemolysis control from Week 5 through to Week 25 was 78.7% (95% CI: 67.8%, 86.6%).1 The difference between the proportion of participants with TA within 24 weeks prior to screening (0.0%) and the proportion of participants with TA from baseline through to Week 25 (51.0%) was statistically significant (p<0.0001). [1]

The global Phase 3 COMMODORE 1 (NCT04432584) and 2 (NCT04434092) studies assessed the efficacy and safety of crovalimab versus eculizumab in participants with PNH that are C5 inhibitor-experienced patients or not previously treated with complement inhibitors, respectively. COMMODORE 1 assessed safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy of crovalimab. Data from the study support the favorable benefit–risk profile of crovalimab, including allowing for SC administration with the option to self-administer. [2] Data from the COMMODORE 2 study presented at European Hematology Association meeting in June 2023 in Frankfurt, Germany demonstrated that SC crovalimab Q4W was non-inferior in disease control to IV eculizumab Q2W with comparable safety for patients who have not been treated with C5 inhibitors. [3]

  1. Liu H, Xia L, Weng J, Zhang F, He C, Gao S, Jia J, Chang AC, Lundberg P, Camelia S. Sima CS, et al. Results from the first Phase 3 crovalimab (c5-inhibitor) study (commodore 3): efficacy and safety in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). Presentation at: ASH Annual Meeting and Exposition; New Orleans, 2022 Dec 10-13; Abstract #293. doi.org/10.1182/blood-2022-162452.
  2. Scheinberg P, Cle D, Edwards J, Giai V, Hus M, Kim JS, Barrenetxea Lekue C, Nagy Z, Nur E, Panse J, et al. Phase III randomized, multicenter, open-label COMMODORE 1 trial: comparison of crovalimab vs eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Hemasphere. 2023; 7(Suppl ): e45540d8. 2023 Aug 8. doi: 10.1097/01.HS9.0000967644.45540.d8
  3. Röth A, He G, Brodsky A, Chai-Adisaksopha CC, Dumagay T, Demichelis R, Höglund M, Kelly R, Lee J-H, Nishimura J-I, et al. The PHASE III, randomized COMMODORE 2 trial: results from a multicenter study of crovalimab vs eculizumab in paroxysmal nocturnal hemoglobinuria (PNH) patients naive to complement inhibitors. Hemasphere. 2023; 7(Suppl ): e72750f1.

“Antibodies to Watch in 2024” is now online!

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In this 15th installment of the annual ‘Antibodies to Watch’ article series, we review commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those granted a first approval in any country in 2023. We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14–32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.

Download or read the full paper here.

The complete abstract is here: The ‘Antibodies to Watch’ article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those recently granted a first approval in any country. In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi)). We briefly review 26 product candidates for which marketing applications are under consideration in at least one country or region, and 23 investigational antibody therapeutics that are forecast to enter regulatory review by the end of 2024 based on company disclosures. These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody–drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa). We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14–32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.