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US FDA Grants Priority Review for the CD20xCD3 T-cell Engaging Bispecific Antibody Mosunetuzumab

San Diego, CA - ASH 2018 - General Views of attendees during the day at the American Society of Hematology 59th Annual Meeting at the San Diego Center here today, Sunday December 2, 2018. The Annual Meeting is the premier hematology event of the year for basic, translational, clinical and population science, in the United States, with more than 20,000 hematology experts from around the world attending the meeting. Photo by © ASH/Scott Morgan 2018

The U.S. Food and Drug Administration (FDA) has accepted the Genentech‘s Biologics License Application (BLA) and granted Priority Review for mosunetuzumab (previously known as BTCT4465A) , a potential first-in-class CD20xCD3 T-cell engaging bispecific antibody, for the treatment of adults with relapsed or refractory (R/R) follicular lymphoma (FL) who have received at least two prior systemic therapies.

Follicular lymphoma is the most common indolent or slow growing form of non-Hodgkin’s lymphoma (NHL), a type of blood cancer, which often returns after initial therapy. Based on recent data, follicular lymphoma accounts for about one in five cases of NHL, with patients having an average age of approximately 60.

The five-year-survival-rate is 87.7%, with younger patients having a higher survival rate. [1]

The disease typically responds well to treatment but is often characterized by periods of remission and relapse. Unfortunately, follicular lymphoma is a heterogenous disease, and about one in five patients relapses within 2 years after the start of initial treatment. Furthermore, it becomes, however, harder to treat each time a patient relapses, and early progression can be associated with poor long-term prognosis. [2] And despite the generally indolent nature of follicular lymphoma, as a result of these ‘characteristics,’ there is a great unmet medical need for efficient treatments for patients with relapsed or refractory follicular lymphoma as well treatment options for later lines of treatment, which are particularly scarce. [1][3]

Port Worthy

In the United States, it is estimated that between 13,000 and 15,000 new cases of follicular lymphoma will be diagnosed in 2022. [1]

First in class
Mosunetuzumab is a first-in-class CD20xCD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T-cells. This dual targeting activates and redirects a patient’s existing T-cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. Following their review of mosunetuzumab, the FDA is expected to make a decision on approval of this novel cancer immunotherapy by December 29, 2022.

“New therapeutic options are needed for follicular lymphoma, which often relapses after initial therapy and becomes increasingly difficult to treat each time it returns. Clinical trial results have demonstrated durable responses with mosunetuzumab in advanced follicular lymphoma, representing a step toward shifting the treatment paradigm,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development.

“Since mosunetuzumab does not require the collection or genetic modification of patient cells, it could become an effective, fixed-duration outpatient option without the barriers of travelling to a major academic center,” Garraway added.

“With mosunetuzumab, we also aim to offer a therapy that can be administered in the outpatient setting to people with this devastating blood cancer,” he further noted

Pivotal Phase 
The BLA is based on positive results from the pivotal GO29781 study of mosunetuzumab. This Phase 1 / 2, multicenter, open-label, dose-escalation and expansion study was designed to evaluate the safety, efficacy and pharmacokinetics of mosunetuzumab in people with relapsed or refractory B-cell non-Hodgkin’s lymphoma. The outcome measures included complete response rate by independent review facility, objective response rate, duration of response, progression-free survival, safety and tolerability.

The results of the study showed high complete response (CR) rates, with the majority of responders (57% [95% CI: 49-70]) maintaining responses for at least 18 months, and manageable tolerability in people with heavily pretreated follicular lymphoma.

After a median follow-up of 18.3 months, the CR rate was 60% (n=54/90) and the objective response rate was 80% (n=72/90). The median duration of response among those who responded was 22.8 months (95% CI: 9.7-not estimable).

Adverse events
The most common adverse event (AE) was cytokine release syndrome (39%; n=86/218), which was generally low grade (grade 1: 25.6%; grade 2: 14%; grade 3: 2.3%; grade 4: 0.5%), and all events resolved. Other common AEs (>20%) included fatigue, headache, neutropenia, fever and hypophosphatemia.

The study authors concluded that, based on the results of the study mosunetuzumab induces deep and durable remissions in patients who had received 2 or more previous lines of treatment, including those with progressive disease within 24 months from the start of initial therapy (POD24) and/or double-refractory disease. [4]

These results were presented for the first time in December 2021 at the 63rd American Society of Hematology (ASH) Annual Meeting & Exposition. During the ASH meeting, new efficacy data demonstrate potential of bispecific antibodies to expand upon current treatment options across hematological malignancies blood.[4]

Priority review
Priority Review designation is granted to medicines that the FDA considers to have the potential to provide significant improvements in the safety and effectiveness of the treatment, prevention or diagnosis of a serious disease. The FDA granted Breakthrough Therapy Designation (BTD) to mosunetuzumab for the treatment of adults with R/R FL who have received at least two prior systemic therapies in June 2020 and Orphan Drug Designation in December 2018.

The Breakthrough Therapy Designation is designed to accelerate the development and review of medicines intended to treat serious or life-threatening conditions with preliminary evidence that indicates they may demonstrate substantial improvement over existing therapies. The European Commission granted conditional marketing authorization for mosunetuzumab for the treatment of people with R/R FL who have received at least two prior systemic therapies in June 2022.

Ongoing clinical development
A robust development program for mosunetuzumab is ongoing including two Phase III studies: CELESTIMO investigating mosunetuzumab plus lenalidomide in second-line plus (2L+) FL, and SUNMO, investigating mosunetuzumab plus Polivy® (polatuzumab vedotin) in 2L+ diffuse large B-cell lymphoma (DLBCL).

Clinical trials
A Safety, Efficacy and Pharmacokinetic Study of BTCT4465A (Mosunetuzumab) as a Single Agent and Combined With Atezolizumab in Non-Hodgkin’s Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL) | GO29781 study – NCT02500407
A Study Evaluating the Efficacy and Safety of Mosunetuzumab in Combination With Lenalidomide in Comparison to Rituximab in Combination With Lenalidomide in Patients With Follicular Lymphoma After at Least One Line of Systemic Therapy (Celestimo) – NCT04712097
A Study Evaluating Efficacy and Safety of Mosunetuzumab in Combination With Polatuzumab Vedotin Compared to Rituximab in Combination With Gemcitabine Plus Oxaliplatin in Participants With Relapsed or Refractory Aggressive B-Cell Non-Hodgkin’s Lymphoma (SUNMO) – NCT05171647

Reference
[1] Buske C. Mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma. Lancet Oncol. 2022 Jul 5:S1470-2045(22)00385-0. doi: 10.1016/S1470-2045(22)00385-0. Epub ahead of print. PMID: 35803285.
[2] Casulo C, Byrtek M, Dawson KL, Zhou X, Farber CM, Flowers CR, Hainsworth JD, Maurer MJ, Cerhan JR, Link BK, Zelenetz AD, Friedberg JW. Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study. J Clin Oncol. 2015 Aug 10;33(23):2516-22. doi: 10.1200/JCO.2014.59.7534. Epub 2015 Jun 29. Erratum in: J Clin Oncol. 2016 Apr 20;34(12):1430. Erratum in: J Clin Oncol. 2016 Apr 20;34(12):1430. PMID: 26124482; PMCID: PMC4879714.
[3] Batlevi CL, Sha F, Alperovich A, Ni A, Smith K, Ying Z, Soumerai JD, Caron PC, Falchi L, Hamilton A, Hamlin PA, Horwitz SM, Joffe E, Kumar A, Matasar MJ, Moskowitz AJ, Moskowitz CH, Noy A, Owens C, Palomba LM, Straus D, von Keudell G, Zelenetz AD, Seshan VE, Younes A. Follicular lymphoma in the modern era: survival, treatment outcomes, and identification of high-risk subgroups. Blood Cancer J. 2020 Jul 17;10(7):74. doi: 10.1038/s41408-020-00340-z. PMID: 32678074; PMCID: PMC7366724.
[4] Budde LE, Sehn LH, Matasar M, Schuster SJ, Assouline S, Giri P, Kuruvilla J, Canales M, Dietrich S, Fay K, et al. Mosunetuzumab Monotherapy Is an Effective and Well-Tolerated Treatment Option for Patients with Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Who Have Received ≥2 Prior Lines of Therapy: Pivotal Results from a Phase I/II Study. Presented during the 63rd annual meeting of the American Society of Hematology (ASH) Session: 623. Mantle Cell, Follicular, and Other B-Cell Lymphomas: Clinical and Epidemiological: Evolution of Immunotherapeutic Regimens in B-cell Lymphomas. Hematology Disease Topics & Pathways: Biological therapies, Lymphomas, non-Hodgkin lymphoma, Bispecific Antibody Therapy, Diseases, indolent lymphoma, Therapies, Lymphoid Malignancies. [Abstract]

Featured image: General Views of attendees during the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, CA. Photo courtesy: © 2018 ASH/Scott Morgan. Used with permission.

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