On December 12, 2023 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science to develop a new generation of small-molecule medicines and transform how disease is treated, reported clinical data from the ongoing Phase 1 dose escalation portion of its Phase 1/2 clinical trial of CFT7455, a MonoDAC degrader of IKZF1/3, for the potential treatment of multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHL) (Press release, C4 Therapeutics, DEC 12, 2023, View Source [SID1234638484]). These data include results from CFT7455 as a monotherapy for relapsed/refractory (R/R) MM patients, which has completed dose escalation, and interim results from CFT7455 in combination with dexamethasone for R/R MM patients, which continues to enroll patients. C4T also continues to enroll patients in the Phase 1 dose escalation trial exploring CFT7455 as a monotherapy for NHL patients.

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"We are excited CFT7455 monotherapy is showing promising signs of anti-myeloma and immunomodulatory activity and anti-myeloma activity when combined with dexamethasone, particularly in patients who have undergone numerous lines of prior therapy for multiple myeloma, including BCMA therapies," said Len Reyno, M.D., chief medical officer of C4 Therapeutics. "We have established 14 days on/14 days off as the optimal dosing schedule, which is consistent with our preclinical data supporting CFT7455 as a rationally designed IKZF1/3 degrader with the potential to offer a new therapy for patients with relapsed/refractory multiple myeloma."

CFT7455 Phase 1 Dose Escalation
The goal of the CFT7455 Phase 1 dose escalation trial is to define the safety profile of CFT7455, determine the maximum tolerated or administered dose, and identify signs of anti-tumor activity in R/R MM and R/R NHL. The Phase 1 dose escalation portion of the trial includes three arms: CFT7455 as a monotherapy for R/R MM patients, which is complete; CFT7455 in combination with dexamethasone for R/R MM patients, which continues to advance through dose escalation; and CFT7455 as a monotherapy for NHL patients, which also continues to advance through dose escalation. The Phase 1 dose escalation portion of the ongoing Phase 1/2 trial has utilized a 14 days on/14 days off dosing schedule within which both daily dosing and Monday/Wednesday/Friday (MWF) dosing were explored.

CFT7455 as a Monotherapy for R/R MM Patients
Monotherapy dose escalation is complete. As of the November 28, 2023 data cutoff date, 22 patients had received CFT7455 as a monotherapy. The maximum dose administered was 75 µg daily for 14 days on/14 days off. A maximum tolerated dose was not defined. Patients were heavily pretreated, with a median of seven prior therapies. The majority of patients (n=12) received prior CAR-T or T-cell engager therapy.

Pharmacokinetic and Pharmacodynamic Results

Clearance of CFT7455 is consistent with a 48-hour half-life.
Daily dosing (14 days on/14 days off) resulted in deep IKZF1/3 degradation.
After day 14, as plasma concentrations of CFT7455 begin to decline, degraded proteins recover through day 28, enabling neutrophil recovery.
Safety and Evidence of Anti-Tumor Effect

CFT7455 was well tolerated.
22 patients were evaluable for safety. The most common adverse events (AEs) Grade 3 or above were neutropenia (n=11), anemia (n=4) and leukopenia (n=4).
No dose-limiting toxicities (DLTs) resulted in discontinuation of therapy.
As of the November 28, 2023 data cutoff date, 20 patients were evaluable for evidence of anti-tumor effect.
Four patients received the maximum dose administered of 75 µg daily. Three patients were refractory to BCMA therapies. Responses were measured in accordance with the International Myeloma Working Group (IMWG) criteria for multiple myeloma. All four patients achieved Stable Disease (SD) or better and one patient achieved a Partial Response (PR).
Immunomodulatory Results

CFT7455 induced CD8+ T-cell activation by increasing the effector memory T-cell subset, as required for effective adaptive immunity.
T-cell activation was observed at well tolerated monotherapy doses, supporting the potential use of CFT7455 in combination with bi-specific T-cell engagers and monoclonal antibody therapies.
CFT7455 in Combination with Dexamethasone for R/R MM Patients
As of the November 28, 2023 data cutoff date, nine patients had received CFT7455 in combination with dexamethasone across two initial dose escalation cohorts (50 µg MWF for 14 days on/14 days off; or 37.5 µg daily for 14 days on/14 days off). Patients were heavily pretreated, with a median of six prior therapies. The majority of patients (n=5) received prior CAR-T or T-cell engager therapy. This arm is ongoing; patients are currently enrolling in either the 62.5 µg escalation cohort or the 37.5 µg expansion cohort.

Safety and Evidence of Anti-Tumor Effect

CFT7455 in combination with dexamethasone is well tolerated to date.
The most common AEs Grade 3 or above were consistent with the monotherapy safety signal.
No AEs have led to dose reductions, discontinuations or DLTs.
All three patients evaluable for efficacy at 37.5 μg daily achieved SD or better according to IMWG criteria. These assessments include:
One patient achieved a Stringent Complete Response (sCR), after initially achieving a Very Good Partial Response (VGPR). This patient was refractory to BCMA therapies.
One patient achieved a PR. This patient was refractory to BCMA therapies.
One patient achieved SD.
Upcoming Data Presentations for CFT7455
C4T expects to present the following data on CFT7455 in 2024:

Complete Phase 1 dose escalation data from the ongoing Phase 1/2 clinical trial in R/R MM.
Complete Phase 1 dose escalation data from the ongoing Phase 1/2 clinical trial in NHL.
C4T Webcast for Analysts and Investors
C4T will host an investor webcast today, December 12, 2023, at 4:30 pm Eastern Time, to discuss the CFT7455 Phase 1 clinical data in relapsed/refractory multiple myeloma. To join the webcast, please visit this link or the "Events & Presentations" page of the Investors section on the company’s website at www.c4therapeutics.com. A replay of the webcast will be archived and available following the event.

On December 12, 2023 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science to develop a new generation of small-molecule medicines and transform how disease is treated, reported that it has entered into an exclusive license and collaboration agreement with Merck (known as MSD outside of the U.S. and Canada) to develop degrader-antibody conjugates (DACs), an emerging modality designed to selectively target and neutralize disease-causing proteins in cancer cells (Press release, C4 Therapeutics, DEC 12, 2023, View Source [SID1234638483]).

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"We are thrilled to collaborate with Merck to innovate within the growing field of antibody-drug conjugates and evaluate the potential for combining the catalytic efficiency, potency, target specificity, and durability of degraders with the specific binding and delivery capabilities of antibodies," said Andrew Hirsch, president and chief executive officer of C4 Therapeutics. "We look forward to leveraging our powerful TORPEDO platform in collaboration with Merck’s antibody-drug conjugation expertise to engineer novel medicines with the potential to transform patients’ lives."

Under the terms of the agreement, C4T will receive a $10 million upfront payment. C4T and Merck will collaborate to develop DACs directed to an initial undisclosed oncology target that is exclusive to the collaboration. For DACs directed to this initial target, C4T is eligible to receive milestone payments totaling approximately $600 million, as well as tiered royalties on future sales. The agreement also provides Merck with the option to extend the collaboration to include three additional targets that would be exclusive to the collaboration, which could yield option exercise payments as well as potential milestones and royalties. If Merck exercises all of its options to extend the collaboration, C4T would be eligible to receive up to approximately $2.5 billion in potential payments across the entire collaboration.

"This collaboration combines Merck’s significant biological chemistry expertise with C4T’s leading protein degradation technology," said George Addona, senior vice president, discovery, preclinical development and translational medicine, Merck Research Laboratories. "At Merck, we continue to evaluate new ways to advance the science of targeted medicine."

As part of the collaboration, C4T will be responsible for using its proprietary TORPEDO platform to develop degrader payloads in the discovery phase. Merck will be responsible for antibody conjugation to create DACs in the discovery phase and for advancing these DAC candidates through preclinical and clinical development as well as commercialization.

On December 12, 2023 Bicara Therapeutics, a clinical-stage biotechnology company developing dual-action biologics to elicit a potent and durable immune response, reported the completion of an oversubscribed $165 million Series C financing (Press release, Bicara Therapeutics, DEC 12, 2023, View Source [SID1234638481]). The financing was co-led by Braidwell LP and TPG, which is investing in the company through TPG Life Sciences Innovations (TPG LSI) and The Rise Fund, with additional new investors including Deerfield Management, Fairmount, Aisling Capital and a leading biotechnology investor associated with one of the largest alternative asset managers. All existing Series B investors also participated in the round.

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Proceeds from the Series C financing will be used to support the continued advancement of Bicara’s lead product candidate, BCA101, a first-in-class bifunctional EGFR/TGF-β inhibitor that is currently in clinical development for multiple cancer types including frontline human papillomavirus (HPV)-negative, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), advanced squamous non-small cell lung cancer (SqNSCLC) and cutaneous squamous cell carcinoma.
At the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting and ESMO (Free ESMO Whitepaper) Congress 2023, Bicara presented positive interim clinical data from its ongoing, open-label Phase 1/1b dose expansion study of BCA101 in combination with pembrolizumab demonstrating clinically meaningful anti-tumor activity and a tolerable safety profile in frontline HPV-negative R/M HNSCC, a cancer with limited treatment options that generally carries a poor prognosis and is increasing in prevalence.
Additional data updates from Bicara’s ongoing Phase 1/1b dose expansion study of BCA101, including in advanced SqNSCLC, are anticipated in 2024.
"Momentum at Bicara is increasing following our BCA101 Phase 1/1b data presentations at key 2023 medical meetings," said Claire Mazumdar, Ph.D., MBA, Chief Executive Officer of Bicara Therapeutics. "Our proof-of-concept data in frontline HPV-negative R/M HNSCC, a very difficult patient population to treat, underscore the promise of BCA101 as a new precision therapeutic option for these patients. With additional data readouts anticipated in 2024, we remain excited about the overall potential of BCA101 to help patients with HPV-negative R/M HNSCC, as well as other solid tumor types. We are thrilled to partner with this syndicate of new and existing leading healthcare investors, who share in our vision for BCA101 and Bicara’s bifunctional antibody platform."

In connection with the Series C financing, Carolyn Ng, Ph.D., Business Unit Partner with TPG LSI, has joined Bicara’s board of directors.

"Bicara’s Phase 1/1b dose expansion study of BCA101 has delivered encouraging, clinically meaningful interim results and offers an excellent foundation from which to continue to build Bicara into a leading oncology company," said Dr. Ng. "I am excited to join Bicara’s board of directors at such an important time and look forward to working with this talented management team and distinguished board of directors to advance new treatments for cancer patients."

With the completion of the Series C financing, Bicara has raised $273 million in 2023.

About BCA101
BCA101 is a first-in-class, dual-action, bifunctional antibody designed to inhibit the epidermal growth factor receptor (EGFR) and disable transforming growth factor beta (TGF-β) directly at the tumor site. This approach is designed with the intent to allow BCA101 to inhibit tumor proliferation, while restoring the cytolytic activity of the local immune cells.

BCA101 is currently being evaluated in a dose expansion phase of an open-label Phase 1/1b study in combination with pembrolizumab in patients with unresectable R/M HNSCC and advanced SqNSCLC and as a monotherapy for cutaneous squamous cell carcinoma.

About Head and Neck Squamous Cell Carcinoma
Head and neck squamous cell carcinomas (HNSCCs) develop from the mucosal epithelium in the oral cavity, pharynx and larynx and are the most common malignancies that arise in the head and neck.

Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be biologically separated into HPV-negative and HPV-positive HNSCC, the latter carrying a more favorable prognosis. Treatment approaches for locally advanced HNSCC generally consist of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary or definitive CRT for pharynx and larynx cancers. The immune checkpoint inhibitors pembrolizumab and nivolumab are approved by the U.S. FDA for treatment of platinum-refractory recurrent or metastatic HNSCC, and pembrolizumab is approved as first-line monotherapy in patients with unresectable or metastatic disease with a CPS ≥1 or combined with platinum and 5-fluorouracil for patients with any CPS score.

HNSCC is the sixth most common cancer worldwide, with approximately 890,000 new cases and 450,000 deaths in 2018. The incidence of HNSCC continues to rise and is anticipated to increase by 30% by 2030.

On December 12, 2023 AbelZeta Pharma, Inc. ("AbelZeta" or the "Company"), a global clinical-stage biopharmaceutical company focused on discovery and development of innovative and proprietary cell-based therapeutic products, reported clinical data for both C-CAR039 for the treatment of patients with relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL), and C-CAR066, for the treatment of patients with r/r large B-cell lymphoma (LBCL) who failed prior CD19 CAR-T therapy at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, AbelZeta, DEC 12, 2023, View Source [SID1234638480]).

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"We are thrilled to share the long-term follow-up results from our clinical studies of C-CAR039 and C-CAR066 at the Annual Meeting of ASH (Free ASH Whitepaper), said Tony (Bizuo) Liu, Chairman and CEO of the Company. "The positive outcomes underscore the potential of these novel therapies in advancing the treatment landscape for patients with r/r B-NHL. The observed response rates, durability, and manageable safety profile demonstrated in both studies reinforce our commitment to pioneering innovative and effective solutions in immuno-oncology for patients suffering from serious hematological malignancies."

"We are proud of our collaboration and license agreement with Janssen to facilitate the global development and accessibility of C-CAR039 and C-CAR066. This strategic partnership aligns with our mission to bring innovative and life-changing therapies to patients worldwide."

In May 2023, AbelZeta Pharma (formerly CBMG) entered into a global collaboration and license agreement with Janssen Biotech, Inc. (Janssen), a Johnson & Johnson company, for C-CAR039, an anti-CD19 & CD20 bi-specific CAR-T therapy, and C-CAR066, an anti-CD20 CAR-T.

Study Conclusions
At a longer median follow-up of 30.0 months, C-CAR039 demonstrated a favorable safety profile with deep and durable response in patients with r/r B-NHL, especially in LBCL patients.
Longer term follow-up demonstrated that C-CAR066 can produce a deep and durable response with a favorable safety profile in patients with r/r LBCL who failed prior CD19 CAR-T therapy.
About the C-CAR039 Study
C-CAR039 has been developed as a novel 2nd generation 4-1BB bi-specific CAR-T targeting both CD19 and CD20 antigens with an optimized bi-specific antigen binding domain. C-CAR039 has consistently shown ability to eradicate CD19/CD20 single or double positive tumor cells in vitro and in vivo. GMP manufacturing of C-CAR039 was carried out in a serum free and fully closed semi-automatic system.

In the Phase I clinical trials in China (NCT04317885, NCT04655677, NCT04696432, NCT04693676), dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide (300mg/m2x3d) plus fludarabine (30mg/m2x3d) conditioning regimen.

Key Results of C-CAR039
Between November 5, 2019, and January 11, 2022, 48 patients received C-CAR039 at the dose ranges of 1.0 x 106 to 5.0×106 CAR-T cells/kg. Of the 48 patients, 44 (91.7%) patients had large B-cell lymphoma (LBCL) (DLBCL, n=37; PMBCL, n=3; tFL, n=4), 3 patients had FL and 1 patient had MCL. The median age was 55 (range, 25-71) years, and 11 (22.9%) patients were ≥ 65 years. Thirty-six (75%) patients were in Ann Arbor Stage III/IV with 3 median prior lines of therapy, 32 (66.7%) patients were refractory to their last treatment, and 22 (45.8%) patients never achieved CR to their prior therapies.

As of September 25, 2023, 45 patients (93.8%) experienced CRS, only 1 (2.1%) were grade 3. Three patients had grade 1 or 2 ICANS at a dose of 5.0×106 CAR-T cells/kg. Grade 3 or higher cytopenia not resolved by Day 30 following C-CAR039 infusion included neutropenia (54.2%), thrombocytopenia (20.8%), and anemia (20.8%). At cutoff date, 66.7% patients had infections with 25% grade 3 or higher. Second primary malignancy after C-CAR039 infusion was observed in 3 patients and none were related to C-CAR039. Fifteen deaths occurred, 11 due to disease progression.

Of the 48 patients, 47 patients were evaluable for efficacy. The median follow-up time was 30.0 months. The ORR and CR rate among evaluable patients were 91.5% and 85.1% respectively. Of the 43 LBCL patients, the ORR was 90.7%, with 86.0% CR. Median duration of response (DOR) was not reached. 23/47 (48.9%) patients remain in CR, 10 of them for more than 36 months. Median PFS has not been reached. KM estimates of 24-m PFS rate were 62.6% (all patients) and 64.1% (LBCL). Median OS has not been reached. KM estimates of 24-m OS rate were 76.5% (all patients) and 79.0% (LBCL).

The complete text of the abstract can be found
View Source

About the C-CAR066 Study
C-CAR066 is a novel second generation CAR-T therapy targeting the CD20 antigen. Preclinical studies suggest that C-CAR066 has superior anti-tumor activity compared to anti-CD20 CAR-Ts derived from scFVs of Leu16, Rituximab and Obinutuzumab, and to anti-CD19 CAR-Ts derived from scFV FMC63.

The Phase I clinical trials (NCT04036019, NCT04316624) were conducted in Shanghai Tongji Hospital and Institute of Hematology & Blood Diseases Hospital in Tianjin, China, to evaluate the safety and efficacy of C-CAR066 in subjects with r/r B-NHL who were previously treated with and failed after an anti-CD19 CAR-T therapy. C-CAR066 was administered as a single intravenous dose after a 3-day cyclophosphamide (300mg/m2x3d) plus fludarabine (30mg/m2x3d) conditioning regimen.

Key Results of C-CAR066
Between October 16, 2019, and August 17, 2021, a total of 14 patients received C-CAR066 at doses of 2.0×106 CAR-T cells/kg and 3.0×106 CAR-T cells/kg. Eleven patients (78.6%) were DLBCL, 3 patients (21.4%) were tFL. The median age was 54.5 years (range, 37-67). Twelve patients (85.7%) were in Ann Arbor Stage III/IV. The median number of prior lines of therapy was 5 (range, 2-7). All patients had prior CD19 CAR-T therapy.

As of October 10, 2023, 12/14 patients (85.7%) experienced CRS, all were grade 1/2, except for 1 patient who experienced a grade 4 CRS. No patients experienced ICANS. Grade 3 or higher cytopenia not resolved by Day 30 following C-CAR066 infusion occurred in 28.6% patients and included neutropenia (21.4%), thrombocytopenia (14.3%), and anemia (14.3%). At cutoff date, 8 patients experienced infections, only 2 were grade 3. Seven deaths occurred and all due to disease progression. No SPM and new safety signals were observed with longer follow-up.

The investigator assessed ORR was 92.9%, with 57.1% CR. With the median follow-up of 27.7 months, median PFS and DOR were 9.4 months and 8.3 months, respectively. Four patients had remained in CR for more than 30 months. The Kaplan-Meier estimate of median OS was 34.8 months (11.4 – NA).

The complete text of the abstract can be found
View Source

On December 12, 2023 Bristol Myers Squibb (NYSE: BMY) and 2seventy bio, Inc. (Nasdaq: TSVT) reported results from the preplanned final progression-free survival (PFS) analysis of KarMMa-3, the pivotal Phase 3, open-label, global, randomized controlled study evaluating Abecma (idecabtagene vicleucel) compared with standard combination regimens in adults with relapsed and refractory multiple myeloma after two to four prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody (triple-class exposed), who were refractory to their last regimen (Press release, 2seventy bio, DEC 12, 2023, View Source [SID1234638479]). At a median follow-up of 30.9 months (range: 12.7-47.8), representing the longest follow-up for a randomized Phase 3 CAR T cell therapy trial in this patient population, significantly improved PFS was maintained with Abecma compared to standard regimens (95% CI: 13.8 months vs. 4.4 months), with a 51% reduction in the risk of disease progression or death (HR: 0.49; 95% CI: 0.38-0.63). These data are being presented today in an oral presentation at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Oral Presentation #1028).

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With extended follow-up, treatment with Abecma (n=254) continued to demonstrate higher overall response rates (ORR) and a deepening of responses versus standard regimens. The ORR with Abecma was 71% (95% CI: 66-77) with a complete response (CR) rate of 44% (95% CI: 38-50), which increased by 5% from the interim analysis. In comparison, the ORR for standard regimens was 41% (95% CI: 34-51), with a CR rate of 5% (95% CI: 2-9), which remained unchanged from the time of interim analysis. The PFS, ORR and CR rates observed in the KarMMa-3 trial in the standard regimens arm are consistent with those that have historically been observed in this heavily pre-treated triple-class exposed patient population, in which PFS is approximately four months and deep and durable responses are limited. With these data, Abecma is the first and only anti-BCMA CAR T cell therapy to demonstrate superiority over standard regimens in a randomized, controlled Phase 3 trial designed to evaluate patients with triple-class exposed relapsed and refractory multiple myeloma.

"With longer follow-up from the KarMMa-3 study, we continue to see the significant clinical benefit that Abecma delivers for triple-class exposed multiple myeloma, illustrating the potential of using Abecma for long-term disease control and remission when used earlier in the treatment paradigm," said Paula Rodriguez-Otero, M.D., Ph.D., Department of Hematology, Clinica Universidad de Navarra, Pamplona, Spain. "As the CAR T therapy with the longest real-world experience in later lines of therapy, and with these latest data which demonstrate clinically meaningful benefit and awell-established and generally predictable safety profile, Abecma has the potential to be a transformative treatment option across lines of therapy for triple-class exposed relapsed and refractory multiple myeloma."

"As the first-in-class anti-BCMA CAR T cell therapy, we have long believed in the clinical value Abecma can deliver across the treatment paradigm for multiple myeloma, transforming outcomes for patients with a relentless disease and continued unmet need," said Anne Kerber, senior vice president, Head of Late Clinical Development, Hematology, Oncology, and Cell Therapy, Bristol Myers Squibb. "These longer-term results from the KarMMa-3 trial clearly demonstrate the potential of Abecma to be an important treatment option to provide improved progression-free survival and durable responses in patients with relapsed and refractory multiple myeloma after being treated with the three main classes of therapy. We are proud to share these data which further advance the use of cell therapies as a new standard of care for more patients in earlier lines of therapy for difficult-to-treat blood cancers."
In the study, which included a patient-centric design that allowed for crossover from standard regimens to Abecma upon confirmed disease progression, overall survival (OS) was a key secondary endpoint. Due to the median PFS observed with standard regimens, more than half (56%) of patients in the standard regimens arm crossed over to receive Abecma as a subsequent therapy. The median OS was 41.4 months with Abecma (95% CI: 30.9-NR) and 37.9 months with standard regimens (95% CI: 23.4-NR) (95% CI: 0.73-1.40; HR: 1.01). However, the prespecified sensitivity analyses adjusting for crossover showed a median OS of 41.4 months for Abecma (95% CI: 30.9-NR) and 23.4 months (95% CI: 17.9-NR) for standard regimens (95% CI: 0.45-1.09; HR: 0.69), suggesting a positive trend in OS benefit for Abecma compared with standard regimens. Historically, based on real-world evidence, median OS for patients with triple-class exposed relapsed and refractory multiple myeloma is approximately 13 months.

"With the adjustments for crossover in the KarMMa-3 study, we clearly see the consistent trend in survival benefit that this anti-BCMA CAR T cell therapy delivers, introducing the potential for Abecma to be an important treatment option for these patients," said Sergio Giralt, M.D., Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center. "These results show remarkable and significantly improved durable outcomes for relapsing triple-class exposed multiple myeloma patients, which is a population that has had poor overall and progression-free survival and no established standard treatment approach that provides durable responses."
"It’s important to bear in mind that management of relapsed refractory multiple myeloma remains challenging; patients are becoming triple-class

exposed earlier in their treatment course and then developing disease that is resistant to existing therapies," said Steve Bernstein, M.D., chief medical officer, 2seventy bio. "We are excited that these positive results from the KarMMa-3 study demonstrate a significant clinical benefit of Abecma across lines of care in triple-class exposed multiple myeloma and look forward to the potential of expanding the benefits of Abecma to these patients earlier in their treatment course."

In the KarMMa-3 study, Abecma continued to exhibit a well-established and generally predictable safety profile, including no new safety signals, with mostly low-grade occurrences of cytokine release syndrome (CRS) and neurotoxicity. In patients treated with Abecma with extended follow-up, occurrences of CRS and neurologic toxicities remained consistent with the interim analysis with 88% of patients experiencing any grade CRS, and Grade 3/4 CRS events occurring in 4% of patients. Two patients (1%) experienced a Grade 5 CRS event. Any grade neurotoxicity occurred in 15% of patients, with Grade 3/4 neurotoxicity occurring in 3% of patients, and no Grade 5 events reported.

Abecma was recently approved in Japan for patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody based on the KarMMa-3 study, making it the first CAR T to receive regulatory approval for use in earlier lines of therapy for patients with relapsed or refractory multiple myeloma. A supplemental Biologics License Application for Abecma based on the KarMMa-3 results is currently under review with the U.S. Food and Drug Administration (FDA), and an Oncologic Drugs Advisory Committee meeting will be held to discuss the data. Regulatory applications for Abecma in earlier lines of therapy for triple-class exposed relapsed and refractory multiple myeloma are also under review with the European Medicines Agency and Swissmedic.

Results from Extended Follow-up for Cohort 2c of the KarMMa-2 Study

Results from extended follow-up for Cohort 2c of the multicohort, Phase 2, multicenter KarMMa-2 study, evaluating Abecma in patients with multiple myeloma who had an inadequate response to frontline therapy with autologous stem cell transplantation (ASCT) are also being presented in a poster presentation (Poster Presentation #2101) at the meeting. At data cutoff with a median follow-up of 39.4 months, the ORR in patients treated with Abecma (n=31) was 87.1% (95% CI: 70.2-96.4), with a CR rate of 77.4% (95% CI: 58.9-90.4). Median duration of response, median PFS and median OS were not reached, and all patients who received Abecma (n=31) remained alive at follow-up. Safety results were generally consistent with the well-established known safety profile of Abecma, with any grade CRS occurring in 58.1% of patients and no reports of Grade >3 CRS.
Abecma is the first-in-class B-cell maturation antigen (BCMA)-directed CAR T cell immunotherapy approved by the FDA for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. Please see the Important Safety Information section below, including Boxed WARNINGS for Abecma regarding CRS, neurologic toxicities, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome and Prolonged Cytopenia. Abecma is also approved in the European Union, Switzerland, Canada, the United Kingdom and Israel for adult patients with triple-class exposed relapsed or refractory multiple myeloma after three to four or more prior lines of therapy.

Memorial Sloan Kettering Cancer Center disclosures: Dr. Giralt and Memorial Sloan Kettering Cancer Center have financial interests associated with the research described in this release.

About KarMMa-3

KarMMa-3 (NCT03651128) is a pivotal, Phase 3, open-label, global, randomized, controlled trial evaluating Abecma compared to standard regimens in patients with relapsed and refractory multiple myeloma who have received two to four prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody, and were refractory to the last treatment regimen. Patients were randomized to receive Abecma or standard regimens that consisted of combinations that included daratumumab, pomalidomide, and dexamethasone (DPd), daratumumab, bortezomib, and dexamethasone (DVd), ixazomib, lenalidomide, and dexamethasone (IRd), carfilzomib and dexamethasone (Kd) or elotuzumab, pomalidomide and dexamethasone (EPd) chosen based on their most recent treatment regimen and investigator discretion. The primary endpoint evaluated in this study is progression-free survival (PFS), defined as time from randomization to the first documentation of progressive disease or death due to any cause, whichever occurs first. Key secondary endpoints include overall response rate (ORR) and overall survival (OS).

About KarMMa-2

KarMMa-2 (NCT03601078) is a Phase 2, open-label, multicohort, multicenter study evaluating the efficacy and safety of Abecma in patients with relapsed and refractory multiple myeloma (Cohort 1), patients with multiple myeloma that has progressed within 18 months of initial treatment including autologous stem cell transplantation (ASCT) (Cohort 2a), or without ASCT (Cohort 2b) or, in patients with inadequate response post-ASCT during initial treatment (Cohort 2c), and patients with newly diagnosed multiple myeloma with suboptimal response to ASCT (Cohort 3). The primary endpoints evaluated in this study are ORR in Cohort 1 and complete response (CR) rate in Cohorts 2a, b, c and Cohort 3. Key secondary endpoints include CR rate in Cohort 1, ORR in Cohorts 2a, b, c and Cohort 3, duration of response, PFS and OS.

About Abecma

Abecma recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. Abecma is being jointly developed and commercialized in the U.S. as part of a
Co-Development, Co-Promotion, and Profit Share Agreement between Bristol Myers Squibb and 2seventy bio.
The companies’ broad clinical development program for Abecma includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-9) in earlier lines of treatment for patients with multiple myeloma. For more information visit clinicaltrials.gov.
Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

•Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
•Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed.
•Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
•Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA. ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS.