On December 11, 2021 The Janssen Pharmaceutical Companies of Johnson & Johnson reported longer-term results from the Phase 1b/2 CARTITUDE-1 study evaluating the efficacy and safety of ciltacabtagene autoleucel (cilta-cel), an investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy administered as a single infusion, in the treatment of patients with relapsed and/or refractory multiple myeloma (Press release, Johnson & Johnson, DEC 11, 2021, View Source [SID1234596856]).1 The data, featured as an oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting (Abstract #549) and selected as part of the Highlights of ASH (Free ASH Whitepaper) programme, show that patients receiving cilta-cel demonstrate deep and durable responses, with a very high overall response rate (ORR) of 98 percent.1

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Responses in the 97 patients treated with cilta-cel deepened over time, with 83 percent of patients achieving a stringent complete response (sCR) at median 22-month follow-up, an increase from 80 percent at the 18-month median follow-up data presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, and from 67 percent at the 12.4-month median follow-up data presented at ASH (Free ASH Whitepaper) 2020.1,2,3 At median follow-up of 22 months, median progression-free survival (PFS) and median overall survival (OS) were not reached, suggesting long-term durability of responses and survival for patients.1 Two-year PFS and OS rates were 61 percent (95 percent Confidence Interval [CI], 48.5–70.4) and 74 percent (95 percent CI, 61.9–82.7), respectively.1 Among 61 minimal residual disease (MRD) evaluable patients, 92 percent of patients achieved MRD negativity (at 10-5).1 The two-year PFS rates in patients who achieved MRD negativity for ≥six and ≥12 months were 91 percent (95 percent CI, 67.1–97.8) and 100 percent, respectively.1

"Unfortunately, patients with multiple myeloma for whom at least three treatment regimens have stopped working, face a median survival of less than a year with currently available treatments," said Thomas Martin, M.D.,* Director of Clinical Research, Clinical Professor of Medicine, Adult Leukemia and Bone Marrow Transplantation Program, Associate Director, Myeloma Program and Co-Leader, Hematopoietic Malignancies Program, at UCSF Helen Diller Family Comprehensive Cancer Center, and principal study investigator. "The CARTITUDE-1 data presented at ASH (Free ASH Whitepaper) 2021 builds upon previous results that show that a single infusion of cilta-cel resulted in durable responses and survival across the study population, further supporting the potential of cilta-cel in offering patients and physicians a valuable new treatment option."

Median time to first response was one month (range, 0.9–10.7), with responses deepening over time.1 Additionally, median time to best response was 2.6 months (range, 0.9–17.8) and median time to complete response or better was 2.9 months (range, 0.9–17.8).1 Twelve percent of patients achieved a very good partial response and three percent achieved a partial response.1 The study included patients who received a median of six prior treatment regimens (range, 3–18).1 All patients were triple-class [immunomodulatory agent (IMiD), proteasome inhibitor (PI) and an anti-CD38 antibody] exposed, while 42 percent of patients were penta-drug refractory and 99 percent of patients were refractory to the last line of therapy.1

"These data add to the growing body of evidence supporting the potential clinical benefit of cilta-cel in the treatment of patients with relapsed and/or refractory multiple myeloma, a population in need of new options," said Sen Zhuang, M.D., Ph.D., Vice President, Clinical Research and Development, Janssen Research & Development, LLC. "We look forward to further evaluation of cilta-cel as part of our comprehensive CARTITUDE clinical development programme that includes studying cilta-cel in patients with newly diagnosed multiple myeloma."

The data demonstrated a consistent safety profile for cilta-cel and no new safety signals were observed with longer follow-up.1 In 18-month follow-up data presented at ASCO (Free ASCO Whitepaper) 2021, the most common haematologic adverse events (AEs) observed were neutropenia (96 percent); anaemia (81 percent); thrombocytopenia (79 percent); leukopenia (62 percent); and lymphopenia (53 percent).2 At 18 months, cytokine release syndrome (CRS) of any grade was observed in 95 percent of patients with a median duration of four days (range, 1–97), and 99 percent of which resolved within 14 days of onset.2 Of the 92 patients with CRS at 18-month follow-up, 95 percent experienced grade 1/2 events.2 Neurotoxicity of any grade was observed in 21 percent (n=20) of patients at 18 months, with grade 3 or higher neurotoxicity observed in 10 percent (n=10) of patients.2 There were no new events of cilta-cel–related neurotoxicity or movement and neurocognitive treatment (MNT) emergent adverse events reported in CARTITUDE-1 since the median 12.4-month follow-up data were presented at ASH (Free ASH Whitepaper) 2020.1,3 At the 22-month data cut-off, more than 200 patients have been dosed with cilta-cel across the CARTITUDE clinical development programme and MNT incidence has decreased to less than one percent since the implementation of MNT mitigation measures.1

"We are pleased that we are again able to present longer-term follow-up data, this time at nearly two years, for this innovative potential treatment for people living with relapsed/refractory multiple myeloma." said Edmond Chan MBChB M.D. (Res), EMEA Therapeutic Area Lead Haematology, Janssen-Cilag Limited. "The sustained efficacy and consistent safety profile build on the strong results seen to date and may bring us one step closer to changing the expectations of what a multiple myeloma diagnosis means for patients."

Subgroup Analysis of the Phase 1b/2 CARTITUDE-1 Study
In the abstract accepted for presentation at ASH (Free ASH Whitepaper) 2021, data demonstrated that cilta-cel resulted in deep, durable responses in all evaluated subgroups in CARTITUDE-1 at median follow-up of 18 months.4 An ORR range of 95 to 100 percent was observed in patients across all subgroups, including those with high-risk cytogenetics, International Staging System (ISS) stage III multiple myeloma, baseline bone marrow cells ≥60 percent, and presence of baseline plasmacytomas.4 In patients with ISS stage III, high risk cytogenetics and with baseline plasmacytomas, median duration of response appeared shorter and 18-month PFS and OS rates lower.4 The cilta-cel safety profile across the subgroups was consistent with the overall population, with no new safety signals.4 The latest data from this analysis will be presented in a poster presentation (Abstract #3938) at ASH (Free ASH Whitepaper) 2021 on Monday, December 13.4

# ENDS #

About CARTITUDE-1
CARTITUDE-1 (NCT03548207)5 is an ongoing Phase 1b/2, open-label, multicentre study evaluating the safety and efficacy of cilta-cel in adults with relapsed and/or refractory multiple myeloma, 99 percent of whom were refractory to the last line of treatment; 88 percent of whom were triple-class refractory, meaning their cancer did not respond, or no longer responds, to an immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 antibody.1

The primary objective of the Phase 1b portion of the study, involving 29 patients, was to characterise the safety and confirm the dose of cilta-cel, informed by the first-in-human study with LCAR-B38M CAR-T cells (LEGEND-2).1,5,6 Based on the safety profile observed in this portion of the study, outpatient dosing is being evaluated in additional CARTITUDE studies. The Phase 2 portion of the study, involving 68 additional patients, is evaluating the efficacy of cilta-cel with overall response as the primary endpoint.1,5

About Ciltacabtagene Autoleucel (cilta-cel)
Cilta-cel is an investigational chimeric antigen receptor T-cell (CAR-T) therapy that is being studied in a comprehensive clinical development programme for the treatment of patients with relapsed or refractory multiple myeloma and in earlier lines of treatment.1 The design consists of a structurally differentiated CAR-T with two BCMA-targeting single domain antibodies.1 In December 2017, Janssen Biotech, Inc. (Janssen) entered into an exclusive worldwide license and collaboration agreement with Legend Biotech to develop and commercialise cilta-cel.7

In April 2021, Janssen announced its submission of a Marketing Authorisation Application (MAA) to the European Medicines Agency seeking approval of cilta-cel for the treatment of patients with relapsed and/or refractory multiple myeloma.8 In December 2020, Janssen announced initiation of a rolling submission of its Biologics License Application (BLA) to the United States (U.S.) Food and Drug Administration (FDA) for cilta-cel.9 In addition to U.S. Breakthrough Therapy Designation in December 2019, cilta-cel received a PRIority MEdicines (PRiME) designation from the European Commission in April 2019, and a Breakthrough Therapy Designation in China in August 2020.10,11 Janssen also received Orphan Drug Designation for cilta-cel from the European Commission in February 2020.12

About Multiple Myeloma
Multiple myeloma is currently an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.13 When damaged, these plasma cells rapidly spread and replace normal cells with tumors in the bone marrow.13 In Europe, more than 50,900 people were diagnosed with multiple myeloma in 2020, and more than 32,500 patients died.14 While some patients with multiple myeloma have no symptoms, most patients are diagnosed due to symptoms, which can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.15

On December 11, 2021 Epizyme, Inc. (Nasdaq: EPZM), a fully integrated, commercial-stage biopharmaceutical company developing and delivering transformative therapies against novel epigenetic targets, reported that preclinical data and the Phase 1/1b trial design for EZM0414, the Company’s novel, first-in-class, oral SETD2 inhibitor, an investigational agent being developed for the treatment of adult patients with relapsed or refractory multiple myeloma (MM) or with diffuse large B-cell lymphoma (DLBCL) (Press release, Epizyme, DEC 11, 2021, View Source [SID1234596855]). The data and the design were presented today at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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The data presented from both in vitro and in vivo preclinical studies (Abstract #1142), demonstrated that targeting SETD2 with EZM0414 resulted in significantly reduced growth of t(4;14) MM cell lines, as well as non-t(4;14) MM and DLBCL cell lines. Additionally, in in vitro studies, EZM0414 showed synergy with MM and DLBCL standard of care and emerging therapies, which supports the potential for the study of EZM0414 in combination with current MM and DLBCL treatments.

"We are excited to share our preclinical data on EZM0414 with the research community at ASH (Free ASH Whitepaper), which highlights its anti-tumor activity in multiple myeloma and DLBCL xenograft models, as well as its in vitro combination activity," said Dr. Jeffery Kutok, MD, PhD, Chief Scientific Officer at Epizyme. "This work has increased our understanding of the potential for EZM0414 in B cell malignancies and formed the basis for our first-in-human studies, beginning with our SET-101 Phase 1/1b trial."

Epigenetic mutations and dependencies have been identified in B cell malignancies, including MM and DLBCL, providing therapeutic rationale for epigenetic inhibitors in these tumor types. Previous data demonstrated that there is broad sensitivity of MM cell lines to SETD2 inhibition, and in particular, t(4;14) MM cell lines, which are dependent on SETD2 due to overexpression of MMSET by the high-risk t(4;14) translocation.

These preclinical data form the basis for SET-101, the Company’s Phase 1/1b clinical study (Abstract #1679), which is designed to evaluate the safety and determine the optimal dose of EZM0414. Under the trial protocol, following the Phase 1 dose ranging portion of the trial, the study will be expanded to evaluate EZM0414 in three patient cohorts: t(4;14) MM, non-t(4;14) MM, and DLBCL.

In the Phase 1 portion of the study, adult patients with relapsed or refractory MM and DLBCL will be enrolled and treated in a Bayesian optimal interval design to evaluate the safety, tolerability, and pharmacokinetics of EZM0414 at six dose levels. Up to 36 patients will be enrolled, and at least nine patients will be evaluated for maximum tolerated dose. At least eight patients, each with t(4;14) MM, non-t(4;14) MM, or DLBCL will be included. The primary endpoints include the safety and tolerability of EZM0414 and the maximum tolerated dose.

The Phase 1b dose expansion portion of the study will include three cohorts, t(4;14) MM, non-t(4;14) MM, and DLBCL, of up to 20 patients each. There will be two interim assessments when clinical data from the first 10 and 15 patients enrolled in each expansion cohort are available. Futility assessments will also be conducted at that time. The final analysis will be performed when all data from the 20 patients in each expansion cohort are available. Primary endpoints include the recommended Phase 2 dose, and secondary endpoints include efficacy and response rates. The trial is currently enrolling patients in the United States and has been screening patients for enrollment.

"There is a significant unmet need for new therapeutic options for patients living with multiple myeloma and DLBCL, which are both very aggressive and difficult-to-treat malignancies," said Dr. Shefali Agarwal, Executive Vice President and Chief Medical and Development Officer at Epizyme. "We are thrilled to bring the first SETD2 inhibitor into the clinic to learn more about its potential in the treatment of these diseases, which is an important milestone for our oncology portfolio. The SET-101 study is open, we’re actively screening patients and we look forward to dosing our first patient and sharing more about EZM0414 as trial data become available."

About EZM0414

EZM0414 is a potent, selective, oral, small molecule, investigational drug agent that inhibits the histone methyltransferase, SETD2, which plays a role in oncogenesis. SETD2 methylates histone as well as non-histone proteins, and this activity is involved in several key biological processes including transcriptional regulation, RNA splicing, and DNA damage repair. Based on the preclinical data on SETD2 inhibition by EZM0414 in multiple settings, including high risk t(4;14) multiple myeloma (MM) and in other B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL), the Company is conducting SET-101, a Phase 1/1b study of EZM0414, for the treatment of adult patients with relapsed or refractory MM and DLBCL.

On December 11, 2021 Aleta Biotherapeutics, a privately held immuno-oncology company focused on transforming cellular therapeutics to allow a broad spectrum of cancer indications to be targeted, reported a summary of ALETA-001 preclinical results from a poster being presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, held in Atlanta, Georgia and in a virtual platform on December 11-14, 2021 (Press release, Aleta Biotherapeutics, DEC 11, 2021, View Source [SID1234596854]).

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The presentation featured preclinical data that support the upcoming Phase 1/2 clinical trial of ALETA-001 being run in collaboration with Cancer Research UK. ALETA-001 is a multifunctional biologic for injection that contains an anti-CD20 llama VHH linked to an optimized CD19 protein and further linked to an anti-albumin llama VHH. Extensive preclinical in vitro modeling demonstrated that ALETA-001 specifically binds to CD20-positive/CD19 negative lymphoma cells with high affinity, thereby densely coating these cancer cells with the CD19 protein. In the presence of anti-CD19 CAR T cells, ALETA-001 mediated cytotoxicity against CD19 negative lymphoma cells at sub-nM concentrations. The administration of ALETA-001 and anti-CD19 CAR T cells in vivo eliminated systemic CD19 negative lymphoma that otherwise produced lethal disease at doses of ALETA-001 as low as 0.5mg/kg. Further, upon stopping dosing in the in vivo lymphoma model, 40% of ALETA-001-treated animals did not relapse through day 43, more than 2 weeks after the last dose, suggesting apparent cures. Additionally, excess ALETA-001 did not interfere with cytotoxicity. ALETA-001 is designed to be administered to patients who have received CAR19 T cell therapy and who fail to achieve a complete response at the time of their first clinical evaluation, or who relapse from a complete response thereafter. Clinical trial development is underway in collaboration with Cancer Research UK.

On December 11, 2021 Schrödinger, Inc. (Nasdaq: SDGR), whose physics-based software platform is transforming the way therapeutics and materials are discovered, reported that new preclinical data from its mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitor program in B-cell lymphomas in a poster session at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition in Atlanta, Georgia (Press release, Schrodinger, DEC 11, 2021, View Source [SID1234596853]). MALT1 is considered a potential therapeutic target for several non-Hodgkin’s B-cell lymphomas as well as chronic lymphocytic leukemia. Schrödinger has identified novel MALT1 inhibitors that demonstrate strong anti-tumor activity across multiple tumor models, including cell- and patient-derived xenograft models, and combination potential with other agents, including standards of care such as ibrutinib.

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"We are pleased that our data strongly underscore the therapeutic potential of our MALT1 inhibitors and present an opportunity to advance a potential best-in-class MALT1 inhibitor into the clinic," said Karen Akinsanya, Ph.D., executive vice president, chief biomedical scientist and head of discovery R&D at Schrödinger. "We are on track to submit the IND for our MALT1 development candidate to the FDA in the first half of 2022."

The data presented suggest that targeting MALT1 may expand therapeutic options for patients with selected B-cell lymphomas, such as activated B-cell (ABC) subtype of diffuse large B cell lymphoma (DLBCL), with the possibility of expanding into other B-cell lymphomas such as mantle cell lymphoma (MCL). Furthermore, these small molecule MALT1 inhibitors demonstrate potential in combination with Bruton’s tyrosine kinase (BTK) inhibitors to overcome drug-induced resistance in patients with relapsed/refractory B-cell lymphomas.

Additional Details About the Study

The presentation, "Characterization of Potent Paracaspase MALT1 Inhibitors for Hematological Malignancies," highlighted preclinical data with multiple lead molecules discovered using Schrodinger’s proprietary physics-based free energy perturbation (FEP+) modeling technology. These molecules demonstrate potent inhibition of MALT1 enzymatic activity and anti-proliferative activity in the ABC-DLBCL cell lines, such as OCI-LY3 and OCI-LY10. In combination with approved agents, these inhibitors demonstrate strong combination potential with Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib in ABC-DLBCL cell lines. In ABC-DLBCL cell line-derived xenograft (CDX) models, the company’s representative MALT1 inhibitor induces tumor regression as a single agent and complete tumor regression in combination with ibrutinib. The representative MALT1 inhibitor, when tested in LY2298 patient-derived xenograft (PDX) models, demonstrates similar results. In addition, the representative MALT1 inhibitor was explored in a CDX model derived from a mantle cell lymphoma REC-1 cell line, and demonstrates strong anti-tumor activity of ~78% tumor growth inhibition as a single agent. Taken together, these data strongly underscore the therapeutic potential of Schrödinger’s MALT1 inhibitors and support further evaluation of a potential best-in-class MALT1 inhibitor in clinical trials.

On December 11, 2021 Orca Bio, a clinical-stage biotechnology company developing purified, high-precision cell therapies for the treatment of cancer, autoimmune diseases and genetic blood disorders, reported positive clinical data on its lead investigational cell therapy, Orca-T, were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Orca Bio, DEC 11, 2021, View Source [SID1234596852]). The data presented on 109 patients with at least 90 days of follow-up in combined data from the Phase 1b and Phase 2 trials showed significantly higher graft-versus-host disease-free, relapse-free survival (GRFS) rates compared to patients who received standard of care.

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"The lower rates of graft versus host disease and improved relapse-free survival suggest Orca-T has the potential to become a safer and more effective treatment option for patients living with serious blood cancers," said Ivan Dimov, Ph.D., cofounder and chief executive officer of Orca Bio. "We are further encouraged by the validation of our platform as we advance Orca-T into our pivotal Phase 3 trial, a significant step toward potential commercialization and, most importantly, to helping more patients in need."

Findings presented today in an oral presentation included pooled results from the single-center Phase 2 and multi-center Phase 1b trials from 109 patients with acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndromes, myelofibrosis and other hematological malignancies. Median follow-up for these patients was 617 days (single-center) and 209 days (multi-center). For comparison purposes, a contemporary, propensity-matched cohort of 95 matched patients undergoing standard of care allogeneic hematopoietic stem cell transplant (alloHSCT) served as the standard of care cohort ("SOC cohort"). Results demonstrated that:

Patients who received Orca-T had a GRFS of 74%. When comparing this non-randomized data to the SOC cohort, the difference was significant (74% vs. 34%; p<0.0001).
Orca-T showed the potential for lower rates of moderate-to-severe chronic graft versus host disease (GvHD) at 1 year post-transplant (3% vs. 43%; p<0.0005).
Overall survival rates with Orca-T (90% vs. 78%; p<0.03) and rates of chronic-GvHD-free survival (87% vs. 45%; p<0.0001) were improved.
Orca-T was manufactured reliably and delivered with vein-to-vein times of 72 hours or less across the continental U.S.
In a poster presentation at ASH (Free ASH Whitepaper), Orca Bio also shared an analysis of treatment impact in patients with myelofibrosis. The analysis compared eight patients with myelofibrosis who were treated with Orca-T with six patients who underwent standard of care (SOC) alloHSCT. Regression of marrow fibrosis to myelofibrosis grade 0 or 1 was observed by Day 100 post-transplant in all eight Orca-T recipients, but was observed in only one of the six SOC patients. Additionally, Orca-T recipients had lower incidence of acute and chronic GvHD.

Along with the positive Phase 1b/2 results, Orca Bio announced that it has completed a successful end of Phase 2 meeting with the U.S. Food and Drug Administration and plans to commence a Phase 3 trial for Orca-T in early 2022.

The full presentation is available on www.orcabio.com.

About Orca-T
Orca-T is an investigational high-precision allogeneic cellular therapy consisting of infusions containing regulatory T-cells, conventional T-cells and CD34+ stem cells derived from peripheral blood from either related or unrelated matched donors. Orca-T has received Regenerative Medicine Advanced Therapy (RMAT) designation from the U.S. Food and Drug Administration and is being studied to treat multiple hematologic malignancies.