On December 12, 2021 Protagonist Therapeutics (Nasdaq: PTGX) ("Protagonist" or "the Company") reported that updated data from two ongoing Phase 2 studies evaluating rusfertide in patients with polycythemia vera (PV), demonstrating its ability to essentially eliminate the need for phlebotomies in patients (Press release, Protagonist, DEC 12, 2021, View Source [SID1234596881]). Rusfertide also showed rapid and sustained hematocrit control in patients requiring frequent phlebotomies or those having high baseline hematocrit levels (>48%). The data were presented in two oral presentations at the American Society of Hematology (ASH) (Free ASH Whitepaper) 2021 Annual Meeting, in addition to the Company’s three poster presentations: one describing the Phase 3 study design for rusfertide in PV; one presenting pre-clinical findings with a hepcidin analog in a mouse model of PV; and another poster on the Phase 2 clinical proof-of-concept data for rusfertide in hereditary hemochromatosis (HH).

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"The latest data continues to demonstrate rusfertide’s potential to maintain rapid and durable control of hematocrit and essentially eliminate the need for phlebotomies in phlebotomy-dependent PV patients, while offering meaningful improvements across various quality of life measures," said Ronald Hoffman, MD, Director of the Myeloproliferative Disorders Research Program at the Icahn School of Medicine at Mount Sinai, and principal investigator for the study. "Early findings for rusfertide induction therapy also demonstrate its ability to rapidly control hematocrit in patients with elevated hematocrit levels above 48 percent, and to sustain those effects in maintenance, highlighting rusfertide’s potential efficacy in a wider spectrum of PV patients."

"We are extremely encouraged by the totality and consistency of the positive results presented today at ASH (Free ASH Whitepaper) for rusfertide in polycythemia vera, and by the support we are garnering from the physician community as we continue to execute against our goal of addressing unmet medical needs through this natural hormone mimetic therapy," said Dinesh V. Patel, PhD, President and Chief Executive Officer of Protagonist. "The upcoming double-blinded, placebo-controlled Phase 3 PV study is a transformative step in the progressive journey of rusfertide, from de novo discovery to a registrational study. In addition, we look forward to providing clarity on our next steps in HH and other iron-overload related diseases in 2022, thereby expanding the potential utility of rusfertide into multiple indications."

Summary of Key Results

Updated Results from Phase 2 Study Evaluating Rusfertide in Patients with PV

In this Phase 2 study, 63 phlebotomy-dependent PV patients were treated with rusfertide for up to 18 months. The results of the study demonstrated the essential elimination of the need for therapeutic phlebotomy (TP). Rapid, sustained, and durable control of hematocrit levels below 45% was observed without a significant increase in white blood cell numbers or PV-related thromboses. During the first 28 weeks on treatment, 84% of patients required no phlebotomies, 14% required one, and 2% required two phlebotomies. The most frequent adverse events were injection site reactions which were transient in nature. Importantly, none of the treated PV patients suffered from thrombotic events. Serious and Grade 3-4 events were limited in number, less than 10 at the time of data cut-off. Two SAEs were previously reported as possible related to study drug.

Among patient reported outcomes, a third of the patients in the study also saw at least a 40% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Scores (MPN-SAF-TSS) from baseline at week 28. Sixty-nine percent of patients reported improvement in Patient Global Impression of Change from baseline at week 8.

New Results from Phase 2 Study Evaluating Rusfertide as an Induction Therapy in Patients with PV

In this Phase 2 study, induction therapy with twice weekly rusfertide was administered alone to patients with confirmed high hematocrit levels above 48%. In all 16 erythrocytotic PV patients, rusfertide demonstrated rapid reduction of hematocrit below 45% within weeks, without the need for TP. The drug was well tolerated. Post-induction, weekly rusfertide treatment maintained hematocrit levels without the need for TP. While this study remains ongoing, most reported drug related adverse events to date were grade 1-2, with injection site reactions being the most common adverse event.

Additional Poster Presentations

The design of Protagonist’s planned three-part, multicenter, global, double-blinded, placebo-controlled Phase 3 clinical trial was presented in a poster. This Phase 3 study is expected to commence in Q1 2022 and will evaluate rusfertide in patients with PV compared to placebo when added onto current therapy. The primary endpoint of the study will be the absence of phlebotomy during weeks 20-32 for patients on rusfertide.

Also presented in a poster were results from a pre-clinical study demonstrating that a rusfertide peptide analog reduced erythrocytosis by restricting iron needed for red blood cell production while normalizing body iron distribution in a murine model with JAK2-V617F mutations. These effects support the use of a hepcidin mimetic, such as rusfertide, for potential utility in PV through dose titration treatment to maintain hematocrit below 45%.

Results from a Phase 2a proof-of-concept study evaluating rusfertide in patients with HH were also presented in a poster, demonstrating that rusfertide reduced serum iron and maintained transferrin saturation below 45% with corresponding significant reductions in phlebotomies. Liver iron concentration measured by MRI were also maintained at pre-study levels in patients at the end of the six-month study. Rusfertide was generally well tolerated in patients with HH, with the most common adverse events being injection site reactions that were mild or moderate.

Details for ASH (Free ASH Whitepaper) 2021 presentations are as follows:

Oral Presentations

Title: "Rusfertide (PTG-300) Controls Hematocrit Levels and Essentially Eliminates Phlebotomy Requirement in Polycythemia Vera Patients"
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis
Authors: Ronald Hoffman, MD, et al.

Title: "Rusfertide (PTG-300) Induction Therapy Rapidly Achieves Hematocrit Control in Polycythemia Vera Patients without the Need for Therapeutic Phlebotomy"
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Novel Therapies for MPNs and JAK inhibitors for Myelofibrosis
Authors: Yelena Ginzburg, MD, et al.

Posters

Title: "A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera"
Session Title: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I
Authors: Srdan Verstovsek, MD, PhD, et al.

Title: "Regulation of Iron Homeostasis and Efficacy of Rusfertide Analog Peptide in a Mouse Model for Polycythemia Vera"
Session Title: 102. Iron Homeostasis and Biology: Poster II
Authors: Roopa Taranath, PhD, et al.

Title: "Rusfertide (PTG-300), a Hepcidin Mimetic, Maintains Liver Iron Concentration in the Absence of Phlebotomies in Patients with Hereditary Hemochromatosis"
Session Title: 102. Iron Homeostasis and Biology: Poster I
Authors: Kris V. Kowdley, MD, et al.

On December 12, 2021 Antengene Corporation Limited ("Antengene" SEHK: 6996.HK), a leading innovative, global biopharmaceutical company dedicated to discovering, developing and commercializing first-in-class and/or best-in-class medicines for cancer and other life-threatening diseases, reported a clinical trial collaboration to evaluate the safety, pharmacokinetics and preliminary efficacy of ATG-017 in combination with Bristol Myers Squibb’s PD-1 checkpoint inhibitor, Opdivo (nivolumab) (Press release, Antengene, DEC 12, 2021, View Source [SID1234596876]). The open-label Phase 1/2 trial will evaluate the investigational combination as a potential treatment option for patients with advanced solid tumors.

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"Our clinical collaboration with Bristol Myers Squibb underscores Antengene’s commitment to explore combination regimens from our portfolio with other mechanisms of action that might transform cancer care", said Jay Mei, M.D., Ph.D., Founder and CEO of Antengene. "We are excited to enter this clinical collaboration with Bristol Myers Squibb and look forward to initiating enrollment in this exciting combination regimen in the first half of 2022."

ATG-017 is an oral and selective inhibitor of extracellular signal–regulated protein kinase 1 and 2 (ERK1/2). Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor expressed on activated T-cells. This collaboration builds on Antengene’s preclinical data set, some of which was presented at the Society for Immunotherapy in Cancer (SITC) (Free SITC Whitepaper) 2021, which showed that the combination of an ERK1/2 inhibitor and an immune checkpoint inhibitor (CPI) worked synergistically to produce improved efficacy in preclinical immune CPI-resistant cancer models.

"Antengene believes that rational combination of targeted therapies and immuno-oncology drugs may offer the greatest chance of success in the next advances of cancer treatments," said Kevin Lynch, M.D., Antengene’s Chief Medical Officer. "We believe ATG-017 could be useful in multiple combination regimens. In preclinical studies, the combination of ATG-017 and an immune CPI demonstrated promising synergy in resistant and refractory murine tumor models. With the initiation of our Phase 1/2 combination trial, we will be working to validate these promising findings in the clinic. We believe these data will inform the design of future studies and, if positive, demonstrate ATG-017’s potential to synergize with immuno-oncology agents and turn "cold" tumors "hot". Potent inhibition of ERK has the potential to reverse an immune-suppressed tumor microenvironment, or block ERK-mediated disease progression that may characterize CPI-resistance and hyper-progressive disease. This represents a major unmet need in cancer therapy," continued Dr. Lynch.

ATG-017 is currently being investigated in a Phase 1/2 open-label, multicenter dose-finding study, the "ERASER" study, in patients with identified mutations in the RAS-MAPK pathway. The trial is being conducted in two parts, with dose-escalation and dose-expansion parts exploring both monotherapy and as a combination therapy, with a PD-1 checkpoint inhibitor as the first partner drug.

Under the terms of the Agreement, Antengene will sponsor and fund the study and Bristol-Myers Squibb will provide Opdivo for the combination dose escalation and combination dose expansion portions of the trial. Antengene has global commercial and development rights to ATG-017. Opdivo is a trademark of Bristol-Myers Squibb Company.

About ATG-017

ATG-017 is a potent and selective small molecule extracellular signal-regulated kinases 1 and 2 (ERK1/2) inhibitor. ERK1/2 are related protein-serine/threonine kinases that function as terminal kinases in the RAS-MAPK signal transduction cascade. This cascade regulates a large variety of cellular processes, including proliferation. The RAS-MAPK pathway is dysregulated in more than 30% of human cancers with the most frequent alterations being observed in RAS or BRAF genes across multiple tumor types. An ERK inhibitor enables the targeting of both RAS and BRAF mutant diseases.

Antengene recently presented data at the 2021 Society for Immune Therapy in Cancer meeting (SITC 2021) detailing compelling preclinical results showing the combination of ATG-017 and an anti-PD-L1 monoclonal antibody (atezolizumab) in an aggressive immune checkpoint resistant murine cancer model rendered "cold" tumors "hot."

On December 12, 2021 IASO Biotherapeutics ("IASO Bio"), a clinical-stage biopharmaceutical company focused on discovering, developing, and manufacturing innovative medicines and Innovent Biologics, Inc. ("Innovent", HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of cancer, metabolic, autoimmune and other major diseases, reported the latest data from the phase 1/2 clinical study of a fully human B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy in an oral presentation at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract # 547) (Press release, IASO Biotherapeutics, DEC 12, 2021, View Source [SID1234596873]). BCMA CAR-T therapy was co-developed by the two companies (IASO Bio: CT103A, Innovent: IBI326) for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). Presentation title: A Phase 1/2 Study of a Novel Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT103A) in Patients with Relapsed and/or Refractory Multiple Myeloma with Professor Chunrui Li, MD, PhD, from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology (HUST) in China as the oral presenter.

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The updated data is based on a single-arm, open-label, multi-center phase 1/2 study being conducted in China. The study mainly enrolled patients with BCMA-positive RRMM who had an Eastern Cooperative Oncology Group (ECOG) performance score of 0-1 and received ≥3 lines of prior therapy. The study’s primary endpoint is objective response rate (ORR), with secondary endpoints including duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, tolerability, pharmacokinetics and pharmacodynamics (PK/PD). As the data cutoff date of Oct.12, 2021, this study included 79 subjects treated with the recommended Phase II dose (RP2D) of 1.0×106 CAR-T cells/kg (9 from the exploratory investigator-initiated trial [IIT] and 70 from the registrational study [Trial Registration# NCT05066646]).

Study results showed that CT103A has excellent safety and efficacy profiles, as corroborated by long in vivo persistence, indicating that CT103A has the potential to be a breakthrough therapy for patients with RRMM.

CT103A demonstrated a favorable and manageable safety profile: Among the 79 patients, 75 (94.9%) experienced cytokine release syndrome (CRS). The majority of them experienced 1~2 CRS; only 2 experienced grade 3 CRS (all occurred during the IIT phase of the study, while the 70 patients in the registrational study did not report any grade 3 or higher CRS). The median time to CRS onset was 6.0 days after infusion, and the median duration of CRS was 5.0 days. Only 1 patient experienced grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS) manifested as transient decrease in consciousness and soon resolved without intervention. All patients with CRS or ICANS have resolved, among which 20% and 34.7% were treated with tocilizumab and steroids respectively.

CT103A showed favorable and durable efficacy: Of the 79 patients, the ORR was 94.9% and the complete response/stringent complete response (CR/sCR) rate was 58.2%, with a trend suggesting a correlation between deeper responses and longer follow-ups. PFS at 6, 9, and 12 months after infusion was 78.0%, 76.0%, and 71.0%, respectively. CT103A also demonstrated favorable efficacy in 11 patients with EMM, achieving an ORR of 100% and a CR/sCR rate of 72.7%. In all 79 patients, 93.7% achieved minimal residual disease (MRD)-negativity with a sensitivity of 10-5 at least once after infusion.

CT103A also demonstrated favorable efficacy in patients who had received prior CAR-T therapy: Among the 13 patients who previously received CAR-T therapy, the ORR was 76.9%, with 61.5% of those patients achieving very good partial response (VGPR) or deeper responses, and 46.2% achieved CR/sCR.

CT103A demonstrated robust expansion and prolonged persistence: The expansion of CT103A in peripheral blood reached the peak at a median of 12 days, with a median Cmax of 92,000 copies/ug DNA. CT103A was still detectable in 10 (55.6%) of the 18 patients who completed 12-month follow-up after infusion. The first enrolled patient still had detectable CT103A transgene (4,040 copies/ug DNA) 34 months (1,030 days) after infusion, and remained in sCR during this time. Soluble BCMA in peripheral blood of patients rapidly declined after CT103A infusion and persistently remained below the detectable limit.

CT103A has low immunogenicity: Only 1.3% (1/79) of patients were tested anti-drug antibody (ADA)-positive within three months after CT103A infusion. At a median follow-up duration of seven months, only 12.7% (10/79) of patients tested ADA-positive.

"While a high rate of relapse remains a major clinical challenge in RRMM, BCMA-targeted CAR-T has thus far showed great promise in its treatment. CT103A is a fully-human BCMA-specific CAR-T therapy that can reduce relapse by bypassing potential anti-CAR immunogenicity in the host. This CT103A study demonstrated favorable efficacy, safety, PK/PD, and low immunogenicity, signifying enormous therapeutic value for the treatment of RRMM as potentially a clinical breakthrough," said the two principal investigators at the primary centers of the study – Prof. Lugui Qiu, MD, from the Chinese Academy of Medical Science Hematology Hospital and Prof. Chunrui Li, MD, PhD, from Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology.

Dr. Wen (Maxwell) Wang, Chief Executive Officer and Chief Medical Officer of IASO Bio, said: "This is our second time reporting CT103A results during an oral session at ASH (Free ASH Whitepaper) Meeting. And this year’s new data for safety and efficacy of CT103A is particularly exciting. It includes some of the results from the registrational study at 11 sites which is worth emphasizing since it’s globally the first registrational study that enrolled patients who had failed prior CAR-T treatment. For these patients, who have no approved treatment options, CT103A also demonstrated favorable and durable efficacy, once again highlighting the enormous therapeutic potential of this innovative candidate. At present, we are also advancing the clinical development of CT103A for early-line treatments, combination therapies and autoimmune diseases, while expanding the development program globally. We’ll submit the new drug application (NDA) soon and look forward to launching this cell therapy to benefit even more patients in the future. "

Dr. Hui Zhou, Senior Vice President of Innovent, said: "Multiple myeloma (MM) is a common hematology malignant disease with high incidence rate, and relapse and refractory are inevitable after current treatments. There’s an urgent unmet need requesting a treatment with well-tolerated and long persistence for patients. We are glad the results from the Phase I/II study of CT-103A (Innovent R&D code: IBI326) were announced in an oral presentation at this year’s ASH (Free ASH Whitepaper) Annual Meeting. These results looks very promising as they have demonstrated favorable and durable efficacy and manageable efficacy of IBI326. We will further accelerate this clinical development of IBI326 to bring forth a treatment option that will bring new hope to patients with MM."

About Multiple Myeloma (MM)
Multiple Myeloma is a deadly blood cancer that often infiltrates the bone marrow causing anemia, kidney failure, immune problems, and bone fractures. For multiple myeloma patients, common first-line drug treatments include proteasome inhibitors, immunomodulatory drugs, and alkylating agents. While treatment may result in remission, most patients will inevitably enter the relapsed or refractory stage as there’s currently no cure. As a result, there is a significant unmet need for patients with relapsed/refractory multiple myeloma. In the United States, MM accounts for nearly 2% of all cancer cases, and more than 2% of cancer-related deaths.

According to Frost & Sullivan, the number of new MM cases in the United States rose from 30,300 in 2016 to 32,300 in 2020 and is expected to increase to 37,800 by 2025. The total number of patients diagnosed with MM in the United States increased from 132,200 in 2016 to 144,900 in 2020 and is expected to rise to 162,300 by 2025.

The number of new MM cases in China rose from 18,900 in 2016 to 21,100 in 2020 and is expected to increase to 24,500 by 2025. The total number of patients diagnosed with MM in China increased from 69,800 in 2016 to 113,800 in 2020 and is expected to rise to 182,200 by 2025.

About CT103A (BCMA CAR-T)
CT103A is an innovative therapy co-developed by IASO Bio and Innovent Biologics. Previous studies indicate subjects with relapsed/refractory multiple myeloma (RRMM) who received high-dose BCMA-targeting CAR-T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re-infusion of CAR-T cells will not be effective. To solve this dilemma, CT103A has been developed, a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4-1BB co-stimulatory and CD3ζ activation domains. Based on strict selection and screening, utilizing a proprietary in-house optimization platform and integrated in house manufacture process improvement, the construct of the BCMA CAR-T is potent and CT103A shows prolonged persistency in patients. In February 2021, CT103A was granted Breakthrough Therapy Designation (BTD) by China’s National Medical Products Administration (NMPA) for the treatment of RRMM. In addition to multiple myeloma, IASO Bio is investigating CT103A in patients with autoimmune diseases.

On December 12, 2021 Wugen, Inc., a clinical-stage biotechnology company developing a pipeline of off-the-shelf cell therapies to treat a broad range of hematological and solid tumor malignancies, reported that new preclinical data supporting the safety and efficacy profile of WU-CART-007 for T-cell malignancies (Press release, Wugen, DEC 12, 2021, View Source [SID1234596862]). Further, today’s data highlighted Wugen’s clinical readiness and robust manufacturing process for WU-CART-007. The U.S. Food and Drug Administration (FDA) has cleared the investigational new drug (IND) application for WU-CART-007 and Wugen is preparing for enrollment of a Phase 1/2 clinical trial for relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (LBL) (NCT#04984356).

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WU-CART-007 is an off-the-shelf, fratricide-resistant CD7-targeted CAR-T cell therapy designed to overcome the technological challenges of harnessing CAR-T cells to treat CD7+ hematological malignancies. Wugen is deploying CRISPR/Cas9 gene editing technology to delete CD7 and the T-cell receptor alpha constant (TRAC), preventing CAR-T cell fratricide and mitigating the risk of graft-versus-host-disease (GvHD). WU-CART-007 is manufactured using healthy donor-derived T-cells to eliminate the risk of malignant cell contamination historically observed in the autologous CAR-T setting.

"Adult and pediatric patients with T-cell malignancies experience high rates of relapse and mortality," said Dan Kemp, Ph.D., President and Chief Executive Officer of Wugen. "We believe WU-CART-007 is the first off-the-shelf allogeneic CAR-T cell therapy targeting this category of hematological cancers to receive an IND clearance from the FDA, and our program has tremendous potential to address this critical unmet need for patients. Today’s preclinical data validate our approach and support the clinical advancement of WU-CART-007. We look forward to enrolling patients in our Phase 1/2 clinical trial to evaluate WU-CART-007 in R/R T-ALL and LBL."

Key findings reported in the poster include:

Wugen has developed a robust manufacturing process to enable clinical development of WU-CART-007, using healthy donor-derived T-cells to eliminate the risk of malignant cell contamination, and CRISPR/Cas9 gene editing to prevent fratricide and mitigate the risk of GvHD.
WU-CART-007 models primarily a T-cell central memory phenotype with enhanced functionality.
WU-CART-007 exhibits strong CD7-specific anti-tumor activity in vitro and in vivo, with a favorable off-target profile.
Robust pre-clinical data support clinical development of WU-CART-007 in CD7+ hematological malignancies. A Phase 1/2 clinical trial evaluating WU-CART-007 in patients with R/R T-ALL/LBL will open for enrollment in December 2021.

On December 12, 2021 Epizyme, Inc. (Nasdaq: EPZM), a fully integrated, commercial-stage biopharmaceutical company developing and delivering transformative therapies against novel epigenetic targets, reported that updated safety and activity data from the Phase 1b portion of its Phase 1b/3 confirmatory study evaluating the investigational use of TAZVERIK (tazemetostat), a first-in-class, oral, selective inhibitor of EZH2, in combination with rituximab + lenalidomide (R2) in patients with relapsed/refractory follicular lymphoma (FL) who have been treated with at least one prior systemic therapy, including patients who are rituximab-refractory and/or POD24, at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Epizyme, DEC 12, 2021, View Source [SID1234596859]).

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Updated data from the Phase 1b portion of the study reported today included 40 FL patients who had received treatment with tazemetostat and R2 (400 mg [n=4], 600 mg [n=18], or 800 mg [n=18]) as of the September 29, 2021 data cut-off. The findings demonstrated that the safety profile of the tazemetostat and R2 combination was consistent with the previously reported safety information in the prescribing information for both tazemetostat and R2, respectively. Additionally, there was no clear dose response for treatment-emergent adverse events (TEAEs) or dose modifications. Thirty-five of the 40 patients were evaluable for tumor assessments as of the data cut off, with 32 patients responding to treatment. The activity findings showed an objective response rate of 91.4 percent (37.1 percent complete response rate and 54.3 percent partial response rate). The duration of response data continue to mature as the study is ongoing.

"The data presented today on the combination of rituximab, lenalidomide and tazemetostat, known as R2 + tazemetostat, have shown promising responses in the second-line FL setting and the side effects observed to date have been consistent with lenalidomide-based combinations," said Connie Lee Batlevi, MD PhD, medical oncologist with Memorial Sloan Kettering Cancer Center. "We are excited to start the randomized Phase 3 portion of the study, with the hope of developing a chemotherapy-free combination regimen for patients with follicular lymphoma."

SYMPHONY-1 (EZH-302) is an international, multicenter, randomized, double-blind, active-controlled, 3-stage, biomarker-enriched, confirmatory Phase 1b/3 study, which is designed to evaluate the safety and efficacy of tazemetostat in combination with R2 in patients with relapsed or refractory FL after at least one prior line of therapy. The Phase 1b portion of the study is designed to determine the recommended Phase 3 dose, activity, and safety of tazemetostat and R2. In addition to the safety run-in analysis, the study also assessed the pharmacokinetics and continues to assess clinical activity of tazemetostat when administered in combination with R2.

The Phase 1b safety run-in component evaluated tazemetostat at three dose levels (400 mg, 600 mg, and 800 mg orally twice daily) in 28-day cycles with standard-dose R2 using a 3 + 3 design. Rituximab was administered at 375 mg/m2 intravenously on days 1, 8, 15 and 22 of cycle 1, then on day 1 of cycles 2 to 5. Lenalidomide was administered at 20 mg (creatinine clearance ≥60 mL/min) or 10 mg (if creatinine clearance <60 mL/min) orally once daily on days 1 to 21 every 28 days for 12 cycles. In the Phase 3 component, approximately 500 patients will be randomly assigned to receive the RP3D of tazemetostat + R2 or placebo + R2. The study will also include a maintenance arm with tazemetostat or placebo following the first year of treatment with tazemetostat + R2 or placebo + R2.

Treatment with tazemetostat and R2 was generally well tolerated. Grade 3/4 TEAEs were observed in 17 (42.5%) patients; the most common grade 3/4 TEAE (≥10%) was neutrophil count decrease/neutropenia (15.0.%) Ten patients (25.0%) reported a total of 16 SAEs (serious adverse events). The only SAE reported in >1 patient was COVID-19, reported in 2 patients; all other SAEs were reported in 1 patient each.

A table of the activity findings as of the data cut off are below:

Best Overall Response (BOR) Ratea, n (%)

Tazemetostat + R2 (n = 35)

Objective Response Rate (ORR)

32 (91.4)

Complete Responseb (CR)

13 (37.1)

Partial Response (PR)

19 (54.3)

Stable Disease (SD)

3 (8.6)

Progressive Disease (PD)

0

a For BOR, there were 27 PET-CT-based responses and 8 CT-based responses.

b For CR, 12 were PET-CT-based responses and 1 was a CT-based response.

"We are encouraged to share progress of our tazemetostat program in follicular lymphoma with the cancer community, as we believe these data support the potential tazemetostat may play as a backbone of therapy in combination with current standards of care for patients living with the disease. We will continue to monitor these patients and we look forward to sharing follow-up data as they mature over time," said Dr. Shefali Agarwal, Executive Vice President and Chief Medical and Development Officer at Epizyme. "At Epizyme, we are committed to advancing the follicular lymphoma treatment landscape for patients, the healthcare teams who treat them, and the families who support them."

In addition to the SYMPHONY-1 presentation (Abstract #2207), two additional tazemetostat studies are being presented during the ASH (Free ASH Whitepaper) Annual Meeting. The first is a trial-in-progress/study design presentation for SYMPHONY-2 (Abstract #3541), a multi-center, open-label, single-arm, Phase 2 study of tazemetostat in combination with rituximab for the treatment of relapsed or refractory FL. The trial is actively enrolling patients across 18 sites in the United States. The second presentation (Abstract #1183) focuses on the analysis of the molecular and genetic characterization of patients treated with tazemetostat to better understand the drivers of response to treatment.

About TAZVERIK (tazemetostat)

TAZVERIK is a methyltransferase inhibitor indicated for the treatment of:

Adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
Adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least two prior systemic therapies.
Adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options.
These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

The most common (≥20%) adverse reactions in patients with epithelioid sarcoma are pain, fatigue, nausea, decreased appetite, vomiting and constipation. The most common (≥20%) adverse reactions in patients with follicular lymphoma are fatigue, upper respiratory tract infection, musculoskeletal pain, nausea and abdominal pain.

View the U.S. Full Prescribing Information here: Epizyme.com