On December 8, 2024 Genmab (Nasdaq: GMAB) reported results from the Phase 1b/2 EPCORE CLL-1 clinical trial evaluating epcoritamab (Abstract #883), a T-cell engaging bispecific antibody administered subcutaneously, demonstrated an overall response rate (ORR) of 61 percent and a complete response (CR) rate of 39 percent in difficult-to-treat adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) treated with epcoritamab monotherapy (Press release, Genmab, DEC 8, 2024, View Source [SID1234648866]). These results, from the monotherapy expansion (EXP) cohort (n=23) of the trial, along with the first safety data from the optimization (OPT) cohort, were presented at the 66th Annual Meeting and Exposition of the American Society of Hematology (ASH) (Free ASH Whitepaper), during the ASH (Free ASH Whitepaper) Annual Meeting Press Program. The data will be presented during an oral session on December 9, 2024.

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In the EXP cohort, the median time to response was two (2.0) months and the median time to CR was 5.6 months. Among all patients in the cohort, median progression-free survival (PFS) was 12.8 months and median overall survival (OS) was not reached (median follow-up was 22.8 months). An estimated 65 percent of patients were alive at 15 months. Among 12 responders evaluable for minimal residual disease (MRD) by next-generation sequencing in peripheral blood, nine patients (75 percent) had undetectable MRD.

The most frequent non-hematologic treatment-emergent adverse events (TEAEs) in the EXP cohort were cytokine release syndrome (CRS; 96 percent), diarrhea (48 percent), peripheral edema (48 percent), fatigue (43 percent), and injection-site reaction (43 percent). Cytopenias were common (anemia, 65 percent; thrombocytopenia, 65 percent; neutropenia, 48 percent); however, most patients had baseline anemia and thrombocytopenia, suggesting that these events were largely disease-related. Three cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported (one Grade 1; two Grade 2), and there was one clinical tumor lysis syndrome (CTLS) case (Grade 2). These cases did not lead to treatment discontinuation. Four fatal TEAEs occurred – two cases of pneumonia, one case of sepsis and one case of squamous cell carcinoma of the skin.

The EXP cohort followed a 2-step step-up dose regimen, and CRS was manageable and primarily low grade (9 percent Grade 1, 70 percent Grade 2, 17 percent Grade 3). In the first data from the separate OPT cohort, which followed a 3-step step-up dose regimen, CRS severity was substantially reduced with only low-grade events (71 percent Grade 1, 12 percent Grade 2). In both cohorts, CRS events primarily occurred following the first full dose, and none led to treatment discontinuation. No ICANS or CTLS cases were reported in the OPT cohort.

"These EPCORE CLL-1 data are encouraging, especially as the majority of patients were heavily pre-treated with at least four lines of therapy," said Alexey Danilov, MD, PhD, Marianne and Gerhard Pinkus, Professor and Director of Early Clinical Therapeutics and Associate Director of the Toni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope. "Despite progress in treating chronic lymphocytic leukemia, there remains a tremendous need for additional therapeutic options for high-risk patients whose disease has progressed following standard chemoimmunotherapy and targeted therapies."

Additional data from the EXP cohort showed high response rates in patients with high-risk factors treated with epcoritamab, including TP53 aberrations, IGHV-unmutated disease and double-exposed disease – prognostic markers that are associated with disease progression and decreased survival.i,ii,iii In patients with TP53 aberrations (n=15), the ORR was 67 percent with a CR of 33 percent. Among patients with IGHV-unmutated disease (n=16), the ORR was 63 percent, and the CR was 44 percent. In double-refractory patients, the ORR was 53 percent, and the CR was 37 percent.

All patients in the trial had prior chemoimmunotherapy, and most patients had previously received targeted therapies such as BTK and BCL2 inhibitors (double-exposed) and had high-risk disease characteristics.

"Chronic lymphocytic leukemia is incurable, and patients often need a variety of treatments throughout their lifetime, especially if their disease has high-risk prognostic factors, has relapsed or has become refractory to the current standard-of-care, including targeted therapies," said Dr. Judith Klimovsky, Executive Vice President & Chief Development Officer, Genmab. "These early data show the potential therapeutic applicability of epcoritamab in relapsed or refractory chronic lymphocytic leukemia, and further reinforce the potential of epcoritamab as a core therapy for the treatment of B-cell malignancies."

Use of epcoritamab in CLL is not approved in the U.S. or in the EU or in any other territory. The safety and efficacy of epcoritamab for use in CLL have not been established.

About Chronic Lymphocytic Leukemia (CLL)
Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia, affecting over 200,000 people in the United States alone.iv Chronic lymphocytic leukemia can be classified as either slow growing (indolent) or fast growing (aggressive).v CLL is incurable, and many patients will likely relapse and progress on frontline therapies.vi Most patients will experience consecutive episodes of disease progression and will require several lines of treatment in their lifetime.vii,viii

About the EPCORE CLL-1 Trial
EPCORE CLL-1 is a Phase 1b/2, open-label, multi-center trial to evaluate the safety and preliminary efficacy of epcoritamab as a monotherapy and in combination with standard of care agents in patients with difficult-to-treat relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), R/R small lymphocytic lymphoma (SLL) and Richter’s Syndrome (RS). The trial consists of two parts: a dose-escalation phase (Phase 1b) and an expansion phase (Phase 2). Patients with RS are only included in the expansion phase. The primary objective of Phase 1b is to determine the recommended Phase 2 dose and the maximum tolerated dose as well as establish the safety profile of epcoritamab monotherapy and epcoritamab plus venetoclax in participants with R/R CLL. The purpose of Phase 2 is to assess and evaluate the preliminary efficacy, safety and tolerability profiles of epcoritamab monotherapy and epcoritamab plus venetoclax for patients with R/R CLL and SLL. Additionally, epcoritamab monotherapy and combination therapy will be evaluated in patients with RS to assess their efficacy, safety and tolerability profiles. More information on this trial can be found at View Source (NCT: 04623541).

About Epcoritamab
Epcoritamab is an IgG1-bispecific antibody created using Genmab’s proprietary DuoBody technology and administered subcutaneously. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B cells and induces T-cell-mediated killing of CD20+ cells.ix

Epcoritamab (approved under the brand name EPKINLY in the U.S. and Japan, and TEPKINLY in the EU) has received regulatory approval in certain lymphoma indications in several territories. Epcoritamab is being co-developed by Genmab and AbbVie as part of the companies’ oncology collaboration. The companies will share commercial responsibilities in the U.S. and Japan, with AbbVie responsible for further global commercialization. Both companies will pursue additional international regulatory approvals for the investigational R/R FL indication and additional approvals for the R/R DLBCL indication.

Genmab and AbbVie continue to evaluate the use of epcoritamab as a monotherapy, and in combination, across lines of therapy in a range of hematologic malignancies. This includes five ongoing Phase 3, open-label, randomized trials including a trial evaluating epcoritamab as a monotherapy in patients with R/R DLBCL compared to investigator’s choice chemotherapy (NCT04628494), a trial evaluating epcoritamab in combination with R-CHOP in adult patients with newly diagnosed DLBCL (NCT05578976), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) in patients with R/R FL (NCT05409066), a trial evaluating epcoritamab in combination with rituximab and lenalidomide (R2) compared to chemoimmunotherapy in patients with previously untreated FL (NCT06191744), and a trial evaluating epcoritamab in combination with lenalidomide compared to chemotherapy infusion in patients with R/R DLBCL (NCT06508658). The safety and efficacy of epcoritamab has not been established for these investigational uses. Please visit www.clinicaltrials.gov for more information.

On December 7, 2024 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science, reported clinical data from the ongoing Phase 1 trial of cemsidomide, an orally bioavailable small molecule degrader of IKZF1/3, at the ASH (Free ASH Whitepaper) Annual Meeting (Press release, C4 Therapeutics, DEC 8, 2024, View Source [SID1234648865]). Presentations included a poster highlighting results for cemsidomide in combination with dexamethasone in multiple myeloma, and an oral presentation delivering initial results for cemsidomide as a monotherapy for non-Hodgkin’s lymphoma. These presentations reinforce the potential of cemsidomide to become a backbone therapy of choice in both multiple myeloma and non-Hodgkin’s lymphoma where IKZF1/3 degradation is warranted.

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C4T designed cemsidomide to be a more potent and selective degrader of IKZF1/3 with unique pharmacokinetic properties, with the goal to improve the therapeutic index to treat multiple myeloma and non-Hodgkin’s lymphoma—both alone and in combination with other therapeutic agents in these therapeutic areas.

"Cemsidomide continues to deliver clinical data demonstrating its potential to be used in both multi-refractory patients and as part of combination therapies across all lines of treatment for a significant number of patients with multiple myeloma or non-Hodgkin’s lymphoma," said Len Reyno, M.D., chief medical officer of C4 Therapeutics. "We look forward to leveraging today’s data to inform clinical development strategies in both multiple myeloma and non-Hodgkin’s lymphoma that has the potential to unlock the value of cemsidomide for patients in need of innovative therapies across treatment lines."

Multiple Myeloma (MM)
At the ASH (Free ASH Whitepaper) Annual Meeting, C4T presented safety and anti-myeloma data demonstrating cemsidomide has the potential to become a best-in-class IKZF1/3 degrader used as a backbone therapy of choice for patients with multiple myeloma where IKZF1/3 degradation is warranted. These data support the future development of cemsidomide across treatment lines in combination with other anti-myeloma agents.

As of the data cutoff date of October 11, 2024, a total of 47 patients received cemsidomide in combination with dexamethasone across four dose levels (50 µg dosed Monday, Wednesday, Friday (MWF); 37.5 µg dosed once daily (QD); 62.5 µg QD; 75 µg QD). Patients were heavily pretreated, receiving a median of six prior therapies. All patients (100 percent) were triple-class exposed, defined as exposure to one or more immunomodulatory agents, one or more proteasome inhibitors, and one anti-CD38 antibody. Thirty-three patients (70 percent) received prior BCMA directed therapy. Thirty-one patients (66 percent) received prior CAR-T or T-cell engager therapy.

Safety: Cemsidomide in combination with dexamethasone was well tolerated.

As of the data cutoff date, 47 patients were evaluable for safety.
The most common adverse events (AEs) Grade 3 or above were neutropenia (n=18), anemia (n=10) and infections (n=8). No patients discontinued therapy due to neutropenia.
No patients experienced a treatment emergent adverse event that led to dose reduction.
The maximum tolerated dose has not yet been identified. Enrollment is currently ongoing at the 100 µg QD dose level.
Anti-myeloma activity: Cemsidomide in combination with dexamethasone demonstrated anti-myeloma activity across a broad range of doses, highlighting a wide therapeutic range.

As of the data cutoff, 42 patients were evaluable for anti-myeloma activity.
Across all dose levels, cemsidomide in combination with dexamethasone achieved a 26 percent ORR and a 40 percent clinical benefit rate (CBR).
At the highest dose level explored to date (75 µg QD), cemsidomide achieved a 36 percent ORR and a 45 percent CBR.
At the two highest dose levels evaluated to date (62.5 µg QD and 75 µg QD), 62 percent of patients remained on therapy as of the data cutoff date.
Binod Dhakal, M.D., M.S., associate professor of medicine, Medical College of Wisconsin, Division of Hematology, presented a poster highlighting the MM results. He commented: "The data presented at the ASH (Free ASH Whitepaper) Annual Meeting demonstrate cemsidomide in combination with dexamethasone is active and well-tolerated over a range of doses in a heavily pretreated, relapsed/refractory multiple myeloma patient population—including a majority of patients who have received T-cell directed therapies who are challenging to treat. I look forward to cemsidomide’s continued development as a potential new treatment option for patients in the evolving myeloma landscape."

C4T has identified 75 µg QD as a target dose for various dexamethasone combination regimens; as dose escalation continues, higher doses may also be considered. For immune-based combination strategies, C4T believes doses lower than 75 µg QD will be optimal based on anti-myeloma activity and immune activation observed in the previously disclosed monotherapy data set.

C4T has identified the following next steps in cemsidomide MM development:

Complete Phase 1 dose escalation trial in MM to establish go forward doses
Initiate initial combination trials
Engage regulatory authorities on registrational path
Non-Hodgkin’s Lymphoma (NHL)
At the ASH (Free ASH Whitepaper) Annual Meeting, C4T also presented safety and anti-lymphoma data that reinforce C4T’s belief that IKZF1/3 degradation remains relevant in lymphoma. Based on the emerging anti-lymphoma signal demonstrated in patients with PTCL, C4T believes cemsidomide could be further developed in areas of high unmet need.

As of the data cutoff date of October 11, 2024, a total of 23 patients received cemsidomide monotherapy across five dose levels (25 µg MWF; 50 µg MWF QD; 37.5 µg QD; 62.5 µg QD; 100 µg QD). Patients were heavily pretreated, receiving a median of three prior therapies. Seventeen patients had refractory progressive PTCL and six patients had refractory progressive B-cell lymphoma.

Safety: Cemsidomide monotherapy was well tolerated and additional dose finding is ongoing.

As of the data cutoff, 23 patients were evaluable for safety.
The most common AEs Grade 3 or above were neutropenia (n=11), infections (n=6), febrile neutropenia (n=4) and anemia (n=4). No patients discontinued therapy due to neutropenia.
At this time, the maximum tolerated dose has not been defined. Two dose-limiting toxicities occurred at the 100 µg QD dose level. As a result, a 75 µg QD cohort was opened to refine the understanding of dose and safety in the NHL population; this cohort is currently enrolling patients. Escalation above 75 µg QD may be explored pending the outcome of the cohort.
Anti-lymphoma activity: Cemsidomide monotherapy demonstrated anti-lymphoma activity across a broad range of doses.

As of the data cutoff, 21 patients were evaluable for efficacy, 16 of which had PTCL.
Cemsidomide displays a differentiated pharmacokinetic profile with an approximate two-day half-life and an ability to induce rapid and potent degradation of IKZF1/3.
Across all dose levels explored, cemsidomide achieved a 38 percent ORR and 19 percent CMR rate.
In patients with PTCL, cemsidomide achieved a 44 percent ORR and 25 percent CMR rate.
Steve Horwitz, M.D., lymphoma specialist and cellular therapist, Memorial Sloan Kettering Cancer Center, delivered an oral presentation highlighting the NHL results at the ASH (Free ASH Whitepaper) Annual Meeting. He commented: "I am pleased to share the first clinical data on monotherapy cemsidomide in non-Hodgkin’s lymphoma, which demonstrated its well-tolerated safety profile and compelling anti-lymphoma activity. These initial data are encouraging, particularly in PTCL where relapsed/refractory patients lack effective targeted therapies. We believe these Phase 1 monotherapy data demonstrate that cemsidomide is well suited for further development in earlier lines of treatment and in combination with other anti-lymphoma agents."

C4T has identified the following next steps in cemsidomide NHL development:

Complete Phase 1 dose escalation trial and identify go forward dose
Initiate expansion cohort for PTCL
Engage regulatory authorities on registrational path
C4T Webcast for Analysts and Investors
C4T will host an investor webcast today December 8, 2024, at 5 pm EST. 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.

About Cemsidomide
Cemsidomide is an investigational, orally bioavailable small-molecule degrader designed to be a more potent and selective degrader of IKZF1/3, transcription factors that drive multiple myeloma (MM) and non-Hodgkin’s lymphomas (NHL), with unique pharmacokinetic properties. Clinical data has shown that cemsidomide is well-tolerated. In MM, cemsidomide displays evidence of anti-myeloma activity and immunomodulatory effects. In NHL, cemsidomide displays evidence of anti-lymphoma activity. More information may be accessed at www.clinicaltrials.gov (identifier: NCT04756726).

About IKZF1/3
IKZF1 (Ikaros) and IKZF3 (Aiolos) are transcription factors that directly regulate the activity of IRF4, a transcription factor that regulates downstream immune cell differentiation. Aberrant IRF4 is associated with both lymphoma and multiple myeloma proliferative T, B and plasma cell populations. Down regulation of IRF4 promotes the death of both myeloma and lymphoma cells.

About Multiple Myeloma
Multiple myeloma (MM) is a rare blood cancer affecting plasma cells. Approximately 36,000 people in the United States are diagnosed with MM each year. Despite advances in treatment, multiple myeloma remains incurable. Treatment combinations include IKZF1/3 degraders, which are established backbone therapies, across lines of therapy.

About non-Hodgkin’s Lymphoma
Non-Hodgkin’s lymphoma (NHL) is one of the most common cancers in the United States. NHL forms in cells of the immune system called lymphocytes. In the United States, approximately 80,000 people are diagnosed with NHL each year. IKZF1/3 degraders are used across NHL subtypes.

On December 8, 2024 Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, reported positive results from the Phase 3 ENERGIZE-T study investigating mitapivat, an oral, small molecule PK activator, in adults with transfusion-dependent alpha- or beta-thalassemia (Press release, Agios Pharmaceuticals, DEC 8, 2024, View Source [SID1234648861]). These findings were shared in an oral presentation (abstract #409) at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, California.

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Thalassemia is a rare inherited blood disorder caused by genetic mutations that lead to a reduced production of healthy hemoglobin, compromising red blood cell development, health and survival, and resulting in chronic anemia. Patients with thalassemia often experience a range of debilitating complications, both from the disease itself and as secondary effects of common management strategies such as blood transfusions and iron chelation therapy, including organ damage, stroke, and other serious health issues.

In the ENERGIZE-T trial, mitapivat demonstrated a statistically significant reduction in transfusion burden compared to placebo in patients with transfusion-dependent alpha- or beta-thalassemia, achieving its primary endpoint. Additionally, the ENERGIZE-T study met all the key secondary endpoints, with mitapivat demonstrating a statistically significant reduction in additional measures of transfusion reduction response compared to placebo. In June 2024, Agios also presented positive results from the Phase 3 ENERGIZE study, which evaluated mitapivat in adults with non-transfusion-dependent alpha- or beta-thalassemia.

"Treatment options for patients with transfusion-dependent thalassemia are extremely limited, and transfusions carry serious risks, such as iron overload, infections and immune reactions. There is a significant need for alternative treatments to manage this debilitating disease," said Maria Domenica Cappellini, M.D., professor, Internal Medicine, University of Milan, Italy. "The strong Phase 3 ENERGIZE-T results build on the positive findings from the Phase 3 ENERGIZE study in patients with non-transfusion-dependent alpha- or beta-thalassemia presented earlier this year, pointing to mitapivat as a potential transformative advancement in thalassemia care."

Phase 3 ENERGIZE-T Study Results
ENERGIZE-T is a Phase 3, double-blind, randomized, placebo-controlled and multicenter 48-week study. A total of 258 patients were enrolled in the study worldwide, with 171 patients randomized to mitapivat 100 mg twice-daily (BID) and 87 patients randomized to matched placebo.

The study’s primary endpoint of transfusion reduction response (TRR) was defined as a ≥50% reduction in transfused red blood cell (RBC) units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline. A TRR was achieved by 30.4% (n=52/171) of patients in the mitapivat arm compared to 12.6% (n=11/87) of patients in the placebo arm (2-sided p=0.0003).

Additionally, mitapivat demonstrated statistically significant reductions in transfusion burden compared with placebo as measured by the three key secondary endpoints of transfusion reduction response reflective of durability of response up to 36 weeks during the 48-week double-blind period. The key secondary endpoint TRR2, defined as a ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with baseline, was achieved in 13.5% (n=23/171) versus 2.3% (n=2/87) of patients in the mitapivat and placebo arms, respectively (2-sided p=0.0003). The key secondary endpoints TRR3 and TRR4 were defined as a ≥33% and ≥50% reduction in transfused RBC units, respectively, from Week 13 through Week 48 compared with baseline. TRR3 was achieved in 14.6% (n=25/171) versus 1.1% (n=1/87) of patients in the mitapivat and placebo arms, respectively (2-sided p<0.0001), and TRR4 was achieved in 7.6% (n=13/171) versus 1.1% (n=1/87) of patients in the mitapivat and placebo arms, respectively (2-sided p=0.0056).

The results for the primary and key secondary endpoints were not driven by any of the individual prespecified subgroups, including but not limited to genotype and baseline transfusion burden, highlighting the overall robustness of the efficacy results.

Further, 17 patients (9.9%) in the mitapivat arm compared with one patient (1.1%) in the placebo arm achieved the secondary endpoint of transfusion independence (transfusion-free for 8 or more consecutive weeks through Week 48). Three patients in the mitapivat arm did not receive any transfusions during the 48-week double-blind period.

Overall, during the 48-week double-blind period, incidence of adverse events (AEs) was similar across the mitapivat and placebo arms. The proportion of patients with any treatment-emergent adverse events (TEAEs) was 90.1% (n=155) in patients on mitapivat and 83.5% (n=71) in patients on placebo. The most frequent TEAEs that occurred in at least 10% of patients on mitapivat were headache, upper respiratory tract infection, initial insomnia, diarrhea and fatigue. Serious treatment-emergent adverse events were reported in 11.0% (n=19) and 15.3% (n=13) of patients on mitapivat and placebo, respectively; 2.3% (n=4) and 1.2% (n=1), respectively, were considered treatment-related. There were 5.8% (n=10) of patients on mitapivat and 1.2% (n=1) on placebo with TEAEs leading to treatment discontinuation. The TEAEs leading to discontinuation of mitapivat, each of which occurred in one patient, were diarrhea, paresthesia oral, concurrent anxiety and insomnia, initial insomnia, supraventricular tachycardia, fatigue, hypertransaminasemia, hepatitis C, hepatic cancer, and renal mass. The TEAE that led to discontinuation of the one patient on placebo was blood creatine phosphokinase increased.

Mitapivat Thalassemia Regulatory Next Steps
Currently, there are no disease-modifying therapies approved to treat the full spectrum of patients with thalassemia across transfusion requirements and genotypes. The standard of care for thalassemia remains centered on supportive care to address symptoms through transfusions, splenectomy, and/or iron chelation therapy, none of which address the underlying pathophysiology of the disease.

Based on the favorable benefit-risk profile observed in both the Phase 3 ENERGIZE and ENERGIZE-T studies, Agios filed regulatory applications for mitapivat (PYRUKYND) for the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia with the U.S., European Union, Kingdom of Saudi Arabia and United Arab Emirates health authorities.

The Phase 3 ENERGIZE and ENERGIZE-T trials enrolled a total of 452 patients reflective of the real-world thalassemia population. The results demonstrated that mitapivat improves hemolytic anemia and quality-of-life related measures, as measured by significant reductions in transfusion burden and significant improvements in hemoglobin and fatigue.

The primary and all the key secondary efficacy endpoints were met, demonstrating the efficacy of mitapivat compared with placebo in the treatment of adult patients with non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia.
Overall, the incidence of AEs was similar for patients on mitapivat and patients on placebo. There were 4.7% (n=14) of patients on mitapivat and 0.7% (n=1) of patients on placebo with TEAEs leading to treatment discontinuation across the two studies.
Two of 301 patients (0.66%) on mitapivat experienced AEs of hepatocellular injury within the first six months of exposure leading to treatment discontinuation. Liver tests improved following discontinuation of mitapivat. Based on the data from the ENERGIZE and ENERGIZE-T studies, Agios included, in its regulatory applications, hepatocellular injury as an important potential risk of mitapivat in patients with thalassemia and proposed monthly monitoring of liver tests for the first six months of treatment with mitapivat. In addition, mitapivat clinical trial protocols across all indications have been updated to incorporate similar monitoring.
"Informed by the robust data from both the Phase 3 ENERGIZE and ENERGIZE-T trials, we believe mitapivat has demonstrated an overall favorable benefit-risk profile in all subtypes of thalassemia, a disease where patients face debilitating challenges and have limited or no treatment options," said Sarah Gheuens, M.D., Ph.D., chief medical officer and head of R&D at Agios. "We are confident that this comprehensive data package will highlight mitapivat’s effectiveness in treating patients with thalassemia with the convenience of an oral medication. We look forward to collaborating with regulators with the goal of bringing this novel therapy to patients with thalassemia as quickly as possible."

Investor Event at ASH (Free ASH Whitepaper) 2024
Agios will host a live and webcast investor event with the company’s leadership team and medical experts. The event will take place on Monday, December 9, in San Diego, starting at 7:00 a.m. PT (10:00 a.m. ET). The webcast will be accessible on the Investors section of the company’s website (www.agios.com) under the "Events & Presentations" tab. The archived webcast will be available on the company’s website approximately two hours after the event.

About PYRUKYND (mitapivat)
PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency in the United States, and for the treatment of PK deficiency in adult patients in the European Union.

IMPORTANT SAFETY INFORMATION
Acute Hemolysis: Acute hemolysis with subsequent anemia has been observed following abrupt interruption or discontinuation of PYRUKYND in a dose-ranging study. Avoid abruptly discontinuing PYRUKYND. Gradually taper the dose of PYRUKYND to discontinue treatment if possible. When discontinuing treatment, monitor patients for signs of acute hemolysis and anemia including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, or shortness of breath.

Adverse Reactions: Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, each of which occurred in 1 patient. In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.

Drug Interactions:

Strong CYP3A Inhibitors and Inducers: Avoid concomitant use.
Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily.
Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage.
Sensitive CYP3A, CYP2B6, CYP2C Substrates Including Hormonal Contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index.
UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.
P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index.
Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment.

Please see full Prescribing Information and Summary of Product Characteristics for PYRUKYND.

On December 7, 2024 Galapagos NV (Euronext & NASDAQ: GLPG) reported additional data from the ongoing Phase 1/2 ATALANTA-1 study of its CD19 CAR T-cell therapy, GLPG5101 (Press release, Galapagos, DEC 7, 2024, View Source [SID1234648899]). The results, featured in an oral presentation at the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, demonstrate an encouraging efficacy and safety profile in patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL). Most patients in the study received GLPG5101 as a fresh, fit, stem-like, early memory CD19 CAR T-cell therapy, with a median vein-to-vein time of seven days.

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"Shorter vein-to-vein time can lead to improved patient outcomes and remains an important unmet need in CAR-T therapy," said Marie José Kersten, MD, ATALANTA-1 Principal Investigator and Professor of Hematology at the Department of Hematology at Amsterdam University Medical Center. "I am impressed by the latest data on GLPG5101, which demonstrate a promising efficacy and safety profile. With a median vein-to-vein time of just seven days, GLPG5101 has the potential to offer speed and scheduling flexibility, comparable to off-the-shelf therapies."

"CAR-T therapies are highly personalized treatments that currently undergo a time-intensive manufacturing process taking multiple weeks to months. For many patients with rapidly progressing cancers, every day counts, and treatment delays can be detrimental," said Jeevan Shetty, MD, Head of Clinical Development Oncology at Galapagos. "We are steadfast in our commitment to bring innovation to cell therapies to address the most significant medical challenges. Our latest data at ASH (Free ASH Whitepaper) strongly support the feasibility of our innovative decentralized cell therapy manufacturing platform in delivering fresh, fit cells with a median vein-to-vein time of just seven days, driving positive patient outcomes."

The new ATALANTA-1 data are summarized below:
The ongoing ATALANTA-1 study included updated data on patients with mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). As of the April 25, 2024, data cut-off, 49 patients received CD19 CAR T-cell therapy infusion, and safety and efficacy results were available for 45 patients and 42 patients, respectively.

High objective response rates (ORR) and complete response rates (CRR) were observed in the pooled Phase 1 and Phase 2 efficacy analysis set, split by indication:
In patients with MCL, all 8 of 8 efficacy-evaluable patients responded to treatment (ORR and CRR 100%).
In patients with MZL, FL, objective and complete responses were observed in 20 of 21 efficacy-evaluable patients (ORR and CRR 95%).
In patients with DLBCL, 9 of 13 efficacy-evaluable patients responded to treatment (ORR 69%), with 7 patients achieving a complete response (CRR 54%). Of the 7 patients with DLBCL who received the higher dose, 6 responded to treatment (ORR 86%) with 5 achieving a complete response (CRR 71%).
Of the 15 minimal residual disease (MRD)-evaluable patients with a complete response, 12 patients (80%) achieved MRD negativity and remained in complete response at data cut-off.
The median study follow-up was 3.3 months for FL and DLBCL with a range of 0.9-21.2 months, and 4.4 months for MCL with a range of 1-24.4 months.
GLPG5101 showed an encouraging safety profile, with the majority of Grade ≥ 3 treatment emergent adverse events being hematological. One case of CRS Grade 3 was observed in Phase 1 and one case of ICANS Grade 3 was observed in Phase 2.
96% of patients (47 of 49) received an infusion with fresh, fit, stem-like early memory CD19 CAR T-cell therapy, with 91.5% (43 of 47) achieving a vein-to-vein time of seven days, thereby avoiding cryopreservation, and eliminating the need for bridging therapy.
Strong and consistent in vivo CAR-T expansion levels and products consisting of stem-like, early memory phenotype T cells were observed in all doses tested.
About the ATALANTA-1 study (EudraCT 2021-003272-13)

ATALANTA-1 is an ongoing Phase 1/2, open-label, multicenter study to evaluate the safety, efficacy and feasibility of decentralized manufactured GLPG5101, a CD19 CAR-T product candidate, in patients with relapsed/refractory non-Hodgkin lymphoma (R/R NHL). GLPG5101 is a second generation anti-CD19/4-1BB CAR-T product candidate, administered as a single fixed intravenous dose. The primary objective of the Phase 1 part of the study is to evaluate the safety and preliminary efficacy to determine the recommended dose for the Phase 2 part of the study. Secondary objectives include assessment of efficacy and feasibility of decentralized manufacturing of GLPG5101. The dose levels that were evaluated in Phase 1 are 50×106 (DL1), 110×106 (DL2) and 250×106 (DL3) CAR+ viable T cells. The primary objective of the Phase 2 part of the study is to evaluate the objective response rate (ORR), while the secondary objectives include complete response rate (CRR), duration of response, progression free survival, overall survival, safety, pharmacokinetic profile, and the feasibility of decentralized manufacturing. Each enrolled patient will be followed for 24 months.

On December 7, 2024 Beam Therapeutics Inc. (Nasdaq: BEAM), a biotechnology company developing precision genetic medicines through base editing, reported new safety and efficacy data from its BEACON Phase 1/2 clinical trial of BEAM-101 in patients with sickle cell disease (SCD) with severe vaso-occlusive crises (VOCs) (Press release, Beam Therapeutics, DEC 7, 2024, View Source [SID1234648891]). The data were featured today in the press program for the 66th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego and will be presented in an oral session on Sunday, Dec. 8, 2024, at 10 a.m. PT.

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Consistent with Beam’s previously announced data, updated data from seven patients treated with investigational base-editing therapy BEAM-101 demonstrated robust and durable increases in fetal hemoglobin (HbF) and reductions in sickle hemoglobin (HbS), rapid neutrophil and platelet engraftment, and normalized or improved markers of hemolysis. No VOCs were reported post-engraftment. A summary of the results from the ongoing clinical study is provided below.

"These initial data from the BEACON trial are very encouraging and highlight the potential of BEAM-101 to deliver meaningful clinical benefits to patients with severe sickle cell disease," said Matthew M. Heeney, M.D., associate chief of hematology at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. "The data from the first seven patients demonstrate the ability for BEAM-101 to dramatically modify the hemoglobin profile to express a majority of protective fetal hemoglobin. All patients mobilized efficiently and had rapid engraftment with a low number of neutropenic days. I look forward to the continued maturation of the data to provide further insights into the long-term benefits of BEAM-101 for people living with sickle cell disease."

"It’s an honor to share the initial results from BEACON with the hematology community at the ASH (Free ASH Whitepaper) Annual Meeting, where there is broad recognition of the significant burden that sickle cell disease places on patients and their families," said John Evans, chief executive officer of Beam. "We believe these early data for BEAM-101 are a testament to the potential of our base-editing technology to provide a differentiated option for sickle cell patients, having demonstrated a robust increase in fetal hemoglobin of >60%, a decrease in hemoglobin S to <40% and resolution of anemia in all patients. Additionally, the data from our ESCAPE nongenotoxic conditioning program – to be presented on Sunday – highlight our commitment to expanding access to treatment by decreasing the burden and complications patients potentially face when undergoing transplantation. We look forward to continuing to rapidly advance both programs for patients with sickle cell disease."

To date, more than 35 patients have cleared screening and enrolled in the BEACON Phase 1/2 clinical trial, and of these, 11 patients have been dosed with BEAM-101. As of an Oct. 28, 2024, data cut-off, a total of seven patients with severe SCD were treated with BEAM-101 and included in the safety and efficacy analysis with follow up ranging from 1 to 11 months.

Key highlights include the following:

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Rapid and Sustained Increases in Protective Fetal Hemoglobin (HbF): All patients achieved endogenous HbF levels exceeding 60% and reduction in corresponding sickle hemoglobin (HbS) below 40% that was durable. A pancellular distribution of HbF was observed after the elimination of transfused blood.

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Robust and Sustained Total Hemoglobin (Hb) Levels: Total hemoglobin levels increased rapidly with resolution of anemia in patients after elimination of the transfused blood.

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Efficient Cell Collection and Rapid Engraftment: All patients achieved the minimum target cell dose in either 1 or 2 cycles of mobilization (average: 1.4). The mean time to neutrophil engraftment was 17.1 days (range: 15–21), with a low mean duration of neutropenia (6.3 days). The mean time to platelet engraftment was 19.1 days (range: 11–34).

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Normalization of Hemolysis Markers: Key markers of hemolysis, including indirect bilirubin, haptoglobin, lactate dehydrogenase and reticulocytes, normalized or improved in all patients following BEAM-101 treatment.

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Safety Profile Consistent with Busulfan and Autologous Hematopoietic Stem Cell Transplantation (HSCT): The safety profile of BEAM-101 was consistent with busulfan conditioning and autologous HSCT. The most common treatment-emergent adverse events (TEAEs) were consistent with busulfan conditioning, including febrile neutropenia, stomatitis and anemia. One patient died four months after BEAM-101 infusion due to respiratory failure that was determined by the investigator to be likely related to busulfan conditioning and deemed unrelated to BEAM-101. No VOCs were reported post-engraftment.

ASH Investor Event Information

Beam will host a live and webcast investor event on Dec. 8, 2024, at 8:00 p.m. PT in San Diego to review the key presentations from this year’s ASH (Free ASH Whitepaper) meeting. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.beamtx.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

About BEAM-101

BEAM-101 is an investigational genetically modified cell therapy for the treatment of severe sickle cell disease (SCD). The one-time therapy consists of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that have been base-edited in the promotor regions of the HBG1/2 genes and are administered via a hematopoietic stem cell transplant procedure. The BEAM-101 edit is designed to inhibit the transcriptional repressor BCL11A from binding to the promoter without disrupting BCL11A expression, leading to increased production of non-sickling and anti-sickling fetal hemoglobin (HbF) and thus mimicking the effects of naturally occurring variants seen in hereditary persistence of fetal hemoglobin. HbF is the predominant hemoglobin variant during development and early life. The safety and efficacy of BEAM-101 is being evaluated in the ongoing BEACON Phase 1/2 study, an open-label, single-arm, multicenter trial in adult patients with SCD with severe vaso-occlusive crises (VOCs).