On June 16, 2024 Electra Therapeutics, Inc., a clinical stage biotechnology company developing antibody therapies against novel targets for immunological diseases and cancer, reported the presentation of clinical data for ELA026 in secondary hemophagocytic lymphohistiocytosis (sHLH), a life-threatening hyperinflammatory condition (Press release, Electra Therapeutics, JUN 16, 2024, View Source [SID1234644353]). The results were presented today as one of six abstracts selected for oral presentation in a late-breaking session at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress in Madrid, Spain.

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Results were reported for sHLH patients in the ongoing Phase 1b clinical study, which has enrolled a majority of patients with the deadliest sHLH subtype, malignancy-associated HLH (mHLH). In treatment naive mHLH patients, ELA026 achieved a 100% overall response rate (ORR) by week 4 and improved survival at two months compared to natural history studies. ELA026 also demonstrated a high response rate across a range of sHLH patients and a favorable safety profile in this patient population.

ELA026 is a first-in-class monoclonal antibody that targets signal regulatory protein (SIRP)-α/β1/γ on the cell surface of myeloid cells and T lymphocytes, the pathological immune cells that induce hyperinflammation in sHLH. The Phase 1b study is an ongoing open-label, multi-dose, single-arm, multicenter study designed to evaluate the safety and efficacy of ELA026, assess biomarkers, and identify a dose for Phase 2/3 testing (ClinicalTrials.gov identifier: NCT05416307).

"These data show very promising results for ELA026 as a potential treatment for sHLH, which is a challenging disease that is devastating for patients and has no approved treatment options," said Swaminathan P. Iyer, MD, Professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. "Notably, the analysis reveals improved survival was achieved with ELA026 in treatment-naïve mHLH patients, suggesting benefit from early treatment intervention for patients with this rapidly progressing disease."

Study Results Presented at EHA (Free EHA Whitepaper) 2024 Congress
The oral presentation at EHA (Free EHA Whitepaper)2024, entitled "ELA026 Targeting of SIRP(+) Immune Cells Results in a High Response Rate and Improved 2-Month Survival of Treatment-naïve Malignancy-associated Hemophagocytic Lymphohistiocytosis in a Phase 1 Study," was presented by the lead author, Abhishek Maiti, MD, Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. The data describe analysis of sHLH patients in three cohorts of the ongoing Phase 1b clinical study, including the following highlights:

A majority of enrolled patients had malignancy-associated HLH (mHLH) which has the poorest prognosis, with a mortality rate of approximately 50% at two months. 1
ELA026 was observed to have a favorable safety profile, with manageable adverse events, in this patient population.
In Cohorts 1 and 2, which have completed enrollment (n=12), ELA026 achieved an overall response rate (ORR) of 75% by week 4. Enrollment in Cohort 3 is ongoing (n=5 as of April 17, 2024).
Across all cohorts, 8 patients had treatment-naïve mHLH; in this group, ELA026 achieved an ORR of 100% by week 4 and survival was 88% at two months.
In the study, pharmacodynamic and biomarker responses correlated with clinical responses.
The Phase 1b study has expanded to include up to 20 patients in Cohort 3 and will continue to evaluate ELA026 in frontline treatment settings in patients with various subtypes of sHLH.
"We are delighted that the results of the clinical study of ELA026 in sHLH were recognized and selected as a late-breaking presentation at EHA (Free EHA Whitepaper). This interim data is extremely encouraging, particularly with the high response rates and improved survival at two months achieved in treatment-naïve mHLH patients, and suggests ELA026’s promise as a first-line treatment. Survival at two months is a clinically meaningful benefit for this patient population and demonstrates the ability of ELA026 to rapidly extinguish the hyperinflammation in sHLH, enabling mHLH patients to pursue curative therapies for their underlying cancer," said Kim‑Hien Dao, DO, PhD, Chief Medical Officer at Electra. "We look forward to continuing enrollment in this study and advancing the clinical program to further assess the safety and efficacy of ELA026 in sHLH patients who currently have no approved therapies."

About Secondary Hemophagocytic Lymphohistiocytosis (sHLH)
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare, life-threatening inflammatory disease for which there is no approved treatment. It can be triggered by cancer (malignancy-associated HLH, or mHLH), infection, autoimmune disease, or immunotherapy. sHLH is associated with a systemic inflammatory response for which patients require immediate intervention. Without treatment, patients may experience multiple organ failure and death. sHLH has a high mortality rate during the first months of diagnosis, with mHLH patients having the poorest outcomes.

On June 15, 2024 CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on innovative CAR T-cell therapies for the treatment of hematologic malignancies and solid tumors, reported that the initial results from the ongoing first-in-human study of CT071 have been presented at the 29th Annual Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) (Press release, Carsgen Therapeutics, JUN 15, 2024, View Source [SID1234644361]).

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The preliminary results of Phase I of CT071 (NCT05838131) were presented as a poster at the 29th EHA (Free EHA Whitepaper) Annual Congress on June 14, 18:00 – 19:00 CEST, which was titled "First-in-human study of GPRC5D-targeted CAR T cells (CT071) with an accelerated manufacturing process in patients with relapsed/ refractory multiple myeloma (RRMM)".[1]

"Multiple myeloma is a common yet incurable hematologic malignancy with high unmet need. Despite the numerous recent advances, most patients relapse and become refractory to available therapies and therefore, novel therapies are needed. GPRC5D, a protein highly expressed on the surface of malignant plasma cells with limited expression on normal tissues, represents a promising target for treating multiple myeloma. CT071 is a fully human GPRC5D-targeting autologous second-generation CAR T-cell product manufactured using our expedited CARcelerateTM platform that shortens the manufacturing time to around 30 hours, supporting a shorter vein-to-vein time and younger T cells. The preliminary results of the ongoing study presented at EHA (Free EHA Whitepaper) shows that CT071 has the potential to be the best-in-class GPRC5D targeting CAR-T therapy," said Raffaele Baffa, M.D., Ph.D., Chief Medical Officer of CARsgen Therapeutics. "We are excited about advancing CT071 and look forward to sharing future updates with the medical community."

As of February 28, 2024, 10 patients were dosed with CT071—7 patients at 1.0×105 cells/kg and 3 patients at 3.0×105 cells/kg. Among them, 80% had high-risk cytogenetics, 30% had one or more extramedullary plasmacytomas (EMD), and 40% were at R-ISS stage III. This was a heavily pre-treated population with a median of 5 prior lines of therapy, including 90% double-class refractory, 70% triple-class refractory, 40% penta-drug refractory, 50% having received autologous stem cell transplantation, and 20% had previously been treated with BCMA/CD19 dual-targeting CAR T cells. None of the patients on the study required bridging therapy due to rapid manufacturing turnaround.

The median follow-up at the time of data cut-off was 4.07 months (range: 2.8-7.4). There were no Grade 3 or higher cytokine release syndrome (CRS) events. No immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. No adverse events of special interest or dose limiting toxicity (DLT) occurred. Four patients experienced treatment-related SAE, including pneumonia (n=1), decreased appetite (n=1) and thrombocytopenia (n=2), and all recovered.

The overall response rate was 90%, including 5 patients (50%) with stringent complete response (sCR), 2 patients (20%) with very good partial response (VGPR), and 2 patients (20%) with partial response (PR). All the 9 patients with evaluable MRD assessment at Week 4 achieved MRD negativity (10-6 threshold) ), including all 5 patients with sCR/CR. The pharmacokinetic analysis demonstrated robust cell expansion and persistence, with median Tmax of 14 days (range: 12-28) and median Cmax of 32280.5 copies/μg gDNA (range: 8372-106060).

About CT071
CT071 is a CAR T-cell therapy candidate developed utilizing CARsgen’s proprietary CARcelerateTM platform targeting GPRC5D for the treatment of R/R MM or relapsed/refractory plasma cell leukemia ("R/R PCL"). An investigator-initiated trial (NCT05838131) is ongoing in China to evaluate the safety and efficacy of CT071 for the treatment of R/R MM or R/R PCL. Another investigator-initiated trial (NCT06407947) is ongoing in China for the treatment of newly diagnosed multiple myeloma (NDMM).

On June 15, 2024 IASO biotechnology ("IASO Bio"), a biopharmaceutical company engaged in discovering, developing, manufacturing and marketing innovative cell therapies and antibody products, reported clinical data on the use of Equecabtagene Autoleucel (Eque-cel), the world’s first approved fully human CAR-T product, for the treatment of transplant-ineligible patients with high-risk newly diagnosed multiple myeloma (NDMM) in an oral presentation at the 2024 European Hematology Association (EHA) (Free EHA Whitepaper) Annual Congress (Press release, IASO Biotherapeutics, JUN 15, 2024, View Source [SID1234644359]).

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Presentation Title: Eque-cel, A Novel Fully Human BCMA-Targeting CAR-T Therapy in Patients with High Risk Newly Diagnosed Multiple Myeloma

Presentation Type: Oral report

Session Date and Time: June 15, 2024, 16:30 – 17:45 (Central European Summer Time)

Location: Madrid, Spain

Publication Number: S206

Presenter: Professor Bing Chen, Nanjing Drum Tower Hospital

The FUMANBA-2 study is a multicenter, open-label, phase I, single-arm study initiated by researchers, with the principal investigators being Professor Lijuan Chen from Jiangsu Province Hospital and Professor Bing Chen from Nanjing Drum Tower Hospital. This study aims to assess the efficacy, safety, and pharmacokinetics/pharmacodynamics characteristics of Eque-cel for the treatment of high-risk NDMM. Subjects must complete four cycles of induction treatment before the infusion of Eque-cel. After the third induction treatment cycle, patients deemed unsuitable for autologous hematopoietic stem cell transplantation (ASCT) by the researcher will undergo peripheral blood mononuclear cell collection and subsequently receive Eque-cel treatment, with an infusion dose of 1×106 CAR-T/kg.

The primary endpoints were the proportion of minimal residual disease (MRD) negative subjects and progression-free survival (PFS), and secondary endpoints included overall response rate (ORR), duration of response (DOR), safety, and pharmacokinetics/pharmacodynamics (PK/PD).

As of January 25th, 2024, 16 subjects received Eque-cel therapy. High-risk cytogenetics were detected in all subjects, including 62.5 percent double-hit and 12.5 percent triple-hit. 25 percent subjects had extramedullary disease. 37.5 percent subjects had R-ISS stage III disease, among whom 6.3 percent with double-hit and 6.3 percent with triple-hit.

Efficacy: After the infusion of Eque-cel, the median follow-up time was 7.46 months (range: 2.8-18.1), the median PFS had not been reached, the 12-month PFS rate was 84.4% (95% CI: 49.31-96.00), all subjects achieved MRD negativity, of which 71.4% (95% CI: 25.8-92.0) maintained MRD negativity for more than 12 months; the overall response rate (ORR) was 100%, with 93.8% achieving stringent complete response (sCR).

Safety: After the infusion of Eque-cel, the incidence of grade 1-2 cytokine release syndrome (CRS) was 68.8%, no grade 3 or above CRS was observed, and no immune effector cell-related neurotoxicity syndrome (ICANS) or other neurological toxicities occurred. The median time of CRS occurrence was the 7th day after infusion (range: 2-9 days), and the median duration of CRS was 3 days (range: 1-8 days). The most common grade 3 or above drug-related adverse event wase blood cell count reduction, and the incidence of grade 3 or above infectious disease adverse events was 25.0%.

PK/PD: The median peak time of CAR copy number in peripheral blood was 10 days after infusion (range: 7-21 days), with a median peak level of 79,681.299 copies/μg DNA. 81.25% of subjects achieved clearance of free B-cell maturation antigen (sBCMA) within one month after infusion; the median peak time of cytokine detection IL-6 and CRP after infusion were the 7th and 10th day, respectively, and the serum ferritin level did not change significantly.

Professor Lijuan Chen from Jiangsu Province Hospital stated: " Eque-cel, as a novel fully human BCMA CAR-T therapy, has shown encouraging efficacy and safety in high-risk patients with newly diagnosed multiple myeloma who are ineligible for transplantation. This is the world’s first report on CAR-T therapy being used as a first-line treatment in this specific patient population. For NDMM patients who are not suitable for transplantation, the application of CAR-T therapy as a first-line treatment is expected to further improve the remission rate, extend survival, and improve patient prognosis compared to traditional chemotherapy and other targeted drug treatments. This allows us to see the application potential of Eque-cel in the front-line treatment of MM. Advancing CAR-T therapy to the first line will provide patients with more diverse and promising treatment options. With further research and the continuous improvement of treatment strategies, we look forward to CAR-T therapy benefiting more patients in the future."

Professor Bing Chen from Nanjing Drum Tower Hospital stated: "High-risk newly diagnosed multiple myeloma patients have a poor prognosis in standard first-line treatment. For high-risk NDMM patients who do not meet the conditions for ASCT, Eque-cel has shown superior efficacy and safety, achieving deep and sustained remission, with all patients achieving MRD negativity. This opens up a new approach to reverse the poor prognosis of high-risk myeloma patients. Moreover, compared with relapsed/refractory multiple myeloma (RRMM) patients, the incidence and severity of CRS in high-risk NDMM patients treated with Eque-cel are lower, showing a more favorable safety profile. We will further investigate the clinical benefits of Eque-cel for high-risk newly diagnosed multiple myeloma patients with longer follow-up."

On June 15, 2024 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported statistically significant and clinically meaningful results from its Phase III STARGLO study of Columvi (glofitamab-gxbm) in combination with gemcitabine and oxaliplatin (GemOx) versus Rituxan (rituximab) in combination with GemOx (R-GemOx) for people with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who have received at least one prior line of therapy and are not candidates for autologous stem cell transplant, or who have received two or more prior lines of therapy (Press release, Genentech, JUN 15, 2024, View Source [SID1234644356]). Data were featured in the congress Press Briefing and presented today in the Plenary Abstracts Session at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 Congress as a late-breaking oral presentation.

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"The results from STARGLO are the first to show the potential of a CD20xCD3 bispecific antibody to make a difference in second or later-line DLBCL in people who are ineligible for transplant and have limited options," said Jeremy Abramson, M.D., director, Jon and Jo Ann Hagler Center for Lymphoma at the Massachusetts General Hospital Cancer Center, and principal investigator of the STARGLO study. "Glofitamab in combination with GemOx showed clinically significant improvement in overall survival, as well as key secondary endpoints, and the benefits were reinforced with an additional 11 months of follow-up."

The primary analysis (median follow-up of 11.3 months) confirmed that the study met its primary endpoint of overall survival (OS), demonstrating that patients treated with Columvi plus GemOx lived significantly longer, with a 41% reduction in the risk of death (hazard ratio [HR]=0.59, 95% CI: 0.40-0.89, p=0.011) versus R-GemOx. Median OS was not reached with the Columvi regimen versus nine months for R-GemOx. Safety of the combination appeared consistent with the known safety profiles of the individual medicines.

Pre-specified exploratory subgroup analyses showed comparable results, including consistency across the clinically relevant stratification factors of line of therapy (second-line versus third-line+) and outcome of last therapy (relapsed versus refractory). Regional inconsistencies were observed, however interpretation is limited given the exploratory nature of these analyses and small subgroups with wide confidence intervals.

"This marks a first step in advancing Columvi combinations in earlier settings to address the urgent need for the 40% of people who will relapse or have refractory disease and who have limited options," said Levi Garraway, M.D., Ph.D., Genentech’s chief medical officer and head of Global Product Development. "Moreover, patients do not have to wait to start treatment with Columvi. This could be particularly important for patients with highly aggressive disease who are at risk of rapid disease progression."

The Columvi combination also met its key secondary endpoints, with a 63% reduction in risk of disease worsening or death (progression-free survival, PFS) compared to R-GemOx (HR=0.37; 95% CI: 0.25–0.55, p<0.0001). A follow-up analysis was conducted after all patients had completed therapy (median follow-up of 20.7 months), which showed continued benefit in both primary and secondary endpoints. Median OS for people treated with the Columvi combination was 25.5 months, nearly double what was seen for people treated with R-GemOx at 12.9 months, and more than twice as many patients experienced a complete response (58.5% versus 25.3%, respectively).

Adverse event (AE) rates were higher with the Columvi combination versus R-GemOx, noting higher median number of cycles received with Columvi combination (11 versus 4). One of the most common AEs was cytokine release syndrome, which was generally low grade (Any Grade: 44.2%, Grade 1: 31.4%, Grade 2: 10.5%, Grade 3: 2.3%) and occurred primarily in Cycle 1.

Columvi is the first CD20xCD3 bispecific antibody to demonstrate a survival benefit in DLBCL in a randomized Phase III trial, demonstrating the potential of this type of therapeutic combination to improve survival outcomes in earlier lines of treatment. The standard second-line therapy for R/R DLBCL patients has historically been high-dose chemotherapy followed by stem-cell transplant, however, not everyone with R/R DLBCL is a candidate due to age or coexisting medical conditions. Newer therapies are also becoming available, but barriers remain for many, and alternative treatment options are needed for these patients. Columvi is given as a fixed-duration treatment, offering people with R/R DLBCL a treatment end date and the possibility of a treatment-free period, unlike continuous treatments.

Results from the STARGLO study will be submitted to global health authorities, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency.

Columvi is also being investigated in other aggressive, hard-to-treat lymphomas and was recently granted Breakthrough Therapy Designation by the FDA for the treatment of adult patients with relapsed or refractory mantle cell lymphoma who have received at least two prior therapies based on results from the Phase I/II NP30179 study.

About the STARGLO Study

The STARGLO study [GO41944; NCT04408638] is a Phase III, multicenter, open-label, randomized study evaluating the efficacy and safety of Columvi (glofitamab-gxbm) in combination with gemcitabine plus oxaliplatin (GemOx) versus Rituxan (rituximab) in combination with GemOx in patients with relapsed or refractory diffuse large B-cell lymphoma who have received at least one prior line of therapy and are not candidates for autologous stem cell transplant, or who have received two or more prior lines of therapy. Outcome measures include overall survival (primary endpoint), progression-free survival, complete response rate, objective response rate, duration of objective response (secondary endpoints), and safety and tolerability.

STARGLO is intended as a confirmatory study to convert Columvi’s accelerated approval in the U.S. and conditional marketing authorization in the EU to full approvals for people with R/R DLBCL after two or more lines of systemic therapy based on the pivotal Phase I/II NP30179 study.

About Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is an aggressive (fast-growing) blood cancer and is the most common form of non-Hodgkin’s lymphoma (NHL) in the U.S. While many people with DLBCL are responsive to treatment, the majority of those who relapse or are refractory to subsequent treatments have poor outcomes. DLBCL not otherwise specified is the most common category of large B-cell lymphoma (LBCL) and accounts for about 80% or more of cases. It applies to cases that do not fall into any specific disease subgroups of LBCL.

About Columvi (glofitamab-gxbm)
Columvi is a CD20xCD3 T-cell engaging bispecific antibody designed to target CD3 on the surface of T cells and CD20 on the surface of B cells. Columvi was designed with a novel 2:1 structural format. This T-cell engaging bispecific antibody is engineered to have one region that binds to CD3, a protein on T cells, a type of immune cell, and two regions that bind to CD20, a protein on B cells, which can be healthy or malignant. This dual-targeting brings the T cell in close proximity to the B cell, activating the release of cancer cell-killing proteins from the T cell. A clinical development program for Columvi is ongoing, investigating the molecule as a monotherapy and in combination with other medicines for the treatment of people with B-cell non-Hodgkin’s lymphomas, including diffuse large B-cell lymphoma and other blood cancers.

Columvi U.S. Indication

Columvi (glofitamab-gxbm) is a prescription medicine to treat adults with certain types of diffuse large B-cell lymphoma (DLBCL) or large B-cell lymphoma (LBCL) that has come back (relapsed) or that did not respond to previous treatment (refractory), and who have received 2 or more prior treatments for their cancer.

It is not known if Columvi is safe and effective in children.

The conditional approval of Columvi is based on response rate and durability of response. There are ongoing studies to establish how well the drug works.

What is the most important information I should know about Columvi?

Columvi can cause Cytokine Release Syndrome (CRS), a serious side effect that is common during treatment with Columvi, and can also be serious and lead to death.

Call your healthcare provider or get emergency medical help right away if you develop any signs or symptoms of CRS, including:

fever of 100.4°F (38°C) or higher
chills or shaking
fast or irregular heartbeat
dizziness or light-headedness
trouble breathing
shortness of breath
Due to the risk of CRS, you will receive Columvi on a "step-up dosing schedule".

A single dose of a medicine called obinutuzumab will be given to you on the first day of your first treatment cycle (Day 1 of Cycle 1).
You will start the Columvi step-up dosing schedule a week after the obinutuzumab dose. The step-up dosing schedule is when you receive smaller "step-up" doses of Columvi on Day 8 and Day 15 of Cycle 1. This is to help reduce your risk of CRS. You should be hospitalized during your infusion and for 24 hours after receiving the first step-up dose on Day 8. You should be hospitalized during your infusion and for 24 hours after receiving the second step-up dose on Day 15 if you experienced CRS during the first step-up dose.
You will receive your first full dose of Columvi a week after the second step-up dose (this will be Day 1 of Cycle 2).
If your dose of Columvi is delayed for any reason, you may need to repeat the "step-up dosing schedule".
If you had more than mild CRS with your previous dose of Columvi, you should be hospitalized during and for 24 hours after receiving your next dose of Columvi.
Before each dose of Columvi, you will receive medicines to help reduce your risk of CRS and infusion-related reactions.
Your healthcare provider will monitor you for CRS during treatment with Columvi and may treat you in a hospital if you develop signs and symptoms of CRS. Your healthcare provider may temporarily stop or completely stop your treatment with Columvi if you have severe side effects.

Carry the Columvi Patient Wallet Card with you at all times and show it to all of your healthcare providers. The Columvi Patient Wallet Card lists the signs and symptoms of CRS you should get emergency medical help for right away.

What are the possible side effects of Columvi?

Columvi may cause serious side effects, including:

Cytokine Release Syndrome.
Neurologic problems. Columvi can cause serious neurologic problems that may lead to death. Your healthcare provider will monitor you for neurologic problems during treatment with Columvi. Your healthcare provider may also refer you to a healthcare provider who specializes in neurologic problems. Tell your healthcare provider right away if you develop any signs or symptoms of neurologic problems, including:
headache
confusion and disorientation
difficulty paying attention or understanding things
trouble speaking
sleepiness
memory problems
numbness, tingling, or weakness of the hands or feet
dizziness
shaking (tremors)
Serious Infections. Columvi can cause serious infections that may lead to death. Your healthcare provider will monitor you for signs and symptoms of infection and treat you as needed. Tell your healthcare provider right away if you develop any signs of an infection, including: fever, chills, weakness, cough, shortness of breath, or sore throat.
Growth in your tumor or worsening of tumor related problems (tumor flare). Tell your healthcare provider if you get any of these signs or symptoms of tumor flare:
tender or swollen lymph nodes
pain or swelling at the site of the tumor
chest pain
cough
trouble breathing
The most common side effects of Columvi include: CRS, muscle and bone pain, rash, and tiredness.

The most common severe abnormal lab test results with Columvi include: decreased white blood cells, decreased phosphate (an electrolyte), increased uric acid levels, and decreased fibrinogen (a protein that helps with blood clotting).

Your healthcare provider may temporarily stop or completely stop treatment with Columvi if you develop certain side effects.

Before receiving Columvi, tell your healthcare provider about all of your medical conditions, including if you:

have an infection
have kidney problems
are pregnant or plan to become pregnant. Columvi may harm your unborn baby
Females who are able to become pregnant:
Your healthcare provider should do a pregnancy test before you start treatment with Columvi.
You should use effective birth control (contraception) during treatment and for 1 month after your last dose of Columvi. Talk to your healthcare provider about what birth control method is right for you during this time.
Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with Columvi.
are breastfeeding or plan to breastfeed. Columvi may pass into your breast milk. Do not breastfeed during treatment and for 1 month after your last dose of Columvi.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

What should I avoid while receiving Columvi?

Do not drive, operate heavy machinery, or do other dangerous activities if you develop dizziness, confusion, shaking (tremors), sleepiness, or any other symptoms that impair consciousness until your signs and symptoms go away. These may be signs and symptoms of neurologic problems.

These are not all the possible side effects of Columvi. Talk to your health care provider for more information about the benefits and risks of Columvi.

You may report side effects to the FDA at (800) FDA-1088 or View Source You may also report side effects to Genentech at (888) 835-2555.

Please see Important Safety Information, including Serious Side Effects, as well as the Columvi full Prescribing Information and Medication Guide or visit View Source

On June 15, 2024 Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in cellular metabolism and pyruvate kinase (PK) activation pioneering therapies for rare diseases, reported detailed results from the global Phase 3 ENERGIZE study of mitapivat in adults with non-transfusion-dependent (NTD) alpha- or beta-thalassemia in a plenary session (abstract #S104) at the European Hematology Association (EHA) (Free EHA Whitepaper) 2024 (EHA2024) Hybrid Congress, which is being held June 13-16, 2024, in Madrid, Spain (Press release, Agios Pharmaceuticals, JUN 15, 2024, View Source [SID1234644352]). In a related poster presentation (abstract #P1529), the company presented additional data from the ENERGIZE study highlighting clinically meaningful improvements in health-related quality of life measures and patient-reported outcomes among patients in the mitapivat arm compared to those in the placebo arm.

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The ENERGIZE study achieved its primary endpoint, with mitapivat demonstrating a statistically significant increase in hemoglobin response rate compared to placebo. Statistical significance was also achieved for both key secondary endpoints associated with change from baseline in FACIT-Fatigue Score and hemoglobin concentration. These improvements were observed across all pre-specified subgroups.

"The data from the ENERGIZE study are compelling, with mitapivat-treated patients achieving meaningful improvements in non-transfusion-dependent thalassemia’s hallmark symptom of anemia as well as in key measures of how patients feel and function," said Sarah Gheuens, M.D., Ph.D., chief medical officer and head of R&D at Agios. "Together with the recently announced positive results from the ENERGIZE-T study of mitapivat in adults with transfusion-dependent thalassemia, the detailed ENERGIZE results underscore mitapivat’s potential to become an important treatment option for all subtypes of thalassemia – alpha- and beta-thalassemia, transfusion-dependent and non-transfusion-dependent – with the convenience of a pill. We look forward to working with regulators as we anticipate filing for approval in the U.S. by the end of this year."

"I am pleased to present the results of the ENERGIZE study to my esteemed colleagues and believe they will share my enthusiasm for the positive impact mitapivat may have for patients with non-transfusion-dependent alpha- or beta-thalassemia," said Ali Taher, M.D., Ph.D., Professor of Medicine, Hematology & Oncology and Director – Naef K. Basile Cancer Institute, American University of Beirut Medical Center in Beirut, Lebanon; an investigator in the ENERGIZE study. "Globally, there are currently no approved oral treatments for non-transfusion-dependent thalassemia, which is characterized by anemia, ineffective erythropoiesis, hemolysis and iron overload and can cause severe complications, reduced quality of life and shortened lifespan. Based on the data collected in the ENERGIZE study, mitapivat has the potential to become a foundational treatment for non-transfusion-dependent thalassemia."

"The ENERGIZE data presented at this congress show that non-transfusion-dependent alpha- or beta-thalassemia patients treated with mitapivat experienced clinically meaningful improvements in fatigue and walking capacity, as well as improvements in patient-reported outcomes across a range of disease symptoms," said Kevin Kuo, M.D., MSc, FRCPC; Division of Hematology, University of Toronto in Ontario, Canada; an investigator in the ENERGIZE study. "There is a tremendous need for oral therapies that can improve how people with thalassemia feel and function and reduce the impact of the disease on their lives. Patients with alpha- or beta-thalassemia, regardless of transfusion status, frequently report negative effects on daily activities and physical functioning. On a number of domains of health-related quality of life, adults with non-transfusion-dependent thalassemia experience even greater symptom burden than their transfusion-dependent counterparts. I am excited about the potential of mitapivat to support quality of life improvements for these individuals."

Agios also recently announced positive results from the Phase 3 ENERGIZE-T study of mitapivat in adults with transfusion-dependent alpha- or beta-thalassemia. The company intends to file for regulatory approval of mitapivat as a treatment for thalassemia by the end of 2024, incorporating all available data from both studies.

Results for the Phase 3 ENERGIZE study were as follows:

A total of 194 patients were enrolled in the study, with 130 randomized to mitapivat 100 mg twice-daily (BID) and 64 randomized to matched placebo. 122 (93.8%) in the mitapivat arm and 62 (96.9%) in the placebo arm completed the 24-week double-blind period of the study.
Baseline demographics and characteristics were balanced between mitapivat and placebo arms, and representative of a population of non-transfusion dependent thalassemia patients.
The study met the primary endpoint of hemoglobin response. Hemoglobin response was defined as an increase of ≥1 g/dL in average hemoglobin concentrations from week 12 through week 24 compared with baseline.
42.3% (n=55/130) of patients in the mitapivat arm achieved a hemoglobin response, compared to 1.6% (n=1/64) of patients in the placebo arm (2-sided p<0.0001).
Among patients who achieved hemoglobin response in the mitapivat arm, the mean change from baseline in average hemoglobin concentration from week 12 to 24 was 1.56 g/dL.
Hemoglobin response rates were higher among those treated with mitapivat compared to placebo across all prespecified subgroups, including:
Thalassemia genotype: 23.8% (n=10/42) of alpha-thalassemia patients in the mitapivat arm achieved a hemoglobin response, compared to no alpha-thalassemia patients in the placebo arm. 51.1% (n=45/88) of beta-thalassemia patients in the mitapivat arm achieved a hemoglobin response, compared to 2.3% (n=1/44) of beta-thalassemia patients in the placebo arm.
Baseline hemoglobin concentration: 47.4% (n=45/95) of patients whose baseline hemoglobin concentration was ≤9.0 g/dL in the mitapivat arm achieved a hemoglobin response, compared to 2.1% (n=1/47) of patients in the placebo arm. 28.6% (n=10/35) of patients whose baseline hemoglobin concentration was between 9.1 and 10.0 g/dL achieved a hemoglobin response, compared to no patients in the placebo arm.
Treatment with mitapivat also demonstrated statistically significant improvements compared to placebo for both key secondary endpoints:
The average change from baseline (95% confidence interval) in FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) subscale score from week 12 to week 24 was 4.85 (3.41, 6.30) in the mitapivat arm compared to 1.46 (–0.43, 3.34) in the placebo arm (p=0.0026).
The average change from baseline (95% confidence interval) in average hemoglobin concentration from week 12 to week 24 was 0.86 (0.73, 0.99) g/dL in the mitapivat arm compared to –0.11 (–0.28, 0.07) g/dL in the placebo arm (p<0.0001).
Improvements were observed in patients treated with mitapivat across measures of health-related quality-of-life, including the six-minute walk test and the Patient Global Impression of Change (PGIC) fatigue, walking capacity, and thalassemia symptoms subscales.
Six-minute walk test: The average change (95% confidence interval) from baseline to week 24 was 30.48 (19.31, 41.64) meters in the mitapivat arm compared to 7.11 (–7.39, 21.62) in the placebo arm.
PGIC: A higher proportion of patients in the mitapivat arm reported improvements in fatigue as per PGIC versus those in the placebo arm at weeks 12, 16, 20, and 24. A higher proportion of patients in the mitapivat arm reported improvements in thalassemia symptoms and walking capacity as per PGIC at week 24 versus those in the placebo arm.
Overall, during the 24-week double-blind period, incidence of adverse events was similar across mitapivat and placebo arms, with 82.9% (n=107) of patients in the mitapivat arm and 79.4% (n=50) of patients in the placebo arm experiencing treatment-emergent adverse events (TEAEs).
The most frequently reported TEAEs were headache, initial insomnia, nausea and upper respiratory tract infection.
3.9% (n=5) of patients in the mitapivat arm experienced Grade ≥3 treatment-related TEAEs. There were no serious TEAEs.
3.1% (n=4) of patients in the mitapivat arm experienced TEAEs leading to discontinuation; there were no TEAEs leading to discontinuation in the placebo arm.
Conference Call Information
Agios will host a virtual investor breakout session tomorrow, June 16, 2024, at 10:00 a.m. ET (4 p.m. CEST) to review the key clinical oral and poster presentations from the EHA (Free EHA Whitepaper)2024 meeting. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors and Media section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning 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.