On December 11, 2023 Geron Corporation (Nasdaq: GERN), a late-stage clinical biopharmaceutical company, reported presentations of data from its IMerge Phase 3 clinical trial evaluating first-in-class investigational telomerase inhibitor imetelstat in patients with lower risk myelodysplastic syndromes (MDS), as well as population analysis of claims data in lower risk MDS (Press release, Geron, DEC 11, 2023, View Source [SID1234638418]). The data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, taking place from December 9-12, 2023, in San Diego, CA and virtually as well as published online in Blood.

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"These latest analyses from IMerge Phase 3 presented at ASH (Free ASH Whitepaper) contribute to a growing body of data from the trial, including a recent publication in The Lancet,which continue to give us confidence in what we believe is a meaningful clinical benefit with imetelstat in these lower risk MDS patients," said Faye Feller, M.D., Executive Vice President, Geron’s Chief Medical Officer. "If approved, we believe that the significant improvement in red blood cell transfusion independence possible with imetelstat could provide an important new treatment option for many lower risk MDS patients who suffer from iron overload and low quality of life associated with transfusion dependence."

"As we continue to see additional analyses from IMerge Phase 3, such as these latest presentations at ASH (Free ASH Whitepaper), the clinical attributes of imetelstat continue to be differentiated, particularly high RBC-TI response rate, durability of response and the consistency of effect across MDS subgroups that have historically been very difficult to treat," said Amer Methqal Zeidan, MBBS MHS, Associate Professor of Internal Medicine (Hematology) and director of hematology Early Therapy Research at Yale School of Medicine and Yale Cancer Center, who is an IMerge lead investigator. "Additionally, the safety profile was well-characterized, with Grade 3/4 neutropenia and thrombocytopenia that were generally transient, reversible to Grade 2 or less, and clinically manageable, and most importantly, had few clinical consequences and did not affect the efficacy of imetelstat."

Below are the highlights of the 6 company-sponsored abstracts:

"Efficacy of Imetelstat in Achieving Red Blood Cell Transfusion Independence Across Different Risk Subgroups in Patients With Lower-Risk Myelodysplastic Syndromes Relapsed/Refractory to Erythropoiesis-Stimulating Agents in IMerge Phase 3 Study"

This oral presentation provides a subgroup analysis from IMerge Phase 3 evaluating RBC-transfusion independence (RBC-TI) rates in patients treated with imetelstat vs. placebo across different risk subgroups as defined by International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) or IPSS molecular (IPSS-M) risk profiles. The results showed that imetelstat consistently had higher RBC-TI response rates than placebo across these different risk subgroups. Overall, durable 24-week and 1-year RBC-TI responses were observed with imetelstat in all lower- and higher-risk subgroups. Reclassifying patients by IPSS-M revealed that one-third of the patients (4/12) identified as higher-risk IPSS-M derived 8-week RBC-TI benefit whereas higher-risk subgroups receiving placebo failed to achieve long-term RBC-TI, regardless of the risk classification scheme used.

"Impact of Mutational Status on Clinical Response to Imetelstat in Patients with Lower Risk Myelodysplastic Syndromes in the IMerge Phase 3 Study"

This poster evaluates the impact of MDS-associated mutations on clinical efficacy of imetelstat for the 165 of 178 patients for whom mutation data were available. Results showed that in patients who had more than one mutation detected at baseline and more than two mutations at baseline, imetelstat significantly improved the 8-week and 24-week RBC-TI response rates compared with placebo. A significantly higher percentage of imetelstat-treated than placebo-treated patients with baseline mutations in SF3B1, a gene commonly mutated in MDS, achieved 8- and 24-week RBC-TI. RBC-TI responses in patients receiving imetelstat occurred regardless of the presence of mutations associated with poor prognosis or the number of mutations. This analysis suggests clinical benefit of imetelstat across different molecularly defined subgroups and independent of the underlying molecular mutation pattern.

"Durable Continuous Transfusion Independence With Imetelstat in IMerge Phase 3 for Patients With Heavily Transfused Non-Del(5q) Lower-Risk Myelodysplastic Syndromes Relapsed/Refractory to or Ineligible for Erythropoiesis-Stimulating Agents"

This poster reports on the patients enrolled in IMerge Phase 3 who achieved one-year or greater continuous RBC-TI response, which included 17.8% of imetelstat-treated patients (21/118; 95% CI, 11.4-25.9) and 1.7% of patients on placebo (1/60; 95% CI, 0-8.9). One-year RBC-TIs were achieved by 44.7% of 8-week RBC-TI responders and 63.6% of 24-week RBC-TI responders. During the one-year or greater RBC-transfusion-free interval, RBC transfusion burden was reduced from a baseline range of 4-9 units and hemoglobin improved a median of 5.2 g/dL. Imetelstat 1-year RBC-TI responders had a median duration of RBC-TI of 123 weeks (95% CI, 80.4-NE) and no patients progressed to acute myeloid leukemia (AML). At the time of data cutoff (May 10, 2023), 13 1-year RBC-TI responders receiving imetelstat and one patient receiving placebo were ongoing on treatment. Of the 18 imetelstat one-year responders for whom mutational data were available, complete elimination of certain mutational clones was observed in 10 of 18 patients (55.5%) for whom mutational data were available and 13 (72.2%) achieved greater than or equal to 50% SF3B1 variant allele frequency (VAF) reduction, including 7 patients with complete elimination of VAF. For these one-year RBC-TI responders and consistent with the overall safety profile for patients on IMerge Phase 3, Grade 3-4 thrombocytopenia and neutropenia occurred in 14 (67%) and 20 (95%) patients, with a mean duration of 1.78 (1.58) and 2.25 (2.48) weeks, respectively. 81% of Grade 3-4 neutropenia and 89% of Grade 3-4 thrombocytopenia were reversible to Grade 2 or below within 4 weeks.

"Improvement of Patient-Reported Outcomes Among Heavily Pretreated Patients With Lower-Risk Myelodysplastic Syndromes and High Transfusion Burden Treated With Imetelstat on the IMerge Phase 3 Trial"

This abstract published in Blood describes exploratory results from patient-reported outcomes (PROs) questionnaires used in IMerge Phase 3. Functional Assessment of Cancer Therapy-Anemia (FACT-An; 55 items) and Quality of Life in Myelodysplasia Scale (QUALMS; 38 items) were the main questionnaires used. Findings consistently showed that imetelstat-treated patients reported improved fatigue, dyspnea, and QUALMS composite scores (total and physical burden) compared to those on placebo. Further, patients treated with imetelstat did not experience greater deterioration in systemic symptoms, pain, physical function or bleeding than those on placebo. These data indicate that, in addition to improving RBC transfusion burden in patients with LR MDS, imetelstat targets multiple core symptoms of LR MDS simultaneously, also improving those respective PROs.

"Characterization and Management of Cytopenias after Imetelstat Treatment in the IMerge Phase 3 Trial of Patients with Lower-Risk Myelodysplastic Syndromes (LR-MDS)"

This abstract published in Blooddescribes treatment-emergent adverse events (TEAEs) of grade 3 or 4 thrombocytopenia and neutropenia, which were more prevalent in cycles 1-3 (68.6% and 62.7% respectively), and their frequency decreased over time. In the imetelstat group, cytopenias were managed with protocol-specified treatment delays and dose adjustments. Dose reductions due to neutropenia and thrombocytopenia occurred in 33.1% and 22.9% of patients, respectively. Thrombocytopenia and neutropenia were also managed by cycle delays in 46.6% and 50.8% of patients, by platelet transfusions in 17.8% of patients, and by concomitant therapy with growth factor support (mostly during cycles 2-4) in 34.7% of patients. Among 47 patients who achieved the primary endpoint of 8-week RBC-TI with imetelstat, 72.3% and 59.6% of patients had grade 3 or4 neutropenia and thrombocytopenia, respectively. This analysis shows that these Grade 3or 4 thrombocytopenia and neutropenia were generally transient, reversible and manageable through treatment delays and dose adjustments, and suggests that these TEAEs do not affect the efficacy of imetelstat.

A Geron-sponsored population analysis of claims data also were presented in poster format.

"Durable Transfusion Independence in Lower Risk Myelodysplastic Syndrome (LR MDS) Is Associated with Better Survival: A Population Level Analysis Based on a Large US Health Insurance Claims Database"

This poster describes a population level analysis of 5,662 lower risk MDS patients identified through Optum Clinformatics between October 2015 and June 2022. In these patients, real-world progression-free survival (rwPFS) from the start of first- and second- line therapy respectively, was significantly longer in patients who achieved 16-week RBC-TI after treatments than in patients who did not (p < .0001). RBC-TI responders also had significantly greater improvement in median overall survival (OS) from first and second line than non-responders (p < .0001 for both). This analysis indicates that achievement of RBC-TI was associated with improved survival, suggesting that transfusion dependence is a modifiable predictor of clinical outcomes in lower risk MDS.

The presentation and posters are available on the Publications Section of Geron’s corporate website and the abstracts are available online in Blood.

About IMerge Phase 3

The Phase 3 portion of the IMerge Phase 2/3 study is a double-blind, 2:1 randomized, placebo-controlled clinical trial to evaluate imetelstat in patients with IPSS Low or Intermediate-1 risk (lower risk) transfusion dependent MDS who were relapsed after, refractory to, or ineligible for, erythropoiesis stimulating agent (ESA) treatment, had not received prior treatment with either a HMA or lenalidomide and were non-del(5q). To be eligible for IMerge Phase 3, patients were required to be transfusion dependent, defined as requiring at least four units of packed red blood cells (RBCs), over an eight-week period during the 16 weeks prior to entry into the trial. The primary efficacy endpoint of IMerge Phase 3 is the rate of red blood cell transfusion independence (RBC-TI) lasting at least eight weeks, defined as the proportion of patients without any RBC transfusion for at least eight consecutive weeks since entry to the trial (8-week RBC-TI). Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks (24-week RBC-TI), the duration of RBC-TI and the rate of hematologic improvement erythroid (HI-E), which is defined under 2006 IWG criteria as a rise in hemoglobin of at least 1.5 g/dL above the pretreatment level for at least eight weeks or a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden. A total of 178 patients were enrolled in IMerge Phase 3 across North America, Europe, Middle East and Asia.

About Imetelstat

Imetelstat is a novel, first-in-class investigational telomerase inhibitor exclusively owned by Geron and being developed in hematologic malignancies. Data from non-clinical studies and clinical trials of imetelstat provide strong evidence that imetelstat targets telomerase to inhibit the uncontrolled proliferation of malignant stem and progenitor cells in myeloid hematologic malignancies resulting in malignant cell apoptosis and potential disease-modifying activity. Imetelstat has been granted Fast Track designation by the U.S. Food and Drug Administration for both the treatment of adult patients with transfusion dependent anemia due to Low or Intermediate-1 risk MDS that is not associated with del(5q) who are refractory or resistant to an erythropoiesis stimulating agent, and for adult patients with Intermediate-2 or High-risk myelofibrosis (MF) whose disease has relapsed after or is refractory to janus associated kinase (JAK) inhibitor treatment. Imetelstat is currently not approved by any regulatory authority.

On December 11, 2023 Ferring Pharmaceuticals and Zürich-based microbiome translation company PharmaBiome reported a research & development collaboration to drive forward new microbiome-based biotherapeutics in the field of gastroenterology (Press release, Ferring, DEC 11, 2023, View Source [SID1234638417]).

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The deal provides Ferring with exclusive rights to develop, manufacture and commercialize next generation microbiome-based therapeutics within the field of gastroenterology arising out of the collaboration. The financial details of this deal are undisclosed.

"This agreement is the latest in Ferring’s long term mission to maximise the therapeutic potential of the gut microbiome for the benefit of patients. PharmaBiome’s unique technology enables identification and manufacturing of defined consortium live microbiome bio-therapeutics that could reverse microbiome dysbiosis linked to disease," said Carl Bilbo, Senior Vice President, Microbiome at Ferring Pharmaceuticals. "This collaboration is a successful example of our strategy to use external innovation to build our pipeline complementary to our in-house research; and we aim to do further collaborations to build a vibrant research community."

Tomas de Wouters, CEO, PharmaBiome said: "The trust of Ferring in our translational approach is an important validation of our work and a unique opportunity to accelerate the development of our rationally designed consortia with an experienced market leader in the microbiome therapeutic field. We are thrilled about the complementary expertise between our companies and look forward to a fruitful collaboration".

Based on two core technologies, PharmaBiome has developed a unique technology platform to select bacterial strains for the design of bacterial consortia as live biotherapeutic products with defined activities – the NicheMapTM and a co-cultivation approach that enables fast and scalable production. PharmaBiome’s programmes aim at a next generation of products that are independent of donor material and deliver exactly the consortium of bacterial strains with the desired activity and therapeutic effect ("defined consortia").

Ferring is the first company to successfully bring forward a first-in-class FDA approved live microbiome-based therapy to US patients. In addition, Ferring has the proven scale and ability to drive forward clinical trials and manufacture microbiome-based products in what is a pioneering field and has a long heritage within gastroenterology.

On December 11, 2023 Eli Lilly and Company (NYSE: LLY) reported updated clinical data from the international Phase 1/2 BRUIN trial of pirtobrutinib, a non-covalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor, in adult patients with a range of B-cell malignancies (Press release, Eli Lilly, DEC 11, 2023, View Source [SID1234638416]). These data, which were presented in oral and poster presentations at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, continue to support the role of pirtobrutinib in the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL).

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"With longer follow-up, we continue to observe efficacy and tolerability data that support the potential utility of pirtobrutinib in CLL and B-cell lymphomas in the post-covalent BTK inhibitor setting," said Matthew S. Davids, M.D., M.M.Sc., Dana-Farber Cancer Institute. "These data demonstrate the ability of pirtobrutinib to potentially lengthen the time patients may benefit from inhibiting BTK, a key target in these diseases. It is also encouraging to see the promising initial data for pirtobrutinib combined with venetoclax, which has the possibility to allow for a time-limited regimen for patients with CLL."

"Following the two FDA accelerated approvals for pirtobrutinib in 2023, we are excited to present these data at ASH (Free ASH Whitepaper), further building the body of evidence for this medicine in CLL, SLL, MCL, and other B-cell malignancies," said David Hyman, M.D., chief medical officer, Lilly. "These data support the potential role that pirtobrutinib, the first and only FDA-approved non-covalent BTK inhibitor, can play in extending the time patients may benefit from BTK inhibition therapy and provide additional efficacy data in patients previously treated with a covalent BTK inhibitor. We look forward to expanding our understanding of the broader potential clinical utility of pirtobrutinib as we continue to progress our series of randomized Phase 3 studies in CLL, SLL, and MCL."

The labeling for pirtobrutinib contains warnings and precautions for infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, and embryo-fetal toxicity.

Data from the BRUIN Phase 1/2 Study
The BRUIN Phase 1/2 clinical trial is evaluating pirtobrutinib in patients previously treated for MCL, CLL/SLL, or other non-Hodgkin lymphomas (NHL). The efficacy data presented at ASH (Free ASH Whitepaper) for CLL/SLL and MCL are based on independent review committee (IRC) assessment. All presentations of safety and efficacy data from the BRUIN Phase 1/2 trial utilized a cutoff date of May 5, 2023.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
An oral presentation (Abstract #325) detailed updated, long-term follow-up data in patients with CLL/SLL. This data set consisted of 282 patients who had received a prior BTK inhibitor. Patients had received a median of four prior lines of therapy (range: 1-11). Efficacy results showed an overall response rate (ORR), including partial response with lymphocytosis (PR-L), of 81.6% (95% CI: 76.5, 85.9) for patients treated with pirtobrutinib. Response rates were consistent across all subgroups analyzed regardless of previous therapies, age, or mutation status. With a median follow-up of 27.5 months, median progression-free survival (PFS) was 19.4 months (95% CI: 16.6, 22.1). With a median follow-up of 29.3 months, median overall survival (OS) was not estimable.

In patients treated with both a prior covalent BTK inhibitor and BCL-2 inhibitor (n=128, median of five prior lines of therapy, range: 1-11), pirtobrutinib demonstrated an ORR, including PR-L, of 79.7% (95% CI: 71.7, 86.3). With a median follow-up of 22.2 months, median PFS was 15.9 months (95% CI: 13.6, 17.5). With a median follow-up of 27.4 months, the median OS was not estimable.

In BCL-2-naïve patients (n=154, median of three prior lines of therapy, range: 1-9), pirtobrutinib demonstrated an ORR, including PR-L, of 83.1% (95% CI: 76.2, 88.7). With a median follow-up of 27.6 months, median PFS was 23.0 months (95% CI: 19.6, 28.4). With a median follow-up of 31.6 months, the median OS was not estimable.

In the CLL/SLL safety cohort (n=282), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (36.9%), neutropenia (34.4%), diarrhea (28.4%), cough (27.3%), and contusion (26.2%).

A second oral presentation (Abstract #326) detailed updated analyses of genomic evolution and resistance during pirtobrutinib therapy in patients with relapsed covalent BTK inhibitor pre-treated CLL who subsequently developed disease progression on pirtobrutinib monotherapy (n=88). These data showed that although many patients harbored BTK mutations (C481 and non-C481) prior to initiation of pirtobrutinib therapy, these baseline genomic features did not predict response to pirtobrutinib. Moreover, while many patients acquired mutations at progression (68%), fewer than half were in the BTK gene.

A poster presentation (Abstract #3269) detailed updated data from the Phase 1b portion of the BRUIN trial, which investigated pirtobrutinib in combination with venetoclax with or without rituximab as a two-year fixed-duration therapy. This data set consisted of 25 patients, 17 of whom had received a prior BTK inhibitor. Patients were enrolled into sequential cohorts, first in the pirtobrutinib plus venetoclax (PV) cohort (n=15) and then the PV plus rituximab (PVR) cohort (n=10). Efficacy results showed an ORR of 96% (95% CI: 79.6, 99.9), with 40% complete responses (PV, n=7; PVR, n=3) and 56% partial responses (PV, n=7; PVR, n=7) across the two arms. Undetectable minimal residual disease (uMRD) was achieved by 87.5% of patients (PV, n=12; PVR, n=9) at some time during the trial. Across the two arms, the PFS rate at 24 months was 79.5% (95% CI: 52.0, 92.3).

The primary endpoint was safety as assessed by TEAEs graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The safety profiles were generally similar among both combination treatment groups, and no dose limiting toxicities were observed. In the PV cohort, the most frequent treatment-related AEs were neutropenia (46.7%), nausea (46.7%), fatigue (33.3%), diarrhea (26.7%), and decreased platelet count (26.7%). In the PVR cohort, the most frequent treatment-related AEs were neutropenia (70.0%), diarrhea (60.0%), nausea (40.0%), infusion-related reactions (40.0%), and chills (30.0%). There were no apparent drug interactions between pirtobrutinib and venetoclax.

These efficacy and safety data support the ongoing BRUIN CLL-322 Phase 3 trial evaluating two years of pirtobrutinib plus venetoclax and rituximab versus two years of venetoclax plus rituximab in previously treated CLL/SLL.

Mantle Cell Lymphoma
An oral presentation (Abstract #981) detailed updated efficacy results, including in high-risk subgroups. This data set consisted of 152 patients who had received a prior covalent BTK inhibitor. Patients had received a median of three prior lines of therapy (range: 1-9). Efficacy results showed an ORR of 49.3% (95% CI: 41.1, 57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51) for patients treated with pirtobrutinib. At a median follow-up of 14.7 months, the median duration of response (DOR) was 21.6 months (95% CI: 9.2, 27.2). Median PFS and OS were 5.6 months (95% CI: 5.3, 9.2) and 23.5 months (95% CI: 17.1, not estimable), respectively. Response rates were consistent across subgroups regardless of prior treatment or high-risk molecular features.

In the MCL safety cohort (n=166), the most frequent TEAEs were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%).

Additionally, Lilly presented posters highlighting pirtobrutinib in relapsed or refractory follicular lymphoma (FL), relapsed or refractory marginal zone lymphoma (MZL), and Richter transformation (RT).

Loxo@Lilly is studying pirtobrutinib in multiple Phase 3 studies. Details on the trials can be found by visiting clinicaltrials.gov.

About the BRUIN Phase 1/2 Trial
The BRUIN Phase 1/2 clinical trial is the ongoing first-in-human, global, multi-center evaluation of pirtobrutinib in patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). The BRUIN trial includes one of the largest prospective cohorts of BTK inhibitor pre-treated CLL/SLL patients ever studied.

The trial includes a Phase 1 dose-escalation phase, a Phase 1b combination arm, and a Phase 2 dose-expansion phase. The primary endpoint of the Phase 1 study is maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D). Secondary endpoints include safety, pharmacokinetics (PK), and preliminary efficacy measured by overall response rate (ORR) for monotherapy. The primary endpoint of the Phase 1b study is safety of the drug combinations. The secondary endpoints are PK and preliminary efficacy measured by ORR for the drug combinations. The primary endpoint for the Phase 2 study is ORR as determined by an independent review committee (IRC). Secondary endpoints include ORR as determined by investigator, best overall response (BOR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and PK.

About Pirtobrutinib
Pirtobrutinib is a highly selective (300 times more selective for BTK versus 98% of other kinases tested in preclinical studies), non-covalent (reversible) inhibitor of the enzyme BTK.1 BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation, and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).2,3 Pirtobrutinib was developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations.

Pirtobrutinib was approved under the FDA’s Accelerated Approval pathway as Jaypirca (pirtobrutinib) on January 27, 2023, to treat adult patients with relapsed or refractory MCL after at least two lines of systemic therapy, including a BTK inhibitor, and on December 1, 2023, to treat adult patients with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. These indications are approved under accelerated approval based on response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

INDICATIONS FOR JAYPIRCA
Jaypirca is a kinase inhibitor indicated for the treatment of

Adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.
Adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
These indications are approved under accelerated approval based on response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

IMPORTANT SAFETY INFORMATION FOR JAYPIRCA (pirtobrutinib)

Infections: Fatal and serious infections (including bacterial, viral, fungal) and opportunistic infections occurred in Jaypirca-treated patients. In a clinical trial, Grade ≥3 infections occurred in 24% of patients with hematologic malignancies, most commonly pneumonia (14%); fatal infections occurred in 4.4%. Sepsis (6%) and febrile neutropenia (4%) occurred. In patients with CLL/SLL, Grade ≥3 infections occurred (32%), with fatal infections occurring in 8%. Opportunistic infections included Pneumocystis jirovecii pneumonia and fungal infection. Consider prophylaxis, including vaccinations and antimicrobial prophylaxis, in patients at increased risk for infection, including opportunistic infections. Monitor patients for signs and symptoms, evaluate promptly, and treat appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.

Hemorrhage: Fatal and serious hemorrhage has occurred with Jaypirca. Major hemorrhage (Grade ≥3 bleeding or any central nervous system bleeding) occurred in 3% of patients, including gastrointestinal hemorrhage; fatal hemorrhage occurred (0.3%). Bleeding of any grade, excluding bruising and petechiae, occurred in 17%. Major hemorrhage occurred in patients taking Jaypirca with (0.7%) and without (2.3%) antithrombotic agents. Consider risks/benefits of co-administering antithrombotic agents with Jaypirca. Monitor patients for signs of bleeding. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Consider benefit/risk of withholding Jaypirca 3-7 days pre- and post-surgery depending on type of surgery and bleeding risk.

Cytopenias: Jaypirca can cause cytopenias, including neutropenia, thrombocytopenia, and anemia. In a clinical trial, Grade 3 or 4 cytopenias, including decreased neutrophils (26%), decreased platelets (12%), and decreased hemoglobin (12%), developed in Jaypirca-treated patients. Grade 4 decreased neutrophils (14%) and Grade 4 decreased platelets (6%) developed. Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.

Cardiac Arrhythmias: Cardiac arrhythmias occurred in patients who received Jaypirca. In a clinical trial of patients with hematologic malignancies, atrial fibrillation or flutter were reported in 3.2% of Jaypirca-treated patients, with Grade 3 or 4 atrial fibrillation or flutter in 1.5%. Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred (0.5%). Patients with cardiac risk factors such as hypertension or previous arrhythmias may be at increased risk. Monitor for signs and symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea) and manage appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.

Second Primary Malignancies: Second primary malignancies, including non-skin carcinomas, developed in 9% of Jaypirca-treated patients. The most frequent malignancy was non-melanoma skin cancer (4.6%). Other second primary malignancies included solid tumors (including genitourinary and breast cancers) and melanoma. Advise patients to use sun protection and monitor for development of second primary malignancies.

Embryo-Fetal Toxicity: Jaypirca can cause fetal harm in pregnant women. Administration of pirtobrutinib to pregnant rats during organogenesis caused embryo-fetal toxicity, including embryo-fetal mortality and malformations at maternal exposures (AUC) approximately 3-times the recommended 200 mg/day dose. Advise pregnant women of potential fetal risk and females of reproductive potential to use effective contraception during treatment and for one week after last dose.

Adverse Reactions (ARs) in Patients Who Received Jaypirca
The most common (≥20%) ARs in the BRUIN pooled safety population of patients with hematologic malignancies (n=593) were decreased neutrophil count (46%), decreased hemoglobin (39%), fatigue (32%), decreased lymphocyte count (31%), musculoskeletal pain (30%), decreased platelet count (29%), diarrhea (24%), COVID-19 (22%), bruising (21%), cough (20%).

Mantle Cell Lymphoma
Serious ARs occurred in 38% of patients. Serious ARs occurring in ≥2% of patients were pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%). Fatal ARs within 28 days of last Jaypirca dose occurred in 7% of patients, most commonly due to infections (4.7%), including COVID-19 (3.1% of all patients).

Dose Modifications and Discontinuations: ARs led to dose reductions in 4.7%, treatment interruption in 32%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dosage modification in >5% of patients included pneumonia and neutropenia. ARs resulting in permanent discontinuation in >1% of patients included pneumonia.

ARs (all Grades %; Grade 3-4 %) in ≥10% of Patients: fatigue (29; 1.6), musculoskeletal pain (27; 3.9), diarrhea (19; -), edema (18; 0.8), dyspnea (17; 2.3), pneumonia (16; 14), bruising (16; -), peripheral neuropathy (14; 0.8), cough (14; -), rash (14; -), fever (13; -), constipation (13; -), arthritis/arthralgia (12; 0.8), hemorrhage (11; 3.1), abdominal pain (11; 0.8), nausea (11; -), upper respiratory tract infections (10; 0.8), dizziness (10; -).

Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥10% of Patients: hemoglobin decreased (42; 9), platelet count decreased (39; 14), neutrophil count decreased (36; 16), lymphocyte count decreased (32; 15), creatinine increased (30; 1.6), calcium decreased (19; 1.6), AST increased (17; 1.6), potassium decreased (13; 1.6), sodium decreased (13; -), lipase increased (12; 4.4), alkaline phosphatase increased (11; -), ALT increased (11; 1.6), potassium increased (11; 0.8). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (10), platelets decreased (7), lymphocytes decreased (6).

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Serious ARs occurred in 56% of patients. Serious ARs occurring in ≥5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Fatal ARs within 28 days of last Jaypirca dose occurred in 11% of patients, most commonly due to infections (10%), including sepsis (5%) and COVID-19 (2.7%).

Dose Modifications and Discontinuations: ARs led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dose reductions in >1% included neutropenia; treatment interruptions in >5% of patients included pneumonia, neutropenia, febrile neutropenia, and COVID-19; permanent discontinuation in >1% of patients included second primary malignancy, COVID-19, and sepsis.

ARs (all Grades %; Grade 3-4 %) in ≥10% of Patients: fatigue (36; 2.7), bruising (36; -), cough (33; -), musculoskeletal pain (32; 0.9), COVID-19 (28; 7), pneumonia (27; 16), diarrhea (26; -), abdominal pain (25; 2.7), dyspnea (22; 2.7), hemorrhage (22; 2.7), edema (21; -), nausea (21; -), pyrexia (20; 2.7), headache (20; 0.9), arthritis/arthralgia (19; 1.8), rash (19; 0.9), peripheral neuropathy (16; 3.6), dizziness (15; -), fall (14; 0.9), constipation (14; -), insomnia (14; -), upper respiratory tract infections (13; 2.7), second primary malignancy (13; 2.7), renal insufficiency (12; 6), hypertension (12; 5), neurological changes (12; 2.7), mucositis (12; 0.9), decreased appetite (12; -), respiratory tract infection (11; 1.8), supraventricular tachycardia (10; 5).

Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥20% of Patients: neutrophil count decreased (63; 45), hemoglobin decreased (48; 19), calcium decreased (40; 2.8), platelet count decreased (30; 15), sodium decreased (30; -), lymphocyte count decreased (23; 8), ALT increased (23; 2.8), AST increased (23; 1.9), creatinine increased (23; -), lipase increased (21; 7), alkaline phosphatase increased (21; -). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (23).

Drug Interactions
Strong CYP3A Inhibitors: Concomitant use with Jaypirca increased pirtobrutinib systemic exposure, which may increase risk of Jaypirca ARs. Avoid use of strong CYP3A inhibitors with Jaypirca. If concomitant use is unavoidable, reduce Jaypirca dosage according to approved labeling.

Strong or Moderate CYP3A Inducers: Concomitant use with Jaypirca decreased pirtobrutinib systemic exposure, which may reduce Jaypirca efficacy. Avoid concomitant use of Jaypirca with strong or moderate CYP3A inducers. If concomitant use with moderate CYP3A inducers is unavoidable, increase Jaypirca dosage according to approved labeling.

Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP Substrates: Concomitant use with Jaypirca increased their plasma concentrations, which may increase risk of adverse reactions related to these substrates for drugs that are sensitive to minimal concentration changes. Follow recommendations for these sensitive substrates in their approved labeling.

Use in Special Populations
Pregnancy and Lactation: Due to potential for Jaypirca to cause fetal harm, verify pregnancy status in females of reproductive potential prior to starting Jaypirca and advise use of effective contraception during treatment and for one week after last dose. Presence of pirtobrutinib in human milk is unknown. Advise women not to breastfeed while taking Jaypirca and for one week after last dose.

Geriatric Use: In the pooled safety population of patients with hematologic malignancies, patients aged ≥65 years experienced higher rates of Grade ≥3 ARs and serious ARs compared to patients <65 years of age.

Renal Impairment: Severe renal impairment increases pirtobrutinib exposure. Reduce Jaypirca dosage in patients with severe renal impairment according to approved labeling.

PT HCP ISI COMBO DEC2023

Please see Prescribing Information and Patient Information for Jaypirca.

On December 11, 2023 Electra Therapeutics, Inc., a clinical stage biotechnology company developing antibody therapies against novel targets for immunological diseases and cancer, reported the presentation of the first clinical data for ELA026, the company’s lead candidate in development for the treatment of secondary hemophagocytic lymphohistiocytosis (sHLH), a life-threatening inflammatory disease (Press release, Electra Therapeutics, DEC 11, 2023, View Source [SID1234638415]). The results were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting being held in San Diego, California, December 9-12, 2023.

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Data from ten sHLH patients in the ongoing Phase 1b clinical study showed favorable safety results and overall response rate (ORR) of 70% in all patients dosed with ELA026. An ORR of 88% was observed in the eight patients with evaluable data. The majority of enrolled patients were difficult-to-treat, malignancy-associated HLH and displayed poor prognostic clinical and biomarker features at baseline.

ELA026 is a monoclonal antibody that targets signal regulatory protein (SIRP)-α/β1/γ on the cell surface of myeloid and T cells, the pathological immune cells that induce the hyperinflammatory response 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).

"sHLH is a life threatening and 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. "The patients enrolled in the study thus far are among the sHLH patient subtypes with the worst prognosis, and we are encouraged by this data showing that ELA026 is well tolerated and leads to promising responses."

Study Results Presented at ASH (Free ASH Whitepaper) Annual Meeting
The poster presentation at ASH (Free ASH Whitepaper), titled "A Phase 1b Study of ELA026, a Monoclonal Antibody Targeting Signal Regulatory Protein-α/β1/γ, in Patients with Newly Diagnosed and Previously Treated Secondary Hemophagocytic Lymphohistiocytosis," 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 an analysis of ten patients in the first two cohorts of the ongoing clinical study, including the following highlights:

Of the ten enrolled patients, eight were associated with a malignancy trigger and two had an unknown trigger. Five patients had relapsed/refractory sHLH.
Overall, ELA026 was well tolerated with a favorable safety profile in the study.
ELA026 achieved ORR of 70% in ten patients dosed and ORR of 88% in eight patients with evaluable data, despite poor baseline prognostic and clinical indicators related to sHLH.
Three patients with ≥ 90% reduction of ferritin and sCD25 from baseline or peak values also had tumor complete responses, including a patient with peripheral T-cell lymphoma refractory to chemotherapy.
ELA026 reduced peripheral monocyte and lymphocyte counts and resulted in early and rapid decrease in c-reactive protein (CRP) and sHLH-associated cytokines and biomarkers.
"We are pleased to present these promising first clinical results for ELA026 in the treatment of sHLH patients," Kim-Hien Dao, DO, PhD, Vice President, Head of Clinical Development at Electra. "We are extremely encouraged by the data from the first two cohorts, and we look forward to continuing enrollment for this study as we advance the ELA026 clinical program."

About Secondary Hemophagocytic Lymphohistiocytosis (sHLH)
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory condition for which there is no approved treatment. It can be triggered by cancer (malignancy-associated HLH, or mHLH), infections, or autoimmune disease. sHLH is associated with a systemic inflammatory response for which patients require immediate and aggressive treatment with intensive care. 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 December 11, 2023 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of emavusertib (CA-4948), an orally available, small molecule IRAK4 inhibitor, reported clinical data from its TakeAim Leukemia Study at the 2023 ASH (Free ASH Whitepaper) Conference (Press release, Curis, DEC 11, 2023, View Source [SID1234638414]).

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"We continue to be pleased with patient enrollment in the TakeAim Leukemia study and are especially pleased that the data confirm our observations to date – that emavusertib demonstrates a safe and manageable safety profile in addition to clear anti-cancer activity," said James Dentzer, President and Chief Executive Officer of Curis.

Data were presented for 92 patients treated with emavusertib monotherapy at doses ranging from 200 mg to 500 mg BID. Substantial reductions in blast counts were observed across all patient groups, irrespective of dose level, mutation status, or prior treatment history. Treatment-related adverse events (TRAEs) of grade ≥ 3 were found to be both manageable and acceptable, with no dose-limiting myelosuppression detected.

In the targeted population of patients with a FLT3 mutation, evidence of clear anti-cancer activity included changes in mutational profiles that suggest disease-modifying activity. These results were observed in patients including those who had progressed on a prior FLT3 inhibitor.

Among relapsed/refractory patients with FLT3 mutation who received ≤ 2 prior lines of treatment and had both baseline and post-treatment marrow evaluations, administering 300 mg emavusertib BID yielded compelling results. Notably, 2 out of 3 patients achieved a Complete Response (CR) with the other achieving morphological leukemia free state, indicating strong activity in patients with FLT3 mutation.

About emavusertib (CA-4948)

Emavusertib is a small molecule IRAK4 inhibitor. IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with cancer. TLRs and the IL-1R family signal through the adaptor protein MYD88, which results in the assembly and activation of IRAK4, initiating a signaling cascade that induces cytokine and survival factor expression mediated by the NF-κB protein complex. Preclinical studies targeting IRAK1/4 in combination with FLT3 have demonstrated the ability to overcome the adaptive resistance incurred when targeting FLT3 alone. Further, emavusertib has shown anti-tumor activity across a broad range of hematologic malignancies including monotherapy activity in patient-derived xenografts and synergy with both azacitidine and venetoclax.

About TakeAim Leukemia Study

TakeAim Leukemia Study (NCT04278768) – study is open for enrollment.