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 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a growing pipeline, including Phase 2 clinical programs, for hard-to-treat tumors and viruses, reported the presentation of preliminary efficacy findings from the Company’s ongoing European Phase 1B/2 clinical trial evaluating Annamycin for the treatment of acute myeloid leukemia or AML (MB-106) to key opinion leaders and current investigators at a meeting held in conjunction with the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Meeting and Exposition (ASH) (Free ASH Whitepaper) in San Diego on December 10, 2023 (Press release, Moleculin, DEC 11, 2023, View Source [SID1234638431]). Additionally, the Company will have a paper published on its MB-106 clinical trial as part of ASH (Free ASH Whitepaper). A link will be provided on the Company’s website once this publication is available online.

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The KOL presentation included an update to the positive preliminary efficacy findings previously reported on MB-106. To date, among patients who had an evaluable post treatment bone marrow biopsy, or who dropped out due to an adverse event (AE), there have been 4 complete responses (CR’s) or 36% of the intent to treat (ITT) subjects (n=11) and 44% of the subjects treated (dosed with Annamycin) (n=9). Two subjects experienced adverse events and were not dosed with one being an allergic reaction to Annamycin, the first the Company has seen in over 70 subjects dosed in the Company’s multiple Annamycin clinical trials; the second dropout was due to an allergic reaction to cytarabine. There continues to be no evidence of cardiotoxicity as measured by ejection fraction, strain analyses, ECGs, and cardiac biomarkers including Troponin-I and T in MB-106.

"We believe that our growing body of preliminary clinical data demonstrated by Annamycin in the treatment of patients with AML continues to be highly encouraging and bolsters our confidence in its potential to be a meaningful option for patients," commented Walter Klemp, Chairman and Chief Executive Officer of Moleculin. "While still preliminary, the complete response rate we are seeing continues to reflect what we believe is an efficacy level greater than we need for eventual approval of Annamycin. Our recruitment rate continues to exceed expectations and we are optimistic that we will be fully recruited within the next few months."

Currently, the median age of subjects in MB-106 is 69 years with a median number of prior therapies for AML of one. While two of the Company’s complete responders are too recent to measure durability, the Company is seeing durability as high as 8 months and climbing, and the Company has yet to see any relapses of CR’s experienced to date in the trial. The Company has recruited 16 subjects to date with 2 subjects withdrawing from the trial due to adverse events and 3 other subjects having received treatment and not having the bone marrow aspirate fully evaluated.

Additionally, one of the subjects treated but not evaluated experienced a grade 4 serious adverse event (SAE) with septic shock caused by Escherichia coli (E. coli) and was reported on a Suspect Adverse Reaction Report to the appropriate regulatory bodies and ethics committees. The subject was treated for the infection, the SAE is still reported as "ongoing," and the subject is recovering. This subject will be evaluated until resolution of the SAE and will be assessed for efficacy per protocol.

The presentation to the KOL’s mentioned above will be posted on the Company’s website and filed on Form 8-K with the Securities and Exchange Commission.

Annamycin currently has Fast Track Status and Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of relapsed or refractory acute myeloid leukemia, in addition to Orphan Drug Designation for the treatment of soft tissue sarcoma. For more information about the MB-106 Phase 1B/2 trial, visit clinicaltrialsregister.eu and reference EudraCT 2020-005493-10 or clinicaltrials.gov and reference NCT05319587.

About Annamycin

Annamycin is the Company’s next-generation anthracycline that has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin. Importantly, Annamycin has also demonstrated a lack of cardiotoxicity in multiple early-stage human clinical trials, including ongoing trials for the treatment of AML and STS lung metastases. For that reason, although additional data will be necessary, the Company believes Annamycin may not face the same usage limitations imposed on doxorubicin, one of the most common currently approved anthracyclines. Annamycin is currently in development for the treatment of AML and STS lung metastases and the Company believes the drug may have the potential to treat additional indications.

About "Complete Remission"

Per the American Cancer Society, the goal of treatment for acute myeloid leukemia is to put the leukemia into complete remission (the bone marrow and blood cell counts return to normal), preferably a complete molecular remission (no signs of leukemia in the bone marrow, even using sensitive lab tests), and to keep it that way. Source: View Source

On December 11, 2023 Laekna (2105.HK), a clinical-stage biotechnology company, reported the results of a phase Ib study to evaluate the efficacy and safety of afuresertib plus fulvestrant in patients with locally advanced or metastatic HR+/HER2- breast cancer who failed standard of care therapies at the 2023 San Antonio Breast Cancer Symposium (SABCS) on December 8 (Press release, Laekna Therapeutics, DEC 11, 2023, View Source;laekna-reports-afuresertib-phase-ib-breast-cancer-study-results-302011286.html [SID1234638464]).

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From May 2022 to April 2023, 20 patients (19 female and 1 male) with locally advanced or metastatic HR+/HER2- breast cancer who had failed 1-2 lines of endocrine therapy were enrolled in the Phase Ib study. The median duration of follow-up was 11 months.

As of October 16, 2023, the main study results are as follows:

– 70% of the patients were previously treated with CDK4/6 inhibitors.

– Among the total patient population, the confirmed ORR was 30% (95% CI, 11.9, 54.3), the median PFS was 7.3 months (95% CI, 3.7, NE). The disease control rate (DCR) was 80%.

– Among the 11 patients with specific biomarker alterations (PIK3CA/AKT1/PTEN), the confirmed objective response rate was 45.4% (95% CI, 16.7, 76.6), the disease control rate was 82%, and the median PFS was 7.3 months (95% CI, 3.6, 8.2).

– Among the 17 Chinese patients, the confirmed ORR was 29.4% (95% CI, 10.3, 60.0), the disease control rate was 82.4%, and the median PFS was 7.3 months (95% CI, 3.6, 8.2).

– The results demonstrated a well-tolerated safety profile of afuresertib plus fulvestrant. No dose modification was required during the safety run-in period. No patient discontinued treatment due to TEAE. No serious adverse event (SAE) was reported.

Investigators concluded that the combination therapy of afuresertib and fulvestrant has shown promising efficacy with a well-tolerated safety profile, supporting further evaluation in the upcoming Phase III part of the study.

Academician Binghe Xu, the lead investigator of the study, said: "While therapies for breast cancer are increasing, the treatment of drug resistance remains one of the clinical challenges. With the approval of the world’s first AKT inhibitor last month, patients with locally advanced or metastatic HR+/HER2- breast cancer now have new hope. The Phase Ib data of the combination therapy of afuresertib and fulvestrant are promising. I look forward to the next Phase III study of afuresertib in breast cancer."

"Biomarkers of response and/or resistance to endocrine-based therapies has become a prominent topic in the field of breast cancer treatment. It is also the central theme of the ‘Poster Spotlight Session’ in which our study was presented," said Dr. Yong Yue, Chief Medical Officer of Laekna. "Compared with the PFS data of 3-4 months for fulvestrant monotherapy[1], the median PFS of afuresertib plus fulvestrant is significantly increased to 7.3 months, with a favorable safety profile."

Lakena has initiated the Phase III pivotal trial of afuresertib plus fulvestrant in the treatment of HR+/HER2- breast cancer. The company strives to bring new hope to patients.

Notes

Breast cancer

The latest data released by the International Agency for Research on Cancer (IARC) of the World Health Organization show that the number of new cases of breast cancer in 2020 reached 2.26 million worldwide, surpassing lung cancer for the first time and becoming the world’s most prevalent cancer with 685,000 deaths. The latest epidemic data of malignant tumors in China also show that breast cancer has ranked first among women, with about 420,000 new cases each year[2].

Approximately 69% of breast cancer patients in the United States are considered HR+/HER2[3], and the proportion of this subtype among Chinese patients is 62%[4]. Although most patients with this type of breast cancer initially benefit from first/second-line endocrine ± CDK4/6 inhibitors and/or chemotherapy, most may develop drug resistance after a period, leading to treatment failure.

With further research on AKT, it has been demonstrated that factors such as PTEN loss and AKT/PIK3CA mutation can lead to excessive activation of the AKT signaling pathway, resulting in the occurrence, development, and drug resistance of tumors, especially prevalent in HR+ breast cancer. AKT has consequently emerged as a popular target for treating tumors.

Afuresertib

Afuresertib (LAE002) is an AKT inhibitor developed by Laekna. Laekna has initiated multiple clinical studies of combination therapies with Afuresertib in patients with PROC, HR+/HER2− breast cancer, mCRPC, TNBC, PD-1-resistant cervical cancer, and endometrial cancer.

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 Mustang Bio, Inc. ("Mustang") (Nasdaq: MBIO), a clinical-stage biopharmaceutical company focused on translating today’s medical breakthroughs in cell and gene therapies into potential cures for difficult-to-treat cancers and rare genetic diseases, reported updated encouraging safety and efficacy data from Mustang’s multicenter Phase 1/2 clinical trial of MB-106, a CD20-targeted, 3rd-generation autologous CAR T-cell therapy for patients with relapsed or refractory B-cell non-Hodgkin lymphomas ("NHL") and chronic lymphocytic leukemia ("CLL") (Press release, Mustang Bio, DEC 11, 2023, View Source [SID1234638432]). The data were presented during a poster session on December 9th (Abstract #2102) at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) ("ASH") Annual Meeting and build upon previously reported data from a single-institution Phase 1/2 clinical trial conducted at Fred Hutchinson Cancer Center ("Fred Hutch"). MB-106 is being developed in a collaboration between Mustang and Fred Hutch.

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"All nine patients have responded clinically to treatment in this multicenter trial and the safety and efficacy profile of MB-106 appears to be consistent with the original single-institution trial. It is especially encouraging that complete responses were observed in all patients with follicular lymphoma in this multicenter trial," said Mazyar Shadman, M.D., M.P.H., Study Chair, Innovators Network Endowed Chair at Fred Hutch, Associate Professor and physician at Fred Hutch and University of Washington. "One patient with follicular lymphoma who had six prior treatments including CD19-targeted CAR T-cell therapy experienced a complete response for the first time with no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS)."

Highlights from the data include:

o All patients responded clinically to treatment with MB-106 (n=9); 100% overall response rate for patients with follicular lymphoma ("FL") and Waldenstrom macroglobulinemia ("WM")
o 100% of patients with FL (n=5) had a complete response; 1 very good partial response and 2 partial responses were observed in WM patients (n=3); and the hairy cell leukemia variant ("HCL-v") patient experienced stable disease, with prolonged, ongoing independence from blood transfusions
o Complete responses observed in patients previously treated with CD19-targeted CAR T-cell therapy
o MB-106 has a tolerable safety profile in patients with indolent NHL, with no occurrence of CRS above grade 1, and no ICANS of any grade, despite not using prophylactic tocilizumab or dexamethasone
o Outpatient administration was allowed and found to be feasible
o MB-106 CAR T-cell expansion and persistence in patients was demonstrated

Efficacy (combined results for dose level 1 & 2)

Best Responses to Date1

Follicular Lymphoma
(n=5)

Waldenstrom
Macroglobulinemia
(n=3)

Overall response rate (ORR),2 n (%)

5 (100%)

3 (100%)

Complete response (CR), n (%)

5 (100%)

0

Very good partial response (VGPR),3 n (%)

N/A

1 (33%)

Partial response (PR), n (%)

0

2 (67%)

Minor response,3 n (%)

N/A

0

Stable disease (SD)

0

0

1. In WM patients, responses are evaluated using the 11th International Workshop on WM (IWWM) criteria (Treon, 2023). In lymphoma patients, PET-CT-based responses are evaluated using the Lugano Classification (Cheson, 2014).
2. ORR is the rate of PR or better in follicular lymphoma. ORR is the rate of minor response or better in WM.
3. VGPR and minor response are WM-specific response categories.
N/A = Not applicable

Safety

CRS and ICANS (combined results for dose level 1 & 2)

Grade 1

Grade 2

Grade 3

Grade 4

CRS, n (%)

5 (56%)

0

0

0

ICANS

0

0

0

0

● CRS = Cytokine release syndrome
● ICANS = Immune effector cell-associated neurotoxicity syndrome
● No related serious adverse events (SAEs) reported, apart from Grade 1 CRS.
● No prophylactic tocilizumab or dexamethasone was administered.

Manuel Litchman, M.D., President and Chief Executive Officer of Mustang, said, "Given the favorable data presented from the multicenter Mustang trial at ASH (Free ASH Whitepaper) and from the original single-institutional Fred Hutch trial, we anticipate finalizing a recommended Phase 2 dose level in early 2024 and moving ahead with the first ever registrational CAR-T trial focused on relapsed or refractory WM. As we plan for an End-of-Phase 1 meeting with the FDA in the first half of 2024 to solicit approval for the design of this trial, we are especially encouraged by the safety of the higher dose level of 1.0×107 CAR T-cells/kg which so far is indistinguishable from the safety of the lower dose level and which we have manufactured successfully for all 5 patients enrolled to date at the higher dose level. Following that meeting, we anticipate initiating a trial enrolling 58 patients across 20 sites in North America, with top-line data expected as early as mid-2026."

The data reported on nine patients from the indolent lymphoma arm of the multicenter clinical trial, including five patients with follicular lymphoma, three patients with Waldenstrom macroglobulinemia, and one patient with transfusion-dependent hairy cell leukemia variant. The patients had been treated with a median of 4 lines of prior therapy (range: 1-9), including 2 patients who had received prior CD19-directed CAR T-cell therapy and 1 patient who had received prior autologous stem cell transplant. The patients received one of two dose levels: dose level 1, 3.3×106 CAR T-cells/kg body weight, or dose level 2, 1.0×107 CAR T-cells/kg.

A link to the poster can be found on the Publications page of the Mustang Bio website here.

Scientists at Fred Hutch played a role in developing these discoveries, and Fred Hutch and certain of its scientists may benefit financially from this work in the future.