On December 12, 2022 Bristol Myers Squibb (NYSE: BMY) reported the first disclosure of results and presentation of new research from its multiple myeloma portfolio across targets and molecular approaches at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, underscoring the company’s commitment to raising standards to transform multiple myeloma outcomes for every patient (Press release, Bristol-Myers Squibb, DEC 12, 2022, View Source [SID1234625089]).

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"At ASH (Free ASH Whitepaper) this year, we are highlighting the next wave of advances from our diverse multiple myeloma portfolio, reflecting our strategy of leveraging an array of approaches and targets against the disease," said Samit Hirawat, M.D., executive vice president, chief medical officer, Global Drug Development, Bristol Myers Squibb. "Through continued partnership with the multiple myeloma community, we are working to push toward a reality in which every patient would have an opportunity to receive a tailored treatment option that offers the best possible outcomes."

Results being presented at ASH (Free ASH Whitepaper) highlight scientific progress across bispecific T cell engagers (TCE), chimeric antigen receptor (CAR) T cell therapies and novel CELMoDTM agents in advancing the treatment of relapsed/refractory multiple myeloma and include:

First multicenter results from the Phase 1 study of bispecific TCE alnuctamab, administered subcutaneously every four weeks after six months, showing a reduction in inflammatory toxicity relative to intravenous administration, while maintaining anti-tumor activity with deep responses (Oral Presentation #162)
First disclosure of Phase 1 results for GPRC5D CAR T (BMS-986393/CC-95266), demonstrating deep and durable responses with a manageable safety profile across all dose levels, including patients previously treated with a B-cell maturation antigen (BCMA)-directed CAR T cell therapy (Oral Presentation #364)
Two first disclosures of results from cohorts 2a and 2c of the Phase 2 KarMMa-2 trial evaluating Abecma (idecabtagene vicleucel), demonstrating durable responses and predictable safety in patients with multiple myeloma after early relapse or suboptimal response to stem cell transplant (Oral Presentation #361, Poster Presentation #3314)
First results from the dose expansion cohort of the mezigdomide Phase 1/2 study evaluating the novel oral CELMoD agent with dexamethasone (DEX), showing durable efficacy and a manageable safety profile in patients who were highly refractory to multiple prior therapies (Oral Presentation #568)
New results from a cohort with patients previously exposed to a BCMA-targeted therapy of the iberdomide Phase 1/2 study, evaluating the novel oral CELMoD agent with DEX, demonstrating clinically meaningful efficacy and safety regardless of type of prior anti-BCMA treatment (Poster Presentation #1918)
"Multiple myeloma continues to be an immensely challenging disease which affects patients across a number of demographics, fitness levels and comorbidities. While scientific advances have driven significant improvements in survival, the disease remains characterized by relapses and a disease burden that greatly impacts a patient’s quality of life," said Brian Durie, M.D., chairman of the board of the International Myeloma Foundation. "These promising data at ASH (Free ASH Whitepaper) represent important progress, and I am encouraged by the next wave of potential advances across a diverse range of targets and platforms, which may provide treating physicians with many options that can be tailored for unique patient needs."

Alnuctamab (BMS-986349/CC -93269) Phase 1 Study Results
Alnuctamab is a bispecific T cell engager (TCE) that simultaneously binds myeloma cells expressing B-cell maturation antigen (BCMA) and T cells (via CD3) in a unique 2:1 fashion. This interaction aims to drive myeloma cell death by inducing T cell activation and release of proinflammatory cytokines and cytolytic enzymes.

In the ongoing alnuctamab CC-93269-MM-001 open-label, Phase 1 study, 138 patients with relapsed/refractory (R/R) multiple myeloma were enrolled (as of November 1, 2022) to receive escalating doses of alnuctamab administered either intravenously (IV) (n=70) or subcutaneously (SC) (n=68). Intravenous alnuctamab was administered as previously reported at target doses of 0.15–10 mg, with both fixed and step-up dosing, while SC alnuctamab was given to patients in two step-up doses (3 mg and 6 mg) followed by escalating target doses of 10, 15, 30, and 60 mg, given every one week for three months, then every two weeks for three months, followed by every four weeks after those six months.

In interim results, SC alnuctamab (n=68) showed an improved safety profile compared to IV delivery, with cytokine release syndrome (CRS) limited to low-grade, short-lived events, allowing for dose escalation to higher target doses. Intravenous and SC alnuctamab both exhibited promising pharmacodynamic effects, triggering the release of the hallmark cytokines of TCEs(e.g., IL-1 and IL-6). However, SC alnuctamab triggered reduced and delayed cytokine production compared to more potent CRS induced by IV delivery. Subcutaneous alnuctamab also demonstrated encouraging dose-dependent anti-tumor activity across all target doses, particularly in patients who received the 30 mg target dose.

Alnuctamab CC-93269-MM-001 Study

Safety

IV alnuctamab
(n=70)

Cytokine Release Syndrome (CRS) – Any Grade

76% (53/70)

Grade >3 CRS

7% (5/70)

SC alnuctamab
(n=68)

CRS – Any Grade

50% (34/68)

Grade >3 CRS

0

Median time to onset of CRS

3 days (range: 1-20)

Median duration of CRS

2 days (range: 1-11)

SC alnuctamab efficacy
(n=68)

Overall response rate (ORR)

53% (36/68)

ORR in patient treated with 30 mg dose

65% (44/68)

Median duration of response (DOR)

NR
(90% of responses ongoing at data cut-off)

Minimal residual disease (MRD)-negativity among patients who achieved a response (n=20 evaluable patients)

80% (16/20)

GPRC5D CAR T (BMS-986393/CC-95266) Phase 1 Study Results
GPRC5D has been identified as an orphan receptor that is highly expressed on multiple myeloma cells, with limited expression in other tissues. BMS-986393 is a GPRC5D-directed autologous CAR T cell therapy.

This Phase 1, first-in-human, multicenter, open-label study is evaluating BMS-986393 in patients with R/R multiple myeloma who had received three or more prior lines of therapy. Prior BCMA-targeted treatment, including CAR T cell therapy, was allowed. Primary objectives of the study were to determine safety and tolerability of BMS-986393 and inform the recommended dose for future development.

At the time of the interim analysis, BMS-986393 demonstrated a well-tolerated safety profile with mostly low-grade and short-lived occurrences of CRS and neurotoxicity across all tested dose levels. Neurotoxicity was infrequent and low-grade, with no Grade 3 or 4 events reported, and events were reversible with steroid treatment. All on-target off-tumor adverse events were Grade 1, and the majority (78.6%) did not require treatment. Preliminary efficacy also supports the potential of BMS-986393 to elicit deep and durable responses.

BMS-986393 Phase 1 Study

Safety
(n=33)

CRS – Any Grade

63.6% (21/33)

Grade 3/4 CRS

6% (2/33)

Median time to onset CRS

3 days (range: 1-9)

Median duration of CRS

4 days

Neurotoxicity – Grade 1/2

6% (2/33)

Duration of neurotoxicity

1-3 days

On-target off-tumor AEs – Grade 1

30% (10/33)

Dysgeusia/taste disorder

15% (5/33)

Nail disorder

9.1% (3/33)

Dysphagia

3% (1/33)

Efficacy
(n=19)
Median follow-up: 5.82 months

ORR

89.5% (17/19)

CRR

CR – Patients treated with prior BCMA-directed CAR T cell therapies
CR – Patients treated with prior BCMA-directed therapies
47.4% (9/19)
7 patients

2 patients

Patients treated with prior BCMA-directed therapies subgroup (n=9)

ORR
CR
77.8% (7/9)
44.4% (4/9)

Patients remaining in follow-up

78.9% (15/19)

Abecma (idecabtagene vicleucel) KarMMa Phase 2 Cohorts 2a and 2c Study Results
KarMMa-2 (NCT03601078) is a multi-cohort, open-label, multicenter Phase 2 trial evaluating Abecma in patients with relapsed and refractory multiple myeloma (Cohort 1), patients with multiple myeloma who have progressive disease within 18 months of initial treatment including autologous stem cell transplant (ASCT) (Cohort 2a), or in patients with inadequate response following ASCT during initial treatment (Cohort 2c). Based on results from Cohorts 2a and 2c, Abecma demonstrated complete and durable responses in a significant proportion of patients, alongside a well-established and predictable safety profile with mostly low-grade occurrences of CRS and neurotoxicity. Abecma is being jointly developed and commercialized in the U.S. as part of a Co-Development, Co-Promotion, and Profit Share Agreement between Bristol Myers Squibb and 2seventy bio.

Abecma KarMMa-2 Study COHORT 2a
(n=37)
Patients with multiple myeloma who had early relapse after frontline ASCT

Efficacy

CRR (primary efficacy endpoint)

45.9%
(95% CI: 29.5-63.1)

ORR

83.8%
(95% CI: 68-93.8)

Median DOR

15.7 months
(95% CI: 7.6-19.8)

Safety

CRS – Grade 1/2

81.1% (30/37)

CRS – Grade 3

2.7% (1/37)

Neurotoxicity – Grade 1/2

21.6% (8/37)

*Median follow-up – 21.5 months

COHORT 2c
(n=31)
Patients with newly diagnosed multiple myeloma who had an inadequate response to ASCT

Efficacy

CRR

74.2%
(95% CI: 55.4-88.1)

ORR

87.1%
(95% CI: 70.2-96.4)

Safety

CRS – Grade 1

45.2% (14/31)

CRS – Grade 2

12.9% (4/31)

Neurotoxicity

6.5% (2/31)
Grade 1 – 1/31
Grade 3 – 1/31

*Median follow-up – 27.9 months

Novel CELMoD agents mezigdomide (CC-92480) and iberdomide (CC-220) Phase 1/2 Study Results
Cereblon E3 ligase modulators (CELMoD) are a class of oral immunomodulatory therapeutics that are designed to stimulate the immune system and directly kill cancer cells by inducing the degradation of tumor-promoting proteins. Bristol Myers Squibb is investigating two novel CELMoD agents, mezigdomide and iberdomide, for multiple myeloma that were intentionally designed to improve upon the demonstrated efficacy of the IMiD agents, along with manageable tolerability, ease of administration, and the potential to improve patient outcomes. These agents co-opt cereblon to induce degradation of target proteins Ikaros and Aiolos, which inhibits tumor cell proliferation, promote tumor cell death, and induce immune-stimulatory effects.

The mezigdomide CC-92480-MM-001 trial is an ongoing open-label, international Phase 1/2 study to investigate the safety and efficacy of mezigdomide in combination with dexamethasone (DEX) in patients with relapsed/refractory (R/R) multiple myeloma. As part of the expansion cohort phase, 101 highly refractory patients that had received three or more prior lines of therapy, including an IMiD agent, a proteasome inhibitor (PI), and an anti-CD38 mAb, were given mezigdomide for 21 of 28 days in combination with weekly DEX at the recommended Phase 2 dose selected in part 1 of the study (1 mg once daily). The primary objective was efficacy as determined by objective response rate (ORR), while safety, tolerability and additional efficacy measures were included as the secondary objectives.

Based on interim results, mezigdomide, in combination with weekly DEX (40 mg; 20 mg if >75 years of age), showed promising efficacy in a highly refractory patient population. As of the data cut-off date, mezigdomide plus DEX showed a manageable safety profile.

Mezigdomide CC-92489-MM-001 Study

Efficacy

ORR in patients receiving three or more prior lines of therapy

40.6% (40/101)
(n=101)

ORR in patients that had also received prior BCMA-targeted therapies

50% (15/30)
(n=30)

Safety

Grade 3/4 treatment-emergent adverse events (TEAEs)

89.1% (90/101)

Hematologic TEAEs

Neutropenia
Anemia
Thrombocytopenia
76.2% (77/101)

Mezigdomide dose interruptions and reductions due to TEAEs

29.7% (30/101)

Treatment discontinuation due to TEAEs

5.9% (6/101)

The iberdomide CC-220-MM-001 study is an ongoing Phase 1/2 multicenter, open-label and multi-cohort trial evaluating orally administered iberdomide in several combinations and segments of patients ​with R/R multiple myeloma. Results at ASH (Free ASH Whitepaper) are being presented from the dose-expansion cohort evaluating iberdomide in combination with DEX in patients with multiple myeloma who have heavily-pretreated refractory disease and also received anti-BCMA therapy.

Iberdomide was given orally, 1.6 mg once daily for 21 of 28 days, plus weekly DEX (40 mg; 20 mg if >75 years of age). The primary objectives were preliminary efficacy measured by ORR and safety. Patients treated with iberdomide with DEX demonstrated meaningful clinical activity, regardless of modality (TCE, CAR T cell or antibody-drug conjugate therapy), suggesting that iberdomideretains its activity in these patients.

Iberdomide CC-220-MM-001 Study

Efficacy
(n=41)

Overall response rate
*As of Sept. 6, 2022

34.1% (13/41)

Safety

Grade 3/4 treatment-emergent adverse events (TEAEs)
*Mostly hematologic, including leukopenia, anemia and thrombocytopenia

80.5% (33/41)

Iberdomide dose interruptions and reductions due to TEAEs

63.4% (26/41)

17.1% (7/41)

Treatment discontinuation due to TEAEs

0

Important Safety Information
BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/or corticosteroids as needed.
Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA.
ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS.
Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA. CRS occurred in 85% (108/127) of patients receiving ABECMA. Grade 3 or higher CRS (Lee grading system) occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time to onset of CRS, any grade, was 1 day (range: 1 – 23 days) and the median duration of CRS was 7 days (range: 1 – 63 days) in all patients including the patient who died. The most common manifestations of CRS included pyrexia (98%), hypotension (41%), tachycardia (35%), chills (31%), hypoxia (20%), fatigue (12%), and headache (10%). Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome and HLH/MAS.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.

Fifty four percent (68/127) of patients received tocilizumab; 35% (45/127) received a single dose while 18% (23/127) received more than 1 dose of tocilizumab. Overall, across the dose levels, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS received tocilizumab.

Overall rate of CRS was 79% and rate of Grade 2 CRS was 23% in patients treated in the 300 x 106 CAR+ T cell dose cohort. For patients treated in the 450 x 106 CAR+ T cell dose cohort, the overall rate of CRS was 96% and rate of Grade 2 CRS was 40%. Rate of Grade 3 or higher CRS was similar across the dose range. The median duration of CRS for the 450 x 106 CAR+ T cell dose cohort was 7 days (range: 1-63 days) and for the 300 x 106 CAR+ T cell dose cohort was 6 days (range: 2-28 days). In the 450 x 106 CAR+ T cell dose cohort, 68% (36/53) of patients received tocilizumab and 23% (12/53) received at least 1 dose of corticosteroids for treatment of CRS. In the 300 x 106 CAR+ T cell dose cohort, 44% (31/70) of patients received tocilizumab and 10% (7/70) received corticosteroids. All patients that received corticosteroids for CRS also received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic Toxicities: Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. CAR T cell-associated neurotoxicity occurred in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 – 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median duration of neurotoxicity was 5 days (range: 1 – 61 days). The median duration of neurotoxicity was 6 days (range: 1 – 578) in all patients including those with ongoing neurotoxicity at the time of death or data cut off. Thirty-four patients with neurotoxicity had CRS. Neurotoxicity had onset in 3 patients before, 29 patients during, and 2 patients after CRS. The rate of Grade 3 neurotoxicity was 8% in the 450 x 106 CAR+ T cell dose cohort and 1.4% in the 300 x 106 CAR+ T cell dose cohort. The most frequently reported (greater than or equal to 5%) manifestations of CAR T cell-associated neurotoxicity include encephalopathy (20%), tremor (9%), aphasia (7%), and delirium (6%). Grade 4 neurotoxicity and cerebral edema in 1 patient has been reported with ABECMA in another study in multiple myeloma. Grade 3 myelitis and Grade 3 parkinsonism have been reported after treatment with ABECMA in another study in multiple myeloma.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of neurologic toxicities. Rule out other causes of neurologic symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient treated in the 300 x 106 CAR+ T cell dose cohort developed fatal multi-organ HLH/MAS with CRS. In another patient with fatal bronchopulmonary aspergillosis, HLH/MAS was contributory to the fatal outcome. Three cases of Grade 2 HLH/MAS resolved. The rate of HLH/MAS was 8% in the 450 x 106 CAR+ T cell dose cohort and 1% in the 300 x 106 CAR+ T cell dose cohort. All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4-9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity. The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia. HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional standards.

ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS. Further information is available at www.AbecmaREMS.com or 1-888-423-5436.

Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.

Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, preemptive, and/or therapeutic antimicrobials according to standard institutional guidelines.

Febrile neutropenia was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

Viral Reactivation: Cytomegalovirus (CMV) infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and ABECMA infusion. In the KarMMa study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. Rate of prolonged neutropenia was 49% in the 450 x 106 CAR+ T cell dose cohort and 34% in the 300 x 106 CAR+ T cell dose cohort. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months. Median time to cytopenia recovery was similar across the 300 and 450 x 106 dose cohort.

Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support according to institutional guidelines.

Hypogammaglobulinemia: Plasma cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with ABECMA. Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA.

Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

The safety of immunization with live viral vaccines during or following ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.

Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, including altered mental status or seizures, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions: The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.

On December 12, 2022 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of MasterKey therapies, reported the formation of Launchpad Therapeutics, Inc. (Launchpad), an antibody-focused precision oncology company, together with a $30 million Series A investment by founding investors, Versant Ventures and New Enterprise Associates (NEA) (Press release, Black Diamond Therapeutics, DEC 12, 2022, View Source [SID1234625088]).

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In connection with the transaction, Black Diamond contributed undisclosed early discovery-stage antibody programs and granted Launchpad a license to use Black Diamond’s Mutation-Allostery-Pharmacology (MAP) Drug Discovery Engine to discover, develop and commercialize large molecule therapeutics. In exchange, Black Diamond received a minority ownership stake in Launchpad.

"The formation of Launchpad demonstrates the broad applicability of our MAP Drug Discovery Engine and computational expertise and provides further validation of our approach to precision medicine. By leveraging our MAP Drug Discovery Engine in new ways, Launchpad is positioned to disrupt the precision oncology and immunology drug discovery and development landscape," said David Epstein, Ph.D., President and Chief Executive Officer of Black Diamond. "We are pleased to partner with Versant and NEA to advance these concepts. The spinout allows Black Diamond to continue our focus on BDTX-1535, BDTX-4933 and small molecule pipeline, while retaining potential upside through our equity stake in Launchpad."

Launchpad’s antibody pipeline will be enabled by Black Diamond’s custom-built cloud-based computational MAP Drug Discovery Engine, with a focus on oncogenicity prediction, biological validation, conformation-based drug design and antibody discovery. Launchpad will focus on the development of an initial set of early-stage antibody programs.

"By utilizing Black Diamond’s MAP Drug Discovery Engine, coupled with a team of highly experienced drug hunters, data scientists and machine learning experts, Launchpad is well positioned to deliver novel antibody drug design," said Alexander Mayweg, Ph.D., Managing Director, Versant Ventures. "When we launched Black Diamond in 2018, the field of precision oncology was still in its early days. We believe that now is the right time to apply a further differentiated approach with Launchpad’s antibody focus and custom-built cloud-based computational pipeline."

"The formation of Launchpad as a unique spinout from Black Diamond enables both companies to focus on their respective areas of expertise with the shared goal of addressing large numbers of targets and mutations for genetically defined cancers," said Ali Behbahani, M.D., General Partner, NEA. "Launchpad’s approach furthers Black Diamond’s mission of bringing precision oncology medicine to a greater number of patients. We’re thrilled to partner with Versant and Black Diamond to support Launchpad and we look forward to the progression of this novel pipeline."

On December 12, 2022 Biomea Fusion, Inc. (Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, reported preclinical data today for BMF-500, an investigational covalent FLT3 inhibitor, at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Biomea Fusion, DEC 12, 2022, View Source [SID1234625087]). The preclinical poster can be viewed at Biomea’s website at View Source

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BMF-500, a novel, orally bioavailable, highly potent and selective covalent small molecule inhibitor of FLT3, was discovered and developed in-house at Biomea using the company’s proprietary FUSION System and designed to have a therapeutic profile to allow for combinations with standard of care and/or novel targeted agents like BMF-219, Biomea’s investigational covalent menin inhibitor. The company is on track to submit an investigational new drug (IND) application for BMF-500 in the first half of 2023 and, subject to successful IND clearance, plans to initiate clinical trials evaluating BMF-500 as a single agent and in novel combinations shortly thereafter.

"The majority of late-stage and approved FLT3 inhibitors fall short of providing sufficient and sustained inhibition of FLT3 signaling required for maximal benefit. We believe the exquisite potency, selectivity and durability of BMF-500, all of which are possible through the design of this novel covalent molecule with our proprietary FUSION system, have the potential to translate to deep and durable remissions in patients with FLT3-mutant AML, representing nearly a third of all AML patients," said Steve Morris, M.D., Biomea’s Chief Medical Officer. "We look forward to advancing BMF-500 toward the clinic in 2023, which will mark our second clinical-stage novel covalent small molecule program for cancer and further solidify our position as a leader in next-generation covalent medicines."

"The impressive profile of BMF-500 speaks to the bench strength of our Discovery Team and to our ability to design and deliver novel therapeutics. We believe that targeting FLT3 with a covalent inhibitor, as we did with menin, represents another significant opportunity to improve the outcomes that reversible inhibition provide. BMF-500 has the potential to be an effective option as a monotherapy as well as in combination," said Thomas Butler, Biomea’s Chief Executive Officer and Chairman of the Board.

The data presented at the ASH (Free ASH Whitepaper) conference today showed that in FLT3-driven AML cell lines, three-hour exposure to BMF-500 produced complete phospho-FLT3 inhibition, which was maintained following washout of the compound. The commercially available reversible (i.e., non-covalent) FLT3 inhibitor gilteritinib required 16 times higher concentration than BMF-500 and continuous exposure for 96 hours to produce the same effect. The covalent small molecule inhibitor BMF-500 exhibited potent inhibition of FLT3 receptor kinase and marked cell killing in FLT3-ITD AML cell lines, as demonstrated by IC90s at physiologically relevant doses. In addition, the kinase profile of BMF-500 revealed high target selectivity and selective cytotoxicity profile against a panel of non-target cancer cell lines suggesting the potential for minimal off-target liabilities. As part of the poster presentation, Biomea also presented the results of two preclinical animal xenograft models in which BMF-500 demonstrated antitumor activity with sustained tumor regression and improved survival while being well tolerated, with body weight maintenance across treatment groups.

About BMF-500

BMF-500 is a novel orally bioavailable, highly potent and selective covalent small molecule inhibitor of FLT3 in preclinical development, which has been shown to exhibit favorable durability, selectivity and tolerability in preclinical studies in comparison to commercially available FLT3 inhibitor gilteritinib. BMF-500 was discovered and developed in-house by Biomea using its proprietary FUSION System and designed to have a therapeutic profile to allow for combinations with standard of care and novel targeted agents like BMF-219, Biomea’s investigational covalent menin inhibitor. The kinase profile of BMF-500 showed high target selectivity, suggesting the potential for minimal off-target liabilities.

About FLT3 (fms-like tyrosine kinase 3)

FLT3 is a receptor tyrosine kinase (RTK) that plays a central role in the survival, proliferation, and differentiation of immature blood cells. Notably, FLT3 gene mutations are common in patients with AML and are associated with a poor prognosis. Nearly 30% of AML patients have a FLT3 mutation, representing more than 6,000 incident patients in the United States each year. While FLT3-specific and pan-tyrosine kinase inhibitors are approved by the FDA across various lines of therapy in AML, these agents have produced relatively low rates of durable responses and overall survival remains an unmet need.

On December 12, 2022 Taiho Oncology, Inc. and Astex Pharmaceuticals, Inc. reported preliminary data from the Phase 3 ASCERTAIN trial assessing overall and leukemia-free survival in adults with intermediate and high-risk myelodysplastic syndromes (MDS) including chronic myelomonocytic leukemia (CMML) harboring biallelic TP53 mutations following treatment with oral decitabine and cedazuridine (ASTX727) (Press release, Astex Pharmaceuticals, DEC 12, 2022, View Source [SID1234625086]). The data are being presented today as an oral presentation (Abstract #854) at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in New Orleans.

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This analysis evaluated the impact mutation profile of patients from the ASCERTAIN trial on overall survival (OS) and leukemia-free survival (LFS); this was based on the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (NCCN Guidelines) in Oncology for Myelodysplastic Syndromes (Version 1.2023-September 12, 2022) with a focus on the TP53 mutant population. In the study, the population of patients harboring a TP53 mutation (44 of 125 patients) was characterized by allelic status: 14 patients had biallelic mutations and 30 patients had monoallelic mutations without other chromosomal deletions. The median OS (mOS) in patients treated with ASTX727 with biallelic vs. monoallelic mutations was 13.0 months (95% Confidence Interval [CI]: 5.3, 29.1) vs. 29.2 months (95% CI: 19.8, NE).

"The overall results of this post-hoc analysis from ASCERTAIN studying the patients with mutated TP53 are of interest given the typically poor outcomes in these patients," said Michael Savona, MD, Director of Hematologic Malignancies Research and Early Therapy Program, and Professor of Internal Medicine and Cancer Biology at Vanderbilt University, and co-principal investigator on the study. "This analysis supports the emerging hypothesis that higher burden of mutant TP53 cells connotes poorer risk, and the fixed-dose combination of oral decitabine and cedazuridine may serve as a reasonable option in these patients."

More broadly, mOS and median LFS (mLFS) in patients with MDS and CMML harboring a TP53 mutation treated with ASTX727 were 25.5 and 22.1 months, respectively, compared to 33.7 and 31.7 months, respectively, in patients with wild-type TP53 status. The mOS and mLFS in the overall ASCERTAIN population were 32 and 29 months, respectively. Of note, the percentage of patients in the trial harboring a TP53 mutation (35%) was substantially higher than the standard patient population, which is approximately 8-12%.[1]

"There remains a significant unmet need for patients with MDS and CMML, particularly for those with mutations that typically don’t respond well to treatment, which is why we are encouraged by what we see in the ASCERTAIN trial," said Tim Whitten, President and CEO of Taiho Oncology, Inc. "The results build on the body of evidence supporting the utility of oral decitabine and cedazuridine, and we look forward to additional research to assess this combination as a treatment option for these patients."

Additional Data Presentations on ASTX727
In a second oral presentation, results of a Phase 1 study (Abstract #461) that explored the optimal dosing schedule of low-dose ASTX727 in patients with lower-risk MDS, were presented. The study found that a dosing schedule of 10 mg decitabine/100 mg cedazuridine daily for five days led to balanced clinical efficacy with an acceptable and manageable safety profile. Based on the results of the study, this dosing schedule was chosen as the recommended dose for an ongoing Phase 2 study that is comparing this regimen to 35 mg decitabine/100 mg cedazuridine for three days in a 28-day cycle. The data were presented by Guillermo Garcia-Manero, MD, on Sunday, December 11 during the "Myelodysplastic Syndromes – Clinical and Epidemiological II" oral session.

In addition, data from the first real-world study on treatment patterns and characteristics for MDS patients initiating ASTX727 (Abstract #1760) were presented by Amer Zeidan, MD, on Saturday, December 10 during the "Myelodysplastic Syndromes – Clinical and Epidemiological: Poster I" session. Parenteral administration of hypomethylating agents has been associated with additional patient burden. Based on the results of this study, characteristics were similar among patients initiating ASTX727 and parenteral hypomethylating agents. Trends in treatment patterns suggest comparable or improved compliance with oral decitabine and cedazuridine treatment regimen at home compared with parenteral treatment in the clinical setting.

About ASCERTAIN
The Phase 3 ASCERTAIN clinical trial was a multicenter, randomized, open-label, crossover pharmacokinetics (PK) study comparing oral decitabine (35mg) and cedazuridine (100mg) fixed-dose combination tablet given once daily for 5 days on a 28-day cycle to IV decitabine (20mg/m2) administered as a daily 1-hour IV infusion for 5 days on a 28-day cycle, in the first 2 cycles in patients with MDS and CMML. Patients continued to receive oral decitabine and cedazuridine from Cycle 3 onwards. The primary endpoint of the study was total 5-day area-under-the-curve (AUC) equivalence of oral decitabine and cedazuridine and IV decitabine.

For more information about ASCERTAIN, please visit: View Source;draw=3&rank=19.

INDICATIONS
Decitabine and cedazuridine, marketed under the brand name INQOVI, is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.[2]

INQOVI is the first and only oral hypomethylating agent approved by the FDA and by Health Canada for the treatment of adults with intermediate and high-risk MDS including CMML.2

Commercialization of INQOVI in the U.S. and Canada is conducted by Taiho Oncology, Inc. and Taiho Pharma Canada, Inc., respectively. Astex and Taiho are members of the Otsuka group of companies.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS

Myelosuppression
Fatal and serious myelosuppression can occur with INQOVI. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of INQOVI dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1%.

Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors and anti‑infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended.

Embryo-Fetal Toxicity
INQOVI can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise patients to use effective contraception during treatment and for 6 months (females) or 3 months (males) after last dose.

ADVERSE REACTIONS
Serious adverse reactions in > 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death.

The most common adverse reactions (≥ 20%) were fatigue (55%), constipation (44%), hemorrhage (43%), myalgia (42%), mucositis (41%), arthralgia (40%), nausea (40%), dyspnea (38%), diarrhea (37%), rash (33%), dizziness (33%), febrile neutropenia (33%), edema (30%), headache (30%), cough (28%), decreased appetite (24%), upper respiratory tract infection (23%), pneumonia (21%), and transaminase increased (21%). The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased (81%), platelet count decreased (76%), neutrophil count decreased (71%), and hemoglobin decreased (55%).

USE IN SPECIFIC POPULATIONS

Lactation
Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for 2 weeks after the last dose.

Renal Impairment
No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min).

Please see the accompanying Full Prescribing Information.

About Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)
Myelodysplastic syndromes are a heterogeneous group of hematopoietic stem cell disorders characterized by dysplastic changes in myeloid, erythroid, and megakaryocytic progenitor cells, and associated with cytopenias affecting one or more of the three lineages. U.S. incidence of MDS is estimated to be 10,000 cases per year, although the condition is thought to be under-diagnosed.[3],[4] The prevalence has been estimated to be from 60,000 to 170,000 in the U.S.[5] MDS may evolve into acute myeloid leukemia (AML) in one-third of patients.[6] The prognosis for MDS patients is poor; patients die from complications associated with cytopenias (infections and bleeding) or from transformation to AML.

CMML is a clonal hematopoietic malignancy characterized by accumulation of abnormal monocytes in the bone marrow and in blood. The incidence of CMML in the U.S. is approximately 1,100 new cases per year,[7] and CMML may transform into AML in 15% to 30% of patients.[8]

About Decitabine and Cedazuridine Fixed-Dose Combination (ASTX727)
ASTX727 is an orally administered, fixed dose combination of the approved anti-cancer DNA hypomethylating agent, decitabine, together with cedazuridine,3 an inhibitor of cytidine deaminase.4 By inhibiting cytidine deaminase in the gut and the liver, the fixed dose combination is designed to allow for oral delivery of decitabine over five days in a given cycle to achieve comparable systemic exposure to IV decitabine administered over five days.

The oral decitabine and cedazuridine fixed-dose combination has been evaluated in a Phase 1/2 pharmacokinetics-guided dose escalation and dose confirmation study, and a Phase 3 exposure equivalence study in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) – the ASCERTAIN study.

On December 12, 2022 Astex Pharmaceuticals reported ASTX727-03: Phase 1 Study Evaluating Oral Decitabine/Cedazuridine (ASTX727) Low-Dose (LD) in Lower-Risk Myelodysplastic Syndromes (LR-MDS) Patients (Press release, Astex Pharmaceuticals, DEC 12, 2022, View Source [SID1234625085]).

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Abstract:

Introduction: The safety and clinical activity of low-dose hypomethylating agents (HMAs; parenteral decitabine or azacitdine) for patients with LR-MDS has been reported (Jabbour et al, 2017). Oral decitabine/cedazuridine (ASTX727; fixed-dose combination of 35 mg decitabine/100 mg cedazuridine) is an oral DNMTi that provides equivalent exposure to intravenous decitabine at a standard dosing (SD) regimen (20 mg/m2 days 1-5 every 28 days; Garcia-Manero et al, 2020). An effective oral HMA therapy for patients with LR-MDS that reduces the number of transfusions while avoiding the toxicity associated with both myelosuppression and parenteral administration could ease the burden of HMA administration on patients and caregivers with potential improvement of quality of life. The Phase 1 part of this study explores the optimal dosing schedule of LD oral decitabine/cedazuridine in patients with LR-MDS.

Methods: A two-part Phase 1/2 study (Phase 2 ongoing) is being conducted at US and EU medical centers in subjects with LR-MDS (IPSS low risk and Int-1). Dose selection for the ASTX727-03 Phase 1 study was divided into two phases (Stage A and Stage B). Phase 1 Stage A was designed to approximate the total dose of intravenous (IV) DEC (20 mg/m2 for 5 days) over a longer dosing period and randomized subjects to 3 Cohort regimens of 5 (Cohort A1), 10 (Cohort A2), or 15 mg (Cohort A3) DEC /100 mg CED daily for 10 days in 28-day cycles. In Phase 1 Stage B, subjects were treated with the following 3 LD oral decitabine/cedazuridine regimens of shorter duration; Cohort B1: 10 mg DEC / 100 mg CED daily for 5 days, Cohort B2: 10 mg DEC / 100 mg CED daily for 7 days, Cohort B3: 20 mg DEC / 100 mg CED daily for 5 days. Primary endpoints include determination of dose-limiting toxicity (DLT), frequency and severity of treatment-emergent adverse events (TEAEs), and the recommended Phase 2 dose (RP2D). Secondary endpoints include: pharmacodynamic (PD) activity, pharmacokinetics (PK), and clinical activity based on International Working Group (IWG) 2006 MDS response criteria and transfusion independence, Leukemia Free survival (LFS), and overall survival (OS).

Results: At the data cut-off date of June 17, 2022, 48 LR-MDS subjects were enrolled, and 47 received study treatment. Characteristics were: median age: 76 years (range 51 – 88), male: 31 (65%), and IPSS LR: 15 (31%) and Int-1: 33 (69%), respectively. The median duration of exposure is 9 cycles (range 1-34).

In Stage A, cohort A2 (10 mg, 10-day) was closed due to hematologic DLT (see Table 1) in all four treated subjects, hence cohort A3 (15 mg, 10-day) was closed prior to any subjects being randomized to that regimen. The final number of subjects treated in cohorts A1 (5 mg, 10-day), A2, and A3 were 10, 4, and 0, respectively. In Stage B, 33 subjects were randomly assigned to cohorts B1 (10 mg, 5-day), B2 (10 mg, 7-day), or B3 (20 mg, 5-day), with 11 subjects each treated with the respective dosing schedules. DLT was observed in 3 (30%), 4 (100%), 3 (27%), 7 (70%), and 7 (64%) subjects in Cohorts A1, A2, B1, B2, and B3, respectively. The DLT incidences were proportional to the dose intensity (total DEC dose per cycle) and number of days of study drug administration. All DLTs were related to neutropenia and in general regimens with higher total doses of DEC per cycle (Cohorts A2 and B3) had deeper neutrophil nadirs while regimens with longer dosing periods (7-10 days; Cohorts A1, A2, and B2) required longer to recover neutrophil counts to baseline and dose reductions and dose delays were observed more frequently than in Cohort B1. Adverse events were similar to those reported for standard dose oral decitabine/cedazuridine, with the most common grade ≥ 3 TEAEs being neutropenia (36%), anemia (28%), and febrile neutropenia (19%).

Clinical activity by dosing schedule is shown in Table 1, and bioavailability was confirmed by PK analysis. Of the 47 treated subjects, 22 subjects (47%) had reached the event of death as of the data cutoff date and median OS time was 929 days (95% CI: 526, NE). Median LFS was 690 days (95% CI: 428, 934).

Conclusions: Based on the results of the Phase 1 study, the dosing schedule of 10 mg DEC / 100 mg CED daily for 5 days, that balanced clinical efficacy

with an acceptable and manageable safety profile was selected as the RP2D. This regimen will be compared to 35 mg DEC / 100 mg CED for 3 days in a 28-day

cycle in the ongoing Phase 2 study.