On December 10, 2023 Sanofi reported that the Phase 3 trial investigating Sarclisa (isatuximab) in combination with carfilzomib, lenalidomide and dexamethasone (KRd) showed a statistically significant improvement in the rate of minimal residual disease (MRD) negativity, compared with KRd alone, after autologous stem cell transplant (ASCT) consolidation in transplant-eligible patients with newly diagnosed multiple myeloma (MM) (Press release, Sanofi, DEC 10, 2023, View Source [SID1234638374]). These results from the IsKia trial conducted by the European Myeloma Network (EMN) were presented during the oral plenary session (#4) at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting by Francesca Gay, Associate Professor at the University Division of Hematology, AOU Città della Salute e della Scienza di Torino, University of Torino and Department of Molecular Biotechnology and Health Sciences – member of the Young EMN board of directors.

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MRD negativity is defined as the absence of myeloma cells in the bone marrow after treatment, as measured by diagnostic techniques that must have a sensitivity of at least 1 in 100,000 cells. In this trial, MRD negativity was detected with a sensitivity of 10-5 (no cancer cells detected within 100,000 bone marrow cells) and 10-6 (no cancer cells detected within 1,000,000 bone marrow cells).

In an intent-to-treat (ITT) analysis, the primary endpoint of rate of MRD negativity using next generation sequencing with a sensitivity of 10-5 after consolidation for patients receiving Sarclisa combination therapy (n=151) was 77% versus 67% for those who received KRd alone (n=151) (odds ratio [OR] 1.67; p=0.049). The respective rates of MRD negativity at sensitivity of 10-6 were 67% versus 48% (OR 1.93; p=0.006). The MRD negativity benefit, both at 10-5 and 10-6 sensitivities, was retained in all subgroups analyzed with similar benefit in both standard-risk and high-risk patients.

There was a statistically significant difference in MRD negativity rates after induction with Sarclisa in combination with KRd versus KRd (10-5: 45% versus 26%, p<0.001; 10-6: 27% versus 14%, p=0.004).

The safety and tolerability of Sarclisa observed in this trial were consistent with the observed safety profile of Sarclisa in other clinical trials, with no new safety signals observed. Rates of grade 3 or higher hematologic adverse events (AEs) were 40% versus 30% and rates of non-hematologic AEs were 41% versus 37% for the Sarclisa combination versus KRd, respectively. Discontinuation rates for AEs were similar in both study arms (7% and 5%, respectively). There were three treatment-related deaths in the Sarclisa combination arm and one in the KRd arm.

Peter C. Adamson
Global Development Head, Oncology, Sanofi

"The statistically significant rates of MRD negativity observed with Sarclisa combination therapy further support our belief in Sarclisa as a potential best-in-class therapy. Effective front-line treatment is critical for newly diagnosed patients, because achieving undetectable levels of disease early in the treatment journey may lead to better long-term outcomes. We look forward to our continued collaboration with the EMN to explore the potential of this novel combination regimen for those with transplant-eligible, newly diagnosed multiple myeloma."

The use of Sarclisa in combination with KRd in this patient population is investigational and has not been evaluated by any regulatory authority.

About the trial

The randomized, open-label Phase 3 IsKia trial enrolled 302 patients with newly diagnosed, transplant-eligible MM across eight countries and 42 sites in Europe. Patients were randomized into two arms. Patients in both arms received induction with four 28-day cycles of KRd followed by cyclophosphamide and stem cell collections, chemotherapy with Melphalan 200 mg/m2 followed by ASCT (Mel200-ASCT), four 28-day cycles of KRd post ASCT consolidation and 12 cycles of KRd light consolidation. Sarclisa was added to KRd in one trial arm only. During the trial, Sarclisa was administered through an intravenous infusion at a dose of 10 mg/kg once weekly for the first four weeks of cycle one, then every other week for the rest of the induction and full consolidation periods, then every four weeks during light consolidation period.

The primary endpoint was the rate of MRD negativity by next-generation sequencing (10-5) after consolidation in the ITT population. MRD was tested in all patients who achieved at least a very good partial response. Key secondary endpoints were the rate of next-generation sequencing MRD negativity (10-5) after induction and progression free survival. MRD rates were evaluated in an ITT analysis.

High-risk patient cytogenetics per the International Myeloma Working Group (IMWG) criteria were defined as the presence of t(4;14), t(14;16), or del(17p). High-risk cytogenetic abnormality (HRCA) was defined as the presence of one of the following abnormalities: del(17p13.1), t(4;14) (p16.3;q32.3), t(14;16) (q32.3;q23), gain(1q21), or amp(1q21). Two or more HRCAs was defined as the presence of at least two high-risk cytogenetic abnormalities.

About Sarclisa

Sarclisa is a monoclonal antibody that binds to a specific epitope on the CD38 receptor on multiple myeloma (MM) cells, inducing distinct antitumor activity. It is designed to work through multiple mechanisms of action including programmed tumor cell death (apoptosis) and immunomodulatory activities. CD38 is highly and uniformly expressed on the surface of MM cells, making it a potential target for antibody-based therapeutics such as Sarclisa.

Based on the Phase 3 ICARIA-MM study, Sarclisa is approved in >50 countries, including the U.S. and EU, in combination with pomalidomide and dexamethasone for the treatment of certain patients with relapsed refractory MM (RRMM) who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor and who progressed on last therapy. Based on the Phase 3 IKEMA study, Sarclisa is also approved in 50 countries in combination with carfilzomib and dexamethasone, including in the U.S. for the treatment of patients with RRMM who have received 1–3 prior lines of therapy and in the European Union for patients with MM who have received at least 1 prior therapy. In the U.S., the generic name for Sarclisa is isatuximab-irfc, with irfc as the suffix designated in accordance with Nonproprietary Naming of Biological Products Guidance for Industry issued by the U.S. Food and Drug Administration (FDA).

The IsKia trial marks the second positive Phase 3 trial of Sarclisa in transplant-eligible newly diagnosed multiple myeloma, and fifth positive Phase 3 readout for Sarclisa overall, demonstrating its best-in-class potential.

Sarclisa continues to be evaluated in multiple ongoing Phase 3 clinical trials in combination with current standard treatments across the MM treatment continuum. It is also under investigation for the treatment of other hematologic malignancies, and its safety and efficacy have not been evaluated by any regulatory authority outside of its approved indication.

For more information on Sarclisa clinical trials, please visit www.clinicaltrials.gov.

About multiple myeloma

MM is the second most common hematologic malignancy.1 Since MM does not have a cure, most patients will relapse. Relapsed MM is the term for when the cancer returns after treatment or a period of remission. Refractory MM refers to when the cancer does not respond or no longer responds to therapy.

On December 10, 2023 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported new and updated data for odronextamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) (Press release, Regeneron, DEC 10, 2023, View Source [SID1234638373]). The data from the pivotal Phase 2 trial (ELM-2) and Phase 1 trial (ELM-1) were shared in several presentations – including two orals – at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition from December 9 to 12 in San Diego, CA. Odronextamab is an investigational CD20xCD3 bispecific antibody designed to bridge CD20 on cancer cells with CD3-expressing T cells to facilitate local T-cell activation and cancer-cell killing.

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"Diffuse large B-cell lymphoma has a high risk of relapse, which is why it is so critical to demonstrate continued disease control over the long term. The totality of the odronextamab data at ASH (Free ASH Whitepaper) reinforces its potential as a promising treatment option for patients with this aggressive blood cancer," said Sabarish Ram Ayyappan, M.D., medical director of hematologic malignancies, City of Hope Atlanta, and a trial investigator. "The primary analysis from the pivotal trial of odronextamab demonstrated impressive response rates, including in certain high-risk subgroups. Furthermore, these responses were durable and consistent with those seen in a Phase 1 trial in patients who had previously progressed on CAR-T therapy, a population with a very poor prognosis."

As presented in an oral session, the primary Phase 2 analysis was performed by independent central review (ICR) among 127 DLBCL patients treated with odronextamab when all had the opportunity for ≥36 weeks of follow-up. Results were as follows:

52% objective response rate (ORR), with 31% achieving a complete response (CR).
Responses were observed across high-risk subgroups, including those with International Prognosis Index (IPI) high-risk scores of 3 to 5, high-grade lymphoma that is double-hit and triple-hit, and transformed DLBCL.
Median duration of response (DoR) was 10 months (95% confidence interval [CI]: 5 to 18 months), with a 30-month median duration of follow-up for efficacy evaluable patients (95% CI: 20 to 33 months). The median duration of CR was 18 months (95% CI: 10 months to not estimable [NE]).
The most common adverse events (AE) in ≥30% patients were cytokine release syndrome (CRS; 55%), pyrexia (43%), anemia (39%) and neutropenia (31%).
In 60 patients that received the recommended step-up regimen, 53% experienced CRS. All cases were resolved with supportive measures, with a median duration of 2 days (range: 1 to 7 days). Among these patients, 40% (n=24) had Grade 1 CRS, 12% (n=7) had Grade 2 CRS, and 2% (n=1) had Grade 3 CRS.
No events of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported.
An additional analysis from the Phase 1 trial demonstrated encouraging and durable antitumor activity with odronextamab in heavily pretreated patients who had progressed after CAR-T therapy. Median duration of exposure was 11 weeks (range: <1 to 122 weeks) among 46 treated patients. Results among 44 efficacy-evaluable patients, including 73% who were CAR-T refractory, as assessed by ICR showed:

48% ORR, with 30% achieving a CR. Notably, 8 patients converted from a partial response to a CR over the study period.
Both median DoR and median duration of CR were not reached (95% CI: 2 to NE) with a 5-month median duration of follow-up (95% CI: 3 to 9 months).
The most common AEs in ≥30% of patients were CRS (52%), anemia, pyrexia and fatigue (each 34%). All CRS events were resolved, with a median time to resolution of 2 days (range: 1 to 8 days). Among these patients, 27% (n=12) had Grade 1 CRS and 25% (n=11) had Grade 2 CRS.
In a separate oral presentation on an exploratory analysis from the Phase 2 trial, data showed a positive association between minimal residual disease (MRD) status, as measured by circulating tumor DNA (ctDNA), and progression-free survival (PFS). Among 70 R/R DLBCL and 65 R/R follicular lymphoma (FL) patients assessed, nearly all were MRD-positive at baseline. Notably, those who were MRD-negative at time of the first response assessment (Cycle 4, Day 15) had significantly longer PFS than those who remained MRD-positive (DLBCL Hazard Ratio [HR]: 0.27, 95% CI: 0.12 to 0.61; FL HR: 0.26, 95% CI: 0.1 to 0.66).

"Our research is among the first to analyze circulating tumor DNA in a pivotal trial in relapsed/refractory stages of diffuse large B-cell lymphoma and follicular lymphoma," said Jon E. Arnason, M.D., hematologist and oncologist, Beth Israel Deaconess Medical Center, and a trial investigator. "These findings strengthen the body of evidence supporting the importance of minimal residual disease status as a monitoring tool in the course of managing patients with lymphoma. As the data for circulating tumor DNA continues to grow, these insights may help inform future response-directed treatment paradigms."

Odronextamab is currently under regulatory review for the treatment of R/R DLBCL and R/R FL by the U.S. Food and Drug Administration (FDA), with a target action date of March 31, 2024, as well as by the European Medicines Agency (EMA). In the U.S., odronextamab has been granted Fast Track Designation for DLBCL and FL by the FDA. In the European Union, odronextamab has been granted Orphan Drug Designation in DLBCL and FL by the EMA.

The potential use of odronextamab in R/R DLBCL and R/R FL is currently under clinical development, and the safety and efficacy have not been fully evaluated by any regulatory authority.

Investor Webcast Information
Regeneron will host a conference call and simultaneous webcast to share updates on the company’s hematology portfolio on Thursday, December 14 at 8:30 AM ET. A link to the webcast may be accessed from the ‘Investors and Media’ page of Regeneron’s website at View Source To participate via telephone, please register in advance at this link. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. A replay of the conference call and webcast will be archived on the company’s website for at least 30 days.

About the Odronextamab Clinical Program
ELM-1 is an ongoing, open-label, multicenter Phase 1 trial to investigate the safety and tolerability of odronextamab in patients with CD20-positive B-cell malignancies previously treated with CD20-directed antibody therapy. The trial includes an expansion cohort evaluating DLBCL patients who had progressed on CAR-T therapy.

ELM-2 is an ongoing, open-label, multicenter pivotal Phase 2 trial investigating odronextamab in 375 patients across five independent disease-specific cohorts, including DLBCL, FL, mantle cell lymphoma, marginal zone lymphoma and other subtypes of B-cell non-Hodgkin lymphoma (B-NHL). The primary endpoint of ELM-2 is ORR according to the Lugano Classification, and secondary endpoints include CR, PFS, overall survival, DoR, disease control rate, safety and quality of life.

Regeneron has initiated a broad Phase 3 development program to investigate odronextamab in earlier lines of therapy and other B-NHLs, representing one of the largest clinical programs in lymphoma.

About Diffuse Large B-cell Lymphoma (DLBCL)
DLBCL is one of the most common subtypes of B-NHL. In the U.S., it is estimated that approximately 31,000 people will be diagnosed with DLBCL in 2023. Globally, there are an estimated 163,000 DLBCL cases each year. DLBCL is an aggressive cancer with up to 50% of patients with advanced stage disease progressing after first-line treatment (e.g., relapsing or becoming refractory to treatment). For patients with relapsed/refractory DLBCL, treatment options are limited, and prognosis is poor.

On December 10, 2023 ImmunoGen Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported new safety and efficacy findings from the newly diagnosed (ND) cohorts of the Phase 1b/2 study of pivekimab sunirine (pivekimab) in combination with azacitidine (Vidaza) and venetoclax (Venclexta), (pivekimab triplet) in patients with ND acute myeloid leukemia (AML) (Press release, ImmunoGen, DEC 10, 2023, View Source [SID1234638371]). These findings will be presented in a poster session at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California.

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"We are pleased to share these new findings at ASH (Free ASH Whitepaper), which demonstrate encouraging anti-leukemia activity of the pivekimab triplet in newly diagnosed AML, a disease in which long-term survival unfortunately remains limited," said Naval Daver, MD, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. "The MRD negativity rates, which are indicative of a deep remission, are particularly promising in the treated patient population. This encouraging activity, along with a manageable safety profile, support the continued evaluation of this novel triplet in this setting."

PIVEKIMAB SUNIRINE, A CD123-TARGETING ANTIBODY-DRUG CONJUGATE, IN COMBINATION WITH AZACITIDINE AND VENETOCLAX IN PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA
Lead Author: Navel Daver, MD
Poster Session: 616 (Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II)
Date and Time: Sunday, December 10, 2023, 6:00-8:00 p.m. PT / 9:00-11:00 p.m. ET
Publication Number: 2906

In the open-label, multicenter, Phase 1b/2 study of pivekimab in combination with azacitidine and venetoclax in patients with ND CD123-positive AML, patients received the recommended Phase 2 dose of pivekimab at 0.045 mg/kg on day 7, azacitidine at 75 mg/m2 daily on days 1-7, and venetoclax at up to 400 mg for at least 14 days or up to 28 days, based on cohort assignment, in a 28-day cycle. The primary endpoints are complete remission (CR) rate, composite CR rate (CCR [CR+CRh+CRp+CRi]), minimal residual disease (MRD) negativity rate, and duration of remission. Key secondary endpoints are safety, pharmacokinetics, and immunogenicity.

Key findings for 50 ND patients (n=25 per cohort) as of September 29, 2023 (data cut-off) include:

Anti-Leukemia Activity

In the overall population, CCR rate was 68% (34/50), CR rate was 54% (27/50), and MRD negativity rate among evaluable patients achieving CCR was 76% (22/29). MRD was assessed centrally by flow cytometry with <0.1% considered negative. Response rates and MRD negativity were numerically comparable between cohorts 1 and 2, despite differences in the venetoclax schedule.
In a post hoc subset analysis of patients unfit for intensive chemotherapy (i.e. patients >75 years of age, and/or with pre-specified comorbidities) (n=23), CCR rate was 78% (18/23), CR rate was 61% (14/23), and MRD negativity rate was 79% (11/14).
In patients known to be TP53wt (n=25), CCR rate was 88% (22/25), CR rate was 84% (21/25), and MRD negativity rate was 80% (16/20). CCR and MRD negativity rates, respectively, were high across other major molecular subsets, including:
FLT3 (ITD or TKD): 100% (6/6) and 100% (6/6)
IDH1 mutant: 100% (4/4) and 67% (2/3)
IDH2 mutant: 100% (6/6) and 83% (5/6)
NPM1 mutant: 100% (8/8) and 86% (6/7)
K/NRAS mutant: 50% (3/6) and 67% (2/3)
TP53 mutant: 50% (7/14) and 50% (3/6)
Among all MRD negative patients, the median time to MRD negativity was 1.87 months (range: 0.79-5.16 months).
Although follow-up duration was short (median 5.2 months), landmark overall survival estimate at 6 months is 86%.
The study is continuing to enroll newly diagnosed unfit AML patients.
Safety

The triplet displayed a manageable safety profile; no new safety signals were observed compared to previously reported data.
The most common non-hematologic treatment-emergent adverse events (TEAEs) (all grades [grade 3+]) seen in ≥20% of all patients were constipation (48% [2%]), peripheral edema (44% [4%]), diarrhea (40% [2%]), hypophosphatemia (34% [2%]), nausea (32% [4%]), hypokalemia (28% [4%]), fatigue (24% [6%]), hypotension (24% [2%]), and pyrexia (24% [0%]). In the overall population:
Rates of cytopenias were similar to those observed with azacitidine and venetoclax, with a median neutrophil recovery to ≥500/µL and platelet recovery to ≥50,000/µL by day 34 and day 22, respectively.
No veno-occlusive disease, capillary leak syndrome, or sinusoidal obstruction syndrome were observed.
Infusion-related reactions (IRRs) occurred in 16% of patients (0 grade 3+ IRRs).
Discontinuations due to an adverse event (AE) were 4% (2 patients).
30-day mortality was 0%.
60-day mortality was 4% (2 patients; due to pneumonia and early disease progression).
"Building upon our initial findings in frontline AML presented last year, these data show broad and consistent response rates in a larger study population and across major molecular subsets of interest, including those patients with biological mutations making them high-risk," said Michael Vasconcelles, MD, ImmunoGen’s Executive Vice President, Research, Development, and Medical Affairs. "We are pleased with the low early mortality and manageable safety profile observed, in particular the lack of prolonged cytopenias. We look forward to continuing to expand our cohort of newly diagnosed unfit patients to inform the development path for pivekimab in AML."

PRECLINICAL POSTERS
ImmunoGen is also presenting two preclinical posters at ASH (Free ASH Whitepaper).

Title: Venetoclax Synergizes with IMGN632, a Novel CD123-Targeting Antibody Conjugated to a DNA Alkylating Payload, By Suppressing DNA Damage Response and Potentiating Apoptosis in Acute Myeloid Leukemia in Vitro Models
Presenter: Anna Skwarska
Session: 604 (Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster III)
Date and Time: Monday, December 11, 2023, 6:00-8:00 p.m. PT / 9:00-11:00 p.m. ET
Publication Number: 4155

Title: Spatial Response to Pivekimab Sunirine In Vivo in a BPDCN Model
Presenter: Margaux Poussard
Session: 604 (Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster II)
Date and Time: Sunday, December 10, 2023, 6:00-8:00 p.m. PT / 9:00-11:00 p.m. ET
Publication Number: 2791

Additional information can be found at View Source, including abstracts.

ABOUT PIVEKIMAB SUNIRINE
Pivekimab sunirine is a CD123-targeting ADC in clinical development for hematological malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), and other CD123+ hematologic malignancies. Pivekimab is currently being evaluated as monotherapy for patients with BPDCN and in combination with azacitidine (Vidaza) and venetoclax (Venclexta) for patients with untreated and relapsed/refractory AML. Pivekimab uses one of ImmunoGen’s novel indolinobenzodiazepine (IGN) payloads, which alkylate DNA and cause single-strand breaks without crosslinking. IGNs are designed to have high potency against tumor cells, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads. The European Medicines Agency (EMA) granted orphan drug designation to pivekimab for the treatment of BPDCN in June 2020. Pivekimab also holds this designation in the US. In October 2020, the FDA granted pivekimab Breakthrough Therapy designation in relapsed/refractory BPDCN.

ABOUT ACUTE MYELOID LEUKEMIA (AML)
AML is a cancer of the bone marrow cells that produce white blood cells. It causes the marrow to increasingly generate abnormal, immature white blood cells (blasts) that do not mature into effective infection-fighting cells. The blasts quickly fill the bone marrow, impacting the production of normal platelets and red blood cells. The resulting deficiencies in normal blood cells leave the patient vulnerable to infections, bleeding problems, and anemia. It is estimated that, in the US alone, more than 20,000 people will be diagnosed with AML and more than 11,000 will die from the disease this year.

ABOUT CD123
CD123, the interleukin-3 alpha chain, is expressed on multiple myeloid and lymphoid cancers including AML, BPDCN, ALL, chronic myeloid leukemia, and myeloproliferative neoplasms. With limited expression on normal hematopoietic cells, rapid internalization, and expression on AML leukemia stem cells, CD123 is a clinically validated therapeutic target.

On December 10, 2023 GlycoMimetics, Inc. (Nasdaq: GLYC), a late clinical-stage biotechnology company discovering and developing glycobiology-based therapies for cancers and inflammatory diseases, reported that the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting will feature two presentations on uproleselan, including an investigator-initiated trial (IIT) studying the first-in-class E-selectin antagonist in patients with treated secondary Acute Myeloid Leukemia (ts-AML) (Press release, GlycoMimetics, DEC 10, 2023, View Source [SID1234638370]).

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"We are excited by the results from this IIT demonstrating the safety and preliminary efficacy of uproleselan in ts-AML patients, a group with few treatment options and persistent high unmet need," said Edwin Rock, M.D., Ph.D., Chief Medical Officer of GlycoMimetics. "These findings underscore the broad potential of uproleselan, if successfully developed in combination with existing therapies, to benefit people with heterogeneous forms of AML. We are committed to exploring this potential across different age groups and disease settings through studies conducted by partners and independent investigators, and we thank them for their continued collaboration."

Uproleselan Added to Cladribine Plus Low Dose Cytarabine (LDAC) in Patients with Treated Secondary Acute Myeloid Leukemia (TS-AML)

Presenter: Emmanuel Almanza Huante, M.D., Department of Leukemia
The University of Texas MD Anderson Cancer Center, Houston, TX
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Time and Location: Sunday, December 10, 2023: 6:00 PM-8:00 PM PST, Halls G-H, San Diego Convention Center
Poster Number: 2922

This Phase 1b/2 clinical trial evaluated safety, tolerability, and preliminary efficacy of uproleselan added to cladribine and LDAC in patients with ts-AML.
This rare, high-risk study population is defined by prior chemotherapy treatment of a previous hematologic disorder, such as myelodysplastic syndrome. Median survival of ts-AML patients is less than 5 months.
A majority of the 20 patients enrolled in this IIT were male (n=14), and median age of enrolled patients was 72 years. All patients had unfavorable cytogenetics and had previously received treatment with a hypomethylating agent. Also, 11 patients (55%) had received prior treatment with venetoclax, and five (25%) had undergone stem cell transplantation.
At a median follow-up of 8.1 months, results from 18 evaluable patients showed that cladribine and LDAC combined with uproleselan generated few treatment-related adverse events. The combination produced an overall response in 7 (39%) patients and reduced bone marrow blasts (morphologic leukemia-free state) in 13 (72%) patients. Median overall survival was 5.3 months.
Disease responses were seen irrespective of previous hypomethylating agent and venetoclax exposure. Three patients went on to receive a potentially curative hematopoietic cell transplantation (HCT). Study investigators concluded these data support this low-risk approach to marrow blast reduction and disease control in preparation for HCT.
Pediatric Acute Leukemia (PedAL) Screening Trial – Developing New Therapies for Relapsed Leukemias (APAL2020SC)

Presenter: Michele S. Redell, MD, Texas Children’s Cancer Center, Baylor College of Medicine, Houston
Session: 613. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster I
Time and Location: Saturday, December 9, 2023, 5:30 PM-7:30 PM PST, Halls G-H, San Diego Convention Center
Poster Number: 1492

This poster reports progress to date of the PedAL Initiative, a screening trial (APAL2020SC/NCT0472624) sponsored by the Leukemia & Lymphoma Society in North America, Australia and New Zealand. Primary aims of PedAL are (1) to use clinical and biological characteristics to screen for eligibility for therapeutic sub-trials; and (2) to maintain a longitudinal data registry and biobank for relapsed leukemia. As a screening protocol, PedAL serves as the entry point for associated therapeutic sub-trials.
One participating sub-trial is a National Cancer Institute sponsored Phase 1 dose escalation study (APAL2020E/PEPN2113), which assesses safety and preliminary activity of uproleselan plus fludarabine and high dose cytarabine in pediatric AML patients after 2 or more prior therapies. Expected enrollment of 18 patients has begun with the first patient receiving study therapy in late 2023.
About Uproleselan

Discovered and developed by GlycoMimetics, uproleselan is an investigational, first-in-class E-selectin antagonist. Uproleselan (yoo’ pro le’se lan), currently in a broad development program including a late-stage Phase 3 trial in acute myeloid leukemia (AML), has received Breakthrough Therapy and Fast Track designations from the U.S. Food and Drug Administration and Breakthrough Therapy designation from the Chinese National Medical Products Administration for the treatment of adult AML patients with relapsed or refractory disease. Uproleselan is designed to block E-selectin binding and stimulation of myeloid cells. E-selectin is expressed on the surface of blood vessels, and its binding to myeloid cells confers a pro-survival effect via NF-kB signaling. Uproleselan is being developed to provide a novel approach to disrupting established mechanisms of leukemic cell resistance.

On December 10, 2023 bluebird bio inc. (NASDAQ: BLUE) reported that data for gene therapy program in transfusion-dependent (TDT) beta-thalassemia were presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (Press release, bluebird bio, DEC 10, 2023, View Source [SID1234638368]). Updated follow-up data showed sustained treatment effect, reduced iron management burden and improved quality of life measures in patients with beta-thalassemia who require regular red blood cell transfusions following treatment with betibeglogene autotemcel (beti-cel) (FDA approved and marketed in the U.S. as ZYNTEGLO).

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"Long-term results presented at ASH (Free ASH Whitepaper) 2023 showed durable transfusion independence and a continued positive safety profile in patients with beta-thalassemia treated with our beti-cel gene therapy through up to nine years of follow-up," said Richard Colvin, M.D., Ph.D., chief medical officer, bluebird bio. "These data represent the longest follow-up with a gene therapy for patients with beta-thalassemia requiring regular transfusions and continue to show that beti-cel is a potentially curative therapy across ages and genotypes, through the achievement of durable transfusion independence and normal or near-normal hemoglobin levels."

As of January 30, 2023, 63 patients had received beti-cel across four clinical studies with a median follow-up of 5 years (60.1 months; range: 23.8-109.5). These include two Phase 3 studies (N=41) that led to the FDA approval of ZYNTEGLO in August 2022 as the first and only gene therapy for patients with beta-thalassemia who require regular red blood cell transfusions.

Sustained Efficacy and Safety Results, and Improved Quality of Life Measures in Adult and Pediatric Patients With Transfusion-Dependent β-Thalassemia Up to 9 Years Post Treatment With Betibeglogene Autotemcel (beti-cel) (poster #1102)

Among patients in the Phase 3 studies, 90.2% (37/41) achieved transfusion independence (TI). As of the data cutoff date, TI was maintained through last follow-up (up to 6 years) across ages and genotypes. Among patients in the Phase 1/2 studies, 68.2% (15/22) achieved TI, with 14 patients sustaining TI through the last follow-up (up to 9 years). One patient, with human immunodeficiency virus complicated by gastrointestinal infection and bleeding, no longer met protocol-defined TI as a result of a hemoglobin level <9 g/dL at year 6. The patient continued to benefit from beti-cell therapy and was not receiving chronic red blood cells transfusions as of the last follow-up.

Among 12 adult patients and 22 pediatric patients in the Phase 1/2 and Phase 3 studies, health-related quality of life (HRQOL) was assessed at baseline and every 6 months. Clinically meaningful improvements in quality of life assessments, including various quality of life assessments for mental, physical and psychosocial health, were demonstrated in both adult and pediatric patients up to 36 months.

As of the cutoff date, the safety results following beti-cel treatment largely reflected the known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen. Overall, 19% of patients experienced ≥1 beti-cel-related AE. The most common beti-cel-related AEs (occurring in ≥3 patients) were abdominal pain (7.9% of patients) and thrombocytopenia (4.8% of patients). Five patients experienced serious veno-occlusive liver disease; all 5 received defibrotide and recovered. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported.

Improvement in Iron Burden in Patients With Transfusion-Dependent β-Thalassemia (TDT) Treated With Betibeglogene Autotemcel (beti-cel) Gene Therapy: Up to 9 Years of Follow-Up (poster #2480)

Additionally, iron management outcomes were presented from patients with transfusion-dependent beta-thalassemia who completed either a Phase 1/2 or Phase 3 beti-cel parent study and subsequently enrolled in the long-term follow-up study and were followed for up to 9 years. Across all studies, 37/51 patients restarted chelation, and 12 received phlebotomy post-infusion; however, 69% (35/51) were able to stop chelation therapy, demonstrating restoration of iron levels over time and reduced iron management burden in those patients.

About ZYNTEGLO (betibeglogene autotemcel) or beti-cel

ZYNTEGLO is a first-in-class, one-time ex-vivo LVV gene therapy. It is approved for the treatment of beta-thalassemia in adult and pediatric patients who require regular red blood cell transfusions and was launched commercially more than a year ago. ZYNTEGLO works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a beta-thalassemia patient’s own hematopoietic (blood) stem cells to enable the production of a modified functional adult hemoglobin (HbAT87Q). Once a patient has the βA-T87Q-globin gene, they have the potential to increase ZYNTEGLO-derived adult hemoglobin (HbAT87Q) and total hemoglobin to normal or near normal levels that can eliminate the need for regular red blood cell (RBC) transfusions.

Indication

ZYNTEGLO is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell (RBC) transfusions.

Important Safety Information

Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with ZYNTEGLO treatment. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 15% of patients had ≥ Grade 3 decreased platelets on or after Day 100.

Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

Risk of Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with ZYNTEGLO. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 500 cells/microliter obtained on different days by Day 43 after infusion of ZYNTEGLO. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with ZYNTEGLO, provide rescue treatment with the back-up collection of CD34+ cells.

Risk of Insertional Oncogenesis

There is a potential risk of LVV mediated insertional oncogenesis after treatment with ZYNTEGLO.

Patients treated with ZYNTEGLO may develop hematologic malignancies and should be monitored lifelong. Monitor for hematologic malignancies with a complete blood count (with differential) at Month 6 and Month 12 and then at least annually for at least 15 years after treatment with ZYNTEGLO, and integration site analysis at Months 6, 12, and as warranted.

In the event that a malignancy occurs, contact bluebird bio at 1 833-999-6378 for reporting and to obtain instructions on collection of samples for testing.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of ZYNTEGLO. The dimethyl sulfoxide (DMSO) in ZYNTEGLO may cause hypersensitivity reactions, including anaphylaxis.

Anti-retroviral and Hydroxyurea Use

Patients should not take prophylactic HIV anti-retroviral medications or hydroxyurea for at least one month prior to mobilization, or for the expected duration for elimination of the medications, and until all cycles of apheresis are completed. If a patient requires anti-retrovirals for HIV prophylaxis, then confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.

Interference with Serology Testing

Patients who have received ZYNTEGLO are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a false-positive test for HIV. Therefore, patients who have received ZYNTEGLO should not be screened for HIV infection using a PCR-based assay.

Adverse Reactions

The most common non-laboratory adverse reactions (≥20%) were mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder, and pruritus. The most common Grade 3 or 4 laboratory abnormalities (>50%) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Drug Interactions

Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. The prescribing information for the iron chelator(s) and the myeloablative conditioning agent should be consulted for the recommendations regarding co-administration with CYP3A substrates.

Some iron chelators are myelosuppressive. After ZYNTEGLO infusion, avoid use of these iron chelators for 6 months. If iron chelation is needed, consider administration of non-myelosuppressive iron chelators. Phlebotomy can be used in lieu of iron chelation, when appropriate.

Pregnancy/Lactation

Advise patients of the risks associated with conditioning agents, including on pregnancy and fertility.

ZYNTEGLO should not be administered to women who are pregnant, and pregnancy after ZYNTEGLO infusion should be discussed with the treating physician.

ZYNTEGLO is not recommended for women who are breastfeeding, and breastfeeding after ZYNTEGLO infusion should be discussed with the treating physician.

Females and Males of Reproductive Potential

A negative serum pregnancy test must be confirmed prior to the start of mobilization and re-confirmed prior to conditioning procedures and before ZYNTEGLO administration.

Women of childbearing potential and men capable of fathering a child should use an effective method of contraception (intra uterine device or combination of hormonal and barrier contraception) from start of mobilization through at least 6 months after administration of ZYNTEGLO.

Advise patients of the option to cryopreserve semen or ova before treatment if appropriate.

Please see full Prescribing Information for ZYNTEGLO.