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Kura Oncology Presents Updated Clinical Data from KOMET-001 Trial of Menin Inhibitor Ziftomenib at American Society of Hematology Annual Meeting

On December 10, 2022 Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, reported updated clinical data from KOMET-001, a Phase 1/2 trial of the Company’s potent and selective menin inhibitor, ziftomenib, including an encouraging safety and tolerability profile and clinical activity in patients with relapsed/refractory acute myeloid leukemia (AML) (Press release, Kura Oncology, DEC 10, 2022, View Source [SID1234625023]).

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These data are being featured during an oral session today at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. A copy of the presentation is available on Kura’s website at www.kuraoncology.com/pipeline/#publications.

"NPM1-mutant and KMT2A-rearranged AML represent diseases of significant unmet need for which no approved targeted therapies exist," said Harry Erba, M.D., Ph.D., Director of the Leukemia Program at the Duke Cancer Institute. "Notably, NPM1-mutant disease accounts for approximately 30% of new AML cases annually. Although typically associated with a more favorable prognosis, the risk of relapse remains high after initial chemotherapy for NPM1-mutant AML, especially when other poor risk mutations such as FLT3 are present as well. Relapsed/refractory NPM1 mutated AML is associated with a poor prognosis. These data reported today demonstrate encouraging activity and manageable toxicity of ziftomenib in heavily pretreated AML patients with NPM1 mutations."

In the Phase 1a dose-escalation trial, ziftomenib demonstrated a wide therapeutic window and encouraging monotherapy activity in an all-comer population of 30 patients with relapsed/refractory AML, including a complete remission (CR) with no evidence of minimal residual disease (MRD) in an NPM1-mutant patient with DNMT3A and KMT2D co-mutations. The patient entered the trial having progressed through seven prior lines of therapy and remains on ziftomenib after two years.

In order to inform an optimal Phase 2 dose and in consultation with the U.S. Food and Drug Administration (FDA) and its Project Optimus initiative, Kura conducted a Phase 1b trial with two randomized expansion cohorts, each comprised of NPM1-mutant and KMT2A-rearranged AML patients. A total of 53 patients were ultimately treated in the Phase 1b trial: 17 at 200 mg and 36 at 600 mg. These patients were heavily pretreated and received a median of three prior lines of therapy (range 1-11), with the majority of patients having received prior venetoclax and a quarter having progressed after at least one prior stem cell transplant. As of the data cutoff on October 24, 2022, 10 of the patients treated at 600 mg remained on ziftomenib and 17 were still in follow-up. Median duration of response has not been reached.

Ziftomenib demonstrated optimal clinical benefit at 600 mg with a 30% CR rate (6/20) in patients with NPM1-mutant AML, compared to 17% (1/6) at 200 mg. Notably, four of the six NPM1-mutant patients who achieved a CR at 600 mg had IDH and/or FLT3 co-mutations. Overall, four of the seven patients with IDH co-mutations achieved a CR on ziftomenib. Of the five patients assessed for MRD at 600 mg, three were MRD negative.

Although meaningful clinical benefit was observed in patients with KMT2A rearrangements, symptoms of differentiation syndrome prevented most patients from receiving sufficient therapy to attain response criteria for CR or CR with partial hematologic recovery (CRh), and only one patient achieved a CR/CRh.

Continuous daily dosing of ziftomenib has been well tolerated. Reported adverse events most often were consistent with features of underlying disease. No evidence of drug-induced QTc prolongation was observed. Six patients discontinued due to adverse events; however, none of these were considered treatment related. The most common treatment-emergent adverse event observed was differentiation syndrome (DS), a known adverse event related to AML treatments that promote differentiation of AML cells. Of the 20 NPM1-mutant patients treated at 600 mg, four (20%) experienced DS; three of these events were less than Grade 3, and only one of these events (5%)was Grade 3. For KMT2A-rearranged patients, rates of DS were similar across doses, and approximately 38% of patients experienced DS; 25-30% of treated KMT2A-rearranged patients experienced Grade 3 or greater events.

Kura believes the higher incidence of DS observed in the KMT2A-rearranged patients is due to their much higher incidence of disease in extramedullary (outside of the bone marrow) sites, induced to differentiate by the high tissue penetrance demonstrated by ziftomenib preclinically. By combining ziftomenib with appropriate standards of care, the Company believes it can reduce this extramedullary disease burden and consequent DS symptoms, keep patients on ziftomenib therapy longer and drive superior treatment outcomes in patients with KMT2A-rearranged AML.

"We are excited by these data and the potential for ziftomenib to improve the lives of patients with acute leukemias," said Stephen Dale, M.D., Chief Medical Officer of Kura Oncology. "In addition to encouraging activity as a monotherapy in patients with NPM1 mutations, we believe ziftomenib is supportive of future combination strategies, with no predicted adverse drug-drug interactions and oral daily dosing that should enable convenient administration with standards of care. We believe that rational combination approaches will also help to mitigate DS in the KMT2A-rearranged population, maximizing patients’ time on therapy and ultimately leading to improved outcomes for patients in dire need of new therapeutic options."

Regulatory Update

Kura also announced that 600 mg has been determined as the recommended Phase 2 dose for ziftomenib in NPM1-mutant AML following a positive Type C meeting with the FDA. Agreement was also reached on key elements of a registration-enabling study design, and the Company is now preparing to initiate the Phase 2 registration-directed trial. Kura expects to dose the first patient in the first quarter of 2023, followed by a series of combination studies in frontline and relapsed/refractory AML that will prioritize development with venetoclax and FLT3 in combination.

"We believe our growing body of data support ziftomenib’s position as a potential best-in-class menin inhibitor," said Troy Wilson, Ph.D., J.D., President and Chief Executive Officer of Kura Oncology. "Through our team’s relentless hard work and dedication, we believe we have optimized the benefit-risk profile and paths forward in both the NPM1-mutant and KMT2A-rearranged subsets. The large number of patients treated in our Phase 1 experience provides a robust data set to support our Phase 2 registration-directed trial as well as combination studies. We have already begun the work needed to initiate both the first potentially registration-enabling study for ziftomenib as well as multiple studies in combination with standards of care and in earlier lines of therapy to realize the full potential of ziftomenib in the treatment of acute leukemias."

Investor Event

Kura’s management will host an investor event at 11:15 a.m. CT / 12:15 p.m. ET today, December 10, 2022, following the oral presentation of updated data from the KOMET-001 clinical trial at the ASH (Free ASH Whitepaper) Annual Meeting in New Orleans. The event will feature members of the Kura management team along with two investigators from the KOMET-001 clinical trial. A live webcast of the event will be available in the Investors section of Kura’s website at www.kuraoncology.com, with an archived replay available shortly after the conclusion of the event.

About Acute Myeloid Leukemia

AML is the most common acute leukemia in adults and begins when the bone marrow makes abnormal myeloblasts (white blood cells), red blood cells or platelets. Despite the many available treatments for AML, prognosis for patients remains poor. Approximately 50% of patients with AML who achieve a CR after induction therapy relapse within one to three years. NPM1-mutations are among the most common genetic alterations, representing approximately 30% of AML. While patients with NPM1-mutant AML have high response rates to frontline therapy, relapse rates are high and survival outcomes are poor. Median overall survival is only six months following relapse for NPM1-mutant patients. KMT2A-rearrangements are less frequent, representing approximately 5-10% of AML, however these patients have a poor prognosis with high rates of resistance and relapse following standard of care therapies. Currently, there are no approved therapies indicated for NPM1-mutant or KMT2A-rearranged leukemias.

About Ziftomenib

Ziftomenib (KO-539) is a novel, once-daily, oral investigational drug candidate targeting the menin-KMT2A/MLL protein-protein interaction for treatment of genetically defined AML patients with high unmet need. In preclinical models, ziftomenib inhibits the KMT2A/MLL protein complex and exhibits downstream effects on HOXA9/MEIS1 expression and potent anti-leukemic activity in genetically defined preclinical models of AML. Ziftomenib has received Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of AML. Additional information about clinical trials for ziftomenib can be found at kuraoncology.com/clinical-trials-komet.

ImmunoGen Presents Findings from Expansion Cohorts in Phase 1b/2 Study of Pivekimab Sunirine with Vidaza® and Venclexta® in Acute Myeloid Leukemia at ASH

On December 10, 2022 ImmunoGen, Inc. (Nasdaq: IMGN), a leader in the expanding field of antibody-drug conjugates (ADCs) for the treatment of cancer, reported initial safety and efficacy findings from dose-escalation and expansion cohorts of the Phase 1b/2 study of pivekimab sunirine (pivekimab) in combination with Vidaza (azacitidine) and Venclexta (venetoclax) in patients with relapsed/refractory (R/R) and frontline acute myeloid leukemia (AML) (Press release, ImmunoGen, DEC 10, 2022, View Source [SID1234625021]). These findings were presented in an oral session at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in New Orleans, Louisiana.

"While azacitidine and venetoclax have improved outcomes for patients with frontline AML, overall survival unfortunately remains poor in both this population and those with relapsed/refractory AML," said Naval Daver, MD, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. "I am very encouraged by the broad anti-leukemia activity of this triplet, particularly the compelling CR/CRh rates in subgroups of relapsed/refractory AML including first relapse and those with IDH2 or FLT3 mutations as well the preliminary data showing encouraging tolerability and complete responses in the frontline setting."

BROAD ACTIVITY FOR THE PIVEKIMAB SUNIRINE, AZACITIDINE, AND VENETOCLAX TRIPLET IN HIGH-RISK PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (Abstract #62)
Lead Author: Naval Daver, MD
Oral Session: 616
Session Date: December 10, 2022
Session Time: 10:30 AM – 12:00 PM ET

Key findings from the open-label, multicenter, Phase 1b/2 study of pivekimab in combination with azacitidine and venetoclax in patients with R/R and frontline CD123-positive AML include:

Safety:

91 patients with CD123-positive R/R AML received pivekimab at 15 mcg/kg or 45 mcg/kg on day 7, azacitidine at 50 mg/m2 or 75 mg/m2 on days 1-7, and venetoclax at 400 mg daily for 8, 14 or 21 days per 28-day cycle.
The triplet displayed a manageable safety profile in R/R AML patients.
The most common treatment emergent adverse events (all grades [grade 3+ events]) were febrile neutropenia (33%, [29%]), thrombocytopenia (23%, [20%]), dyspnea (22% [6%]), infusion-related reactions (22%, [2%]), hypokalemia (21% [2%]) and fatigue (20% [2%]).
Rates of cytopenias were similar to those observed with a hypomethylating agent and venetoclax.
No tumor lysis syndrome, veno-occlusive disease, capillary leak syndrome, or cytokine release syndrome were reported.
Discontinuations due to pivekimab-related adverse events were 5%.
30-day mortality was 6%, with no treatment-related deaths.
Anti-leukemia activity:

In the R/R cohort, objective response rate (ORR [CR, CRh, CRp, CRi, MLFS) was 45% with a composite complete remission (CCR [CR, CRh, CRp, CRi]) rate of 25%.
Venetoclax-naïve patients had an ORR of 53% and CCR of 38%; in patients who had prior venetoclax exposure, the ORR was 36% and CCR was 11%.
Responses were observed in 9 of 11 patients with FLT3-ITD AML with an ORR of 82% and a CCR of 64%.
Enrollment in the R/R cohort is complete.
In the 10 frontline patients enrolled, pivekimab was administered at 45 mcg/kg on day 7, azacitidine at 75 mg/m2 on days 1-7, and venetoclax at 400 mg for at least 14 days per 28-day cycle.
5/10 (50%) patients achieved a CR and 3/4 (75%) patients tested had a minimal residual disease (MRD)-negative CR.
At the time of data cut-off, 5 patients remain on treatment.
Enrollment in the frontline cohort continues in the US and EU.
"These data presented at ASH (Free ASH Whitepaper) demonstrate this triplet’s encouraging anti-leukemia activity and tolerability, and reinforce our belief in pivekimab’s potential as a novel addition to the azacitidine and venetoclax regimen for AML," said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen. "Based upon the strong results from the first 10 frontline patients we have enrolled, we have moved forward with gathering more data for the triplet using 14 days of venetoclax and have opened a second cohort of up to 50 frontline patients with a goal of evaluating up to 28 days of venetoclax per cycle to optimize the duration of therapy. Tolerability and efficacy outcomes from these cohorts will guide pivotal development of the triplet in frontline AML."

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 being evaluated as monotherapy for patients with BPDCN, as a doublet with magrolimab in patients with relapsed/refractory AML, and as a triplet with Vidaza (azacitidine) and Venclexta (venetoclax) in patients with frontline 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 and have been observed in preclinical studies and clinical trials to have 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.

Fate Therapeutics Announces Clinical Safety and Activity Data of First-ever iPSC-derived CAR T-cell Therapy at 2022 ASH Annual Meeting

On December 10, 2022 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, reported interim clinical data from the dose-escalation stage of its ongoing Phase 1 study of FT819 for patients with relapsed / refractory B-cell lymphoma (r/r BCL) at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Fate Therapeutics, DEC 10, 2022, View Source [SID1234625019]). The landmark trial is the first-ever clinical investigation of a T-cell product candidate manufactured from a clonal master induced pluripotent stem cell (iPSC) line, a renewable cell source that enables mass production of engineered T-cell therapies with greater product consistency, off-the-shelf availability, and broader patient accessibility. FT819 incorporates several first-of-kind features including the integration of a novel CD19-targeted 1XX chimeric antigen receptor (CAR) construct into the T-cell receptor alpha constant (TRAC) locus, which is intended to promote uniform CAR expression, enhance T-cell potency, and prevent graft-versus-host disease (Eyquem et al. Nature, 543, 113–117, 2017).

"We are very excited about the early safety and efficacy data emerging from our groundbreaking clinical study of the first-ever iPSC-derived T-cell therapy. Data from the initial dose-escalation cohorts of a single dose of FT819 are indicative of a favorable safety profile and clearly demonstrate activity in heavily pre-treated patients with aggressive large B-cell lymphoma, including in patients that were not eligible for or had previously failed autologous CD19-targeted CAR T-cell therapy," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "In addition to the rapid responses we observed with a single dose of FT819, the ability to quickly intervene upon the first signs of disease recurrence is a differentiating benefit of off-the-shelf cell therapy and we are also excited by the reinduction of objective response with the administration of a second cycle of FT819 to a patient following disease progression."

Interim Phase 1 Dose-escalation Efficacy Data
The multi-center Phase 1 clinical trial of FT819 is designed to assess its safety and clinical activity in adult patients with r/r BCL and to determine the recommended Phase 2 dose and schedule. As of the September 8, 2022 data cutoff date, 10 patients with aggressive large B-cell lymphoma have been treated with FT819, including 8 patients in Regimen A with a single dose of FT819 and 2 patients in Regimen B with three fractionated doses of FT819 on Days 1, 3, and 5. Patients received standard conditioning chemotherapy consisting of cyclophosphamide (Cy) at 500 mg/m2 and fludarabine (Flu) at 30 mg/m2 for 3 days prior to the initiation of each regimen. Patients were heavily pre-treated having received a median of 4 prior lines of therapy (range 3-7), including 7 of 10 patients (70%) having previously received autologous CD19-targeted CAR T-cell therapy.

In Regimen A, of the 8 patients with aggressive large B-cell lymphoma (median of 4.5 prior lines of therapy [range 3-7]) treated with a single dose of FT819 ranging from 90 million cells to 360 million cells (see Table 1):

1 of 2 patients naïve to CAR T-cell therapy achieved an objective response (1 CR) at Day 30, which was a complete response in a patient with diffuse large B-cell lymphoma (DLBCL) previously treated with 5 prior lines of therapy; and
2 of 6 patients previously treated with CAR T-cell therapy achieved an objective response (1 CR, 1 PR) at Day 30, which included a complete response in a patient with DLBCL previously treated with 7 prior lines of therapy who did not respond to autologous CD19-targeted CAR T-cell therapy.
In Regimen B, 2 patients with aggressive large B-cell lymphoma (each of whom received 3 prior lines of therapy) treated with three fractionated doses at 30 million cells per dose did not respond to therapy at Day 30.

Table 1: Aggressive Large B-cell Lymphoma 1,2,3
FT819 Regimen A: Single Dose (n=8)
CAR T-cell Therapy Naïve Prior CAR T-cell Therapy
Cells 90M 180M 360M 90M 180M 360M
N 1 n/a 1 4 1 1
OR / CR 0 / 0 n/a 1 / 1 2 / 1 0 / 0 0 / 0
FT819 Regimen B: Three Fractionated Doses (n=2)
CAR T-cell Therapy Naïve Prior CAR T-cell Therapy
Cells / Dose 30M 30M
N 1 1
OR / CR 0 / 0 0 / 0
OR = objective response; CR = complete response; M = million
1 As of data cutoff date of September 8, 2022
2 Includes diffuse large B-cell lymphoma (n=8) and high-grade B-cell lymphoma (n=2)
3 Day 30 protocol-defined response assessment per Lugano 2014 criteria
As of the September 8, 2022 data cutoff date, an additional 5 patients with r/r BCL have been treated with FT819. One patient with Grade 3a follicular lymphoma (with 5 prior lines of therapy, including CAR T-cell therapy) treated in Regimen A with a single dose of FT819 at 180 million cells achieved a complete response at Day 30. Four patients with Richter’s Transformation (median of 5.5 prior lines of therapy [range 2-9]) did not respond to therapy at Day 30.

Interim Phase 1 Dose-escalation Safety Data
No dose-limiting toxicities, and no Grade 3 or greater FT819-related adverse events (AEs) or serious AEs, were observed. Of the 15 patients treated in Regimens A and B, three patients (20%) experienced Grade 2 cytokine release syndrome (CRS) characterized by fever, hypotension, and hypoxia, which events resolved with single-dose tocilizumab and supportive care. No treatment-emergent AEs (TEAEs) of any grade of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GvHD) were reported by investigators. The FT819 treatment regimen was well tolerated. Grade 3 or greater TEAEs not related to FT819 primarily included hematologic cytopenias associated with conditioning chemotherapy. There were no study discontinuations or deaths due to TEAEs other than one patient with stable disease who died on Day 38 due to sepsis not considered related to FT819 by the study investigator.

FT819 Patient Case Study: Retreatment to Reinduce Response
The ASH (Free ASH Whitepaper) presentation featured a patient case study demonstrating the potential to safely administer more than one treatment cycle of FT819 and reinduce an objective response following disease progression. The 73 year-old female with DLBCL had previously been treated with 4 prior lines of therapy, including commercial autologous CD19-targeted CAR T-cell therapy with best response of PR, and was refractory to last prior therapy (investigational cord blood-derived NK cell therapy). The patient received a first treatment cycle with a single dose of FT819 at 90 million cells, achieving a PR at Day 30 with 94% reduction in size of target lesions. Continued follow-up through November 8, 2022 was significant for disease progression on Day 72, for which the patient received a second treatment cycle with a single dose of FT819 at 180 million cells on Day 134 with consent from the U.S. Food and Drug Administration and achieved a PR at Day 163 with 61% reduction in size of target lesions. Both treatment cycles were well tolerated with no Grade 3 or greater FT819-related AEs or serious AEs, no reports of any grade of CRS, ICANS, or GvHD, and no evidence of new or worsening toxicity with the second treatment cycle. Following each treatment cycle, FT819 was detected in the peripheral blood with peak level at Day 4 in Cycle 1 and at Day 8 in Cycle 2, with maximum peak level at Day 8 in Cycle 2 at 8,152 transgene copies/μg DNA.

Dose escalation is currently ongoing in Regimen A as a single dose of FT819 at 360 million cells and in Regimen B with three fractionated doses at 60 million cells per dose. The Company has also amended the FT819 study protocol to allow for the use of bendamustine at 90 mg/m2 for 2 days as an alternative to Cy / Flu conditioning chemotherapy.

About Fate Therapeutics’ iPSC Product Platform
The Company’s proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that are designed to be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Company’s first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Company’s platform is uniquely designed to overcome numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics’ iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

About FT819
FT819 is an investigational, universal, off-the-shelf, T-cell receptor (TCR)-less CD19 chimeric antigen receptor (CAR) T-cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line, which is engineered with the following features designed to improve the safety and efficacy of CAR19 T-cell therapy: a novel 1XX CAR signaling domain, which has been shown to extend T-cell effector function without eliciting exhaustion; integration of the CAR19 transgene directly into the T-cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR19 expression and enhanced T-cell potency; and complete bi-allelic disruption of TCR expression for the prevention of graft-versus-host disease. FT819 demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of primary CAR T cells, and persisted and maintained tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia. FT819 is being investigated in a multicenter Phase 1 clinical trial for the treatment of relapsed / refractory B-cell malignancies, including B-cell lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia (NCT04629729).

Fate Therapeutics Highlights iPSC-derived, Off-the-shelf CAR NK Cell Programs for Multiple Myeloma at 2022 ASH Annual Meeting

On December 10, 2022 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for patients with cancer, reported interim clinical data from the dose-escalation stage of its ongoing Phase 1 study of FT576 for patients with relapsed / refractory multiple myeloma (r/r MM) at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (Press release, Fate Therapeutics, DEC 10, 2022, View Source [SID1234625018]). The off-the-shelf product candidate, which is derived from a clonal master engineered induced pluripotent stem cell (iPSC) line, incorporates a chimeric antigen receptor (CAR) targeting B-cell maturation antigen (BCMA) as well as a high-affinity, non-cleavable CD16 (hnCD16) Fc receptor to maximize antibody-dependent cellular cytotoxicity (ADCC) and enable dual-antigen targeting of myeloma cells through combination with monoclonal antibody (mAb) therapy. Preclinical data published last month in the journal Nature Communications (Cichocki et al. 2022, 13:7341) demonstrated that single-dose administration of FT576 was effective at controlling tumor growth in vivo, with deeper and more sustained anti-tumor activity observed through multi-dose administration of FT576 as well as in combination with the CD38-targeted monoclonal antibody daratumumab.

"The interim Phase 1 data from the low-dose cohorts of single-dose administration of FT576 in patients with relapsed / refractory disease provide encouraging clinical evidence of BCMA-targeted activity," said Yu-Waye Chu, Chief Medical Officer of Fate Therapeutics. "In addition, initial safety observations of FT576 as monotherapy and in combination with daratumumab, with no reported events of cytokine release syndrome and ICANS as well as no study discontinuations due to treatment-emergent adverse events, indicate that the off-the-shelf product candidate has the potential to be safely administered in the outpatient setting. Dose escalation is currently ongoing with multi-dose regimens, and we look forward to evaluating the effect of increasing dose and dose frequency to define the product candidate’s therapeutic profile."

Interim Phase 1 Dose-escalation Efficacy Data
The multi-center Phase 1 clinical trial of FT576 is designed to assess its safety and clinical activity in adult patients with r/r MM, and to determine the recommended Phase 2 dose and schedule, as monotherapy (Regimen A) and in combination with daratumumab to simultaneously target BCMA and CD38 (Regimen B). As of the October 7, 2022 data cutoff date, 9 patients with r/r MM have been treated with a single dose of FT576, including 6 patients in Regimen A and 3 patients in Regimen B (see Table 1). Patients received standard conditioning chemotherapy consisting of cyclophosphamide (Cy) at 300 mg/m2 and fludarabine (Flu) at 30 mg/m2 for 3 days prior to the initiation of each regimen. Patients were heavily pre-treated having received a median of 5 prior lines of therapy (range 3-10), including 6 patients (67%) that were refractory to last therapy.

In Regimen A, 6 patients were treated with a single dose of FT576 as monotherapy in the first dose cohort at 100 million cells (n=3) and the second dose cohort at 300 million cells (n=3). In the second dose cohort, one patient, who had received 5 prior lines of therapy, was triple-refractory to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 mAb, and was refractory to last therapy (pomalidomide, daratumumab and dexamethasone), achieved a very good partial response (VGPR) with the other two patients showing stable disease (SD). Further evidence of FT576 activity was observed in the second dose cohort, with two patients for whom serum BCMA levels were evaluable showing a substantial treatment-induced decrease in soluble BCMA.
In Regimen B, 3 patients were treated with a single dose of FT576 in combination with daratumumab in the first dose cohort at 100 million cells, with one patient achieving a partial response (PR) and one patient achieving a minor response (MR). All 3 patients showed a substantial treatment-induced decrease in soluble BCMA.
The Company has now initiated enrollment of two-dose escalation cohorts at 300 million cells per dose in both regimens.

Table 1: Patient Characteristics, Safety, and Activity 1,2
Patient Characteristics Safety Activity
Patient # # Prior Therapies Triple Refractory DLTs CRS ICANS Related ≥G3 AEs Related ≥G3 SAEs % Change in sBCMA 3 BOR
Regimen A: Single-dose FT576 as Monotherapy (n=6)
100M Single-dose FT576
1 10 N N N N Y N 2.3% PD
2 6 Y N N N Y N 50.9% PD
3 8 Y N N N N N -0.8% SD
300M Single-dose FT576
4 5 N N N N N N -30.6% SD
5 5 Y N N N N N -82.3% VGPR
6 5 N N N N N N NA SD
Regimen B: Single-dose FT576 in Combination with Daratumumab (n=3)
100M Single-dose FT576
7 3 N N N N N N -64.4% MR
8 4 N N N N N N -37.8% PR
9 5 Y N N N N N -40.3% SD
AE = adverse event; BOR = Best overall response; CRS = cytokine release syndrome; DLT = dose-limiting toxicity; ICANS = immune effector cell-associated neurotoxicity syndrome; MR = minor response; N = no; NA = not available; PD = progressive disease; PR = partial response; SAE = serious adverse event; SD = stable disease; sBCMA = soluble BCMA; VGPR = very good partial response; Y = yes
1 As of data cutoff date of October 7, 2022
2 Protocol-defined response assessment per International Myeloma Working Group (IMWG) response criteria (Kumar et al. 2016)
3 % change at Day 29 from pre-treatment baseline
Interim Phase 1 Dose-escalation Safety Data
No dose-limiting toxicities, and no events of any grade of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD), were observed. Both FT576 treatment regimens were well tolerated. Two patients experienced Grade 3 or greater FT576-related adverse events (AEs), with one patient having Grade 3 diarrhea and one patient having two episodes of Grades 3 through 4 neutropenia and 3 episodes of Grade 3 anemia, all of which resolved. There were no serious AEs related to FT576. Grade 3 or greater treatment-emergent AEs (TEAEs) not related to FT576 primarily included hematologic cytopenias associated with conditioning chemotherapy. There were no study discontinuations or deaths due to TEAEs.

FT555 GPRC5D-targeted CAR NK Cell Program
Under its collaboration with Janssen Biotech, Inc. (Janssen), one of the Janssen Pharmaceutical Companies of Johnson & Johnson, the Company is currently conducting preclinical development of FT555, a multiplexed-engineered CAR NK cell product candidate derived from a clonal master engineered iPSC line incorporating four functional components: a proprietary CAR optimized for NK cell biology that targets GPRC5D, an orphan G-protein-coupled receptor expressed on myeloma cells with a distribution that is similar to but independent of BCMA; a novel hnCD16 Fc receptor for enhanced ADCC; an IL-15 receptor fusion (IL-15RF) that augments NK cell activity; and the deletion of the CD38 gene (CD38KO), which promotes persistence and function in high oxidative stress environments.

At ASH (Free ASH Whitepaper), scientists from the companies jointly presented preclinical data demonstrating that single-dose administration of FT555 as monotherapy resulted in robust and durable antigen-mediated tumor regression in two independent disseminated tumor models of aggressive myeloma, which activity was further improved in combination with daratumumab to simultaneously target GPRC5D and CD38 antigens. Administration of three doses of FT555 as monotherapy further improved tumor clearance and showed superior activity compared to single-dose primary CAR T cells.

In May 2022, Janssen exercised its commercial option to FT555, pursuant to which the Company granted Janssen an exclusive license for development and commercialization of FT555. The Company is eligible to receive clinical, regulatory, and commercial milestones, plus double-digit royalties on worldwide commercial sales of the product candidate. In addition, the Company retains the right to elect to co-commercialize, and share equally in profits and losses, in the United States, subject to its payment of certain clinical development costs and adjustments in milestone and royalty payments.

About FT576
FT576 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with four functional components: a proprietary chimeric antigen receptor (CAR) optimized for NK cell biology that targets B-cell maturation antigen (BCMA); a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies; an IL-15 receptor fusion (IL-15RF) that augments NK cell activity; and the deletion of the CD38 gene (CD38KO), which promotes persistence and function in high oxidative stress environments. In preclinical studies, FT576 has demonstrated that the high-avidity binding of the BCMA-targeted CAR construct enables sustained tumor control against various multiple myeloma cell lines, including in long-term in vivo xenograft mouse models. Additionally, in combination with daratumumab, FT576 has shown complete tumor clearance and improved survival compared to primary BCMA-targeted CAR T cells in a disseminated xenograft model of multiple myeloma. FT576 is being investigated in a multicenter Phase 1 clinical trial for the treatment of relapsed / refractory multiple myeloma as a monotherapy and in combination with daratumumab (NCT05182073).

CRISPR Therapeutics and Vertex to Present at the American Society of Hematology (ASH) Annual Meeting and Exposition

On December 10, 2022 CRISPR Therapeutics (Nasdaq: CRSP) and Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) reported an oral, encore presentation of clinical data from patients with sickle cell disease (SCD) or transfusion-dependent beta-thalassemia (TDT) treated with the investigational therapy exagamglogene autotemcel (exa-cel) in CLIMB-111 or CLIMB-121 and followed in CLIMB-131, a long-term follow-up study (Press release, CRISPR Therapeutics, DEC 10, 2022, View Source [SID1234625015]). Vertex will also present new health economics and outcomes research from multiple studies in patients with SCD and TDT.

"We are excited to be at ASH (Free ASH Whitepaper) and share data from the pivotal exa-cel trials and from multiple real-world studies examining the burden of severe SCD and TDT," said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex. "We remain on track to complete submission of the first ever CRISPR-based therapy in the EU and U.K. this year, and we have initiated our rolling submission in the U.S., which we plan to complete in Q1 2023. We are working with urgency to bring forward this potential therapy to patients who are waiting."

Vertex will have the following presentations at ASH (Free ASH Whitepaper) this year.

Oral presentation, abstract #12 combined with abstract #2137, in partnership with CRISPR Therapeutics, entitled "Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Transfusion-Dependent Beta-Thalassemia and Severe Sickle Cell Disease," will be presented on Saturday, December 10 at 10:45 a.m CST. The presentation will include encore data as presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress in June 2022 on patients with SCD or TDT who received the investigational therapy exa-cel in the CLIMB-111 or CLIMB-121 study and were followed in CLIMB-131, a long-term follow-up study.
Oral presentation, abstract #577, entitled "Health-Related Quality of Life, Disease Impacts, and Health Equity Concerns in Adults with Sickle Cell Disease with Recurrent Vaso-Occlusive Crises: Preliminary Results from a Global Longitudinal Survey," will be presented on Sunday, December 11 at 12:00 p.m. CST. The study quantifies the symptoms, quality of life and work impacts of living with SCD with recurrent vaso-occlusive crises (VOCs). This presentation represents preliminary results from an ongoing longitudinal study.
Poster presentation, abstract #4820, entitled "Clinical and Economic Outcomes in Patients with Transfusion-Dependent Beta-Thalassemia and Patients with Sickle Cell Disease with Recurrent Vaso-Occlusive Crises Receiving Hematopoietic Stem Cell Transplants in the United States," will be presented on Monday, December 12 from 6:00-8:00 p.m. CST. The study analyzes the demographics, transplant-related complications and costs of patients with SCD and TDT who undergo a hematopoietic stem cell transplant (HSCT) in the United States utilizing a claims database.
Poster presentation, abstract #4882, entitled "Health-Related Quality of Life and Disease Impacts in Adults with Transfusion-Dependent Beta-Thalassemia: Preliminary Results from the Global Longitudinal Survey," will be presented on Monday, December 12 from 6:00-8:00 p.m. CST. The study quantifies the symptoms, quality of life and work impacts of living with TDT. This presentation represents preliminary results from an ongoing longitudinal study.
The accepted abstracts are available online on the ASH (Free ASH Whitepaper) website.

About exagamglogene autotemcel (exa-cel)

Exa-cel, formerly known as CTX001, is an investigational, autologous, ex vivo CRISPR/Cas9 gene-edited therapy that is being evaluated for patients with SCD or TDT, in which a patient’s own hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. The elevation of HbF by exa-cel has the potential to reduce or eliminate painful and debilitating VOCs for patients with SCD and alleviate transfusion requirements for patients with TDT. Earlier results from these ongoing trials were published in The New England Journal of Medicine in January of 2021 and presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress in June 2022.

Based on progress in this program to date, exa-cel has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration (FDA) for both SCD and TDT. Exa-cel has also been granted Orphan Drug Designation from the European Commission, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA), for both SCD and TDT.

The companies have begun the rolling Biologics License Application (BLA) submission for exa-cel to the U.S. FDA and plan to complete the BLA by the end of the first quarter 2023 and remain on track to submit exa-cel to the Medicines and Healthcare products Regulatory Agency in the U.K. and the EMA in the European Union by the end of the year.

About CLIMB‑111 and CLIMB‑121

The ongoing Phase 1/2/3 open-label trials, CLIMB‑111 and CLIMB‑121, are designed to assess the safety and efficacy of a single dose of exa-cel in patients ages 12 to 35 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now closed for enrollment. Patients will be followed for approximately two years after exa-cel infusion. Each patient will be asked to participate in CLIMB‑131, a long-term follow-up trial.

About CLIMB-131

The ongoing long-term, open-label trial, CLIMB-131, is designed to evaluate the safety and efficacy of exa-cel in patients who received exa-cel in CLIMB‑111, CLIMB‑121, CLIMB‑141, CLIMB‑151 or CLIMB-161. The trial is designed to follow participants for up to 15 years after exa-cel infusion.

About CLIMB‑141 and CLIMB‑151

The ongoing Phase 3 open-label trials, CLIMB‑141 and CLIMB‑151, are designed to assess the safety and efficacy of a single dose of exa-cel in patients ages 2 to 11 years with TDT or with SCD, characterized by recurrent VOCs, respectively. The trials are now open for enrollment and currently enrolling patients ages 5 to 11 years and will plan to extend to ages 2 to less than 5 years at a later date. Each trial will enroll approximately 12 patients. Patients will be followed for approximately two years after infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial.

About CLIMB-161

The ongoing Phase 3b study, CLIMB-161, is to support expansion of our manufacturing footprint after initial potential approval and launch. This study will enroll approximately 12 patients with either SCD or TDT ages 12 to 35 years. Patients will be followed for approximately one year after infusion. Each patient will be asked to participate in CLIMB-131, a long-term follow-up trial.

About the Gene-Editing Process in These Trials

Patients who enroll in these trials will have their own hematopoietic stem and progenitor cells collected from peripheral blood. The patient’s cells will be edited using the CRISPR/Cas9 technology. The edited cells, exa-cel, will then be infused back into the patient as part of an autologous hematopoietic stem cell transplant (HSCT), a process which involves a patient being treated with myeloablative busulfan conditioning. Patients undergoing HSCT may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of exa-cel. Patients will initially be monitored to determine when the edited cells begin to produce mature blood cells, a process known as engraftment. After engraftment, patients will continue to be monitored to track the impact of exa-cel on multiple measures of disease and for safety.