On June 11, 2021 Agios Pharmaceuticals, Inc. (NASDAQ: AGIO), a leader in the field of cellular metabolism to treat genetically defined diseases, reported positive results from its Phase 2, open-label, multicenter study of mitapivat in adults with non-transfusion dependent α- or β-thalassemia (Press release, Agios Pharmaceuticals, JUN 11, 2021, View Source [SID1234583887]). Data from the study will be featured in an oral presentation on Tuesday, June 15, at the European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress.

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Consistent with previously announced proof-of-concept data, the study met its primary endpoint, with 16 of the 20 patients (80%) achieving a hemoglobin increase of ≥1.0 g/dL from baseline at one or more assessments during Weeks 4-12. Additionally, a sustained hemoglobin response and improvements in hemolysis and ineffective erythropoiesis were observed in both α- or β-thalassemia patients treated with mitapivat. Mitapivat was well tolerated, and the safety profile was consistent with previous studies. Mitapivat is a first-in-class, investigational, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase R (PKR) enzymes.

"These data continue to validate the potential of PK activation as an entirely new mechanism for treating thalassemia, a disease for which there have been few medical advancements. In particular, we are excited to see data generated, for the first time, in α-thalassemia, demonstrating an increase in hemoglobin from baseline in all five patients in this subgroup," said Kevin Kuo, M.D., hematologist at University Health Network, University of Toronto, and an investigator in the study. "The impressive results reported today underscore the potential of mitapivat to meaningfully improve hallmarks of this disease, including hemolysis and ineffective erythropoiesis."

Mitapivat Phase 2 Proof-of-concept Study
The open-label Phase 2 study evaluated the efficacy, safety, pharmacokinetics and pharmacodynamics of mitapivat treatment in adults with either non-transfusion-dependent α- or β-thalassemia who have a baseline hemoglobin (Hb) concentration of ≤10 g/dL. The trial enrolled 20 patients. All patients were treated with an initial dose of mitapivat 50 mg twice daily followed by a dose-level increase to 100 mg twice daily at the Week 6 visit based on safety evaluations and hemoglobin concentrations. Following the completion of the 24-week core period, patients had the opportunity to enroll in an optional 10-year extension period which will evaluate long-term efficacy and safety of mitapivat in this population.

Of the 20 patients, 5 patients had α-thalassemia, and 15 patients had β-thalassemia.
Median hemoglobin at baseline was 8.43 (range 5.13-9.8) g/dL.
Median age was 44 (range 29-67) years.
Efficacy Data

The primary endpoint, defined as a ≥1.0 g/dL increase in hemoglobin concentration from baseline at one or more assessments between Week 4 and Week 12, was met by 16 of 20 (80%) patients (1-sided p<0.0001), including all 5 (100%) α-thalassemia patients and 11 of 15 (73.3%) β-thalassemia patients. The 1-sided p-value associated with the test of H0: hemoglobin response rate =30% vs H1: hemoglobin response rate >30%, based on the Clopper-Pearson method.
The secondary endpoint of sustained hemoglobin response, defined as a primary endpoint response and a ≥1.0 g/dL increase in hemoglobin concentration from baseline at two or more assessments between Week 12 and Week 24, was met by 13 of 20 (65%) patients, including all 5 (100%) α-thalassemia patients and 8 of 15 (53.3%) patients with β-thalassemia.
During Weeks 12-24, the mean hemoglobin change from baseline was 1.3 g/dL. The mean change was 1.2 g/dL for α-thalassemia patients, and 1.3 g/dL for β-thalassemia patients.
Among hemoglobin responders, mean time to first ≥1.0 g/dL increase in hemoglobin concentration was 4.5 weeks.
Markers of hemolysis and erythropoiesis – including indirect bilirubin, lactate dehydrogenase and erythropoietin – demonstrated improvements that were consistent with the hemoglobin increase in both α- and β-thalassemia patients.
Adenosine triphosphate (ATP) levels showed mean increases of up to 86.7% from baseline.
Safety Data
The majority of adverse events (AEs) observed were consistent with previously published data for mitapivat in healthy volunteers and patients with pyruvate kinase (PK) deficiency.

Dose escalation to 100 mg twice daily was well tolerated.
The most commonly reported AEs were initial insomnia (n=10 [50%]), dizziness (n=6 [30%]) and headache (n=5 [25%]).
One patient (5%) discontinued treatment during the study; the adverse event leading to study drug discontinuation was not treatment-related.
Seventeen patients continued to the extension period of the study, and as of March 27, 2021, 17 patients remain on study drug.
"We are pleased to present data from our Phase 2 trial of mitapivat, which is the first clinical study of a PK activator in thalassemia and the first drug trial in α-thalassemia, and represents a potentially innovative therapeutic approach for these patients who are in need of new treatment options," said Chris Bowden, chief medical officer at Agios. "Our focus now is to advance the development of mitapivat in thalassemia as quickly and efficiently as possible, with the initiation of two Phase 3 studies of mitapivat, ENERGIZE and ENERGIZE-T, in not regularly transfused and regularly transfused adults with thalassemia. Additionally, we look forward to further advancing mitapivat as a potential treatment for other underserved patients with hemolytic anemias, including individuals with pyruvate kinase deficiency, where our U.S. and EU regulatory filing plans are on track, and sickle cell disease, where our pivotal development program is on track to initiate by year-end."

Oral Presentation Information

Title: Results from a Phase 2, open-label, multicenter study of the oral pyruvate kinase activator mitapivat in adults with non-transfusion dependent alpha- or beta-thalassemia
Live Q&A Session Date and Time: Tuesday, June 15, 2021, at 8:45 p.m. CEST / 2:45 p.m. ET
Oral Abstract Session: Changing the scene on thalassemias
Abstract: S267
Presenter: Kevin H. M. Kuo, M.D., Division of Hematology, University of Toronto, Toronto, Canada

Mitapivat Clinical Development
In addition to the Phase 2 extension study of mitapivat in adults with non-transfusion-dependent α- and β-thalassemia, Agios is initiating two Phase 3 studies of mitapivat in adults with thalassemia in the second half of 2021. They are:

ENERGIZE: A placebo-controlled trial with a 2:1 randomization evaluating patients who do not receive regular transfusions. The primary endpoint of the trial is hemoglobin response, defined as a ≥1.0 g/dL increase in average hemoglobin concentration from Week 12 through Week 24 compared with baseline.
ENERGIZE-T: A placebo-controlled trial with a 2:1 randomization evaluating patients who receive regular transfusions. The primary endpoint of the trial is transfusion reduction response, defined as a ≥50% reduction in transfused red blood cell units with a reduction of ≥2 units of transfused red blood cells in any consecutive 12-week period through Week 48 compared with baseline.
In addition to its Phase 2 study of mitapivat in adults with non-transfusion-dependent α- or β-thalassemia, Agios has completed two global, pivotal trials in adults with pyruvate kinase (PK) deficiency. Final data from these studies will be presented in an oral session at the EHA (Free EHA Whitepaper) Virtual Congress. They are:

ACTIVATE: A placebo-controlled trial with a 1:1 randomization evaluating patients who do not receive regular transfusions. The primary endpoint of the study was hemoglobin response, defined as a ≥1.5 g/dL increase in hemoglobin concentration from baseline that is sustained at two or more scheduled assessments at Weeks 16, 20 and 24 during the fixed dose period.
ACTIVATE-T: A single arm trial of regularly transfused patients with a primary endpoint of reduction in transfusion burden, a reduction of ≥33 percent in the number of red blood cell units transfused during the 24-week fixed dose period compared with the historical transfusion burden standardized to 24 weeks.
ACTIVATE and ACTIVATE-T are intended to support global regulatory filings for mitapivat in adults with PK deficiency in the U.S. in the second quarter of 2021 and in the EU in mid-2021. Agios also is conducting an extension study for adults with PK deficiency previously enrolled in ACTIVATE or ACTIVATE-T, which is designed to evaluate the long-term safety, tolerability and efficacy of treatment with mitapivat.

In addition, mitapivat is being evaluated as a potential treatment for sickle cell disease under a Cooperative Research and Development Agreement (CRADA) with the U.S. National Institutes of Health. Mitapivat has been shown to decrease 2,3-diphosphoglycerate (2,3-DPG) and increase adenosine triphosphate (ATP), and through this mechanism, it may reduce hemoglobin S polymerization and red blood cell sickling. Preliminary clinical data establishing proof-of-concept for mitapivat in sickle cell disease were disclosed in June 2020, and updated data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2020. Agios is initiating its pivotal Phase 2/3 study in sickle cell disease by year-end 2021.

Mitapivat has been granted orphan drug designation for the treatment of PK deficiency by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. Additionally, mitapivat has received orphan drug designation from the FDA for the treatment of thalassemia and sickle cell disease.

Mitapivat is not approved for use by any regulatory authority.

CONFERENCE CALL INFORMATION

Agios will host a virtual investor event today at 7:30 a.m. ET to review the mitapivat clinical data. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors and Media section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

On June 11, 2021 The board of directors of Abbott (NYSE: ABT) reported a quarterly common dividend of 45 cents per share (Press release, Abbott, JUN 11, 2021, View Source [SID1234583886]).

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This marks the 390th consecutive quarterly dividend to be paid by Abbott since 1924. The cash dividend is payable Aug. 16, 2021, to shareholders of record at the close of business on July 15, 2021.

Abbott has increased its dividend payout for 49 consecutive years and is a member of the S&P 500 Dividend Aristocrats Index, which tracks companies that have increased dividends annually for at least 25 consecutive years.

On June 11, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported the latest data from three pivotal phase III studies of Venclexta/Venclyxto (venetoclax) – CLL14, MURANO and VIALE-A – to be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Virtual Congress, June 9-17 (EHA2021) (Press release, Hoffmann-La Roche, JUN 11, 2021, View Source [SID1234583877]). Long-term follow-up data from the CLL14 and MURANO studies support the primary analysis of Venclexta/Venclyxto in chronic lymphocytic leukaemia (CLL) and the possibility of tailoring treatment approaches based on genetic risk factors. Furthermore, the latest research shows the potential of minimal residual disease (MRD) as a key measure of disease response in CLL and acute myeloid leukaemia (AML).

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"The data from these Venclexta/Venclyxto combinations support our continued commitment to provide valuable therapeutic options for patients with hard-to-treat blood cancers," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "These data also advance our understanding of minimal residual disease, which we believe is a useful endpoint that may help identify patients more quickly who are in need of additional treatment."

Four-year follow-up analysis of the phase III CLL14 study
This four-year post-hoc analysis of investigator-assessed progression-free survival (PFS) had a median follow-up of 52.4 months (interquartile range: 49.5-56.2 months). The fixed treatment duration (12 months) study indicated that the chemotherapy-free Venclexta/Venclyxto plus Gazyva/Gazyvaro (obinutuzumab) regimen had an estimated PFS rate of 74.0% vs 35.4% for Gazyva/Gazyvaro plus chlorambucil. Importantly, the time to next treatment (TTNT) was significantly longer among patients treated with the Venclexta/Venclyxto plus Gazyva/Gazyvaro regimen versus the comparator (four-year TTNT 81.1% vs 59.9%; HR 0.46, 95% CI [0.32-0.65], p<0.0001).1

Furthermore, 30 months after the end of treatment, 26.9% of the Venclexta/Venclyxto-treated patients still had undetectable MRD (uMRD) compared with 3.2% of those treated with the comparator.1 Undetectable MRD, sometimes referred to as MRD-negativity, means that no cancer cells could be detected using a specific and highly sensitive test, and is defined as less than one cancer cell in 10,000 leukocytes.4 Undetectable MRD is emerging as a measure of disease response that may be useful to consider in treatment decision-making.

Common grade 3-4 adverse events with Venclexta/Venclyxto and Gazyva/Gazyvaro at 28 months follow-up were low white blood cell count and infections.5

Substudy from the phase III MURANO study
Results from this substudy suggested that increased prevalence of certain unfavourable genetic risk factors negatively impacted the MRD response of patients who were retreated with Venclexta/Venclyxto plus MabThera/Rituxan (rituximab) after progression on treatment with that regimen. These data indicate the potential to tailor treatment approaches for patients with previously treated CLL based on genetic risk factors.2

Post-hoc analysis of the phase III VIALE-A study
Additionally, a post-hoc analysis from the phase III VIALE-A study suggested the value of continued research to understand the role of MRD monitoring in AML. In the analysis, patients who achieved a composite complete remission and uMRD following treatment with Venclexta/Venclyxto and azacitidine, a hypomethylating agent, had improved survival outcomes compared with those who were MRD-positive following treatment. The 12-month estimates for duration of response, overall survival and event-free survival for both groups are listed below:

Achieved composite complete remission and uMRD (MRD<10-3) Did not achieve composite complete remission and uMRD (MRD≥10-3)
Duration of response 81.2% (95% CI 69.3-88.9) 46.6% (95% CI 35.6-56.8)
Overall survival 94.0% (95% CI 84.7-97.7) 67.9% (95% CI 57.6-76.2)
Event-free survival 83.2% (95% CI 71.6-90.3) 45.4% (95% CI 35.2-55.0)
Adverse events of grade ≥3 (MRD<10-3/MRD≥10-3) were febrile neutropenia (50%/43%), neutropenia (50%/35%), and thrombocytopenia (44%/44%), similar to the overall population.3

Roche is collaborating with regulatory authorities and others in the industry to advance understanding of MRD. The company continues to investigate Venclexta/Venclyxto in a robust clinical development programme, including in the phase III CRISTALLO trial in previously untreated CLL, which uses MRD as a primary endpoint.

Venclexta/Venclyxto is approved in the US and EU in combination with MabThera/Rituxan for the treatment of adult patients with CLL who have received at least one prior therapy; in combination with Gazyva/Gazyvaro for the treatment of adult patients with previously untreated CLL; and as a monotherapy for the treatment of CLL in the presence of 17p deletion or TP53 mutation in people who are unsuitable for or have failed a B-cell receptor pathway inhibitor.

Venclexta is also approved in the US in combination with azacitidine, decitabine, or low dose cytarabine for the treatment of newly diagnosed AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. In the EU, Venclyxto is approved in combination with a hypomethylating agent for the treatment of adult patients with newly diagnosed AML who are ineligible for intensive chemotherapy.

About the CLL14 study
CLL14 [NCT02242942] is a randomised phase III study evaluating the combination of fixed-duration Venclexta/Venclyxto (venetoclax) plus Gazyva/Gazyvaro (obinutuzumab) compared to Gazyva/Gazyvaro plus chlorambucil in adult patients with previously untreated chronic lymphocytic leukaemia (CLL) and co-existing medical conditions. Four hundred and thirty-two patients with previously untreated CLL were randomly assigned to receive either a 12-month duration of Venclexta/Venclyxto alongside six-month duration of Gazyva/Gazyvaro (Arm A) or six-month duration of Gazyva/Gazyvaro alongside 12-month duration of chlorambucil (Arm B). Arm A started with an initial dosing of Gazyva/Gazyvaro followed by a five-week Venclexta/Venclyxto dose ramp-up to help reduce the risk of tumour burden. The primary endpoint of the study is investigator-assessed progression-free survival (PFS). Secondary endpoints included PFS assessed by independent review committee, minimal residual disease status, overall response rate, complete response rate, and safety. The CLL14 study is being conducted in cooperation with the German CLL Study Group, headed by Michael Hallek, M.D., University of Cologne.

About the MURANO study
MURANO [NCT02005471] is a phase III open-label, international, multicentre, randomised study evaluating the efficacy and safety of fixed-duration Venclexta/Venclyxto (venetoclax) in combination with MabThera/Rituxan (rituximab) compared to bendamustine in combination with MabThera/Rituxan (BR). All treatments were of fixed duration. Following a five-week dose ramp-up schedule for Venclexta/Venclyxto, patients on the Venclexta/Venclyxto plus MabThera/Rituxan arm received six cycles of Venclexta/Venclyxto plus MabThera/Rituxan followed by Venclexta/Venclyxto monotherapy for up to two years total. The study included 389 patients with chronic lymphocytic leukaemia (CLL), with or without 17p deletion, who had been previously treated with at least one line of therapy. A substudy from 2018 onward enrolled 34 relapsed or refractory CLL patients who progressed after initial treatment to receive Venclexta/Venclyxto plus MabThera/Rituxan as retreatment (n=25) or who crossed over from the BR arm (n=9). The primary endpoint of the study was progression-free survival. Secondary endpoints included overall survival, overall response rate and complete response rate (with or without complete blood count recovery).

About the VIALE-A study
VIALE-A [NCT02993523] is a phase III, randomised, double-blind, placebo-controlled multicentre study evaluating the efficacy and safety of Venclexta/Venclyxto (venetoclax) plus azacitidine, a hypomethylating agent, compared to placebo with azacitidine, in 431 people with previously untreated acute myeloid leukaemia who are ineligible for intensive chemotherapy. Two-thirds of patients (n=286) received 400 mg Venclexta/Venclyxto daily, in combination with azacitidine, and the remaining patients (n=145) received placebo tablets in combination with azacitidine. Patients enrolled in the study had a range of mutational subtypes, including IDH1/2 and FLT3. VIALE-A met its primary and key secondary endpoints.

About Venclexta/Venclyxto
Venclexta/Venclyxto (venetoclax) is a first-in-class targeted medicine designed to selectively bind and inhibit the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other tumours, BCL-2 builds up and prevents cancer cells from dying or self-destructing, a process called apoptosis. Venclexta/Venclyxto blocks the BCL-2 protein and works to restore the process of apoptosis.

Venclexta/Venclyxto is being developed by AbbVie and Roche. It is jointly commercialised by AbbVie and Genentech, a member of the Roche group, in the US and commercialised by AbbVie outside of the US. Together, the companies are committed to research with Venclexta/Venclyxto, which is currently being studied in clinical trials across several types of blood cancers.

In the US, Venclexta has been granted five Breakthrough Therapy Designations by the U.S. Food and Drug Administration: one for previously untreated chronic lymphocytic leukaemia (CLL), two for relapsed or refractory CLL and two for previously untreated acute myeloid leukaemia.

About Roche in haematology
Roche has been developing medicines for people with malignant and non-malignant blood diseases for over 20 years; our experience and knowledge in this therapeutic area runs deep. Today, we are investing more than ever in our effort to bring innovative treatment options to patients across a wide range of haematologic diseases. Our approved medicines include MabThera/Rituxan (rituximab), Gazyva/Gazyvaro (obinutuzumab), Polivy (polatuzumab vedotin), Venclexta/Venclyxto (venetoclax) in collaboration with AbbVie, and Hemlibra (emicizumab). Our pipeline of investigational haematology medicines includes T-cell engaging bispecific antibodies, glofitamab and mosunetuzumab, targeting both CD20 and CD3, and cevostamab, targeting FcRH5 and CD3; Tecentriq (atezolizumab), a monoclonal antibody designed to bind with PD-L1; and crovalimab, an anti-C5 antibody engineered to optimise complement inhibition. Our scientific expertise, combined with the breadth of our portfolio and pipeline, also provides a unique opportunity to develop combination regimens that aim to improve the lives of patients even further.

On June 11, 2021 Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, reported updated data from its ongoing Phase 1/2 open-label, single arm, dose escalation and expansion trial of CA-4948, a novel, small molecule IRAK4 kinase inhibitor, in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress (EHA) (Free EHA Whitepaper) (Press release, Curis, JUN 11, 2021, View Source [SID1234583875]).

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"As we have observed increasingly mature sets of data, we continue to be pleased by the steady progression of clinical activity demonstrated by CA-4948 monotherapy in this historically difficult-to-treat late-line population," said James Dentzer, President and Chief Executive Officer of Curis. "We believe these updated data further support the growing body of evidence that CA-4948’s anti-cancer activity continues to deepen the longer patients remain on drug, which is enabled by its safety and durability profile to date. Further, after backfilling patient cohorts and evaluating additional data after the April 30, 2021 cut-off date for today’s presentation, we have concluded 300mg BID is the optimal dose to take into Phase 2 studies."

Mr. Dentzer added, "We are especially pleased with the outcomes seen to date for patients with spliceosome or FLT3 mutations. All three patients with a spliceosome mutation achieved an objective response. The FLT3 patient also achieved an objective response and, after two cycles of CA-4948, the patient’s FLT3 mutation was found to be completely eradicated. While these are early days, and we have a limited set of patient data, we are very encouraged about the potential CA-4948 may have to become a disease-modifying alternative for these late-line patients, where no approved therapies currently exist."

Mr. Dentzer continued, "In addition to the updated clinical data presented today, we are also excited by the preclinical combination synergy data announced, demonstrating that CA-4948 increases anti-cancer activity in AML cell lines resistant to clinically relevant concentrations of azacitidine and venetoclax, as well as synergistic antileukemic activity in combination with venetoclax and azacitidine. We look forward to initiating dosing in the Phase 1/2 combination study of CA-4948 plus azacitidine and CA-4948 plus venetoclax in patients with R/R AML and MDS later this year."

"As a clinician for patients with high-risk MDS or AML, I am acutely aware of the challenges of these diseases and the limitations of existing treatments. I continue to be very encouraged by the data coming out of this study," said Dr. Guillermo Garcia-Manero, Chief of the Section of Myelodysplastic Syndromes within the Department of Leukemia at The University of Texas MD Anderson Cancer Center and a lead investigator in the study. "This is a late-line population, in which patients have few options following repeated treatment failures and as a result, have deeply damaged and dysfunctional marrow, which severely limits their odds of hematologic recovery. Having an effective, non-myelosuppressive drug that does not further damage their already fragile marrow is of critical importance. The fact that some hematologic recovery has been observed and appears to continue while patients remain on therapy is an indication that CA-4948 may have the potential to provide, for the first time, a well-tolerated and clinically active treatment for this subset of heavily diseased patients."

The reported data are from Curis’s ongoing open-label, single arm Phase 1/2 dose escalation 3+3 study of orally administered CA-4948 monotherapy in adult patients with AML or high-risk MDS. A total of 22 patients (11 with high-risk MDS, 11 with AML) were enrolled across dose cohorts of 200 mg BID, 300 mg BID, 400 mg BID, and 500 mg BID. The primary objective of the study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) for CA-4948 based on safety and tolerability, dose-limiting toxicities (DLT), and any biologic activity, pharmacokinetic (PK), and pharmacodynamic (PD) findings from the trial population. Additional objectives include characterization of CA-4948’s pharmacokinetic parameters and biomarker correlations.

Key findings from an oral presentation today at EHA (Free EHA Whitepaper) presented by Dr. Garcia-Manero from an April 30, 2021 cutoff in 17 evaluable patients (9 MDS and 8 AML), include:

Bone marrow blast reductions observed at all tested doses in 10 of 12 patients who were evaluable for bone marrow response (elevated blast count at baseline and at least one malignancy assessment following first cycle).
5 objective responses observed included:
1 patient experiencing a full hematologic recovery CR
1 patient with CRi with negative minimal residual disease
1 patient with partial response
2 patients with marrow CRs
3 patients had SF3B1 or U2AF1 spliceosome mutation and all 3 achieved marrow CR or better.
All patients with objective responses also saw signs of hematologic recovery.
Genomic analyses from multiple patients show disease modification by CA-4948:
DNA sequencing demonstrates disease modification with the reduction of cancer-associated variant allele frequency after CA-4948 treatment
RNA sequencing demonstrates disease modification with the reduction of long/short ratio of IRAK4 after CA-4948 treatment
No significant myeloid suppressive adverse events were observed.
Key findings from additional information included in today’s management’s KOL presentation:

An AML patient with spliceosome mutation SF3B1 who has experienced a durable objective response has been on study for over 8 months. In December 2020, this patient was reported as having a Marrow CR and has since improved to a CRi with negative minimal residual disease.
An AML patient with a FLT3 mutation, whose disease had relapsed after prior treatment with decitabine and venetoclax and was refractory to subsequent treatment with gilteritinib, experienced a partial response (90% decrease in marrow blast count, from 60% to 6%) as well as elimination of detectable FLT3 mutation based on genomic analysis post-treatment with CA-4948.
An AML patient with 4 prior lines of chemotherapy treatment showed reduction of IRAK4-L expression following CA-4948 treatment as well as a full recovery of hematologic parameters and has been on study for over 7 months.
Key findings in determining 300mg BID to be the Recommended Phase 2 Dose include:

Safety: No DLTs observed
PK/PD: PK exposure correlates with 98% target inhibition
Efficacy: 12 evaluable patients in the study had elevated blasts at baseline;
4 of these patients were dosed at 300mg BID;
All 4 patients achieved blast reductions, including CRi and negative MRD
Including additional patients enrolled after the April 30, 2021 cut-off at doses higher than the Recommended Phase 2 Dose, a total of 4 DLTs were observed:
400mg: 13% of patients experienced DLT (2 Grade 3 rhabdomyolysis)
500mg: 66% of patients experienced DLT (1 Grade 3 rhabdomyolysis and 1 Grade 3 syncope)
All three rhabdomyolysis cases were quickly detected by elevated CPK and resolved after dosing interruption; no cases involved renal dysfunction.
Key findings from a poster presentation today at EHA (Free EHA Whitepaper) of preclinical data in AML cell lines:

Combination with CA-4948 increased the antitumor effect of azacitidine
Combination with CA-4948 increased the antitumor effect of venetoclax
Combination with CA-4948 increased the antitumor effect of venetoclax + azacitidine
We believe synergistic activity observed in leukemia cells provides a rationale for clinical testing of CA-4948 + azacitidine, CA-4948 + venetoclax, and the triplet combination of all three agents together in patients with AML.
Webcast Event Information

Curis management will host a virtual KOL event today, June 11, 2021 at 8:00 am ET to discuss these results with Dr. Guillermo Garcia-Manero. To access the webcast, please visit the Events & Presentations section of the Curis website at www.curis.com.

About CA-4948

CA-4948 is an IRAK4 kinase inhibitor and IRAK4 plays an essential role in the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways, which are frequently dysregulated in patients with AML and MDS. Third parties have recently discovered that the long form of IRAK4 (IRAK4-L) is oncogenic and preferentially expressed in over half of patients with AML and MDS. The overexpression of IRAK4-L is believed to be driven by a variety of factors, including specific spliceosome mutations such as SF3B1 and U2AF1.

On June 11, 2021 Celyad Oncology SA (Euronext & Nasdaq: CYAD), a clinical-stage biotechnology company focused on the discovery and development of chimeric antigen receptor T cell (CAR T) therapies for cancer, reported preliminary data from the Phase 1 IMMUNICY-1 trial of CYAD-211 for the treatment of relapsed/refractory multiple myeloma (r/r MM) patients were presented at the European Hematology Association (EHA) (Free EHA Whitepaper) 2021 Virtual Congress (Press release, Celyad, JUN 11, 2021, View Source [SID1234583874]).

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Filippo Petti, Chief Executive Officer of Celyad Oncology, commented, "We believe the initial data presented today are meaningful beyond the demonstrated clinical activity of CYAD-211. This is the first clinical trial evaluating the potential of shRNA as an allogeneic technology to underpin off-the-shelf CAR T candidates for the treatment of cancer, and today’s data continue to demonstrate the potential value of non-gene edited technology to generate allogeneic CAR T cells. We are extremely encouraged by the cell kinetic, clinical activity and tolerability data for CYAD-211. As we work to establish shRNA as a platform for developing allogeneic CAR T therapies, these early data from the IMMUNICY-1 trial are key. In addition, we believe our future ability to employ multiple shRNAs in our CAR T candidates while leveraging our streamlined All-in-One Vector approach could be fundamental to the allogeneic CAR T landscape."

Dr. Sébastien Anguille, IMMUNICY-1 trial investigator and professor in the Division of Hematology of the Antwerp University Hospital said, "Even with great strides made in recent years, multiple myeloma remains largely incurable, creating a need for new therapeutic options. Unfortunately, most patients eventually relapse and we observe shorter duration and depth of responses to treatments over time. We are pleased with the encouraging initial data from the IMMUNICY-1 trial and we’re eager to move forward with higher doses and continue to evaluate CYAD-211 in treating myeloma patients."

CYAD-211 and IMMUNICY-1 Phase 1 Trial Update

Background:

CYAD-211 is an allogeneic CAR T candidate engineered to co-express a BCMA targeting chimeric antigen receptor and a single short hairpin RNA (shRNA), which interferes with the expression of the CD3ζ component of the T cell receptor complex.
IMMUNICY-1 is a first-in-human, open-label, dose-escalation Phase 1 trial to determine the recommended dose of CYAD-211 in patients with r/r MM following preconditioning with cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) given three consecutive days.
The trial is designed to evaluate proof-of-concept that shRNA-mediated knockdown of the CD3ζ can generate allogeneic CAR T cells.
Safety and tolerability data:

Of the six patients dosed at the first two dose levels (30×106 and 100×106 cells per infusion):

No dose limiting toxicity (DLT), Graft-versus Host disease (GvHD) or CAR T-cell-related encephalopathy syndrome (CRES) were observed in the first two dose cohorts.
One cytokine release syndrome (CRS) Grade 1 (fever) requiring hospitalization occurred 10 days post CYAD-211 administration in patient 1 (dose level 1) who achieved a partial response (PR).
One patient experienced an anemia adverse event (Grade 3) and neutropenia (Grade 4) possibly related to CYAD-211.
Clinical activity:

Of the five evaluable patients at the first two dose levels (30×106 and 100×106 cells per infusion):

Two patients achieved a PR. Both patients were ‘triple-therapy exposed’ (previously treated with an immunomodulator (IMiD), a proteasome inhibitor and an anti-CD38 antibody).
The three additional patients had stable disease (SD).
Cell kinetics:

CYAD-211 cells were detected by PCR-based methods in all six patients from dose cohorts 1 and 2.
Cell engraftment was seen in all three patients at dose level 2 at a similar magnitude. In addition, preliminary data suggest that all patients in dose level 2 showed deep lymphodepletion. Across dose level 1, the depth of lymphodepletion appears to correlate with the degree of observed systemic CAR T engraftment.
Next steps:

Enrollment in dose cohort 3 (300×106 cells per infusion) is ongoing.
Additional clinical data from the dose escalation trial are expected during second half 2021.
shRNA technology platform to be highlighted at upcoming virtual R&D Day in Q3 2021.
Conference Call and Webcast Details

Celyad Oncology will host a conference call to discuss the update from EHA (Free EHA Whitepaper) on Friday, June 11, 2021 at 2 p.m. CET / 8 a.m. ET. The conference call can be accessed through the following numbers:

United States: #1 877-407-9208

International: #1 201-493-6784

The conference call will be webcast live and can be accessed here. The event will also be archived and available on the "Events " section of the company’s website. Please visit the website several minutes prior to the start of the broadcast to ensure adequate time for registration to the webcast.