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 [SID1234583891]).

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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 Constellation Pharmaceuticals, Inc. (Nasdaq: CNST), a clinical-stage biopharmaceutical company using its expertise in epigenetics to discover and develop novel therapeutics, reported that three posters relating to the MANIFEST clinical trial of pelabresib (CPI-0610) in myelofibrosis (MF) were published online in association with the European Hematology Association (EHA) (Free EHA Whitepaper) annual meeting (Press release, Constellation Pharmaceuticals, JUN 11, 2021, View Source [SID1234583890]). The data in these posters are based on a data cutoff of September 29, 2020 from the MANIFEST Phase 2 clinical trial and reflect an analysis of pelabresib clinical and translational activity.

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"We are particularly enthusiastic about the publication of centrally reviewed translational data, which describe early improvements in bone marrow fibrosis in patients treated with pelabresib, and we believe these results support our thesis of disease-modifying treatment effects that go beyond symptom management," said Patrick Trojer, chief scientific officer of Constellation Pharmaceuticals. "We are currently enrolling patients in the Phase 3 pivotal study of MANIFEST-2 and our goal is to transform the standard of care for the treatment of myelofibrosis."

Data Highlights

Translational data, across all three arms of the Phase 2 MANIFEST study, support the disease-modifying potential of pelabresib

Centrally reviewed bone marrow fibrosis (BMF) pathology conducted in 63 patients showed similar improvements as reported previously for local review of BMF grade. 23 out of 63 patients (37%) achieved at least a 1 grade improvement in BMF. Of these patients, 83% achieved improvements in BMF by 24 weeks.
17% of the patients with BMF improvement (4 out of 23), improved by at least 2 grades.
31 out of 63 patients (49%) were stabilized or had no change, and only 4 out of 63 patients (6%) worsened.
An increase in BM erythroid progenitor cells and reduction of the number and cluster formation of megakaryocytes in the BM was observed in 59% and 65%, respectively, of 37 samples from patients treated with pelabresib either as a monotherapy or in combination with ruxolitinib.
Pelabresib durably reduced inflammatory cytokines such as tumor necrosis factor alpha (TNF alpha) and interleukin 18 (IL18) as early as 2 weeks and maintained through 24 weeks of treatment, based on an analysis of patient samples.
Arm 3 (1L) – CPI-0610 + ruxolitinib interim efficacy subgroup analysis in JAK-inhibitor-naïve patients

As previously reported at ASH (Free ASH Whitepaper) 2020, 42 of 63 evaluable patients (67%) achieved a ≥35% reduction in spleen volume (SVR35) at 24 weeks (the primary endpoint for Arm 3). 34 of 60 evaluable patients (57%) achieved a ≥50% reduction in Total Symptom Scores (TSS50) at 24 weeks.
Strong response was observed with pelabresib, irrespective of baseline risk status or demographic and disease characteristics.
Central pathology review of 27 1L patient bone marrow samples showed at least a one-grade improvement in bone marrow fibrosis in 9 out of 27 patients (33%); in all of these patients, improvement was observed within 6 months of starting treatment. 16 out of 27 patients (59%) showed stabilization of bone marrow fibrosis, while only 1 out of 27 patients (4%) showed worsening.
Arm 1 and 2 (2L) – Interim analysis demonstrating that pelabresib monotherapy in JAK-inhibitor-experienced or -ineligible patients, and with pelabresib + ruxolitinib in ruxolitinib-experienced patients, resulted in improvements in anemia

As previously reported at ASH (Free ASH Whitepaper) 2020, 3 of 14 evaluable Transfusion Dependent (TD) patients (21%) in Arm 1A achieved transfusion independence (the primary endpoint for arms 1A and 2A) and 13 of 36 evaluable TD patients (36%) in Arm 2A achieved transfusion independence.
9 out of 15 evaluable TD patients (60%) in Arm 1A, and 25 out of 47 of evaluable TD patients (53%) in Arm 2A achieved a ≥50% reduction in red blood cell transfusions.
Safety

As of the September 29, 2020 data cutoff, pelabresib was generally well tolerated in MANIFEST, both as monotherapy and in combination with ruxolitinib, and in both JAK-inhibitor-naïve and -ineligible as well as JAK-inhibitor-experienced patients.

Among the most common treatment-emergent adverse events (TEAEs) for CPI-0610 monotherapy in 46 safety-evaluable patients in Arm 1, those that were Grade 3 were thrombocytopenia (15%), anemia (13%), diarrhea (4%), constipation (2%), respiratory tract infection (2%), and weight decrease (2%). Amongst the most common TEAEs, there were no Grade 4. Other Grade 3/4 TEAEs (≥5%) include hyperuricemia (9%), hyperkalemia (7%) and dyspnea (7%). Nine patients discontinued treatment because of TEAEs. No Grade 5 events were observed.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 2, those that were Grade 3 were thrombocytopenia (23%), anemia (10%), respiratory tract infections (5%), diarrhea (4%), asthenic conditions (4%), and nausea (3%). Amongst the most common TEAEs, Grade 4 events included thrombocytopenia (3%) and anemia (1%). Nine patients discontinued treatment due to TEAEs, including six Grade 5 TEAEs, which were acute kidney injury, traumatic subdural hematoma, brain stem hemorrhage (no concomitant thrombocytopenia), disease progression, congestive heart failure, and transformation to AML.

Among the most common TEAEs in 78 safety-evaluable patients in Arm 3, those that were Grade 3 were anemia (28%) and thrombocytopenia (5%). Amongst the most common TEAEs, Grade 4 events included thrombocytopenia (3%), anemia (1%), and respiratory tract infection (1%). Two patients discontinued treatment due to TEAEs. In addition, there were two Grade 5 TEAEs, each resulting from multi-organ failure due to sepsis.

EHA Poster Presentations

TITLE: Pelabresib (CPI-0610) improved anemia associated with myelofibrosis: interim results from MANIFEST Phase 2 study (Abstract Code: EP1077)

TITLE: Clinical benefit of pelabresib (CPI-0610) in combination with ruxolitinib in JAK-inhibitor treatment naïve myelofibrosis patients: Interim efficacy subgroup analysis from Arm 3 of MANIFEST Phase 2 study (Abstract Code: EP1085)

TITLE: BET inhibitor pelabresib decreases inflammatory cytokines, improves bone marrow fibrosis and function, and demonstrates clinical response irrespective of mutation status in myelofibrosis patients (Abstract Code: EP1080)

Date and Time: June 11, 9:00 AM CEST/ 3:00 AM EDT

About MANIFEST

MANIFEST is an open-label Phase 2 clinical trial of pelabresib (CPI-0610) in patients with myelofibrosis (MF), a rare cancer of the bone marrow that disrupts the body’s normal production of blood cells. Constellation is evaluating pelabresib in combination with ruxolitinib in JAK-inhibitor-naïve MF patients (Arm 3), with a primary endpoint of the proportion of patients with a ≥35% spleen volume reduction from baseline (SVR35) after 24 weeks of treatment. Constellation Pharmaceuticals is also evaluating pelabresib either as a monotherapy in patients who are resistant to, intolerant of, or ineligible for ruxolitinib and no longer on the drug (Arm 1), or as add-on therapy in combination with ruxolitinib in patients with a sub-optimal response to ruxolitinib or MF progression (Arm 2). Patients in Arms 1 and 2 are being stratified based on TD status. The primary endpoint for the patients in cohorts 1A and 2A, who were TD at baseline, is conversion to transfusion independence for 12 consecutive weeks. The primary endpoint for patients in cohorts 1B and 2B, who were not TD at baseline, is the proportion of patients with a ≥35% spleen volume reduction from baseline after 24 weeks of treatment.

On June 11, 2021 Aptose Biosciences Inc. ("Aptose" or the "Company") (NASDAQ: APTO, TSX: APS), a clinical-stage company developing highly differentiated therapeutics that target the underlying mechanisms of cancer, reported that highlights from a corporate update event being held today, Friday, June 11, 2021, at 8:00 a.m. ET, in concurrence with participation at the EHA (Free EHA Whitepaper)2021 Virtual Congress (EHA) (Free EHA Whitepaper) (Press release, Aptose Biosciences, JUN 11, 2021, View Source [SID1234583888]). The event is focused on the current clinical status of luxeptinib, Aptose’s oral, first-in-class FLT3 and BTK kinase inhibitor currently in two Phase 1 a/b trials, one trial in patients with relapsed or refractory acute myeloid leukemia (AML), and the other trial in patients with relapsed or refractory B cell malignancies. The live and archived webcast of the presentation is available on Aptose’s website here.

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"Our recent clinical experience has confirmed that luxeptinib is an active drug in several indications across both myeloid and lymphoid malignancies, which is consistent with our hypotheses from our broad portfolio of preclinical work," said William G. Rice, Ph.D., Chairman, President and Chief Executive Officer. "We are especially encouraged to see this anti-tumor activity — including meaningful blast reductions — emerging even in heavily pretreated and clinically challenging patients, and we now look forward to continuing dosing at higher exposures for longer periods in order to explore fully the potential of this singular drug."

Aptose’s presentation provides a recap on luxeptinib, including the following key highlights:

Luxeptinib clinical program in AML

In the ongoing Phase 1a/b study in patients with relapsed or refractory AML, we completed the first two dose cohorts (450mg and 600mg) and have escalated to the third cohort (750mg). We plan to dose escalate further and have observed no safety trends likely to prevent continued escalation.
We achieved anticipated steady state PK levels and PD inhibition of target kinases, in line with our parallel study in different patient populations.
The first two dose cohorts delivered encouraging anti-leukemic activity in multiple patients, including a durable MRD-negative complete response in a FLT3-ITD AML patient who had relapsed after two allogeneic stem cell transplants, multiple lines of chemotherapy, and prior FLT3 inhibitor therapy.
Based on the totality of our preclinical and clinical observations to date, we expect to select an expansion dose and expansion cohort strategy for AML during 2H21 and aim to explore select disease genotypes under monotherapy and combination therapy programs.
Luxeptinib clinical program in B-cell malignancies

In the ongoing Phase 1a/b study in B-cell malignancies, intermediate dose levels to date have delivered all leading indicators of clinical activity, including target engagement with dose-dependent inhibition of phospho-BTK, treatment-related lymphocytosis in patients presenting with classic CLL, and tumor reductions across different B-cell malignancies (FL, CLL, SLL, WM).
We continue to observe cases of clear reversal of aggressively growing disease upon intra-patient dose-escalation and longer times on drug, suggesting that even aggressive disease may be successfully challenged with higher exposure levels and extended dosing duration of luxeptinib.
We currently are treating patients at 750mg BID, and we plan to continue further escalation to higher dose levels and for extended duration to tackle an increasingly treatment refractory presenting population.
We plan to continue exploring the spectrum of B-cell malignancies in line with the preliminary anti-tumor activity observed in the study to date.
In addition, clinical data for luxeptinib and APTO-253 were presented at EHA (Free EHA Whitepaper) this morning. The APTO-253 poster presentation contained a full update of the clinical status of APTO-253, a first-in-class small molecule MYC inhibitor in a Phase 1a/b trial in patients with relapsed or refractory AML or high-risk myelodysplastic syndrome (MDS). The posters are now available on the presentations page of Aptose’s website here.

Key highlights from the APTO-253 poster:

In the ongoing Phase 1a/b study in patients with relapsed or refractory AML and high-risk MDS, APTO-253 has been well-tolerated in the patients treated at 20, 40, 66, 100 and 150 mg/m2 over multiple cycles.
In the peripheral blood of patients, APTO-253 monomer rapidly transforms to and co-exists with the mechanistically active Fe(253)3 conjugate, and the serum levels of APTO-253 and the Fe(253)3 conjugate are dose proportional with significantly higher concentrations of Fe(253)3 conjugate that are sustained for longer periods of time compared to monomer, suggesting that further dose escalations may provide more sustained pressure on the MYC target gene and alter the biology of the tumor cells.
Collectively, the findings from the ongoing Phase 1a/b study support continued dose escalation of APTO-253. The study is current enrolling patients with AML and MDS at the sixth dose level of 210 mg/m2, and subsequent dose escalations are anticipated.

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.