On November 4, 2020 Caelum Biosciences and Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) reported that two abstracts on CAEL-101, a first-in-class amyloid fibril targeted therapy, have been accepted for presentation at the 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place virtually from December 5 to 8, 2020 (Press release, Caelum Biosciences, NOV 4, 2020, View Source [SID1234569847]). New data, from Cleveland Clinic, will be presented on the safety, efficacy and tolerability of CAEL-101 in combination with standard-of-care therapy in AL amyloidosis from the Phase 2 open-label dose escalation study that suggest early evidence of organ response. Data, from Caelum, that further demonstrate the safety and tolerability of CAEL-101 and support the selection of the 1000 mg/m2 dose for the Phase 3 study will also be presented.

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The accepted abstracts are listed below and are now available on the ASH (Free ASH Whitepaper) website:

Oral Presentation
Safety, Tolerability and Efficacy of CAEL-101 in AL Amyloidosis Patients Treated on a Phase 2, Open-Label, Dose Selection Study to Evaluate the Safety and Tolerability of CAEL-101 in Patients with AL Amyloidosis. Abstract #729. An oral symposium presentation is scheduled for December 7, 2020, 2:45 p.m. PST.

ePoster Presentation
CAEL-101 is Well-Tolerated in AL Amyloidosis Patients Receiving Concomitant Cyclophosphamide-Bortezomib-Dexamethasone (CyborD): A Phase 2 Dose-Finding Study (NCT04304144), Abstract #2277 – poster presentation, poster session II, December 6, 2020, 7:00 a.m. – 3:30 p.m. PST.

As was previously announced, the Cardiac Amyloid Reaching for Extended Survival (CARES) Phase 3 clinical program to evaluate CAEL-101 in combination with standard-of-care (SoC) therapy in AL amyloidosis has begun. Enrollment is underway in two parallel Phase 3 studies – one in patients with Mayo stage IIIa disease and one in patients with Mayo stage IIIb disease – and will collectively enroll approximately 370 patients globally. The Phase 2 program continues with the addition of a study arm to evaluate CAEL-101 in combination with SoC therapy plus daratumumab.

About CAEL-101
CAEL-101 is a first-in-class monoclonal antibody (mAb) designed to improve organ function by reducing or eliminating amyloid deposits in the tissues and organs of patients with AL amyloidosis. The antibody is designed to bind to misfolded light chain protein and amyloid and shows binding to both kappa and lambda subtypes. In a Phase 1a/1b study, CAEL-101 demonstrated improved organ function, including cardiac and renal function, in 27 patients with relapsed and refractory AL amyloidosis who had previously not had an organ response to standard of care therapy. CAEL-101 has received Orphan Drug Designation from both the U.S. Food and Drug Administration and European Medicine Agency as a therapy for patients with AL amyloidosis.

About AL Amyloidosis
AL amyloidosis is a rare systemic disorder caused by an abnormality of plasma cells in the bone marrow. Misfolded immunoglobulin light chains produced by plasma cells aggregate and form fibrils that deposit in tissues and organs. This deposition can cause widespread and progressive organ damage and high mortality rates, with death most frequently occurring as a result of cardiac failure. Current standard of care includes plasma cell directed chemotherapy and autologous stem cell transplant, but these therapies do not address the organ dysfunction caused by amyloid deposition, and up to 80 percent of patients are ineligible for transplant. AL amyloidosis is a rare disease but is the most common form of amyloidosis. There are approximately 22,000 patients across the United States, France, Germany, Italy, Spain and the United Kingdom. AL amyloidosis has a one-year mortality rate of 47 percent, 76 percent of which is caused by cardiac amyloidosis.

On November 4, 2020 XNK Therapeutics AB ("XNK") reported it has received Orphan Drug Designation (ODD) from the U.S. Food and Drug Administration (FDA) for its leading investigational drug candidate in the treatment of multiple myeloma (MM) (Press release, XNK Therapeutics, NOV 4, 2020, View Source [SID1234569846]).

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Receiving ODD status from the FDA for the treatment of multiple myeloma is a critical next step for the development of XNK’s leading investigational drug candidate. XNK has already received ODD status in the EU.

"Obtaining an ODD by the FDA is a significant milestone for XNK and our goal of taking the present drug candidate to the next level," said Johan Liwing, CEO of XNK Therapeutics. "This is the starting point for us to expand clinical development into the most important market globally for cancer treatment."

XNK has already completed its first-in-human Phase I/II clinical trial (ACP-001) in multiple myeloma at the Karolinska University Hospital in Stockholm, Sweden, showing a very good safety profile, and promising efficacy data. The company is continuing the clinical development in multiple myeloma in Europe and plans to initiate a Phase II clinical trial in the near future.

On November 4, 2020 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the field of cellular metabolism to treat cancer and rare genetic diseases, reported that a broad set of clinical and translational data from its oncology and rare genetic diseases programs will be presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting being held virtually December 5–8, 2020 (Press release, Agios Pharmaceuticals, NOV 4, 2020, View Source [SID1234569845]).

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In total, eight abstracts led by Agios will be presented, as well as three abstracts led by external collaborators. The accepted abstracts are listed below and are available online on the ASH (Free ASH Whitepaper) conference website: View Source

Presentations by Agios

Oral Presentation

Abstract #625: Ivosidenib Improves Overall Survival Relative to Standard Therapies in Relapsed or Refractory Mutant IDH1 AML: Results from Matched Comparisons to Historical Controls
Date & Time: Monday, December 7, 2020 at 10:15 a.m. PST
Oral Session: 903. Health Services Research – Malignant Conditions (Myeloid Disease): Treatment and Publication Patterns in Myeloid Malignancies

Poster Presentations – Rare Genetic Diseases

Abstract #1627: Mortality Among Veterans with a Diagnosis of Pyruvate Kinase (PK) Deficiency: A Real-World Study Using US Veterans Health Administration Data
Poster Session Date & Time: Saturday, December 5, 2020 from 7:00 a.m. – 3:30 p.m. PST
Poster Session: 904. Outcomes Research – Non-Malignant Conditions: Poster I

Abstract #1679: Early-Onset Osteopenia and Osteoporosis in Patients with Pyruvate Kinase Deficiency
Poster Session Date & Time: Sunday, December 6, 2020 from 7:00 a.m. – 3:30 p.m. PST
Poster Session: 101. Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron: Poster II

Abstract #2538: Baseline Characteristics of Patients in Peak: A Global, Longitudinal Registry of Patients with Pyruvate Kinase Deficiency
Poster Session Date & Time: Monday, December 7, 2020 from 7:00 a.m. – 3:30 p.m. PST
Poster Session: 101. Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron: Poster III

Abstract #2600: Proof of Concept for the Oral Pyruvate Kinase Activator Mitapivat in Adults with Non-Transfusion-Dependent Thalassemia: Interim Results from and Ongoing, Phase 2, Open-Label, Multicenter Study
Poster Session Date & Time: Monday, December 7, 2020 from 7:00 a.m. – 3:30 p.m. PST
Poster Session: 112. Thalassemia and Globin Gene Regulation: Poster III

Poster Presentations – Oncology

Abstract #1943: Molecular Characterization of Clinical Response and Relapse in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib and Azacitidine
Poster Session Date & Time: Sunday, December 6, 2020 from 7:00 a.m. – 3:30 p.m. PST
Poster Session: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Poster II

Abstract #2814: AGILE: Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Ivosidenib in Combination with Azacitidine in Adults with Newly Diagnosed Acute Myeloid Leukemia and an IDH Mutation
Poster Session Date & Time: Monday, December 7, 2020 from 7:00 a.m. – 3:30 p.m. PST
Poster Session: 613. Acute Myeloid Leukemia: Clinical Studies: Poster III

Abstract #2900: Longitudinal Molecular Profiling in Patients with IDH1-Mutant Newly Diagnosed Acute Myeloid Leukemia Treated with Ivosidenib
Poster Session Date & Time: Monday, December 7, 2020 from 7:00 a.m. – 3:30 p.m. PST
Poster Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis Prognosis: Poster III

Presentations by External Collaborators

Oral Presentations

Abstract #84: The Pyruvate Kinase Activator AG-348 ameliorates anemia and prevents iron overload in a mouse model of hereditary spherocytosis
Date & Time: Saturday, December 5, 2020 at 10:15 a.m. PST
Oral Session: 101. Red Cells and Erythropoiesis, Structure, and Functions, Metabolism, and Survival, Excluding Iron: Mechanisms, Diagnosis and Treatment of Inherited
Presenter: Alessandro Mattè, BSc, PhD University of Verona and AOUI Verona

Abstract #681: Phase 1 Multiple Ascending Dose Study of Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Mitapivat (AG-348) in Subjects with Sickle Cell Disease
Date & Time: Monday, December 7, 2020 at 2:30 p.m. PST
Oral Session: 114. Hemoglobinopathies Excluding Thalassemia – Clinical: Novel Treatments for Sickle Cell Disease
Presenter: Julia Z. Xu, Sickle Cell Branch, National Heart, Lung, and Blood Institute

Poster Presentation

Abstract #2402: A Phase I Study of the IDH2 inhibitor enasidenib as maintenance therapy for IDH2-mutant myeloid neoplasms following hematopoietic
Date & Time: Sunday, December 6, 2020 from 7:00 a.m. – 3:30 p.m. PST
Poster Session: 723. Clinical Allogeneic and Autologous Transplantation: Late Complications and Approaches to Disease Recurrence: Post II

Event and Webcast Information
Agios will host a virtual investor event on December 8, 2020 at 8:00 a.m. ET to review the data from the company’s rare genetic diseases program. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors 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 November 4, 2020 TG Therapeutics, Inc. (NASDAQ: TGTX), reported the release of four abstracts that will be presented at the upcoming 62nd American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting and exposition, to be held virtually December 5 – 8, 2020 (Press release, TG Therapeutics, NOV 4, 2020, View Source [SID1234569844]). Abstracts are now publicly available online via the ASH (Free ASH Whitepaper) meeting website at www.hematology.org. The Company is also hosting a zoom conference call tomorrow, November 5, 2020, at 8:45 AM ET, with leading investigators from the UNITY-NHL and UNITY-CLL trials. Abstract highlights and conference call details are outlined below.

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Michael S. Weiss, Executive Chairman and Chief Executive Officer, stated, "We are excited to share the first data from the pivotal UNITY-CLL Phase 3 trial evaluating the combination of ublituximab and umbralisib (U2) in treatment naïve and relapsed/refractory CLL, which is the first randomized trial with a PI3K inhibitor in treatment naïve CLL. In addition, we are equally excited to present updated data from the UNITY-NHL trial which supported our NDA for umbralisib, and updated data from two triple therapy datasets, including U2 plus TG-1701, our BTK inhibitor, and U2 plus venetoclax in CLL. Importantly, we believe these data showcase the differentiated tolerability profile of umbralisib, our once daily, dual PI3K-delta and CK1-epsilon inhibitor and the potential of umbralisib monotherapy and the U2 combination in FL, MZL, and CLL. We look forward to discussing these data sets during tomorrow’s call with some of our leading investigators from the UNITY-CLL and UNITY-NHL trials."

ABSTRACT HIGHLIGHTS:

Oral Presentation Title: Umbralisib Plus Ublituximab (U2) Is Superior to Obinutuzumab Plus Chlorambucil (O+Chl) in Patients with Treatment Naïve (TN) and Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Results from the Phase 3 UNITY-CLL Study

•421 patients were randomized to the U2 (n=210) or O+Chl (n=211) arms; 57% of patients were treatment-naïve and 43% had R/R CLL
•At a median follow-up of 36.2 months, U2 significantly prolonged progression-free survival (PFS) vs O+Chl (median 31.9 months vs 17.9 months; hazard ratio 0.546 (p<0.0001))
•PFS improvement with U2 vs O+Chl was consistent across all subgroups examined including treatment naïve patients (median 38.5 months vs 26.1 months, hazard ratio 0.482) and relapsed/refractory patients (median 19.5 months vs 12.9 months, hazard ratio 0.601)
•Overall response rate (ORR) was significantly higher with U2 compared to O+Chl (83.3% vs 68.7%; p<0.001)
•Grade 3/4 Adverse Events (AE) of interest regardless of causality (U2 vs O+Chl) included neutropenia (30.6% vs 34.7%), thrombocytopenia (3.4% vs 13.1%), diarrhea (12.1% vs 2.5%), infusion related reaction (1.9% vs 3.5%), elevated AST/ALTs (8.3% vs 2%), colitis (3.4% vs 0%) and pneumonitis (2.9% vs 0%)
•Conclusion: U2 exhibited a well-tolerated safety profile, and significantly improved PFS vs. standard of care chemoimmunotherapy in patients with treatment naïve and relapsed/refractory CLL
Poster Presentation Title: Umbralisib, the Once Daily Dual Inhibitor of PI3Kδ and Casein Kinase-1ε Demonstrates Clinical Activity in Patients with Relapsed or Refractory Indolent Non-Hodgkin Lymphoma: Results from the Phase 2 Global UNITY-NHL Trial

•A total of 208 patients with iNHL received at least 1 dose of umbralisib, including 69 marginal zone lymphoma (MZL), 117 follicular lymphoma (FL), and 22 small lymphocytic lymphoma (SLL) patients
•MZL patients were relapsed/refractory to ≥1 prior lines of treatment, including an anti-CD20. At a median follow up of 27.8 months, the following was observed:
•49.3% ORR with 15.9% Complete response (CR) rate
•Median PFS was not reached, with an estimated 12-month PFS rate of 64.2%; no patients who achieved a CR have experienced disease progression to date
•FL patients were relapsed or refractory to ≥2 prior lines, including an anti-CD20 and an alkylating agent. At a median follow up of 27.5 months the following was observed:
•45.3% ORR with 5.1% achieving a CR
•Median PFS was 10.6 months, with an estimated 12-month PFS rate of 45.9%
•The most common AEs of > Grade 3 were neutropenia (11.5%), diarrhea (10.1%) and increased ALT/AST (7.2%). Other AEs of interest included pneumonitis (all Grades 1.4%, > Grade 3 1.0%) and colitis (all Grades 1.4%, >Grade 3 0.5%)
•Conclusion: Umbralisib achieved meaningful clinical activity in a heavily pretreated iNHL population. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and AE-related discontinuations.
Poster Presentation Title: A Phase 1/2 Study of Umbralisib, Ublituximab, and Venetoclax (U2-Ven) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)
•Regimen was administered with 3 cycles of U2, followed by umbralisib plus venetoclax in cycles 4 through 12. Patients that had undetectable minimal residual disease (uMRD) in the bone marrow after cycle 12 were permitted to stop all therapy, while MRD detectable patients continued on single agent umbralisib.
•40 patients have been treated as of the data cutoff
•Among evaluable patients, ORR was 76% (26/34) after cycle 3 (U2 only), 100% (26/26) after cycle 7, and 100% (19/19) after cycle 12.
•Among the 19 patients who finished 12 cycles of therapy:
•42% achieved Complete Response (CR) by iwCLL criteria
•95% achieved undetectable MRD in the peripheral blood
•68% achieved undetectable MRD in the bone marrow
•Grade 3/4 AEs occurring in > 5% of patients were neutropenia (23%), leukopenia (13%), and infusion related reactions (8%). No TLS events were observed during venetoclax administration.
•Conclusion: Results suggest that this chemotherapy-free regimen can provide undetectable MRD after only 12 cycles of treatment, representing an effective 12-month treatment option for this population
Poster Presentation Title: Clinical Activity of TG-1701, As Monotherapy and in Combination with Ublituximab and Umbralisib (U2), in Patients with B-Cell Malignancies

•A total of 102 patients have been treated with TG-1701, with patients receiving monotherapy in the dose-escalation cohort (n=25) or in the dose-expansion cohort (n=63), or TG-1701 in combination with U2 in the dose escalation cohort (n=14)
•TG-1701 monotherapy was well tolerated and the maximum tolerated dose was not reached up through 400 mg QD
•The most common Grade ≥3 treatment-related adverse events (TRAE) were neutropenia (5%) on monotherapy, and neutropenia and ALT/AST increases for 1701+U2 (both 21%). There were no G4 TRAE with TG-1701 monotherapy
•With a median follow up of 4.6 months in the 200 mg QD monotherapy expansion cohorts, preliminary overall response rates (ORR) were: 85% (17/20) in CLL, 42% (5/12) in MCL, and 86% (12/14) in WM
•The ORR for 1701+U2 was 100% in patients with WM, CLL, MZL and DLBCL (n=7) and 67% (4/6) in FL
Abstracts are now publicly available via the ASH (Free ASH Whitepaper) meeting website at www.hematology.org and also accessible via the publications page of TG corporate website at View Source

CONFERENCE CALL INFORMATION
The Company is hosting a zoom conference call tomorrow, November 5, 2020, which will begin at 8:45 AM ET.

In order to participate in the call, please join via the zoom webinar link: https://bit.ly/37XZai1, which will also be available on the Events page, located within the Investors & Media section, of the Company’s website at View Source Attendees may also join via phone by dialing 1-877-407-8029 (U.S.), 1-201-689-8029 (outside the U.S.), Conference Title: TG Therapeutics ASH (Free ASH Whitepaper) Abstract Review Call. A recording of the conference call will also be available for replay at www.tgtherapeutics.com, for a period of 30 days after the call.

On November 4, 2020 Kura Oncology reported that Preliminary data on a Phase 1/2A first in human study of the menin-KMT2A (MLL) inhibitor KO-539 in patients with relapsed or refractory acute myeloid leukemia (Press release, Kura Oncology, NOV 4, 2020, View Source [SID1234569843]).

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Eunice S. Wang1, Jessica Altman2, Kristen Petit3, Stephane DeBotton4, Roland Walter5, Pierre Fenaux6, Francis Burrows7, Blake Tomkinson7, Bridget Martell7 and Amir T Fathi8

Roswell Park Comprehensive Cancer Center, Buffalo, NY

Northwestern Medical Faculty Foundation, Chicago IL

University of Michigan, Ann Arbor, MI

Institut Gustave Roussy Service d’Hématologie Clinique, France

Fred Hutchinson Cancer Research Center, Seattle, WA

Hospital Saint Louis, France

Kura Oncology, San Diego, CA

Massachusetts General Hospital, Harvard Medical School, Boston, MA

The histone-lysine-N-methyltransferase 2A (KMT2A) gene (formerly known as mixed-lineage leukemia (MLL)) plays an essential role in regulating gene expression including homeobox (HOX) and MEIS1 genes. In 5-10% of AML cases, specific KMT2A gene perturbations can occur which result in an aggressive and poor prognostic group of blood cancers. The KMT2A complex also appears to play a central role in the epigenetic dysregulation in AMLs with co-mutations such as NPM1, IDH1/2, EZH2, and DNMT3A. Therefore, there is strong rationale for targeting these AML subsets which may be exquisitely sensitive to inhibition of the menin-KMT2A chromatin complex.

KO-539 is a novel, once daily, oral investigational drug candidate targeting the menin-KMT2A protein-protein interaction.

KOMET-001 (NCT04067336) is an ongoing Phase 1/2A open-label study evaluating KO-539 in adult patients (pts) with relapsed and/or refractory AML agnostic to oncogenic mutational type. The Phase 1 dose-escalation objectives are to assess safety and tolerability, characterize the pharmacokinetics (PK), and determine a recommended Phase 2 dose. The Phase 2A dose expansion portion will assess anti-leukemic activity, PK, safety and tolerability in select genetic subtypes of AML. Preclinically, the drug is shown to be highly protein bound (>99%) across animal species. Using physiologically-based PK (PBPK) modeling, the estimated human efficacious dose was estimated to be 600 mg po qd.

As of data cutoff on August 10, 2020, 6 pts with relapsed and/or refractory AML have been enrolled in the trial. Dose escalation began with single pt cohorts at 50 mg po qd in 28 day cycles and has proceeded through to 200 mg dosing cohorts. An expansion of 3 pts at 200 mg was initiated to better characterize the PK and exposure of KO-539.

To date, 3 enrolled pts have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28 day DLT-assessment window. Grade 3 (G3) or higher drug related adverse events have included G3 tumor lysis syndrome (TLS) at 50 mg and a G3 embolic event at 100 mg. KO-539 has been well tolerated with no dose interruptions or discontinuations due to drug related adverse events. There were no treatment-related deaths, and two pts discontinued treatment due to disease progression. Peak drug concentrations were attained between 2-3 hours after daily oral dosing with an elimination half-life of greater than 24 hours.

KO-539 has demonstrated evidence of biologic activity in pts in the first 3 dose levels treated to date. The 50 mg pt with a KMT2A-r and the 200 mg pt with a p53 mutation and PICALM-AF10 fusion exhibited evidence of tumor lysis syndrome and markedly decreased hydroxyurea requirements with blood count stabilization, respectively. A third pt (100 mg dose level) with SETD2 and RUNX1 co-mutations achieved a complete remission with confirmed negative MRD by flow cytometry after two cycles of therapy and continues on treatment. The biologic activity of KO-539 at lower doses may be explained by inhibition of the CYP3A4 enzyme by concomitantly administered azole antifungals. KO-539 is metabolized into at least two metabolites with comparable activity to KO-539; total drug concentrations (i.e., KO-539 plus active metabolites) exhibited a dose-dependent increase.

Although KO‑539 is a CYP3A4 substrate, preclinical data suggest both KO-539 and its metabolites act as inhibitors, potentially providing an advantage in overcoming drug resistance attributable to CYP3A4 metabolism by bone marrow stroma. The physiology of the bone marrow sinusoids also allows both unbound and protein-bound drug to reach the sites of leukemic involvement. The high level of protein binding may therefore provide an opportunity for organ-specific targeted action while possibly limiting off target effects. The potential advantage associated with the CYP3A4 inhibitory characteristics of KO-539 to overcome drug-resistance in the bone marrow stroma also continues to be investigated.

In conclusion, the early biologic activity of KO-539 in relapsed AML is encouraging, and its unique PK characteristics may be advantageous for clinical benefit. In addition to the above, any updated safety, PK, and efficacy data will be presented at the time of the conference.