Pipeline/Programs

We have developed a robust clinical and preclinical pipeline through a combination of internal discovery efforts and focused asset acquisition. The following chart summarizes our product pipeline, including our clinical-stage candidates ENTO, LANRA and KB-0742, as well as our discovery programs and our next anticipated milestones.

TRN

Candidate & Indication

Discovery

IND-enabling

Phase 1

Phase 2

Phase 3

HOX/MEIS

HOX/
MEIS

Entospletinib
(SYK Inhibitor)

Lanraplenib
(SYK Inhibitor)

Target #1
(PPI Modulator)

AR

Target #2 Modulator
(Cofactor Modulator)

Additional programs from mapping and screening the MYC, AR, MYB, IRF4 and other TRNs

*IND filed

We may not be successful in identifying product candidates that can selectively modulate the specific oncogenic TRNs associated with such programs. 

Color Band

Selective SYK Inhibitors

Our lead product candidate, entospletinib (ENTO), is a selective inhibitor targeting SYK, a critical node in a dysregulated TRN within acute myeloid leukemia (AML) defined by persistent high expression of the transcription factors HOXA9 and MEIS1 (HOX/MEIS). While directly targeting HOX/MEIS has been historically challenging, we believe that inhibiting SYK represents a tractable strategy to collapse the HOX/MEIS TRN by inhibiting phosphorylation of downstream target genes and by disrupting a positive feedback loop that maintains high levels of MEIS1. Through analysis of AML patient sample datasets, we selected the NPM1c mutation as a robust genomic biomarker of HOX/MEIS elevation in AML. The NPM1c mutation is present in approximately 30% of adult AML patients.

Data from a Phase 1b/2 trial of ENTO in 53 newly diagnosed AML patients support the role of SYK as a critical node in HOX/MEIS high AML, with compelling complete response (CR) rates in NPM1c mutated patients and patients with elevated HOX/MEIS expression. Based on these data and following discussions with the U.S. FDA, we have initiated a registrational Phase 3 trial for ENTO in patients newly diagnosed with NPM1-mutated AML. This trial is assessing measurable residual disease (MRD) negative complete response (CR) as the primary endpoint to support potential accelerated approval of ENTO for patients who are newly diagnosed with NPM1-mutated AML and eligible for intensive induction chemotherapy.

Our second SYK inhibitor, lanraplenib (LANRA), is a next-generation SYK inhibitor that has previously been studied as a potential treatment for autoimmune diseases. In preclinical studies, LANRA was shown to have anti-leukemic activity against NPM1-mutated and FLT3-mutated AML samples. We are developing LANRA or the treatment of patients with relapsed/refractory FLT3-mutated AML and patients newly diagnosed with NPM1-mutated and/or​ FLT3-mutated AML ​who are older than 75 years old or are not eligible for intensive induction chemotherapy.

SYK is a critical dependency in HOXA9/MEIS1-high AML

SYK
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CDK9 Inhibitor

Our second product candidate, KB-0742, was derived from SMM-based discovery. KB-0742 is a selective, orally bioavailable inhibitor of CDK9, a global regulator of transcription and a critical node in the oncogenic TRN resulting from MYC overexpression. MYC is a well-known transcription factor and cancer driver that is dysregulated in a significant proportion of human cancers, often via genomic copy number gain, or amplification. We intend to develop KB-0742 initially for the treatment of MYC-amplified solid tumors in a tumor type-agnostic approach. We have initiated a Phase 1/2 clinical trial and reported interim positive data in the fourth quarter of 2021.

CDK9 is an essential co-factor for the MYC TRN

MYC regulation