Kronos Bio Stock

Kronos Bio, Inc. operates as an integrated discovery through clinical development biopharmaceutical company.

The company’s product engine, which includes its proprietary small molecule microarray (SMM) screening platform, provides it with the capability to map and target transcription regulatory networks (TRNs) in a differentiated manner to enable discovery of novel compounds and improve its ability to discover and optimize clinical development candidates. In the company’s research efforts, it is leveraging its product engine to drive multiple oncology discovery programs targeting dysregulated transcription factors and their associated TRNs. In November 2021, the company announced the advancement of two programs, one focused on the MYC TRN and one focused on the androgen receptor (AR) TRN, which it is continuing to advance.

The company takes a systems biology approach to unlocking therapeutic mechanisms within dysregulated TRNs using its differentiated product engine. The company’s product engine includes three interconnected components, each of which is informed by its translational expertise, and which enables efficient discovery and development of new product candidates:

Map TRNs – Leverage the company’s computational biology expertise, engineered cell systems and high throughput transcriptomic profiling to map the structure of TRNs defined by specific dysregulated transcription factors and identify the gene expression signature of selective TRN modulation that can be carried forward into discovery and clinical translation.

Define Dependencies – Apply causal and mechanistic insights to analyze TRNs and to identify critical nodes that may represent tractable targets for drug discovery. The company does this by identifying which genetic sequences transcription factors bind to, which proteins they interact with, and which genes they regulate in specific cellular contexts.

Identify Modulators – Conduct high throughput screens using the company’s proprietary SMM screening platform against dysregulated transcription factors in tumor cell lysates to identify selective TRN modulators and determine mechanism of action. Such modulators are then further optimized to refine their pharmacological properties.

Pipeline

The company has developed a robust clinical pipeline through a combination of internal discovery efforts and focused asset acquisition. The company is executing on robust discovery programs across multiple TRNs, which focus on four cancer types where dysregulated transcription plays a central role: hematologic malignancies, prostate cancer, MYC-driven cancers, and small cell/neuroendocrine cancers.

KB-0742: CDK9 Inhibitor

KB-0742 was generated from the company’s product engine’s SMM screening platform. KB-0742 is an oral cyclin dependent kinase 9 (CDK9) inhibitor with a differentiated biochemical selectivity and clinical PK profile. CDK9 is a serine/threonine kinase that forms the catalytic core of the positive transcription elongation factor b (P-TEFb). CDK9 is a global regulator of transcription, and has been recognized as a high-value oncology drug target due to its essential role in maintaining high levels of transcription for oncogenes and short-lived anti-apoptotic proteins.

The FDA cleared the company’s IND submission of KB-0742 in December 2020. In February 2021, the first patient was dosed in the Phase 1 stage of the company’s Phase 1/2 clinical trial to evaluate KB-0742’s safety, PK and PD properties across multiple dose levels. In November 2021, the company reported initial results from the first three dose levels of its ongoing dose escalation stage of its Phase 1/2 trial of KB-0742 in patients with solid tumors. In December 2022, the company announced the selection of 60mg as its recommended Phase 2 dose (RP2D).

While continuing to dose escalate in the Phase 1 portion of the trial, the company is actively enrolling expansion cohorts of patients with MYC-amplified solid tumors and other transcriptionally addicted tumor types at the RP2D. The subsequent development path to registration will be based on the frequency, magnitude and durability of responses observed in these expansion cohorts.

The company’s initial development focus for KB-0742 is for potential use in advanced transcriptionally addicted solid tumors, including tumors with MYC genomic copy number gain (amplification). MYC is a well-characterized transcription factor and a long-recognized driver of cancer that is dysregulated in a significant proportion of malignancies, including lung, breast, ovarian, and various gastrointestinal cancers, as a result of genomic amplification and other mechanisms. CDK9 is a critical node in the MYC TRN, acting both as an upstream driver of MYC expression and a downstream co-factor of MYC itself that is required to drive the MYC-dependent oncogenic gene expression program. Preclinical characterization of KB-0742 has demonstrated that MYC over-expression resulting from genomic amplification and other mechanisms is associated with increased tumor sensitivity across multiple histologies, potentially enabling a tissue of origin-agnostic development strategy.

Lanraplenib: SYK Inhibitor

Lanraplenib is a small molecule selective inhibitor targeting SYK, a critical node in a dysregulated TRN within AML defined by persistent high expression of the transcription factors HOX/MEIS. SYK is a non-receptor tyrosine kinase and is an important mediator of immunoreceptor signaling in hematopoietic cells with a clearly established role in both malignant and non-malignant hematologic disease.

SYK is a critical dependency in biomarker-defined subsets of AML patients characterized by persistent high HOX/MEIS expression. Multiple AML driver mutations, including NPM1, MLL (KMT2A) gene rearrangements (MLL-r) and DNMT3A, have been associated with elevation of HOX/MEIS, which increases quantity and activity of SYK as part of an oncogenic TRN. SYK contributes to the leukemia cell state through multiple mechanisms, including direct modulation of downstream growth-promoting transcriptional programs, phosphorylation of FLT3, a known driver of leukemogenic signaling, and participation in a positive feedback loop to MEIS1 that maintains high MEIS1 expression.

The company’s expertise in TRN biology allowed it to recognize SYK as a critical node in the HOX/MEIS TRN, and in July 2020, the company acquired a portfolio of selective, orally bioavailable small molecule SYK inhibitors from Gilead. The acquisition included two clinical-stage product candidates:

Lanraplenib – A next generation SYK inhibitor with improved PK and pharmacologic properties compared with entospletinib, including once daily (QD) dosing, no food restrictions and compatibility with proton pump inhibitors. Lanraplenib was previously studied in clinical trials that included more than 250 healthy volunteers and patients with autoimmune diseases, establishing an acceptable safety profile. The company’s preclinical evaluation of lanraplenib showed equivalent anti-leukemic activity in head-to-head comparisons with entospletinib. The company dosed the first patient in a Phase 1b/2 clinical trial in August 2022. This clinical trial includes a dose-escalation and an expansion cohort study design. In this trial, the Phase 1b stage will evaluate initial safety, PK and anti-leukemic activity of escalating once-daily doses of lanraplenib in combination with the standard approved dose of gilteritinib in relapsed or refractory FLT3-mutated AML patients. Once a recommended dose is established and pending the data from the Phase 1 stage, the company plans to initiate the Phase 2 stage of the trial, with an expansion cohort of approximately 30 patients to further evaluate the safety of lanraplenib and assess its anti-leukemic activity as measured by composite CR rate and duration of response. The company anticipates sharing initial data, along with the recommended Phase 2 dose, in the fourth quarter of 2023 or first quarter of 2024.

Entospletinib – An orally administered SYK inhibitor with high selectivity, dosed twice-daily (BID). In December 2021, the company initiated a registrational Phase 3 clinical trial of entospletinib using MRD-negative CR as the primary endpoint in support of potential accelerated approval. In November 2022, the company announced the decision to close enrollment of the Phase 3 clinical trial for strategic reasons. The trial was not discontinued due to adverse events or lack of efficacy signals. Final study closure is anticipated in mid-2023.

Discovery Programs

The company continually invests in early discovery efforts utilizing its proprietary product engine, with the goal of expanding its pipeline of future product candidates, either alone or with third party collaborators. The company’s efforts are focused on four cancer types where dysregulated transcription plays a central role: hematologic malignancies, prostate cancer, MYC-driven cancers, and small cell/neuroendocrine cancers (SCNC). The company is developing a deep understanding of the underlying disease biology within these cancer types, engineering robust systems to characterize transcription factor perturbation signatures, and is evaluating multiple potential opportunities for therapeutic intervention through modulation of key TRN components. The company selects its discovery targets based on scientific, translational and competitive considerations, prioritizing those where dependency has been demonstrated in a defined patient population with high unmet medical need, and where it can design an efficient early clinical translation strategy based upon its understanding of the disease biology.

Strategy

The key elements of the company’s strategy are to establish clinical proof of concept for KB-0742 (CDK9 program); determine RP2D for lanraplenib and pursue rational combinations in AML (SYK program); leverage its product engine to grow its pipeline of internally-generated product candidates; selectively enter into strategic collaborations to maximize the potential of and to expand its pipeline; and leverage its experienced management team to build a fully-integrated, science-driven biopharmaceutical company addressing high unmet medical needs.

Product Engine

The company’s differentiated product engine comprises three interconnected components. First, the company integrates diverse multiomic data from cancer model systems with clinical real-world evidence to map the TRN of interest. Next, the company applies its expertise in systems biology and drug discovery to define the mechanistic basis of TRN tumor dependency. Third, the company uses this tumor dependency information to identify small molecule modulators in one of two ways: either through use of its proprietary SMM screening platform in an ‘unbiased’ manner, or through a more ‘biased’ approach where it directs its screening efforts against identified TRN critical nodes.

Strategic Agreements

Genentech Collaboration Agreement

In January 2023, the company entered into a Collaboration and License Agreement with Genentech, a member of the Roche Group. Pursuant to the agreement, the parties have agreed to initially collaborate on two discovery research programs in oncology, each focused on a designated transcription factor, to discover small-molecule GLP-Tox-ready candidates that modulate transcription factor targets selected by Genentech. Each discovery research program will primarily consist of a mapping phase with the goal of identifying the transcription regulatory network for such designated transcription factor, and a screening phase having the goal of identifying and characterizing multiple screening hits suitable for nomination as a preclinical development program.

The company will lead discovery and research activities under the discovery research programs and will use its proprietary drug discovery platform, including its SMM, for hit finding. Following the completion of initial discovery and research activities, Genentech will have the exclusive right to pursue further preclinical and clinical development and commercialization of compounds identified in the discovery research programs and designated by Genentech (each, a Hit Program).

Harvard License Agreement

In January 2018, the company entered into a license agreement with President and Fellows of Harvard College (Harvard), pursuant to which Harvard granted it a non-exclusive, worldwide, royalty-free license to certain patent rights covering aspects of its SMM platform.

Intellectual Property

The company’s patent portfolio in general includes patents and patent applications directed to its lead product candidates, lanraplenib and KB-0742 and its other research-stage candidates, all of which are solely owned by it. The company also has patents and patent applications directed to entospletinib.

With respect to lanraplenib as of February 1, 2023, the company’s patent portfolio included seven issued U.S. patents, 106 issued or granted foreign patents, and 28 pending U.S. and foreign patent applications claiming lanraplenib as a composition-of-matter, methods of using lanraplenib, and its polymorphic forms and their use, all with nominal terms extending to between 2034 and 2043.

With respect to KB-0742, as of February 1, 2023, the company had one issued U.S. patent, two issued or granted foreign patents, and 42 pending U.S. and foreign patent applications directed to the KB-0742 compound, compositions, methods of treating CDK9-mediated diseases with KB-0742, analogs and polymorphic forms of KB-0742, and other research-stage candidate compounds that modulate CDK9 activity, all with nominal terms extending to between 2039 and 2042.

As of February 1, 2023, the company’s patent portfolio related to entospletinib included over 17 issued U.S. patents, 149 issued or granted foreign patents, and 28 pending U.S. and foreign patent applications, claiming entospletinib as a composition of matter, formulations, polymorphic forms or their methods of use or manufacture, all with nominal terms extending to between 2029 and 2043.

The company’s SMM platform component of its product engine is protected both by certain patents that it has licensed under the Harvard License, as well as proprietary know-how it has generated, including with respect to its use in drug discovery screening against transcription factors in tumor cell lysate.

Trademarks and Service Marks

Kronos Bio, Kronos, the Kronos logo and other trademarks, trade names or service marks of the company.

Research and Development

The company’s research and development expenses were $93.7 million for the year ended December 31, 2022.

Government Regulation

Any products manufactured or distributed by the company pursuant to FDA approvals are subject to pervasive and continuing regulation by the U.S. Food and Drug Administration (FDA).

History

Kronos Bio, Inc. was founded in 2017. The company was incorporated under the laws of the state of Delaware in 2017.