HPK1 inhibitors - Pipeline Insight, 2024

This “HPK1 inhibitors - Pipeline Insight, 2024” report provides comprehensive insights about 8+ companies and 10+ pipeline drugs in HPK1 inhibitors pipeline landscape. It covers the pipeline drug profiles, including clinical and nonclinical stage products. It also covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space.

Geography Covered

• Global coverage

HPK1 inhibitors: Understanding

HPK1 inhibitors: Overview

Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-restricted member of the serine/threonine Ste20-related protein kinases, is a negative regulator of the T cell receptor, B cell receptor, and dendritic cells. Loss of HPK1 kinase function increases cytokine secretion and enhances T cell signaling, virus clearance, and tumor growth inhibition. Therefore, HPK1 is considered a promising target for tumor immunotherapy. Several HPK1 inhibitors have been reported to regulate T cell function. In addition, HPK1-targeting PROTACs, which can induce the degradation of HPK1, have also been developed.

Hematopoietic progenitor kinase-1 (HPK1) is a negative-feedback regulator of T cell receptor signaling, which dampens T cell proliferation and effector function. A recent report showed that a catalytic dead mutant of HPK1 phenocopies augmented T cell responses observed in HPK1-knockout mice, indicating that kinase activity is critical for function. In all structures HPK1-KD displays a rare domain-swapped dimer, in which the activation segment comprises a well-conserved dimer interface. Biophysical measurements show formation of dimer in solution. The activation segment adopts an α-helical structure which exhibits distinct orientations in active and inactive states.

Cell biological studies reveal that HPK1 is catalytically responsive to activation signals generated by a variety of cell surface receptors that are present on many sub-types of hematopoietic cells, including: the TCR and LPS receptors, presumably via TLR2 or TLR4. Among the receptors that regulate HPK1 kinase activity, signal transduction mechanisms used by TCR to activate HPK1 is best understood. Upon TCR engagement, HPK1 is recruited to the cholesterol- and sphingomyelin-rich lipid raft microdomain via the interactions with LAT, and Gads. Once complexed with LAT, HPK1 is phosphorylated on tyrosine 379 by ZAP-70, creating the high affinity binding site for the SH2 domain of SLP-76.

Once HPK1 becomes catalytically active, HPK1 carries out its role as a negative regulator of TCR-induced signal transduction by phosphorylating SLP-76 at serine residue 376 and Gads at threonine residue 262. HPK1 serves as one of the negative feedback loops that limits the strength and duration of TCR signals by disrupting the SLP-76/LAT signalosomes.

HPK1 may have the potential to become a new IO drug target as suggested by the genetic evidence. These data have stimulated a large number of pharmaceutical companies, as well as academic research institutions, to undertake pre-clinical research focusing on the development of small molecule kinase inhibitors of HPK1. It is clear that developing selective kinase inhibitors as an IO drug poses a significant challenge for the drug discovery teams than would the typical screen for small molecule drugs designed to block kinase drivers of cancer growth. However, in the case of HPK1 inhibitor, the bar for acceptable off-target liability is significantly higher since the mechanism of action of the HPK1-based IO drug depends on provoking the dormant or exhausted immune system to engage cancer.

“HPK1 inhibitors - Pipeline Insight, 2024" report outlays comprehensive insights of present scenario and growth prospects across the mechanism of action. A detailed picture of the HPK1 inhibitors pipeline landscape is provided which includes the disease overview and HPK1 inhibitors treatment guidelines. The assessment part of the report embraces, in depth HPK1 inhibitors commercial assessment and clinical assessment of the pipeline products under development. In the report, detailed description of the drug is given which includes mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, HPK1 inhibitors collaborations, licensing, mergers and acquisition, funding, designations and other product related details.

Report Highlights

The companies and academics are working to assess challenges and seek opportunities that could influence HPK1 inhibitors R&D. The therapies under development are focused on novel approaches to treat/improve HPK1 inhibitors.

HPK1 inhibitors Emerging Drugs Chapters

This segment of the HPK1 inhibitors report encloses its detailed analysis of various drugs in different stages of clinical development, including phase II, I, preclinical and Discovery. It also helps to understand clinical trial details, expressive pharmacological action, agreements and collaborations, and the latest news and press releases.

HPK1 inhibitors Emerging Drugs

CFI-402411: Tradewell Therapeutics

CFI-402411 is a highly potent inhibitor of HPK1, which in preclinical studies has been shown to have an immune-activating effects including the alleviation of inhibition of T cell receptors (TCR), disruption of abnormal cytokine expression, alteration of the tumor immunosuppressive environment through effector cells (i.e. Regulatory T cells or Treg), and potent anti-leukemic effects in several mouse models. TWT-101 is a Phase I/II clinical trial of CFI-402411 in advanced solid malignancies. The study is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of CFI-402411, as well as to determine optimal dosing as a monotherapy and in combination with the anti-PD1 antibody, pembrolizumab.

NDI-101150: Nimbus Therapeutics

NDI-101150 is a potent, selective, oral inhibitor of hematopoietic progenitor kinase 1 (HPK1), with a different immunotherapy mechanism to other checkpoint inhibitors. NDI-101150 reactivates anti-tumor activity of T-cells, B-cells and dendritic cells (DCs), even under immunosuppressive conditions. Currently, the drug is in Phase I/II stage of its clinical trial for the treatment of Solid Tumor.

BGB-15025: BeiGene

BGB-15025 is an investigational hematopoietic progenitor kinase 1 (HPK1) inhibitor discovered and being developed by BeiGene. HPK1 is a key negative feedback regulator of T-cell receptor signaling, which is believed to play a key role in antitumor immune response. In preclinical studies, the inhibition of HPK1 enhanced T-cell activation, which is expected to enhance the anti-tumor activity of anti-PD-1 inhibitors such as BeiGene’s tislelizumab. Currently, the drug is in Phase II stage of its clinical trial for the treatment of solid tumour.

HPK1 inhibitors: Therapeutic Assessment

This segment of the report provides insights about the different HPK1 inhibitors drugs segregated based on following parameters that define the scope of the report, such as:

Major Players in HPK1 inhibitors

There are approx. 8+ key companies which are developing the therapies for HPK1 inhibitors. The companies which have their HPK1 inhibitors drug candidates in the most advanced stage, i.e. Phase I/II include, Tradewell Therapeutics.

Phases

The report covers around 10+ products under different phases of clinical development like

• Late stage products (Phase III)
• Mid-stage products (Phase II)
• Early-stage product (Phase I) along with the details of
• Pre-clinical and Discovery stage candidates
• Discontinued & Inactive candidates

Route of Administration

HPK1 inhibitors pipeline report provides the therapeutic assessment of the pipeline drugs by the Route of Administration. Products have been categorized under various ROAs such as

• Intra-articular
• Intraocular
• Intrathecal
• Intravenous
• Oral
• Parenteral
• Subcutaneous
• Topical
• Transdermal
• Molecule Type

Products have been categorized under various Molecule types such as

• Oligonucleotide
• Peptide
• Small molecule
• Product Type

Drugs have been categorized under various product types like Mono, Combination and Mono/Combination.

HPK1 inhibitors: Pipeline Development Activities

The report provides insights into different therapeutic candidates in phase II, I, preclinical and discovery stage. It also analyses HPK1 inhibitors therapeutic drugs key players involved in developing key drugs.

Pipeline Development Activities

The report covers the detailed information of collaborations, acquisition and merger, licensing along with a thorough therapeutic assessment of emerging HPK1 inhibitors drugs.

HPK1 inhibitors Report Insights

• HPK1 inhibitors Pipeline Analysis
• Therapeutic Assessment
• Unmet Needs
• Impact of Drugs

HPK1 inhibitors Report Assessment

• Pipeline Product Profiles
• Therapeutic Assessment
• Pipeline Assessment
• Inactive drugs assessment
• Unmet Needs

Key Questions

Current Treatment Scenario and Emerging Therapies:

• How many companies are developing HPK1 inhibitors drugs?
• How many HPK1 inhibitors drugs are developed by each company?
• How many emerging drugs are in mid-stage, and late-stage of development for the treatment of HPK1 inhibitors?
• What are the key collaborations (Industry-Industry, Industry-Academia), Mergers and acquisitions, licensing activities related to the HPK1 inhibitors therapeutics?
• What are the recent trends, drug types and novel technologies developed to overcome the limitation of existing therapies?
• What are the clinical studies going on for HPK1 inhibitors and their status?
• What are the key designations that have been granted to the emerging drugs?

Key Players

• TradeWell Therapeutics
• BeiGene
• ABM Therapeutics
• Nimbus Therapeutics
• Arvinas

Key Products

• CFI-402411
• BGB-15025
• ABM-2752
• NDI101150
• HPK1 (I-O Program)

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