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Neoplasms

Other Diseases

Congenital Disorders

Small molecule drug

Oncolytic virus

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Disease Domain	Count

Neoplasms	4
Nervous System Diseases	1
Immune System Diseases	1
Infectious Diseases	1

Top 5 Drug Type	Count

Small molecule drug	8
Oncolytic virus	1

Top 5 Target	Count

ALPK1(alpha kinase 1)	1

This Phase 1/2a study will explore the safety and efficacy of PTT-936, an Alpha Kinase 1 (ALPK1) activator, used alone or in combination with anti-PD-1/L1 therapy in patients with locally advanced or metastatic solid tumors. The study is divided into two parts: Phase 1 (Part A) focuses on determining the pharmaceutically active dosage range and evaluating the safety profile of PTT-936 when administered as a monotherapy. Phase 2a (Part B) will assess the safety and efficacy of PTT-936 combined with anti-PD-1/L1 therapy in patients suitable for anti- PD-1/L1 monotherapy. The study aims to understand how PTT-936, alone or in combination, impacts tumor progression and patients' overall response.

Start Date26 Jan 2024

Sponsor / Collaborator

Pyrotech Therapeutics, Inc.

100 Clinical Results associated with Pyrotech Therapeutics, Inc.

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0 Patents (Medical) associated with Pyrotech Therapeutics, Inc.

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1

Literatures (Medical) associated with Pyrotech Therapeutics, Inc.

22 Mar 2024·Cancer Research

Abstract 2461: Discovery of an orally available and liver-targeted ALPK1 agonist for cancer immunotherapy

Author: Shao, Feng ; Li, Liang ; Hong, Yuan ; Wang, Hexiang ; Wang, Juan ; Shi, Zhichen ; Liu, Yinxin ; Dong, Xiaona ; Hu, Nan ; Zhang, Yaxin ; Ji, Zhijiang ; Li, Zhihong ; O’Yang, Counde ; Wang, Yupeng ; Ding, Jingjin ; Gao, Yajuan ; Bley, Keith ; Lv, Yun ; Hou, Xiaofu ; Sun, Xuebing ; Wang, Qianyu ; Yang, Xiaolong ; Mao, Rui ; Du, Nana

AbstractBoosting anti-tumor immune responses can be achieved by activating the innate immune system. Despite the ongoing development of numerous STING and TLR agonists for this purpose, none of them have progressed to late-stage clinical evaluation. Alpha protein kinase-1 (ALPK1) is an intracellular innate immune receptor newly identified for its ability to detect ADP-heptose, a metabolite released during the biosynthesis and degradation of lipopolysaccharides (LPS). Since heptose is not naturally present in mammalian cells, the recognition of heptose metabolites by ALPK1 serves as a reliable mechanism to identify bacterial infections. When ADP-heptose binds to ALPK1, it initiates the phosphorylation of TIFA, thereby triggering a cascade of immune responses. Systemic administration with ADP-heptose induces robust ALPK1-dependent cytokine responses in mice. While high doses of ADP-heptose demonstrate anti-tumor effects, its instability and low in vivo potency hinder its clinical development. Through a SBDD medicinal chemistry effort, a novel, stable, and potent ADP-heptose analog, designated PTT-936, has been discovered and is progressing into clinical evaluation in cancer patients. PTT-936 exhibits remarkable nanomolar potencies for ALPK1 activation in various cellular assays. Notably, in human PBMCs, PTT-936 induces both concentration-dependent release of cytokines and activation of NK and T cells. Consistent with in vitro studies, oral administration of PTT-936 triggered significant cytokine responses in mice at microgram dose levels. However, overt toxicities were observed only at milligram dose levels, indicating a wide therapeutic window for this compound. In syngeneic tumor models, oral administration of PTT-936 induced dose-dependent tumor growth inhibition, which correlated with elevations in several cytokine biomarkers. Mechanistic studies show that PTT-936, working exclusively through the ALPK1 pathway, elicited strong innate and adaptive immune responses, as evidenced by robust cytokine induction and immune cell activation and recruitment. In syngeneic mouse models, the anti-tumor effects of PTT-936 were significantly hindered by either CD8+ T cell depletion or neutralization of select cytokines. Besides monotherapy studies, compelling evidence demonstrates strong synergistic anti-tumor effects when combining PTT-936 with immune checkpoint inhibitors. Intriguingly, PTT-936 exhibits favorable tolerability and a wider therapeutic index compared to certain clinical-stage STING and TLR agonists. Furthermore, PTT-936 does not enhance cytokine elevations induced by checkpoint inhibitors, which have been linked to adverse events (including CRS) observed in clinical combination studies. The dosing frequency of PTT-936 in the upcoming first-in-human clinical trial is carefully designed to prioritize both tolerability and patient compliance.Citation Format: Yupeng Wang, Nana Du, Xiaona Dong, Xuebing Sun, Yuan Hong, Xiaolong Yang, Zhijiang Ji, Qianyu Wang, Yun Lv, Zhichen Shi, Yajuan Gao, Xiaofu Hou, Yaxin Zhang, Juan Wang, Rui Mao, Yinxin Liu, Liang Li, Jingjin Ding, Hexiang Wang, Nan Hu, Counde O’Yang, Zhihong Li, Keith Bley, Feng Shao. Discovery of an orally available and liver-targeted ALPK1 agonist for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2461.

100 Deals associated with Pyrotech Therapeutics, Inc.

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100 Translational Medicine associated with Pyrotech Therapeutics, Inc.

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Pipeline

Pipeline Snapshot as of 04 Oct 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Preclinical

8

1

Phase 2 Clinical

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

ALPK1 agonists(Pyrotech Therapeutics) ( ALPK1 )	Locally Advanced Malignant Solid Neoplasm More	Phase 2 Clinical
PTT-009	Neoplasms More	Preclinical
PTT-008	Neoplasms More	Preclinical
PTT-005	Genetic Diseases, Inborn More	Preclinical
PTT-004	Inflammation More	Preclinical