Delving into the Latest Updates on LOX-24350 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

FGFR3 Selective

+ [4]

Target

FGFR3

Mechanism

FGFR3 antagonists(Fibroblast growth factor receptor 3 antagonists)

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Advanced Malignant Solid NeoplasmBladder CancerFGFR3 Mutant Neoplasms+ [2]

Inactive Indication-

Originator Organization

Loxo Oncology, Inc.

Active Organization

Eli Lilly & Co.

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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The main purpose of this study is to evaluate how much of the study drug (LY3866288), administered as a single dose that has the radioactive substance 14C incorporated into it, passes from blood into urine, feces and expired air in healthy participants. The study will also measure how much of the study drug gets into the bloodstream when taken orally, compared to when injected directly into the vein, how its broken down, and how long it takes the body to get rid of it. The study will also evaluate the safety and tolerability of LY3866288.The study is conducted in two parts. The study is expected to last approximately 68 days.

Start Date01 Oct 2024

Sponsor / Collaborator

Eli Lilly & Co.

NCT06641037 / Not yet recruitingPhase 1

A Phase 1, Open-label, Randomized, Crossover Study to Assess the Effect of Food on the Pharmacokinetics of LY3866288 in Healthy Participants

The purpose of this study is to evaluate how well LY3866288 is tolerated and what side effects may occur in healthy participants. The study drug will be administered orally. Blood tests will be performed to check how much LY3866288 gets into the bloodstream and how long it takes the body to eliminate it.
The study will last up to approximately 9 weeks including screening.

Start Date01 Oct 2024

Sponsor / Collaborator

Eli Lilly & Co.

CTR20240035 / RecruitingPhase 1

一项 LOXO-435（LY3866288）治疗携带FGFR3变异的晚期恶性实体肿瘤的开放标签、多中心研究

[Translation] An open-label, multicenter study of LOXO-435 (LY3866288) in patients with advanced solid tumors harboring FGFR3 mutations

主要目的：本研究的主要目的是更多地了解 LOXO-435 的安全性、副作用和有效性。

[Translation]

Primary Objective: The primary objective of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435.

Start Date12 Jun 2024

Sponsor / Collaborator

Eli Lilly Suzhou Pharmaceutical Co. Ltd.

[+2]

100 Clinical Results associated with LOX-24350

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100 Translational Medicine associated with LOX-24350

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100 Patents (Medical) associated with LOX-24350

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4

Literatures (Medical) associated with LOX-24350

18 Oct 2024·Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Achondroplasia: aligning mouse model with human clinical studies shows crucial importance of immediate postnatal start of the therapy.

Article

Author: Nonaka, Yosuke ; Koudelka, Adolf ; Fafilek, Bohumil ; Sedlacek, Radislav ; Czyrek, Aleksandra ; Nakamura, Yoshikazu ; Lopez, Marcos Gonzalez ; Prochazka, Jan ; Krejci, Pavel ; Rico-Llanos, Gustavo ; Krakow, Deborah ; Blahova, Eva ; Krivanek, Jan ; Prochazkova, Michaela ; Spoutil, Frantisek

Achondroplasia is the most common form of human dwarfism caused by mutations in the FGFR3 receptor tyrosine kinase. Current therapy begins at two years of age and improves longitudinal growth but does not address the cranial malformations including midface hypoplasia and foramen magnum stenosis, which lead to significant otolaryngeal and neurologic compromise. A recent clinical trial found partial restoration of cranial defects with therapy starting at 3 months of age, but results are still inconclusive. The benefits of achondroplasia therapy are therefore controversial, increasing skepticism among the medical community and patients. We used a mouse model of achondroplasia to test treatment protocols aligned with human studies. Early postnatal treatment (from day 1) was compared to late postnatal treatment (from day 4, equivalent to ~5 months in humans). Animals were treated with the FGFR3 inhibitor infigratinib and the effect on skeleton was thoroughly examined. We show that premature fusion of the skull base synchondroses occurs immediately after birth and leads to defective cranial development and foramen magnum stenosis in the mouse model to achondroplasia. This phenotype appears significantly restored by early infigratinib administration when compared to late treatment, which provides weak to no rescue. In contrast, the long bone growth is similarly improved by both early and late protocols. We provide clear evidence that immediate postnatal therapy is critical for normalization of skeletal growth in both the cranial base and long bones and the prevention of sequelae associated with achondroplasia. We also describe the limitations of early postnatal therapy, providing a paradigm-shifting argument for the development of prenatal therapy for achondroplasia.

26 Sep 2024·Journal of Medicinal Chemistry

Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia

Article

Author: Iyer, Samhita ; Bensen, Daniel C. ; Patel, Piyush ; Nelson, Kirk J. ; Allen, Eric ; Hoffman, Isaac D. ; Starrett, Jacqueline H. ; Swanson, Ronald V. ; Harris, Todd ; Balcer, Alexandra ; Ye, Qing ; Hudkins, Robert L. ; Rideout, Marc ; Neal, Melissa

Activating FGFR3 alterations have been identified in up to 15-20% of muscle-invasive bladder cancer and metastatic urothelial carcinoma (mUC), and as high as 80% in nonmuscle invasive bladder cancers. FGFR3 germline mutations have also been associated with a variety of skeletal dysplasias. Achondroplasia, the most common form of dwarfism in humans, results from a G380R mutation in FGFR3. The pan-FGFR inhibitor erdafitinib was approved for the treatment of mUC with FGFR3 alterations but is limited due to FGFR isoform off-target toxicities and the development of on-target gatekeeper resistance mutations. TYRA-300 (22) was conceived using a structure-based approach as a potent FGFR3-selective inhibitor to avoid the toxicities associated with inhibition of FGFR1, FGFR2, and FGFR4, and to be agnostic for the FGFR3 gatekeeper mutations. TYRA-300 is being evaluated in a Phase 1 clinical trial in urothelial cancers and solid tumors, with intention to initiate Phase 2 studies in urothelial cancers and achondroplasia.

01 Apr 2024·Nature Reviews Clinical Oncology

FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions

Review

Author: Katoh, Masuko ; Wainberg, Zev A ; Katoh, Masaru ; Brandi, Giovanni ; Loriot, Yohann ; Tavolari, Simona

Fibroblast growth factor (FGF) signalling via FGF receptors (FGFR1-4) orchestrates fetal development and contributes to tissue and whole-body homeostasis, but can also promote tumorigenesis. Various agents, including pan-FGFR inhibitors (erdafitinib and futibatinib), FGFR1/2/3 inhibitors (infigratinib and pemigatinib), as well as a range of more-specific agents, have been developed and several have entered clinical use. Erdafitinib is approved for patients with urothelial carcinoma harbouring FGFR2/3 alterations, and futibatinib and pemigatinib are approved for patients with cholangiocarcinoma harbouring FGFR2 fusions and/or rearrangements. Clinical benefit from these agents is in part limited by hyperphosphataemia owing to off-target inhibition of FGFR1 as well as the emergence of resistance mutations in FGFR genes, activation of bypass signalling pathways, concurrent TP53 alterations and possibly epithelial-mesenchymal transition-related isoform switching. The next generation of small-molecule inhibitors, such as lirafugratinib and LOXO-435, and the FGFR2-specific antibody bemarituzumab are expected to have a reduced risk of hyperphosphataemia and the ability to overcome certain resistance mutations. In this Review, we describe the development and current clinical role of FGFR inhibitors and provide perspective on future research directions including expansion of the therapeutic indications for use of FGFR inhibitors, combination of these agents with immune-checkpoint inhibitors and the application of novel technologies, such as artificial intelligence.

100 Deals associated with LOX-24350

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Bladder Cancer	Phase 1	GB	Eli Lilly & Co.	12 Jan 2023
Bladder Cancer	Phase 1	KR	Eli Lilly & Co.	12 Jan 2023
Bladder Cancer	Phase 1	NL	Eli Lilly & Co.	12 Jan 2023
Bladder Cancer	Phase 1	IL	Eli Lilly & Co.	12 Jan 2023
Bladder Cancer	Phase 1	DE	Eli Lilly & Co.	12 Jan 2023
Bladder Cancer	Phase 1	CA	Eli Lilly & Co.	12 Jan 2023
Bladder Cancer	Phase 1	CN	Eli Lilly & Co.	12 Jan 2023
Bladder Cancer	Phase 1	AU	Eli Lilly & Co.	12 Jan 2023
Bladder Cancer	Phase 1	US	Eli Lilly & Co.	12 Jan 2023
Bladder Cancer	Phase 1	IT	Eli Lilly & Co.	12 Jan 2023