CSF1R/colony stimulating factor 1 receptor
Pimicotinib targets CSF1R (colony-stimulating factor-1 receptor, also known as c-Fms), a receptor tyrosine kinase. It is highly selective for CSF1R, with minimal inhibition of c-Kit and PDGFR, which reduces potential off-target toxicities associated with broader kinase inhibition.

An N-(azaaryl)cyclolactam-1-carboxamide derivative having a structure of formula (1), a preparation method therefor, and a use thereof, each substituent being defined in the description and claims. The compound can be widely applied to the preparation of medicaments for treating cancer, tumor, autoimmune diseases, metabolic diseases, or metastatic diseases, in particular for treating ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, or bone metastatic cancer, and is expected to be developed into CSF1R inhibitor drugs[1].

---

A typical CSF1R biochemical inhibition assay is performed using purified recombinant human CSF1R kinase domain. Increasing concentrations of Pimicotinib (0.1-1000 nM) are incubated with the enzyme and ATP. The amount of ADP produced is measured using an ADP-Glo detection system to determine the IC50 value (19.48 nM). Selectivity is assessed by profiling against a panel of other kinases.

Tenosynovial giant cell tumor (TGCT) is a rare, locally invasive soft tissue tumor arising from the synovium of joints, bursa and tendon sheaths and is associated with the overexpression of the colony-stimulating factor 1 (CSF-1) gene. Pimicotinib is an orally available, highly selective and potent small molecule CSF-1 receptor (CSF-1R) inhibitor with robust efficacy and safety profile in patients with TGCT and is under development in multiple diseases. In an open-label Phase I study in patients with TGCT not amenable to surgery, pimicotinib showed superior efficacy and safety. In this article, we elucidate the rationale and study design of the multi-region Phase III MANEUVER trial (NCT05804045), which is designed to assess the efficacy and safety of pimicotinib in patients with TGCT not amenable to surgical resection in Asia, North America and Europe [2].

---

No detailed cellular efficacy data is provided for Pimicotinib. As a potent CSF1R inhibitor, it is expected to suppress the proliferation and survival of CSF1R-dependent cells such as tumor-associated macrophages (TAMs), thereby modulating the tumor immune microenvironment.

Randomization & Blinding [2]
Approximately 90 eligible participants will be randomized in a 2:1 ratio to pimicotinib 50 mg QD or matching placebo (Figure 1). Randomization will be conducted across all sites using a central interactive web response system and will be stratified by China sites and non-China sites. In Part 1, treatment assignment will remain blinded to participants, investigators, study site personnel, safety laboratory personnel, central imaging readers and reviewers, as well as the sponsor. After all participants complete Part 1 and reach the primary efficacy analysis time point, unblinding (for the sponsor only) and analysis will be conducted following data cleaning and database lock.

---

Study interventions [2]
Pimicotinib or matching placebo is administered QD with a dose of 50 mg in Part 1, and the drug can be taken with or without food. Participants will continue with the same dosage in Part 2 (and Part 3, if applicable) as they were receiving at the conclusion of Part 1. The study drug may be interrupted or dose reduced at the investigator's discretion at any time, e.g., due to AEs. A reduction to 25 mg QD is permissible as the maximum dose adjustment. If a participant requires a therapeutic dose below 25 mg QD, they must discontinue from the treatment.

---

Safety & AEs [2]
An AE is defined as any untoward medical occurrence, regardless of its causal relationship to the investigational drug, that occurs in a participant from the time of signing the informed consent form until 30 days (including Day 30) after the last dose of study drug. A treatment-emergent adverse event (TEAE) is defined as any adverse event that occurs or worsens after the initiation of treatment in this study, up to 30 days after the last dose of the study drug, following guidance from the US FDA. The severity of AEs will be graded by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

---

No in vivo efficacy data is detailed for Pimicotinib. As an orally active and highly selective CSF1R inhibitor, it is expected to demonstrate anti-tumor activity in mouse models of advanced solid tumors by reducing the number and activity of tumor-associated macrophages (TAMs).

As an orally active compound with an IC50 of 19.48 nM, Pimicotinib is designed to have favorable pharmacokinetic properties including good oral bioavailability. Specific PK parameters such as half-life, Cmax, and AUC have not been reported.

No specific toxicology data is detailed for Pimicotinib, though it is described as having a favorable safety profile in patients with advanced solid tumors. Selectivity for CSF1R with minimal c-Kit/PDGFR inhibition is expected to reduce class-related toxicities such as cardiovascular events.

[1]. N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method and application. World Intellectual Property Organization, WO2018214867 A1. 2018-11-29.

[2]. MANEUVER: A Phase III study of pimicotinib to assess efficacy and safety in tenosynovial giant cell tumor patients. Future Oncol . 2024 Sep 17:1-8.

Pimicotinib is an orally bioavailable colony-stimulating factor 1 receptor (CSF1R; CSF-1R; CD115; M-CSFR) inhibitor with potential immunomodulatory and antitumor activity. After oral administration, Pimicotinib targets and binds to CSF1R, thereby blocking CSF1R activation and CSF1R-mediated signaling. This inhibits the activity of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) and prevents immunosuppression in the tumor microenvironment (TME). This enhances the immune response of antitumor T cells and inhibits tumor cell proliferation. CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) and CD115 (differentiation cluster 115), is a cell surface receptor that plays an important role in tumor cell proliferation and metastasis.

---

Tenosheath giant cell tumor (TGCT) is a rare soft tissue tumor that grows in soft tissue around joints or areas of body activity. It is caused by excessive levels of a protein called CSF-1. Although surgery is the preferred treatment, some patients may be unable to undergo surgery due to the location, complexity, or risk of serious complications or disease after surgery. Therefore, there is still a need for new, safe, effective, and quality-of-life therapies for this disease. Pimicotinib is a CSF-1 blocker that has been shown to be safe and effective for the treatment of TGCT in early small studies. To validate these results, researchers have launched a large study called MANEUVER in parts of Asia, North America, and Europe. The study aims to confirm whether Pimicotinib is safe and effective for patients with TGCT who may be unable to undergo surgery. Clinical Trial Registration Number: NCT05804045 (ClinicalTrials.gov). [2] The MANEUVER study uses a robust three-phase design, first blinding the evaluation of efficacy and safety, followed by an extended open-label phase to observe secondary endpoints for a longer period. Notably, the trial includes a placebo crossover design, which is expected to further enhance the evidence for the efficacy and safety of Pimicotinib. In addition to objective imaging evaluations, most of the key secondary analyses will focus on multiple clinical outcome assessments. These indicators are crucial for demonstrating significant clinical benefits of Pimicotinib. In addition, it is essential to confirm, based on data from the Phase I study, that Pimicotinib does not have conventional hepatotoxicity. The results of this study are expected to clarify the role of Pimicotinib as a treatment option in patients who require intervention to maintain physical function and improve quality of life. More importantly, these results will contribute to a deeper understanding of disease characteristics and potential efficacy differences between different populations, such as Chinese and Western populations. This is the first clinical trial to include Asian and Western TGCT patients in a balanced manner globally. Specifically, Asian subjects (mainly from China) account for half of our study population. This strong representativeness allows us to conduct detailed efficacy comparisons based on stratified factors (Chinese research centers vs. non-Chinese research centers), which will contribute to a deeper understanding of disease characteristics and potential efficacy differences between different populations. Although previous studies have confirmed that the anatomical distribution of Chinese and Western patients with testicular germ cell tumors (TGCT) is similar, there are still significant differences in the mean time from disease onset to diagnosis and the history of trauma [References 15, 16]. This will help fill key gaps in the existing literature and deepen our understanding of the clinical characteristics of TGCT in different demographic contexts. [2]

---

Pimicotinib (ABSK021; CAS: 2253123-16-7) is a selective and orally active CSF1R inhibitor with an IC50 value of 19.48 nM (determined by inhibiting ADP production). It is a novel, orally bioavailable, highly selective small-molecule CSF-1 receptor inhibitor with robust efficacy and a favorable safety profile in patients. It exhibits anti-tumor activity and can be used to study advanced solid tumors. Molecular formula: C22H24N6O3; molecular weight: 420.46.

C22H24N6O3

420.464364051819

420.19

C, 62.84; H, 5.75; N, 19.99; O, 11.42

2253123-16-7

2866305-19-1 (HCl); 2253123-16-7

139549388

White to off-white solid powder

2

1

6

4

31

674

0

CC1=C(C=CC(=N1)NC(=O)N2CCC(C2=O)(C)C)OC3=CC(=NC=C3)C4=CN(N=C4)C

NXFPMDWYDKHFMM-UHFFFAOYSA-N

InChI=1S/C22H24N6O3/c1-14-18(31-16-7-9-23-17(11-16)15-12-24-27(4)13-15)5-6-19(25-14)26-21(30)28-10-8-22(2,3)20(28)29/h5-7,9,11-13H,8,10H2,1-4H3,(H,25,26,30)

3,3-dimethyl-N-[6-methyl-5-[2-(1-methylpyrazol-4-yl)pyridin-4-yl]oxypyridin-2-yl]-2-oxopyrrolidine-1-carboxamide

pimicotinib [INN]; Pimicotinib (USAN/INN); HV1XI8HST2; ABSK021; ABSK-021; CHEMBL5314535;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

---

Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

View More

Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

---

Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

View More

Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

---

Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

---

 (Please use freshly prepared in vivo formulations for optimal results.)