Delving into the Latest Updates on CCX-354 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [2]

Target

CCR1

Mechanism

CCR1 antagonists(C-C chemokine receptor type 1 antagonists)

Therapeutic Areas

Immune System DiseasesSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Rheumatoid Arthritis

Originator Organization

ChemoCentryx, Inc.

Active Organization-

Inactive Organization

ChemoCentryx, Inc.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC22H22ClN7O2

InChIKeyZIMLRKWQDLVPEK-UHFFFAOYSA-N

CAS Registry1010073-75-2

OBJECTIVESCCX354-C is a specific, orally administered antagonist of the C-C chemokine receptor 1, which regulates migration of monocytes and macrophages to synovial tissue. This clinical trial evaluated the safety and efficacy of CCX354-C in patients with rheumatoid arthritis (RA).METHODSCARAT-2 is a 12-week double-blind, randomised, placebo controlled trial in 160 patients with RA, with 68 tender joint count and 66 swollen joint count ≥8 and C-reactive protein (CRP) >5 mg/l, despite being on methotrexate for at least 16 weeks. Subjects received placebo, CCX354-C 100 mg twice daily, or 200 mg once daily for 12 weeks. Endpoints included safety (primary) and RA disease activity assessments based on American College of Rheumatology (ACR) response, and changes in 28-joint disease activity score-CRP, individual ACR components, as well as soluble bone turnover markers.RESULTSCCX354-C was generally well tolerated by study subjects. The ACR20 response at week 12 was 39% in the placebo group, 43% in the 100 mg twice daily group (difference and 95% CI compared with placebo, 4.5 (-14.1 to 23.1); p=0.62) and 52% in the 200 mg once daily group (13.0 (-5.8 to 31.8); p=0.17) in the intention-to-treat population, and 30% in the placebo group, 44% in the 100 mg twice daily group (14.4 (-5.9 to 34.8); p=0.17), and 56% in the 200 mg once daily group (25.8 (5.3 to 46.4); p=0.01) in the prespecified population of patients satisfying CRP and joint count eligibility criteria at the screening and day 1 (predose) visits.CONCLUSIONSCCX354-C exhibited a good safety and tolerability profile and evidence of clinical activity in RA.

16 Aug 2012·BloodQ1 · MEDICINE

CCR1 blockade reduces tumor burden and osteolysis in vivo in a mouse model of myeloma bone disease

Q1 · MEDICINE

Article

Author: Schall, Thomas J. ; Miao, Shichang ; Zeng, Yibin ; Powers, Jay P. ; Oyajobi, Babatunde O. ; Seitz, Lisa C. ; McCluskey, Brandon ; Zhang, Penglie ; Gupta, Anjana ; Wang, Yu ; Dairaghi, Daniel J. ; Jaen, Juan C.

AbstractThe chemokine CCL3/MIP-1α is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly potent and selective CCR1 antagonist CCX721, an analog of the clinical compound CCX354. We also show that doses of CCX721 selected to completely inhibit CCR1 produce a profound decrease in tumor burden and osteolytic damage in the murine 5TGM1 model of MM bone disease. Similar effects were observed when the antagonist was used prophylactically or therapeutically, with comparable efficacy to that of zoledronic acid. 5TGM1 cells were shown to express minimal levels of CCR1 while secreting high levels of CCL3, suggesting that the therapeutic effects of CCX721 result from CCR1 inhibition on non-MM cells, most likely osteoclasts and osteoclast precursors. These results provide a strong rationale for further development of CCR1 antagonists for the treatment of MM and associated osteolytic bone disease.

01 May 2012·Current Opinion in RheumatologyQ2 · MEDICINE

Novel small-molecular therapeutics for rheumatoid arthritis

Q2 · MEDICINE

Review

Author: Fleischmann, Roy

PURPOSE OF REVIEWSince the introduction of biologic therapies into the treatment paradigm of rheumatoid arthritis (RA), there has been hope that oral small molecule immune modulators would be developed that would have a risk : benefit profile at least similar to biologic therapies, be more convenient for the patient and, hopefully, be less expensive. This article reviews the progress made in the development of these compounds over the past year.RECENT FINDINGSAdditional information has become available in the past year on five oral compounds including kinase inhibitors (tofacitinib, fostamatinib, VX-509), an S1P lyase inhibitor (LX 3305) and a chemokine receptor-1 antagonist (CCX354-C). Efficacy has been shown in phase III with tofacitinib and in phase II with fostamatinib and VX-509; safety was the primary endpoint of the trials of CCX354-C and LX3305. Regarding side effects, liver test elevation and neutropenia occurred with tofacitinib, VX-509 and fostamatinib; lipid elevation with tofacitinib and VX-509; creatinine elevation and anemia with tofacitinib, and hypertension and diarrhea with fostamatinib.SUMMARYCompounds that inhibit tyrosine kinase pathways involved in cellular signalling have been shown to be effective in the treatment of RA with a reasonable risk : benefit ratio. It is too early to tell about inhibitors of other pathways.

100 Deals associated with CCX-354

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12963

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Rheumatoid Arthritis	Phase 2	DE	ChemoCentryx, Inc.	01 Sep 2010
Rheumatoid Arthritis	Phase 2	RO	ChemoCentryx, Inc.	01 Sep 2010
Rheumatoid Arthritis	Phase 2	BE	ChemoCentryx, Inc.	01 Sep 2010
Rheumatoid Arthritis	Phase 2	PL	ChemoCentryx, Inc.	01 Sep 2010
Rheumatoid Arthritis	Phase 2	CZ	ChemoCentryx, Inc.	01 Sep 2010
Rheumatoid Arthritis	Phase 2	NL	ChemoCentryx, Inc.	01 Sep 2010
Rheumatoid Arthritis	Phase 2	HU	ChemoCentryx, Inc.	01 Sep 2010
Rheumatoid Arthritis	Phase 2	UA	ChemoCentryx, Inc.	01 Sep 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


EULAR2012	Phase 2	Rheumatoid Arthritis CRP \| ESR \| C-telopeptide ... View more	160	Placebo	(eamcajgclu) = xeyptqudmo xsrrtmyorg (droumlfnkt ) View more	Positive	06 Jun 2012
				CCX354-C 100 mg BID	(eamcajgclu) = rtaorxqlxk xsrrtmyorg (droumlfnkt ) View more