Increasing evidence indicates that immune abnormalities are associated with the pathogenesis of depression. CCR4 is a chemokine receptor that regulates regulatory T cell (Treg) and Th17 cell migration. Here, using a lipopolysaccharide (LPS)-induced depression mouse model, we demonstrated that CCR4 deficiency exacerbated depressive-like behavior. Tregs and M2 macrophages, but not Th17 cells, were decreased in the brain of CCR4-deficient mice. Consistently, treatment with a CCR4 inhibitor reduced Tregs and M2 macrophages in the brain and exacerbated depressive-like behavior. Thus, CCR4 may contribute to the reduction of depressive symptoms by promoting Treg recruitment to the brain and subsequent M2 macrophage polarization.

项与 CCR4抑制剂(ChemoCentryx) 相关的新闻（医药）

2024-11-11

·Firstwordpharma

Regulatory woes scuttle RAPT's zelnecirnon programme

RAPT Therapeutics announced on Monday that it is terminating development of its lead drug candidate zelnecirnon (RPT193) following negative FDA feedback. The news sent company shares plunging as much as 45% in early trading.The oral CCR4 inhibitor was being evaluated in two separate mid-stage studies, one for atopic dermatitis and another targeting asthma. RAPT's stock took a major hit in February after the FDA slapped a clinical hold on the trials due to a serious adverse event of liver failure requiring transplant in a patient enrolled in the atopic dermatitis study.The company went on to close and unblind both trials in May as it continued to investigate the incident. At the time, CEO Brian Wong seemed optimistic, saying, "We believe we will have sufficient data, even if not statistically significant, to inform our path forward and support our discussions with the FDA." Prior to the hold, a total of 229 patients had been enrolled in the Phase IIb atopic dermatitis trial, with roughly 110 having completed the 16-week dosing period.No viable pathHowever, Wong said Monday that "in light of the agency's feedback, we do not see a viable path forward for zelnecirnon, although we continue to believe that CCR4 remains an exciting target with the potential to provide a safe, oral therapeutic option across a number of inflammatory diseases."The company will now focus on advancing its next generation of CCR4 compounds, with plans to identify a new drug candidate in the first half of 2025, while also pursuing in-licensing opportunities for clinical-stage assets to supplement its pipeline.In a recent note, UBS analysts said that while they believed zelnecirnon had "activity and potential" in atopic dermatitis, RAPT would likely face an "uphill battle" given the high safety bar in this space. UBS also highlighted the company's oral tivumecirnon (FLX475) candidate, which is also designed to block CCR4 and is in Phase II testing for cancer. "If RAPT is able to partner/monetise/establish a path forward for tivumecirnon, this could potentially drive shares higher, but we think investors are cautious on this asset," they said.RAPT announced in July that it was reducing its headcount by about 40% in order to conserve cash.

临床2期临床失败

2024-02-20

·Firstwordpharma

RAPT Therapeutics sinks after FDA halts two zelnecirnon trials

RAPT Therapeutics said it has been told by the FDA that it placed clinical holds on two trials of its CCR4 inhibitor zelnecirnon (RPT193) after a serious adverse event of liver failure was reported in a patient participating in one of them. The news sent company shares plummeting as much as 70% on Tuesday.The hold affects the company's Phase IIb trial of zelnecirnon in atopic dermatitis and its Phase IIa trial of the drug in asthma. The atopic dermatitis study, which is where the liver failure event occurred, was expected to read out in mid-2024.According to a recent note to clients, Barclays called RAPT an "underappreciated company… set up for a transformative" year based partly on the promise of zelnecirnon offering a safe oral option in atopic dermatitis prior to patients having to resort to biologics.Complex medical historyThe cause of the adverse event "is currently unknown, but…has been characterised as potentially related to zelnecirnon," RAPT said Tuesday.The company says the patient in question had a "complex medical history" that included drug allergy to Dupixent (dupilumab), an autoimmune disease resulting in thyroid hormone replacement therapy, and also used an herbal supplement "known to be associated with liver failure." They also had COVID-19 during the time of the event."This is an unfortunate and unexpected event, and we are working diligently to get more information on this case," said CEO Brian Wong. RAPT is expecting to receive a formal clinical hold letter.Some 350 patients have been enrolled in three trials assessing zelnecirnon - the two mid-stage studies and an earlier Phase Ia/Ib study - with no instances of liver toxicity detected among any of the other participants. No signs of liver toxicity have been observed in nonclinical studies of the drug either, the company noted.Potential upsideBarclays analysts suggested in December that the company's depressed stock price was likely due to a lack of near-term catalysts and the novelty of the CCR4 target, against the backdrop of a challenging broader biotech environment. However, they said the situation nevertheless "presents an attractive risk/reward opportunity," with potential upside coming from positive efficacy data readouts, which could exceed expectations compared to the standard Dupixent, and development opportunity from RAPT's tivumecirnon (FLX475) candidate, which is also designed to block CCR4.The company said the FDA clinical hold does not apply to its ongoing trial of tivumecirnon in oncology.

临床2期

100 项与 CCR4抑制剂(ChemoCentryx) 相关的药物交易

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