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Cenicriviroc for Inflammation and HIV

By Sean R. Hosein

October 25, 2010

A company called Tobira Therapeutics is developing a drug called cenicriviroc (also known as TBR-652, formerly TAK-652). This drug has both anti-inflammatory and anti-HIV activity. Cenicriviroc works by blocking a receptor called CCR5, found on the surface of cells of the immune system. HIV needs this receptor to enter and infect cells. By masking CCR5, cenicriviroc makes it difficult for HIV to infect cells.

Cenicriviroc has another property -- it can mask another receptor called CCR2. This other receptor plays a role in several inflammatory conditions, such as:

In theory, blocking receptors such as CCR5 and CCR2 may interfere with the functioning of the immune system. This is why long-term monitoring of people who use the approved CCR5 inhibitor maraviroc (Celsentri) is important. However, after several years of monitoring, no increased risk for infections, cancer or immune dysfunction has been found in maraviroc users.

Because cenicriviroc also blocks CCR2 receptors, long-term monitoring of people who are exposed to this drug will be needed.

Cenicriviroc remains in the blood for prolonged periods; its half-life is 35 to 40 hours. As a result, it can be taken just once daily. Taking this drug with food enhances its absorption. An advantage of cencriviroc is that it generally does not interfere with enzymes in the liver that are used to process many other drugs.

Cenicriviroc has recently been tested in a Phase II study to explore preliminary safety and effectiveness. Specifically, researchers sought to understand the effect of different doses of cenicriviroc monotherapy in a randomized double-blind trial for 10 days. The drug was given in the following doses once daily to small groups of people:

Between eight and 10 people received each dose of cenicriviroc, while a small number received placebo. The average profile of participants at the start of the study was as follows:

The study team also assessed levels of the following chemical signals associated with inflammation in blood samples:


Results

Most doses of cenicriviroc -- 50, 75, 100 and 150 mg -- were associated with a significant decrease in viral load, ranging from 1.4 to 1.8 log. By contrast, only a 0.3 log decrease in viral load occurred with placebo.

Although the drug was only given for 10 days, viral load continued to fall for several days after the study ended.

Levels of inflammatory markers such as hsCRP decreased during exposure to cencriviroc.

The following side effects associated with the drug were reported by some participants:

No one left the study prematurely because of side effects and no one died as a result of exposure to cenicriviroc.

Further studies are planned for 2011 to assess cencriviroc's impact on assessments of cardiovascular, immunologic and metabolic health.


References

  1. Zhao Q. Dual targeting of CCR2 and CCR5: therapeutic potential for immunologic and cardiovascular diseases. Journal of Leukocyte Biology. 2010 Jul;88(1):41-55.
  2. Martin DE, Palleja S, Gathe J, et al. TBR-652, a potent dual chemokine receptor 5/chemokine receptor 2 (CCR5/CCR2) antagonist in phase 2 development for treatment of HIV infection. In: Program and abstracts of the 18th International Conference on AIDS, 18-23 July 2010, Vienna, Austria. Abstract MOAB0104.




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