SUMMARY: Tobira Therapeutics' investigational CCR5 antagonist TBR-652 was shown to have potent anti-HIV activity and it appeared safe and well-tolerated in its first small trial in people with HIV, researchers reported last week at the 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010) in San Francisco. The drug also blocked CCR2, suggesting it might be useful as an anti-inflammatory agent.

By Liz Highleyman

HIV can use 2 different surface co-receptors to enter CD4 T-cells, known as CCR5 and CXCR4. CCR5 antagonists are designed to block one of these gateways, and people considering such agents require a tropism test to ensure that they only have virus that uses this co-receptor.

Unlike the approved CCR5 antagonist maraviroc (Selzentry) and the more advanced candidate vicriviroc, TBR-652 also interacts with the CCR2 co-receptor found on monocytes, dendritic cells, and memory T-cells. CCR2 primarily binds to monocyte chemoattractant protein 1 (MCP-1). Though not fully understood, CCR2 appears to play a role in inflammation, and it has been linked to inflammatory diseases including atherosclerosis and metabolic syndrome. To date, there have been no safety signals associated with blocking this co-receptor.

TBR-652 was previously shown to have promising antiviral activity and favorable pharmacokinetic properties in laboratory studies and in healthy HIV negative volunteers. The drug has a half-life of 35-40 hours, making once-daily dosing feasible. It has good oral bioavailability, but the primary formulation works better with food. It is neither an inducer nor inhibitor of CYP450 enzymes, so it is expected to have few drug-drug interactions

In this Phase 2 proof-of-concept trial, Calvin Cohen from the Community Research Initiative of New England and colleagues enrolled 54 HIV positive participants with exclusively CCR5-tropic virus.

Most participants (89%) were men, the average age was about 40 years, and the mean CD4 cell count was approximately 450 cells/mm3. Participants were treatment-experienced, but had been off antiretroviral therapy for at least 6 weeks at study entry and had never taken any other CCR5 antagonists.

Successive groups of 10 patients were randomly assigned in a 4:1 manner to receive once-daily TBR-652 monotherapy at escalating does -- 25, 50, 750, 100, or 150 -- or else placebo for 10 days. The 100 mg dose group used a different formulation than the rest.

Results

	By the end of the 10-day dosing period, HIV viral load had declined from baseline as follows:
	25 mg group: median 0.5 log drop; 50 mg group: median 1.3 log drop; 75 mg group: median 1.6 log drop; 100 mg group: median 1.2 log drop; 150 mg group: median 1.5 log drop; Placebo: 0.1 log drop.
	Viral load continued to decrease for up to 4 days after the last dose.
	The largest median viral load declines (nadirs) in each group were as follows:
	25 mg group: median 0.7 log drop; 50 mg group: median 1.7 log drop; 75 mg group: median 1.8 log drop; 100 mg group: median 1.4 log drop; 150 mg group: median 1.7 log drop; Placebo: 0.3 log drop.
	At all dose levels, TBR-652 was associated with increases in MCP-1, with the largest change (about 350-fold) in the 150 mg group, the smallest (about 5-fold) in the 75 mg group, and essentially none in the placebo group.
	TBR-652 appeared safe and well-tolerated.
	4 patients in the 25 mg group, 3 in the 50 mg group, none in the 75 mg group, 5 in the 100 mg group, 8 in the 150 mg group, and 3 in the placebo group reported any adverse events, mostly mild.
	There were no serious adverse events, laboratory abnormalities, or deaths during the study.
	The most common adverse events were gastrointestinal symptoms (e.g., nausea, diarrhea, abdominal discomfort) and systemic symptoms (headache, fatigue, fever).
	There were no clinically significant changes in heart rhythm.
	No participants showed evidence of a change from CCR5-tropic to CXCR4-tropic virus.
	No TBR-652 resistance mutations were identified in this short study.

Notably, TBR-652 did not demonstrate consistent dose relationships. The 2 highest dose groups experienced the most adverse events without a corresponding increase in antiviral activity. The 75 mg dose appeared to be optimal against HIV, with the greatest efficacy (all recipients with >1 log decrease in HIV RNA) and fewest side effects (none); however, it also had the least CCR2 activity.

Based on these findings, the researchers concluded, "TBR-652 warrants further investigation as an unboosted, once-daily, oral CCR5 antagonist with potentially important anti-inflammatory effects."

"These data demonstrate that TBR-652 offers potent viral suppression and excellent safety and tolerability in this short-term study," Cohen stated in a press release issued by Tobira. "This compound provides the potential for once-daily dosing, without the need for a pharmacologic boosting agent, an important benefit for simplified dosing and ease of administration in early stage disease."

"TBR-652's unique properties, including once-daily dosing that may facilitate co-formulation with other antiretrovirals, such as nucleoside-sparing or ritonavir-sparing combinations, distinguish it from the early CCR5 antagonists," said Tobira president and CEO James Sapirstein. "Further, TBR-652's added CCR2 antagonism and potential anti-inflammatory benefits suggests a bright future for this high-potential compound."

The company indicated that based on the favorable results from this proof-of-concept trial, it will move forward with Phase 2b studies of the drug.

Tobira Therapeutics, Inc, Princeton, NJ; Community Research Initiative of New England, Boston, MA; AIDS Research Consortium of Atlanta, GA; Orlando Immunology Ctr, FL; Central Texas Clinical Research, Austin, TX; Whitman Walker/Elizabeth Taylor Clinic, Washington, DC; CIBIC, Rosario, Argentina.

2/23/10

References
S Palleja, C Cohen, J Gathe, and others. Efficacy of TBR 652, a CCR5 Antagonist, in HIV-1-infected, ART-experienced, CCR5 Antagonist-naive Patients. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 53.

D Martin, S Palleja, L Pheng, and others. Pharmacokinetics (PK) and pharmacodynamics (PD) of TBR-652, a Chemokine Receptor 5 (CCR5) Antagonist, in HIV-infected, Antiretroviral (ARV) treatment-experienced, CCR5 Antagonist-naive Patients. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 598.

Other source
Tobira Therapeutics. Tobira's Next-Generation Once-Daily CCR5 Receptor Antagonist Demonstrates Efficacy, Safety and Tolerability in Treatment-Experienced Patients With HIV. Press release. February 17, 2010 (www.tobiratherapeutics.com).