Tobira dual CCR5/CCR2 inhibitor efficacy comparable, safety better than Sustiva in Phase IIb for HIV
This article was originally published in Scrip
Tobira Therapeutics' oral, once-daily HIV drug cenicriviroc (CVC) was just as effective as Sustiva (efavirenz) and had a better safety profile than the Bristol-Myers Squibb drug in a Phase IIb clinical trial, positioning CVC as an alternative to the only approved CCR5 inhibitor Selzentry (maraviroc) and as an attractive component of a combination therapy.
CVC inhibits the chemokine receptors CCR5 and CCR2, providing both antiviral and anti-inflammatory activity. Based on the drug's Phase IIb data reported today in a late-breaker oral abstract presentation during the Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta, Georgia, Tobira president and CEO Andrew Hindman told Scrip that the company is preparing for an end-of-Phase II meeting with the US FDA and determining which HIV drugs it will combine with CVC for Phase III clinical trials.
South San Francisco-based Tobira recently hired a director of pharmaceutical sciences named Mark Menning, who most recently was a senior research scientist working in formulation and process development at Gilead Sciences working on fixed-dose combination (FDC) drugs for HIV, to formulate Tobira's FDC for HIV. Menning was a co-inventor of Gilead's Truvada, Atripla, Complera and Stribild.
CVC at 100mg and 200mg doses and Sustiva at 600mg were administered in combination with Gilead's Truvada (emtricitabine/tenofovir disoproxil fumarate) during Tobira's 143-patient Phase IIb study, which was not powered to show the statistical significance.
"The fact that we're as good as the standard of care on efficacy is really significant," Mr Hindman said. "And the safety profile is better, which is important because patients are living longer."
The primary objective was to assess safety and show a percentage of CCR5-trophic study participants with HIV-1 RNA less than 50 copies per mL (c/mL) at week 24 in the intent-to-treat (ITT) population. Baseline HIV-1 RNA was at least 100,000c/mL. Secondary objectives looked at immune and inflammatory biomarkers.
Virologic success at week 24 was 76% in the study's 100mg CVC arm, 73% for 200mg CVC and 71% for patients treated with Sustiva with virologic non-response rates of 12%, 14% and 4%, respectively.
Also, the number of CD4-positive cells increased across all groups from the mean baseline level of 402 cells/mm3 – by 147 in the 100mg CVC arm, 170 in the 200mg CVC arm and 135 in the Sustiva arm.
Tobira will have 48-week data from the ongoing Phase IIb study by mid-2013.
There were no meaningful differences in safety across the three arms of the randomized, double-blind study with the exception of cholesterol levels. Unlike Sustiva and many other HIV therapies, total and LDL cholesterol decreased for patients treated with CVC.
One out of 56 ITT patients in the 200mg CVC arm and five out of 28 ITT patients in the Sustiva arm discontinued therapy due to treatment-related adverse events. Six of the 59 ITT patients in the 100mg CVC arm, six in the 200mg arm and two in the Sustiva arm discontinued for other reasons.
There were no Grade IV and only one Grade III adverse event and side effects observed during the study included central nervous system toxicities and rash that are well-characterized for Sustiva.
"The third and most important finding is that not only is cenicriviroc a very effective antiviral, but it potentially has anti-inflammatory properties as well," Mr Hindman said.
The Phase IIb analysis at 24 weeks assessed anti-inflammatory biomarkers in addition to antiviral efficacy and drug safety.
The data showed that MCP-1, the ligand of the CCR2 receptor found on monocytes, increased in a dose-dependent manner for patients treated with CVC. Also, sCD14 levels – a marker of monocyte activation and an independent predictor of mortality in HIV infection – decreased by 0.18x106 pg/mL for the 100mg CVC group and 0.19x106 pg/mL for the 200mg arm of the study, but increased 0.13x106 pg/mL for patients treated with Sustiva.
Mr Hindman said CVC is the first HIV drug to show both antiviral activity and anti-inflammatory activity in one molecule. He said that factor could be an important differentiator for CVC, because co-morbidities tied to inflammation frequently are observed even in patients with undetectable HIV when on antiretroviral therapy.
The drug's anti-inflammatory properties will be explored more thoroughly in Phase III.
CVC is the only CCR2 inhibitor in clinical development for HIV, according to Sagient Research's BioMedTracker service, but there is one CCR5 inhibitor on the market and at least two others are in the clinic.
CCR5 is a host protein that the HIV virus uses to access and infect host cells.
The approved CCR5 inhibitor Selzentry, which is marketed by GlaxoSmithKline's Viiv Healthcare subsidiary, generated $204 million in 2012 worldwide sales versus $177 million in 2011. The US FDA approved Selzentry in 2007 for combination antiretroviral treatment of adults with CCR5-tropic HIV-1 after they failed other therapies.
The drug's label notes that more treatment-naïve patients on Selzentry experienced virologic failure and developed resistance to Epivir (lamivudine) compared with patients treated with Sustiva. Tobira is targeting the treatment-naïve population with CVC.
Two other companies have biologics targeting CCR5 in development – CytoDyn with PRO 140 and Sangamo Biosciences with SB-728-T.
CytoDyn acquired the monoclonal antibody PRO 140 from Progenics in October for $3.5 million upfront, $6.5 million in milestone payments and a 5% royalty on future product sales.
The company's chief scientific officer Richard Trauger told Scrip recently that CytoDyn is working to produce enough of the antibody to restart the Phase II program for PRO 140.
The therapeutic candidate is delivered every two weeks with an epi-pen injection – as opposed to CVC's daily oral dosing – but Dr Trauger said there is interest from both doctors and patients for an intermittently dosed HIV therapy.
With positive Phase IIb data in hand, Tobira is planning for a Phase III clinical trial that will compare a drug combination that includes CVC to another combination regimen starting in late 2013 or early 2014. The FDA and other regulatory agencies will require 48-week data to consider marketing applications for CVC, so if Phase III data are available in 2015, Mr Hindman anticipates approval by 2016.
"We've done a lot of work on developing a strategy on who we would take the drug forward into Phase III with on a go-it-alone or a partnered basis," Mr Hindman said.
Without an announced partner, among the combinations that Tobira is considering for Phase III is CVC plus Epivir, which also is known as 3TC. The nucleoside analogue reverse transcriptase inhibitor is marketed by Viiv Healthcare. The CVC-Epivir combination may be evaluated against a combination that includes Truvada.
However, Tobira also is talking to companies with novel agents in development about potential FDC options, which could be similar to Gilead's FDC arrangements with other companies for its various one-pill combination drugs, such as Atripla, which includes Sustiva.
"We're evaluating all the ranges of opportunity," Mr Hindman said.
Tobira raised $31 million in a Series B financing round in 2010 on the back of positive Phase IIa results for CVC (scripintelligence.com, 30 September 2013 and 19 February 2010).
Its Series A round also totaled $31 million in 2007 (scripintelligence.com, 22 August 2007).