By Doug Macron
With a key piece of intellectual property now licensed, Calimmune is preparing to move its expressed RNAi-based HIV treatment CAL-USA-11 into phase I/II testing this year, a company official told Gene Silencing News.
According to Calimmune CEO Louis Breton, the clinical program will comprise multiple studies at different locations worldwide in order to examine the drug in different HIV patient populations, although the company has not yet finalized where the first trial will be conducted.
Still, based on discussions with regulatory agencies in the US and abroad, “it looks like we will be in [the] clinic in 2012,” he said. And last week, Calimmune announced that it had non-exclusively licensed Benitec Biopharma's expressed RNAi technology in order to pave the way for these studies (GSN 3/8/2012).
Calimmune was founded in 2007 to develop an HIV therapeutic approach that originated in the labs of the UCLA AIDS Center's Irvin Chen and the California Institute of Technology's David Baltimore. The method involves knocking down CCR5, a chemokine receptor used by HIV as a co-receptor in order to infect cells.
“Back in 1996, there was a small population identified … that, despite being consistently exposed to HIV, was not getting infected,” Breton explained. “This population … was shown to … not have CCR5 on the surface of their T cells as receptors.”
Meantime, a heterozygous population with approximately half the amount of CCR5 on the surface of their T cells was found to be susceptible to HIV infection, but experienced a delay in progression of the disease between three and five years, he added.
In light of these findings, Chen and Baltimore began developing shRNAs targeting CCR5 as a treatment for HIV. Since then, Calimmune has added a fusion inhibitor to the therapy in order to address any potential viral resistance.
“What we're looking to do is [trigger] a significantly [greater] decrease of CCR5 on the surface of T cells,” Breton said. “In addition to that, [we also want to] provide the capabilities of an intracellular cocktail … to help support the cell and prevent fusion of HIV if it uses a different type of co-receptor.”
The idea behind the approach, he noted, is to protect a patient's immune system rather than going after HIV directly.
HIV “is quite virulent and, as we've seen throughout the decades, very difficult to control,” Breton said. “If you attack it head on ... it's been shown to mutate faster.
“But if we can create a basis where your immune system is able to sustain and be resilient, it's different that trying to attack the virus,” he said.
CAL-USA-11 treatment involves isolating a patient's T cells and stem cells from peripheral blood, then treating them with the drug. The cells would then be re-infused during an out-patient procedure. Delivering the agent to T cells is expected to provide immediate protection to a patient, while delivery to stem cells will offer long-term protection.
“If we are able to engraft enough stem cells back into the patient that create progeny of T cells with the protection against HIV, then this could be a long-term therapy for HIV-positive patients” requiring one-time or infrequent treatment, Breton said.
In December, Calimmune presented its clinical-development plan for CAL-USA-11 to the National Institutes of Health's Recombinant DNA Advisory Committee, which is charged with reviewing human applications of recombinant DNA techniques. Breton said that the company received the green light from the group after agreeing to make “some minor modifications” to the study's protocols.
According to Calimmune's presentation, the therapy will be tested in three cohorts of HIV-infected patients: one receiving CAL-USA-11 alone, and the other two receiving the drug in addition to either low-dose or moderate-dose busulfan as a conditioning agent to improve engraftment of transduced stem cells.
The study's primary endpoint is safety and feasibility of the therapeutic approach, while secondary endpoints include T cell count, viral load, and development of resistance.
Breton said that the initial clinical studies will also give Calimmune some indication of the best patient population in which to conduct further trials.
“We are first starting our trials in HIV-positive patients ... at different stages of the disease,” he said. “We'll know better, as we go through the trials, at what stage and which cohorts will be best suited for the therapy.”
A Slightly Different Tack
Calimmune is not alone in using an expressed RNAi approach to fight HIV.
As reported by Gene Silencing News, investigators at the City of Hope have been testing a therapy in AIDS lymphoma patients that involves treating their stem cells with a lentiviral vector containing three therapeutic genes: DNA that encodes for shRNAs targeting the tat-rev exon, a ribozyme that cleaves the mRNA for CCR5, and a nucleolar-localizing TAR decoy.
After achieving some success in a small study (GSN 3/17/2011), the City of Hope team has begun recruiting patients for a follow-on trial, which it expects to be underway by the summer.
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