Argos HIV Immunotherapy Offers Potential Reprieve From Antiretrovirals
HIV patients armed with a new immunotherapy targeted at their personal viral load may be able to take a break from the oppression of antiretroviral therapy or even drop it altogether, if Argos Therapeutics' AGS-004 continues to meet with clinical success.
"There was just an unexpected level of viral control in the treated patients," Argos Chief Scientific Officer Charles Nicolette said in an interview. Of the 16 evaluable patients so far from an ongoing Phase IIa trial, 13 were responders. And the responder population is averaging greater than 80 percent reduction in viral load compared to what their load was when they started their antiretroviral drugs, he said.
Simply stated, after priming with the therapeutic vaccine the patients dropped antiretroviral therapy for three months and ended up with lower viral loads than when they first discovered they were infected. "If there was no effect, we would have expected the vast majority of patients to rebound to their pre-drug levels," said Nicolette. Instead, the patients actually went below the predrug levels.
Argos announced these interim results, including viral load, immune response and safety data from the ongoing Phase IIa trial of AGS-004 at the AIDS Vaccine 2009 Conference in Paris Oct. 21. As a therapeutic vaccine, AGS-004 doesn't have the same headline pull of the preventive vaccine efforts, but it may have more short-term potential for changing the AIDS treatment landscape. Full data from the controversial RV144 preventive vaccine study also were presented at the Paris meeting. The complete analysis appears to have diminished the effect touted when the initial results were released in September ('The Pink Sheet' DAILY, Sept. 24, 2009).
Argos' current trial builds on a Phase I study testing its therapeutic vaccine in 10 patients, in which seven produced the anticipated immune response. "The type of T-cells being raised were what we had engineered the product to be able to do," Nicolette said.
The next step for Argos is to launch a placebo-controlled, randomized trial in the first half of 2010 to confirm the positive signal. "We'll randomize patients to placebo or the actual product, and then we'll compare what happens when they stop taking ART drugs for three months. Hopefully, what we'll see is the placebo patients will approximate their pre-drug viral loads, and the patients treated with the product will have this considerable reduction," Nicolette said.
For the studies, Argos gathers plasma samples from patients at the time of diagnosis, before they begin antiretroviral therapy. Typically when patients first seek treatment, their immune system and the virus have come to a "set point," in which their virus swarm's replication capacity has come into balance with the immune system's pressure. The make-up of that swarm is peculiar to the individual and never changes, Nicolette explained.
The patient then goes on ART immediately, and generally with current regimens the virus becomes undetectable. It doesn't continue to mutate as long as it's suppressed because replication is stopped. Mutation is a problem with HIV because the virus is poor at replicating and makes errors. If replication is stopped, mutation frequency is frozen in time.
Argos' Immunotherapy Platform
The therapeutic vaccine, AGS-004, is a product of the company's Arcelis platform. The technology isolates viral RNA from the patient's pre-ART plasma, and then loads that payload into highly engineered dendritic cells - the cells that identify and target antigens in the immune system, triggering the body's immune response. The RNA payload then put into the vaccine trains the dendritic cells to excite an immune response against the patient's unique viral load.
In the current trial, patients were given four months of AGS-004 therapy (once a month) to prime their immune response before ART was interrupted; patients were then given two more therapeutic booster shots afterward to counter any viral rebound.
"We know the immune response we primed is perfectly matched to what's going to rebound in the patient," said Nicolette. "We believe that's why we're seeing the reduction in viral load signal."
In the coming placebo-controlled study, Argos plans to dose the patients monthly for a full year and then offer quarterly dosing. Time to best response in the current study was four weeks after the last dose, and then patients began to experience viral load increase. That indicated "we probably ought to keep the monthly dosing going longer before we switch to spaced dosing in the booster phase, which probably would be quarterly dosing," Nicolette said.
In 2006, the company was awarded a five-year, $21.3 million contract by the National Institutes of Health to further develop AGS-004. The Phase IIb study is supported by that contract, which Nicolette sees as a valuable validation of the research.
Is A Personalized HIV Therapy Practical?
Nicolette argues that a personalized HIV therapy is a practical endeavor. Through automation and economies of scale, Argos can be "cost competitive with current therapies," he maintained.
Argos, a venture backed company, had to address the question of scalability early on in order to be a viable business. "We have invested significantly in being able to automate the entire manufacturing process," Nicolette explained. The company has invested "tens of millions of dollars" in the automated solution in parallel with its research so it will be ready to commercialize the product when the time comes.
A single production run from a patient's serum sample produces roughly three years worth of therapy in cryopreserved doses. Nicolette estimated the sunk cost for a production run at under $20,000.
Argos, based in Durham, N.C., built its Arcelis immunotherapy platform on technology developed at Duke University by its founders. In 2004, the biotech, then called Merix, formed a development and commercialization collaboration with the pharmaceutical division of Kirin Brewery, now Kyowa Hakko Kirin, headquartered in Tokyo.
The Japanese drug maker took a $5 million equity stake in Argos and a seat on the board. Under the shared expenses and profits arrangement, Kirin contributed over $40 million to development of Argos' immunotherapies through 2008. Kirin has commercialization rights in key Asian markets, while Argos has rights in North America. Other geographies are to be determined jointly (See Elsevier's Strategic Transactions Database, June 2004).
But while the Kirin partnership has been a boon, Argos is seeking other partners to develop the HIV therapy. "For something like the HIV product, we would most certainly need another partner to come in to make this a reality," said Nicolette. The IPO window is "not looking attractive," but with the new data from the Paris meeting in hand, Argos may be able to find a partner willing to "assume the interest the [VCs] have in the company."
Arcelis Platform Has Broad Applications
The technology that creates AGS-004 for HIV could just as easily be aimed at hepatitis C or any other type of chronic virus, Nicolette noted, adding to the company's attractiveness for investors. And in addition to the pathogen-targeted technology, Arcelis generates immunotherapies to fight cancer.
Argos' RNA-loaded dendritic cells targeted at cancers are different from other attempts at therapeutic vaccines because, unlike the others, they are not based on "normal non-mutated selfantigens that happen to be over-expressed in tumors." Instead, the Arcelis vaccines also include antigens mutated in the tumors. "We developed a way to amplify all of the RNA in the tumor at the time we harvest the tissue. We're programming the dendrites with every single antigen in the cell," he said.
The firm has had positive results from a clinical study in metastatic renal cancer after removal of the diseased kidney. "We saw stabilization or regression metastatic tumors ... with no autoimmune attack on the remaining normal kidney," said Nicolette.
With the approval of tyrosine kinase inhibitors for renal cancer, however, Argos had to rethink its clinical strategy. "It became difficult for us to accrue to our studies because the patients just had to take a pill," he said. The solution was to adopt a combination approach. An ongoing Phase II study is testing RCC therapy AGS-003 in combination with Pfizer's Sutent (sunitinib) with data due in 2010.
In actuality, "it doesn't really matter to us what type of tumor" we're aiming at, argues Nicolette. "Once we have the tumor tissue in hand and the blood product to make the dendritic cells, all cancers are equal."
Argos has licensing agreements for the Arcelis platform with Geron, Novo Nordisk, and Therakos, a Johnson & Johnson company. Outside of the platform, the company is looking to partner its soluble recombinant protein, CD83, licensed in 2006 from Beckman Coulter, as a potential therapy for autoimmune disorders and transplantation rejection.
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