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Alnylam Touts Phase II RSV Data as First Human Proof of Concept; Some Disagree

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Alnylam Pharmaceuticals last week announced positive results from the phase II trial of its siRNA-based respiratory syncytial virus therapy ALN-RSV01, calling the data the “first human proof of concept for an RNAi therapeutic.” However, two industry insiders have raised issues that cast doubt on the accuracy of the claim, including the possibility that the trial results may not have been entirely due to an RNAi effect.
 
Alnylam reported that in the study, called GEMINI, administration of ALN-RSV01 to adult volunteers experimentally infected with the virus led to a statistically significant decrease in infection rate and an increase in the number of patients who remained infection free.
 
During a conference call held to discuss the data, Alnylam CEO John Maraganore said GEMINI represents “the first ever human proof of concept for an RNAi therapeutic … [and is] an important de-risking event in our overall efforts to advance RNAi therapeutics.”
 
But to City of Hope researcher John Rossi, it is not yet certain whether the outcomes in Alnylam’s trial were entirely due to an RNAi effect or to an immune response associated with the activation of toll-like receptors.
 
“We’re using siRNAs as therapeutic agents … but don’t forget that our bodies are actually well-armed to fight off invading nucleic acids,” Rossi told RNAi News this week. “You really have to be careful about not activating these toll-like receptors.”
 
Rossi — who is also a co-founder of RNAi drug firms Dicerna Pharmaceuticals (see RNAi News, 11/8/2007) and Calando Pharmaceuticals (see RNAi News, 4/29/2005) — pointed to a 2005 paper published in Nature Medicine by investigators from Ludwig Maximilian-University of Munichthat showed certain siRNA sequences could trigger a TLR-mediated type-1 interferon response in plasmacytoid dendritic cells.
 
That same year, researchers from Protiva Biotherapeutics reported in Nature Biotechnology that siRNAs formulated in non-viral delivery vehicles could act as “potent inducers of interferons and inflammatory cytokines both in vivo in mice and in vitro in human blood.”
 
Although Rossi said that Alnylam maintains that “they are not activating the TLRs,” he noted that it remains unclear “how the naked siRNAs [that make up ALN-RSV01] are getting into the tissue that the virus infects.
 
“It seems to me that there could be toll-like receptor activation in [Alnylam’s] trial because [it involved] naked siRNAs being sprayed into the lungs, which are loaded with macrophages,” he said. Such a treatment “could, in fact, be triggering a type 1 interferon response — a mild one, but enough to knock down the viral replication and the virus at the same time.”
 
While it is possible that the effects seen in Alnylam’s phase II study are entirely due to TLR activation, Rossi stressed that a more likely scenario is one in which “there is a combination of two things going on: you have TLR activation and siRNA function that are working in” the clinical study.
 
Another challenge to Alnylam’s first proof of concept claim came from Sam Reich, executive vice president of ophthalmologics at Opko Health, who told RNAi News this week that he considers his company’s phase III wet age-related macular degeneration drug bevasiranib as having been the first RNAi drug shown to be effective in humans.
 
The drug was originally developed by Acuity Pharmaceuticals, which Reich co-founded and which was acquired by Opko last year (see RNAi News, 3/29/2007).
 

“We’re using siRNAs as therapeutic agents … but don’t forget that our bodies are actually well-armed to fight off invading nucleic acids. You really have to be careful about not activating these toll-like receptors.”

“We completed phase II [trials] in 129 patients in the spring of ‘06 and released that data in September” of that year, he said (see RNAi News, 9/14/2006). We “maintain that we released the first therapeutic proof of concept in the early fall of ‘06.”
 
Bevasiranib entered phase III testing last summer (see RNAi News, 7/12/2007).
 
While an argument has been made that the phase II bevasiranib data wasn’t statistically significant while Alnylam’s was, Reich noted that in these mid-stage trials, “you can use any endpoint and claim statistical significance.” By comparison, in phase III statistical significance must be demonstrated for an endpoint deemed meaningful by the US Food and Drug Administration, he said.
 
“The important thing is whether something is clinically meaningful,” Reich said. “We believe that our phase II in wet AMD had a clinically meaningful result, showing dose-dependent response to the most clinically meaningful endpoint: choroidal neovascularization.
 
“In a phase II, what’s more important for therapeutic proof of concept: something that is clinically meaningful or something that is statistically significant?” he asked.
 
In the GEMINI study, no significant differences in clinical symptoms were observed between subjects receiving ALN-RSV01 and those given a placebo. Akshay Vaishnaw, vice president of clinical research at Alnylam, attributed this to the small size of the clinical study and the fact that it evaluated the drug in an experimental setting.
 
He added during the conference call that this issue would be addressed in an upcoming trial.
 
“There are certainly intrinsic limitations to an experimental infection study as compared with natural infection and bona fide human disease,” he said. “However, we believe that GEMINI points to the significant potential for clinical benefit with ALN-RSV01 in a naturally infected patient population.”
 
Alnylam plans to begin the next phase II trial of ALN-RSV01, which will look at the drug in adults naturally infected with RSV, during the first half of this year. That study will evaluate the drug when delivered directly to the lung, where the virus naturally resides.
 
Officials from Alnylam did not return requests for additional comment.
 
GEMINI
 
The GEMINI trial was a double-blind study of ALN-RSV-01 in 88 adults experimentally infected with RSV. Patients received either the drug or placebo intranasally for five consecutive days — two days prior to viral inoculation and three days after. The study evaluated the drug’s effect on infection rate, viral dynamics, and clinical symptoms.
 
Three of the study’s subjects dropped out due to non-trial-related circumstances.
 
According to Vaishnaw, “the data demonstrated a clear antiviral effect as evidenced by a statistically significant reduction in RSV infection rate, which was the primary efficacy outcome, and consistent improvements across a range of other viral measures.”
Specifically, study subjects receiving ALN-RSV01 experienced a 38.1 percent reduction in infection rates as measured by plaque assay, which “is the most sensitive and specific of the RSV assays, and the one which has been previously used with other anti-RSV agents such as [MedImmune’s prophylactic drug] Synagis,” Vaishnaw said during the conference call.
 
Similar reductions in infection rate were obtained with other measurements of viral infection including RT-qPCR, spin-enhanced culture, and RV antigen assay, Alnylam said.
 
“We then looked at the number [of trial participants] who remained infection-free” using the plaque assay, Vaishnaw said. These data showed that treatment with ALN-RSV01 resulted in a 95 percent increase in the number of subjects who remained free of infection. Of the 43 subjects receiving ALN-RSV01, 24 were uninfected, compared with 12 of 42 subjects receiving placebo.
 
“While we did not power the study for additional disease measures, we were gratified to see very consistent trends favoring ALN-RSV01 treatment effect across other endpoints,” he added. “These measures included viral area under the curve rates, peak viral load, duration of viral shedding, and mean daily viral load.
 
No significant adverse events were observed in patients receiving the drug.
 
Pursuing a Partner
 
After Alnylam dropped its wet age-related macular degeneration program in 2005 (see RNAi News, 9/23/2005), the RSV program moved to the front of the company’s pipeline and became the first chance Alnylam has had to demonstrate that it is more than the holder of some of the field’s most important intellectual property.
 
The RSV program became even more important once Alnylam delayed plans to begin phase I testing of an RNAi-based treatment for pandemic influenza indefinitely after hitting a development roadblock (see RNAi News, 8/16/2007).
 
Now, with the GEMINI trial completed, Alnylam appears poised to take ALN-RSV01 forward — possibly with a partner.
 
“Programs in clinical development with positive phase II data are very highly valued assets in the marketplace and we believe there is a significant opportunity for partnerships with that program,” Alnylam’s Maraganore said last month when the company first announced that the RSV data was positive (see RNAi News, 2/14/2008).
 
At the time, he said that Alnylam was discussing potential alliances with a number of undisclosed companies, and that “the level and quality of those discussions has accelerated quite a bit with the advent of the [phase II RSV] data.”

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