This story has been updated from a previous version to include comment from Arrowhead Research.
By Doug Macron
Alnylam Pharmaceuticals last month reported preliminary phase I data showing that its systemically delivered transthyretin-mediated amyloidosis treatment ALN-TTR01 could safely trigger statistically significant reductions in serum levels of a target protein.
“By all accounts, the data … are the most robust data ever achieved for RNAi in humans,” Alnylam CEO John Maraganore said during a conference call held to discuss the clinical results. “In fact, we believe [they] actually represent the first time RNAi has been shown to silence a disease-causing gene in man.
“Indeed, it should be self-evident from these results that we will be able to silence [gene targets in other company programs] like PCSK9, like protein C, like hepcidin, and many others to build a … pipeline in genetic disease indications,” he added.
The trial was a single dose-escalation study in up to 36 patients with TTR amyloidosis, a hereditary, systemic disease caused by a mutation in the transthyretin gene. ALN-TTR01 is designed to inhibit both mutant and wild-type versions of the gene.
Patients were randomized into seven, four-patient cohorts of increasing doses ranging from 0.01 mg/kg to 1 mg/kg or placebo, according to Alnylam. Following the completion of dose escalation, additional patients were enrolled at 1.0 mg/kg. The data available were for 31 patients, 23 of whom received treatment and eight of whom received placebo.
Measurements of the drug's clinical activity were based on serum levels of circulating TTR protein, and showed a dose-dependent reduction in protein levels with a mean 41 percent drop at the highest dose.
All five patients receiving 1 mg/kg doses showed a reduction in serum TTR protein between 25 percent and 81 percent.
“Nadir levels were achieved approximately 7 days after dosing and serum TTR levels remained decreased through at least 24 days,” Alnylam said. “These effects were exemplified by one patient dosed at 1.0 mg/kg who showed 63 percent lowering at 48 hours, peak suppression of 81 percent at 7 days, and approximately 50 percent lowering of serum TTR protein at 28 days post dose.”
Serum TTR reductions also correlated with changes in levels of retinol binding protein and vitamin A, both of which are normally carried by the TTR protein and are used as biomarkers for the disease.
During the conference call, Maraganore noted that Alnylam did not conduct 5' RACE analysis, which is commonly used to confirm an RNAi effect, because doing so would require taking liver biopsies from the patients.
Such a procedure “was viewed by us and others to be something a little bit too aggressive in this patient population,” he said. “Unless somebody comes forward with a breakthrough way of doing it from plasma or serum,” any determination of an RNAi effect in patients receiving ALN-TTR01 is “going to be limited to serum-type measurements or protein levels.”
ALN-TTR01 was found to be well tolerated, with no serious adverse events related to the drug observed. Additionally, no patients dropped out of the study due to drug-related side effects and the investigators saw no significant increases in liver function test parameters.
Additional data from the phase I trial, which would incorporate results obtained from patients still receiving treatment, will be made available later, but Maraganore said that the company has not yet decided upon a specific timeframe.
“We'll provide some further updates,” he said, but “certainly nothing between now and year's end.”
Based on these positive data, Alnylam Chief Medical Officer Akshay Vaishnaw said that the company remains on track to begin filing the necessary paperwork to begin clinical testing of a follow-on drug candidate, ALN-TTR02, around the end of 2011.
“ALN-TTR02 has demonstrated a greater than 10-fold improvement in preclinical studies, with potent, dose-dependent, and durable TTR silencing,” he noted, adding that data from that study would likely be available in 2012.
Notably, ALN-TTR02 also uses what Alnylam calls a proprietary lipid nanoparticle delivery vehicle, compared with the one developed by partner Tekmira Pharmaceuticals that is used for ALN-TTR01. However, Tekmira's President and CEO has publicly laid claim to the delivery technology used in ALN-TTR02, stating that it is enabled by his company's technology (GSN 11/10/2011). Tekmira and Alnylam are also currently embroiled in a lawsuit over the rights to the lipid nanoparticles, as well as related technology.
During the conference call, Maraganore said that in light of the strong safety profile of ALN-TTR01, “we don't see any reason” why Alnylam could not conduct additional clinical testing of the drug at higher dose levels, and that it is considering doing so in parallel with ALN-TTR02's clinical development.
“At the same time, we have TTR02, which, based on all the preclinical experience in non-human primates, is clearly a superior formulation,” he said. As such, “we haven't decided one way or the other if we will or won't. But we have that flexibility.”
First in Man?
While Alnylam's claim that it is the first to show that RNAi can be used to silence a “disease-causing gene in man” may be accurate, the company was not the first to demonstrate a therapeutic RNAi effect in humans.
That distinction belongs to Arrowhead Research subsidiary Calando Pharmaceuticals, which early last year reported that its siRNA-based cancer drug CALAA-01 could knock down its intended target mRNA and protein inside a tumor through an RNA interference mechanism when delivered intravenously (GSN 3/25/2010).
CALAA-01 is designed to silence the M2 subunit of ribonucleotide reductase, which Arrowhead President and CEO Christopher Anzalone noted would “probably not be defined as a 'disease-causing gene.'
“It is involved in DNA synthesis, so it is a good target for cancer due to its up-regulation in rapidly dividing cells,” he noted in an e-mail to Gene Silencing News. “We use it not because it causes cancer per se, but because knocking it down in cancer cells could be a very powerful therapeutic tool.”
Officials from Alnylam did not return a request for comment.
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