Alnylam Pharmaceuticals and Silence Therapeutics this week provided quick glimpses at new phase I data on their respective siRNA-based cancer drugs, showing that both are well tolerated and providing hints about their possible efficacy.
The data were made available this week in abstracts for the companies' upcoming poster presentations at the American Society of Clinical Oncology meeting early next month.
Alnylam's drug, ALN-VSP02, comprises siRNAs against two targets: vascular endothelial growth factor, which is associated with angiogenesis, and kinesin spindle protein, which has been linked to cell proliferation in various cancers.
The data to be presented were generated from 31 patients with advanced solid tumors and at least one measurable liver lesion, and who received intravenous infusions of ALN-VSP02 at one of seven dose levels ranging from 0.1 to 1.5 mg/kg, according to the poster's abstract. A total of 140 doses were administered.
"Treatment was generally well tolerated, with no dose-dependent trends in clinical or laboratory adverse events," the poster states, although there was one death — from liver failure in a patient with a near-complete replacement of the organ by a tumor — that was possibly related to the drug at the 0.7 mg/kg dose.
Incidences of low-grade acute infusion reactions were successfully managed by slowing the infusion rate, and dose-limiting toxicities at doses greater than 0.7 mg/kg included single incidences of reversible grade 3 thrombocytopenia and hypokalemia, according to the poster.
Post-treatment biopsies from 10 patients — seven with liver tumors and three with tumors outside the liver — showed pharmacologically relevant concentrations of both siRNAs. Meantime, 5' RACE analysis provided molecular evidence of RNAi-mediated VEGF mRNA cleavage in tumors both inside and outside the liver.
Among the 27 patients whose response to treatment could be evaluated, one out of 12 receiving doses at or below 0.4 mg/kg achieved stable disease for at least two months. However, disease stabilized for seven out of 15 during that time frame at doses of 0.7 mg/kg or higher.
"Several patients in the phase I trial have advanced to an extension protocol, including one patient who has received drug for one full year — itself, a very important milestone for the advancement of RNAi therapeutics," Jared Gollob, Alnylam's senior director of clinical research, said in a statement.
Silence's agent, Atu027, is a blunt-ended siRNA targeting the protein kinase PKN-3, which is associated with cellular morphology and locomotion in endothelial and cancer cells.
According to the data to be released at ASCO, 21 patients received the infusions of the drug at one of seven dose levels up to 0.12 mg/kg.
Atu027 was generally well tolerated, with no cytokine activation observed with treatment, according to the abstract for Silence's poster. Cases of transient activation of the complement system did not have any clinical relevance.
Preliminary pharmacokinetic data showed a dose-dependent increase in plasma siRNA, as well as lipid levels.
Across the dose levels tested, Atu027 was generally well-tolerated, with no dose-limiting toxicities observed.
Adverse events possibly related to Atu027 included fatigue, hair loss, sweating, and abdominal pain, but none were considered dose-limiting
Disease stabilization was observed in six patients after three months. One patient with neuroendocrine cancer had disease stabilization for nine months, and another with the same disease experienced partial regression of pulmonary metastases, the abstract states. Another patient with breast cancer had regression of liver metastases.
The "positive data to date [are] very encouraging, and we believe the disease stabilization and anti-tumor activity, in particular, are suggestive of a potential therapeutic benefit for extremely ill patients who have no other treatment options," Silence CEO Philip Haworth said in a statement.