RNA Interference Drug Demonstrated Activity and Safety in Phase I Trial

Newswise — WASHINGTON, D.C. — Early results from a phase I, first in-human study indicate that a potential new class of drugs, RNA interference (RNAi) drugs, can be safely administered in humans, according to a researcher who presented data on the safety and preliminary efficacy of TKM-080301 at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10. TKM-080301, also known as TKM-PLK1, is an RNAi drug being developed by Tekmira Pharmaceuticals Corporation.

“RNAi therapies are a unique approach to cancer treatment as they have the potential to ‘turn off’ the genes’ coding for proteins involved in cancer cell division,” said Ramesh K. Ramanathan, M.D., medical director of the Virginia G. Piper Cancer Center Clinical Trials Program at Scottsdale Healthcare and deputy director of the Clinical Translational Research Division of the Translational Genomics Research Institute (TGen) in Phoenix, Ariz. “Using a lipid nanoparticle, the RNAi drug can be delivered to a cancer cell to block the expression of specific proteins involved in tumor growth.”

TKM-080301 targets a specific gene called polo-like kinase 1 (PLK1), which codes for a protein involved in tumor cell growth. Prior research has shown that high levels of PLK1 are present in many types of cancer, including many of the more aggressive forms.

“Our preclinical results have shown that by decreasing PLK1 levels in cancer cells, we can stop tumor growth and kill the cancer cells,” Ramanathan said.

He and his colleagues have been enrolling patients with advanced solid tumors or lymphoma into the ongoing multicenter, open-label, dose-escalation study. Sequential cohorts of three to six patients have been assigned to escalating doses of TKM-080301 as a 30-minute intravenous infusion. To date, the researchers have assigned 23 patients to the drug at doses ranging from 0.15 mg/kg per week to 0.9 mg/kg per week.

The most common drug-related adverse events have been mild to moderate and include fever, chills, nausea, vomiting and fatigue. Dose-limiting toxicities were observed at the 0.9 mg/kg per-week dose. One patient with a history of asthma experienced shortness of breath and hypoxia; another patient had thrombocytopenia. The researchers subsequently reduced the maximum dose to 0.75 mg/kg per week.

Two patients have been assigned to TKM-080301 for more than six months and have shown no evidence of cumulative toxicity. One of these patients has stable disease and the other has a durable confirmed partial response.

“RNAi therapies, such as the one used in our study, have the potential to make a significant and broad impact on how we treat cancer because we have the ability to target virtually any protein involved in the disease,” Ramanathan said. “This approach has the potential to augment the currently available cancer treatments to improve outcomes for the patient.”

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Abstract Number: LB-289

Presenter: Ramesh K. Ramanathan, M.D.

Title: A phase 1 dose escalation study of TKM-080301, a RNAi therapeutic directed against PLK1, in patients with advanced solid tumors

Authors: Ramesh K. Ramanathan1, Solomon I. Hamburg2, Mitesh J. Borad3, Mahesh Seetharam1, Madappa N. Kundranda3, Peter Lee2, Paul Fredlund4, Mark Gilbert4, Cathy Mast1, Sean C. Semple4, Adam D. Judge4, Brynne Crowell5, Linda Vocila5, Ian MacLachlan4, Donald W. Northfelt3. 1Virginia G.Piper Cancer Center/TGen, Scottsdale, AZ; 2Tower Hematology Oncology, Beverly Hills, CA; 3Mayo Clinic, Scottsdale, AZ; 4Tekmira Pharmaceuticals Corporation, Burnaby, BC, Canada; 5TGen Drug Development (TD2), Scottsdale, AZ

Background: Polo-like kinase 1 (PLK1) is a serine/threonine kinase that regulates multiple critical aspects of cell progression. PLK1 is over-expressed in many human tumor types and its over-expression is a negative prognostic indicator of patient outcome in a variety of cancers. TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1 that has been shown to effect highly selective reductions in PLK1 mRNA in vitro and in tumor xenograft models in mice.

Methods: A Phase 1 multi-center, open-label, non-randomized, dose-escalation study of TKM-080301 is ongoing in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKM-080301 as a 30-minute IV infusion on Days 1, 8 and 15 of a 28-day cycle. Primary objectives include determination of safety, maximum tolerated dose (MTD) and dose limiting toxicities (DLTs). Secondary objectives include characterization of pharmacokinetics (PK) and preliminary assessment of anti-tumor activity and pharmacodynamic effects. Pre-and post-dose biopsy samples are being collected from patients treated after DLT has been established.

Results: Twenty-three (23) patients, receiving a cumulative total of 128 doses, have been treated with TKM 080301 at doses ranging from 0.15 to 0.9 mg/kg/week. The most common drug-related adverse events have been mild-to-moderate infusion related reactions with delayed onset, pyrexia, chills, nausea, vomiting and fatigue. Mild, transient increases in certain cytokines (e.g., IL 6, IL 8, MCP 1) have been observed at dose levels ≤0.75 mg/kg/week and generally correlated with the timing of delayed infusion reactions. DLTs were observed at 0.9 mg/kg/week and included hypoxia/dyspnea in one patient (with a previous history of asthma) and thrombocytopenia in another patient. The dose level was subsequently reduced to 0.75 mg/kg/week. Pharmacokinetic parameters determined after the first dose in Cycles 1 and 2 demonstrated dose proportional Cmax and AUC and no obvious accumulation. Two patients have received TKM 080301 for at least 6 months (6 cycles) with no evidence of cumulative toxicity, including one patient with stable disease (colon) and one patient with a durable confirmed partial response (carcinoid tumor) who has received 8+ cycles of treatment.

Conclusions: Preliminary results from this first-in-human trial indicate TKM-080301 was generally well-tolerated by the majority of patients. Preliminary antitumor efficacy has been observed, supporting PLK1 as a therapeutic target. As two DLTs were observed at the dose of 0.9 mg/kg/week, patient accrual is continuing at the 0.75 mg/kg/week dose level.

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