Phase I Data of TKM-PLK1 Are Encouraging
On April 9, 2013, Tekmira Pharmaceuticals (NASDAQ:TKMR) announced the results of its Phase I clinical trial with TKM-PLK1 at the annual meeting of the American Association for Cancer Research (AACR) in an oral presentation entitled "A phase I dose escalation study of TKM-080301, a RNAi therapeutic directed against PLK1, in patients with advanced solid tumors."
As a reminder, TKM-PLK1 is Tekmira's lead internal product candidate, which employs Tekmira's lipid nanoparticle (LNP) delivery technology, and targets PLK1 (polo-like kinase 1), a protein involved in tumor cell proliferation and a validated oncology target. Tekmira initiated the Phase I clinical trial of TKM-PLK1 in December, 2010. The Phase I clinical trial is an open label, multi-dose, dose escalation study with
- Primary Objectives: to evaluate safety, tolerability and determine maximum tolerated dose (MTD);
- Secondary Objectives: to evaluate pharmacokinetics and anti-tumor activity;
- Exploratory Objectives: to evaluate pharmacodynamic measures including RNAi effects in pre- and post-dose biopsy samples;
In this Phase I trial, TKM-PLK1 was administered to 24 patients at doses ranging from 0.15 mg/kg to 0.90 mg/kg. Patients were dosed on a weekly protocol with each four week cycle consisting of three once weekly doses followed by a rest week. A total of 152 doses were administered with a mean number of 6.3 doses per patient (range of 1-31 doses). Patients had a mean of 5.1 prior treatment regimens (range of 1-14). Treatment may continue until disease progression.
Below are the highlights of the Phase I results:
- TKM-PLK1 was generally well-tolerated. The most common grade 1-2 adverse events were rigors (33%) and fever (25%). No dose-dependent changes in liver function tests were observed. Dose-limiting toxicities included: one grade 3 transient thrombocytopenia in one patient (at 0.9 mg/kg) and one grade 3 hypoxia/dyspnea in another patient (at 0.9 mg/kg).
- Based on these data, the MTD is estimated to be 0.75 mg/kg. A 10-patient expansion cohort is currently enrolling patients at 0.75 mg/kg, with 5 subjects treated and data expected later this year.
- Of 9 patients evaluable for response, treated at a dose equal to or greater than 0.6 mg/kg, 4 (44%) showed clinical benefit. In particular, one patient with progressive, metastatic appendiceal carcinoid (neuroendocrine, NET) cancer had a durable partial tumor response based on RECIST criteria, continuing for more than 10 months. Three other patients achieved stable disease, including one patient with metastatic appendiceal carcinoid cancer, another patient with metastatic colorectal cancer, and a third patient with metastatic adrenocortical carcinoma.
- Pharmacokinetic data showed that Cmax (peak serum concentration of drug) and area under the curve (AUC) were dose proportional, without evidence of drug accumulation, and that the pharmacokinetic profile of TKM-PLK1 is maintained through multiple cycles.
- Importantly, the data confirm that the drug exposure levels achieved in this trial, incorporating Tekmira's second generation LNP formulation specifically designed to facilitate siRNA delivery to disseminated disease sites, are several fold greater than were achieved in clinical trials using earlier LNP formulations.
- RNAi effect was confirmed in biopsy samples.
We think the Phase I data of TKM-PLK1 are encouraging though it was a small trial. We are pleased to see that TKM-PLK1 was generally well-tolerated and has shown some anti-tumor activity. We are especially impressed by the 44% evaluable patients who showed clinical benefit.
Phase II Trial of TKM-PLK1 is Planned in 2H13
Based on the Phase I data, Tekmira plans to initiate a Phase II clinical trial of TKM-PLK1 in patients with previously treated gastrointestinal carcinoid (neuroendocrine) cancer in 2H2013.
The rationale for neuroendocrine cancer is that although a variety of tumor types were treated in this Phase I study including colorectal, neuroendocrine, cholangiocarcinoma, adrenocortical, breast, ovarian, mesothelioma, lung, and unspecified adenocarcinoma, neuroendocrine cancer patients had the best response. Of the two patients enrolled with gastrointestinal carcinoid (neuroendocrine) cancer, both responded to treatment with TKM-PLK1 with one partial response and on in stable disease.
The company is currently working on the design of the Phase II trial. Details of the trial design will be disclosed later this year. Tekmira is also evaluating additional indications for Phase II development and will provide guidance later this year.
Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. According to the Carcinoid Cancer Foundation, it is estimated that more than 12,000 new cases of carcinoid/NETs are diagnosed each year, and at least 115,000 people are living with carcinoid/NETs in the United States. Metastatic gastrointestinal carcinoid (neuroendocrine) tumors often have a poor prognosis and may have an aggressive clinical course.
Currently, treatment options for patients with neuroendocrine tumors are limited. Tekmira's TKM-PLK1 has the potential to become a standard of care for NET patients if successful.