Nektar Therapeutics presented positive preclinical data for its lead oncolytic candidate, NKTR-102 (PEG-irinotecan), which demonstrated enhanced anti-tumour activity in a mouse xenograft model of colorectal cancer when co-administered with bevacizumab. The data also featured the enhanced pharmacokinetic profile and tolerability of NKTR-102, as compared to irinotecan in animal models.
NKTR-102 is a PEGylated form of irinotecan developed using Nektar's innovative small molecule PEGylation technology platform. NKTR-102 is currently in a phase II development programme to evaluate its safety and efficacy as a second-line colorectal cancer therapy in combination with cetuximab. Nektar had previously announced its intention to expand the NKTR-102 phase II clinical development programme later this year with additional indications.
"NKTR-102 is demonstrating important promise as a solid tumour treatment that could be used in a number of critical cancer care regimens," said Tim Riley, Ph.D., vice president, PEGylation Research, Nektar. "These data reinforce our confidence in the potential of our small molecule PEGylation technology platform to improve the therapeutic potential of oncolytics that are widely used to treat cancer. We look forward to presenting new data from our clinical trials at additional major oncology conferences this year."
In the preclinical studies presented, NKTR-102 was co-administered with bevacizumab to evaluate the effects of combination therapy. The combination therapy had an additive effect, inhibiting tumour growth by up to 97 per cent in an irinotecan-resistant mouse xenograft model of colorectal cancer (HT29), which was greater than monotherapy with either NKTR-102 or bevacizumab. NKTR-102 at 46 mg/kg, co-administered with bevacizumab, also resulted in eight partial tumour regressions and one complete tumour regression. This compares to no tumour regressions observed with bevacizumab monotherapy, and two partial regressions and one complete regression with NKTR-102 monotherapy. NKTR-102 alone, and in combination with bevacizumab, was well-tolerated, with minimal weight loss.
NKTR-102 also exhibited superior pharmacokinetics in a repeated dose study in dogs, with a 6-fold increase in exposure (AUC) and a 4-fold lower peak plasma concentration (Cmax) of SN38, the active metabolite of irinotecan, as compared to the equivalent dosing of irinotecan. The lower peak plasma concentration of NKTR-102 was associated with a superior tolerability profile, with less gastrointestinal and haematopoietic toxicity than comparable doses of irinotecan.
In animal models, NKTR-102 had a markedly improved safety and tolerability profile when compared to irinotecan in animal models. Both the incidence and severity of diarrhoea and neutropenia were lower in dogs treated with NKTR-102 as compared to irinotecan. Diarrhoea and neutropenia are the most common side effects associated with irinotecan treatment, and can limit treatment with the therapy.
Nektar is developing NKTR-102, a PEGylated form of irinotecan, which was invented by Nektar using its world-leading small molecule PEGylation technology platform. The product is currently in phase II clinical development. Irinotecan is an important chemotherapeutic agent used for the treatment of solid tumours, including colorectal and lung cancers. By applying Nektar's small molecule PEGylation technology to irinotecan, NKTR-102 may prove to be a more powerful and tolerable anti-tumour agent. Preclinical studies show that treatment with NKTR-102 results in significant suppression of tumour growth in an irinotecan-resistant mouse colorectal tumour model and in similar models of breast and lung cancer. Administration of NKTR-102 in an animal model also results in a markedly improved time-concentration profile for SN38, the active metabolite of irinotecan, as compared to treatment with irinotecan.
Nektar PEGylation technology can enhance the properties of therapeutic agents by increasing drug circulation time in the bloodstream, decreasing immunogenicity and dosing frequency, increasing bioavailability and improving drug solubility and stability. It can also be used to modify pharmaceutical agents to preferentially target certain systems within the body. It is a technique in which non-toxic polyethylene glycol (PEG) polymers are attached to therapeutic agents, and it is applicable to most major drug classes, including proteins, peptides, antibody fragments, small molecules, and other drugs.
Nektar PEGylation technology is also used in eight additional approved partnered products in the US or Europe today, including Roche's Pegasys for hepatitis C and Amgen's Neulasta for neutropenia.