Nektar Therapeutics announced that it has presented positive preclinical data on its proprietary product candidate NKTR-102 (PEG-irinotecan) at the AACR-NCI-EORTC International Conference in San Francisco, California.
The presentations highlighted the anti-tumour activity and unique pharmacokinetic profile of NKTR-102 in preclinical models of colorectal, lung and breast cancer. NKTR-102 is a PEGylated form of irinotecan developed using Nektar's innovative small molecule PEGylation technology platform and is in Phase 1 clinical development for the treatment of solid tumours.
In the two data presentations, NKTR-102 inhibited tumour growth by greater than 90 per cent in mouse xenograft models of colorectal (HT29), lung (NCI- H460) and breast (MCF-7) cancers as compared to controls. The studies also demonstrate that Nektar's small molecule PEGylation technology improves the pharmacokinetics of irinotecan by increasing the effective half-life of irinotecan's active metabolite in tumour tissues. In a colorectal cancer model, the half-life was increased to 15 days following NKTR-102 administration versus 4 hours following irinotecan.
"The studies presented at the 2007 AACR-NCI-EORTC Conference highlight the superior tumoursuppression properties of NKTR-102 relative to irinotecan in colorectal, lung and breast cancer models," stated Hoyoung Huh, M.D., Ph.D., chief operating officer and head, PEGylation Business Unit, Nektar. "NKTR-102 demonstrates improved half-life and tumourexposure to irinotecan's active metabolite, effectively inhibiting the cellular replication process in solid tumours. These findings validate the potential of our small molecule PEGylation technology platform to improve a wide range of oncolytics in critical cancer treatment regimens."
Preclinical studies in mouse xenograft tumour models evaluated comparative anti-tumour activity and pharmacokinetics of NKTR-102 and irinotecan as compared to controls. In each model, a single IV administration of NKTR-102 on days 0, 4 and 8 in tumor-bearing mice resulted in substantial tumour growth inhibition in a statistically-significant dose-related manner. Anti-tumour activity was measured as changes in tumour weight, tumour growth inhibition and tumour regression.
In all models, NKTR-102 was well-tolerated with no drug toxicity deaths. In the colorectal and lung cancer models, NKTR-102 inhibited tumour growth at all dose levels with 94 per cent tumour suppression at the highest dose of 90 mg/kg relative to controls. Tumour regression was also observed with NKTR-102 at this same dose level, while no regression was observed with irinotecan administration. Irinotecan dosing at 90 mg/kg resulted in only modest tumour growth inhibition of 6 per cent in colorectal and 24 per cent in lung.
In the breast cancer model, NKTR-102 suppressed tumour growth by 92 per cent at all dose levels relative to controls with irinotecan only resulting in tumour growth inhibition of up to 56 per cent.
Favourable Pharmacokinetics of NKTR-102 in Lung and Colorectal Mouse Xenograft Models
Following NKTR-102 administration, exposure to the active metabolite of irinotecan in colorectal and lung tumour tissue was increased substantially relative to irinotecan. In colorectal tumour tissue, the effective half-life of the metabolite was increased from 4 hours with irinotecan to 15 days with NKTR-102. In lung tumour tissue, the effective halflife of the metabolite was increased from 15 hours with irinotecan to 6 days with NKTR-102.
This increased and prolonged metabolite exposure following administration of NKTR-102 was associated with its anti-tumour activity in lung and colorectal models using pharmacokinetic (PK) and pharmacodynamic (PD) modeling. Further, PK/PD simulations performed with irinotecan administration show that a continuous infusion of irinotecan at 240 mg/kg would be required to achieve the equivalent tumour exposure of the active metabolite and associated tumour growth inhibition found with NKTR-102. This 240 mg/kg dose of irinotecan would be expected to cause significant mortality in mice.
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 1 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.
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.
Nektar Therapeutics is a biopharmaceutical company that develops and enables differentiated therapeutics with its industry-leading PEGylation and pulmonary drug development technology platforms. Nektar PEGylation and pulmonary technology, expertise, manufacturing capabilities have enabled nine approved products for partners, which include the world's leading pharmaceutical and biotechnology companies