NKTR-102

Therapeutic Area	Nektar Discovered	Indication	Phase
Oncology
NKTR-102
		Metastatic Breast Cancer	Phase 3
		Platinum-Resistant Ovarian Cancer	Phase 2
		Second-Line Colorectal Cancer	Phase 2
		GI and solid tumors In combination with 5-FU	Phase 1

Market Overview

NKTR-102 is in Phase 3 clinical development for patients with metastatic breast cancer and Phase 2 clinical development for patients with solid tumor malignancies, including ovarian and colorectal cancers. Each year, approximately 3 million patients worldwide are diagnosed with one of these types of cancer.

NKTR-102 Clinical Data and Product Profile

NKTR-102 is a next generation topoisomerase I-inhibitor with a unique pharmacokinetics profile that provides a continuous concentration of active drug with reduced peak concentrations. NKTR-102 was invented by Nektar using its polymer conjugate technology platform which conjugates cytotoxic small molecules to a uniquely engineered macromolecular polymer core using specialized linkers.

Topo I inhibitors are important chemotherapeutic agents used to treat cancer. Immediately after dosing, however, standard topo I inhibitors reach high peak concentrations and diffuse quickly throughout the body---penetrating and damaging healthy tissue, such as bone marrow, as well as tumor tissue. Subsequent rapid metabolism limits topo I exposure in tumor cells, reducing the duration of their effect and resulting in a much lower tumor exposure to the active metabolite that may limit their efficacy.

NKTR-102 is a novel macromolecular chemotherapeutic designed to enhance the anti-cancer effects of topo I inhibition while minimizing its toxicities. Unlike first generation topo I inhibitors that exhibit a high initial peak concentration and short half-life, NKTR-102’s unique pro-drug design results in a lowered initial peak concentration of active topo I inhibitor in the blood. The large NKTR-102 molecule is inactive when administered. Over time, the body’s natural enzymatic processes slowly metabolize the linkers within the molecule, continuously freeing active drug that then works to stop tumor cell division through inhibition of topo I.

Clinical and preclinical studies with NKTR-102 have been shown to increase the life and exposure profiles relative to irinotecan, resulting in significant anti-tumor activity. In preclinical models, NKTR-102 achieved a 300-fold increase in tumor concentration as compared to a first generation topo 1 inhibitor. Because NKTR-102 is a large molecule, it is believed to penetrate the leaky vasculature within the tumor environment more readily than normal vasculature, concentrating and trapping NKTR-102 in tumor tissue.

Clinical studies have shown that the half-life of active drug generated from NKTR-102 is greatly extended to 50 days and that active drug remains in circulation throughout the entire chemotherapy cycle, providing sustained exposure to topo I inhibition.

NKTR-102 is currently in development for the treatment of breast, ovarian and colorectal cancers.

Ongoing clinical development for NKTR-102:

• In metastatic breast cancer, a Phase 3 randomized, head to head study of NKTR-102 compared to Treatment of Physician's Choice (TPC) is currently enrolling.

• In ovarian cancer, an expanded Phase 2 study of single-agent NKTR-102 in platinum refractory/resistant ovarian cancer in women who failed prior Doxil therapy is currently enrolling up to 125 patients in total. Phase 3 planning is also underway.

• In colorectal cancer, a 174-patient Phase 2 randomized, head-to-head study of NKTR-102 compared to irinotecan in patients with second-line colorectal cancer with the KRAS gene mutation is in progress, along with a Phase 1 study to explore the use of NKTR-102 in a combination regimen with 5-FU based therapy.

Highlighted Data Presentations:

Data from a Phase 2 clinical study of NKTR-102 in metastatic breast cancer were presented in an oral abstract session at the 2011 ASCO Breast Cancer Symposium by Agustin Garcia, MD. View presentation slides.

Data from a Phase 2 clinical study of NKTR-102 in metastatic breast cancer were presented at the 2011 ASCO Annual meeting (click here to download this presentation). Data from a Phase 2 clinical study of NKTR-102 in a subpopulation of patients with platinum-resistant/refractory ovarian cancer and prior Doxil® (pegylated liposomal doxorubicin or PLD) treatment were presented at the 2011 ASCO Annual Meeting (click here to download this presentation).

Data from a Phase 2 clinical study of NKTR-102 in metastatic breast cancer were presented at the 2010 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium (click here to download this presentation).

Data from a Phase 2 clinical study of NKTR-102 in platinum-resistant/refractory ovarian cancer were presented at the 2010 ASCO Meeting (click here to download this presentation).

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