The U.S. Food and Drug Administration (FDA) earlier today designated etirinotecan pegol (NKTR-102; Nektar Therapeutics, San Francisco, CA) as a Fast Track development program for the treatment of patients with locally recurrent or metastatic breast cancer progressing after treatment with an anthracycline, a taxane, and capecitabine (ATC).

Etirinotecan pegol is a unique, targeted topoisomerase I inhibitor based on Nektar’s proprietary PEGylation and advanced polymer conjugation technology which attached irinotecan to a polyethylene glycol (PEG) polymer using a biodegradable linker. The drug candidate is currently being evaluated in a Phase III study in women with metastatic breast cancer.

More than one million people worldwide are diagnosed with breast cancer globally every year.[1] The chance of developing invasive breast cancer at some time in a woman’s life is a little less than one in eight (12%). There are approximately 200,000 new cases of breast cancer in the United States and 430,000 in Europe each year. [2] Metastatic breast cancer refers to cancer that has spread from the breast to distant sites in the body.

Treatment options
Anthracyclines and taxanes (AT) are the most active and widely used chemotherapeutic agents for breast cancer, but the increased use of these agents at an early stage of disease often renders tumors resistant to these drugs by the time the disease recurs, thereby reducing the number of treatment options for metastatic disease. Drugs used to treat patients who progress following AT treatment can have response rates of 20-30%, however, resistance develops rapidly and new agents with different mechanisms of action, such as topoisomerase I inhibitors, are needed that have the potential to overcome the problem of drug resistance to prior therapies. [3] There are currently no FDA-approved topoisomerase I inhibitors to treat breast cancer.

Improved efficacy
“Patients with advanced breast cancer who have progressed following ATC therapies have limited treatment options to manage their disease. As a novel targeted topoisomerase I inhibitor, etirinotecan pegol is a different mechanism of action than currently approved therapies and has the potential to deliver improved efficacy while offering a more tolerable therapy for women with this aggressive disease,” noted Robert Medve, MD, Chief Medical Officer of Nektar Therapeutics.

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Non-overlapping mechanism of action
Nektar requested Fast Track designation from the FDA for etirinotecan pegol based upon what is known about its safety and efficacy profile to-date from the nonclinical, Phase I and Phase II clinical studies, as well as etirinotecan pegol’s potential to deliver better efficacy and a more tolerable therapy for patients with locally recurrent or metastatic breast cancer progressing after treatment with ATC. The drug candidate, a new topoisomerase I inhibitor, was designed to improve the efficacy of irinotecan by modifying the distribution of the drug candidate within the body.

As a new topoisomerase I inhibitor, etirinotecan pegol has a non-overlapping mechanism of action with other agents used to treat breast cancer which may mitigate potential cancer cross-resistance and reduce overlapping toxicities.

Irinotecan released from NKTR-102 following administration is further metabolized to the active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), that causes DNA damage through inhibition of topoisomerase. The goal in designing NKTR-102 was to attenuate or eliminate some of the limiting side effects of irinotecan while improving efficacy by modifying the distribution of the agent within the body. The size and structure of NKTR-102 results in marked alteration in pharmacokinetic (PK) profile for the SN38 derived from NKTR-102 compared to that following irinotecan. The maximal plasma concentration (Cmax) is reduced 5- to 10-fold and the half-life (t1/2 ) of SN38 is increased from 2 days to approximately 50 days. This altered profile leads to constant exposure of the tumor to the active drug. In addition, the large NKTR-102 molecule does not freely pass out of intact vasculature, which may account for relatively higher concentrations of the compound and the active metabolites in tumor tissues in in vivomodels, where the local vasculature may be relatively more permeable.

Fast Track program
Under the FDA Modernization Act of 1997, the Fast Track program facilitates interactions with the FDA before and during the submission of a New Drug Application (NDA) for therapeutics being investigated as a treatment for serious or life-threatening conditions, which demonstrate the potential to address an unmet medical need for such conditions. The program enables a company to file sections of an NDA on a rolling basis as data becomes available. This permits the FDA to review portions of the NDA as they are received, rather than waiting for the entire NDA filing prior to commencing the review process. With a Fast Track designation, there is the possibility of a priority review and a more opportunity for more frequent interactions with the FDA, which could decrease the typical development time and review period.

Ongoing trials
The Phase III BEACON Study (BrEAst Cancer Outcomes with NKTR-102) will enroll approximately 840 metastatic breast cancer patients who have had prior treatment with ATC in either the adjuvant or metastatic setting. The primary endpoint of the BEACON study is overall survival (OS). Secondary endpoints include progression-free survival (PFS), objective tumor response rates (ORR), clinical benefit rate, duration of response, pharmacokinetic (PK) data, safety, quality-of-life measurements, and measurement of healthcare resource utilization for the two study arms. Exploratory objectives of the study include collecting specific biomarker data which will be correlated with efficacy outcome measures. Enrollment in the BEACON study began in December 2011 and is expected to be completed by the end of 2013.

Etirinotecan pegol is also tested in other clinical trials, including platinum-Resistant Ovarian Cancer (phase II), second-Line Colorectal Cancer (phase II),in Bevacizumab-Resistant High Grade Glioma (phase II; NCT01663012) and GI and solid tumors in combination with 5-FU (phase I).

[1] American Cancer Society, 2007 Global Cancer Facts and Figures Report.
[2] American Cancer Society, 2009 Global Cancer Facts and Figures Report.
[3] Alvaro and Perez, Mayo Clin Proc. 2009; 84(6):533-545

Clinical trials:

– [NCT01457118] An Open-Label, Multicenter, Extension Study of NKTR-102 in Subjects Previously Enrolled in NKTR-102 Studies (Malignant Solid Tumour, Breast Cancer, Ovarian Cancer, Colorectal Cancer)

– [NCT00806156] Study to Evaluate the Safety and Efficacy of NKTR-102 in Patients With Metastatic or Locally Advanced Ovarian Cancer (Ovarian Cancer)

– [NCT00802945] Study to Evaluate the Safety and Efficacy of NKTR-102 in Patients With Metastatic or Locally Advanced Breast Cancer (Breast Cancer)

– [NCT00598975] A Phase 2a/2b Multicenter, Open-Label Study to Evaluate NKTR 102 (PEG-Irinotecan) in Combination With Cetuximab Versus Irinotecan in Combination With Cetuximab in Second Line Colorectal Cancer Patients (Colorectal Cancer)

– [NCT01
]Phase II NKTR-102 In Bevacizumab-Resistant High Grade Glioma (Anaplastic Astrocytomas, Anaplastic Oligodendrogliomas, Glioblastomas/GBM)

– [NCT01492101] The BEACON Study – Breast Cancer Outcomes With NKTR-102 (Locally Recurrent Breast Cancer, Metastatic Breast Cancer)

– [NCT00856375] NKTR-102 Versus Irinotecan in Patients With Second-Line, Irinotecan-Na?ve, KRAS Mutant, Colorectal Cancer.
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