GlaxoSmithKline's strategy of building its oncology business is paying off with a range of new chemical entities entering Phase III development within the next year for cancer-related indications, executives said during an oncology R&D update in New York.

Products highlighted during the Nov. 30 review include the dual kinase inhibitor Tykerb (lapatinib) for breast cancer, the VEGF inhibitor pazopanib, the anti-emetic casopitant and the thrombocytopenia therapy eltrombopag (see chart: " ¹ Moving Down the Pipeline...', p. 6).

"We have one of the largest oncology and supportive care pipelines in the industry," R&D Chairman Tachi Yamada said. "Ours compares with any other company."

GSK bolstered its oncology portfolio and pipeline following the merger of Glaxo Wellcome and SmithKline Beecham in 2001, with the expectation that oncology would become one of the fastest-growing therapeutic areas, Yamada said.

"We knew when we formed the new company in 2001 that we were very strong in many therapeutic areas," the exec said. "But we also knew that the biggest therapeutic areas and the biggest opportunities for growth were areas in which we were not amongst the leaders, in particular oncology."

GSK recruited several leading researchers in the field, including Merck's former head of oncology Allen Oliff; Paolo Paoletti, the former head of oncology at Lilly; and former Abbott VP-Global Oncology Development Perry Nisen.

GSK also developed external collaborations with companies such as Exelixis, Cytokinetics, Human Genome Sciences and Corixa, as well as with academia, including the University of Pennsylvania, Imperial College and Oxford University, Yamada said.

"Today, we can feel pretty proud of our oncology programs," Paoletti declared.

One of the cornerstones of GSK's oncology pipeline is the investigational breast cancer therapy lapatinib, which will carry the trade name Tykerb.

The company is expanding the clinical program for lapatinib, demonstrating GSK's confidence in the drug, Paoletti said. Paoletti is senior VP of the Oncology Medicine Development Center.

Three new Phase III trials investigating lapatinib are scheduled to start by January, including two studies in first-line therapy and one in refractory breast cancer. GSK plans to submit an NDA for the oral tyrosine kinase inhibitor by either the end of 2006 or the first half of 2007.

Registration will focus initially on a refractory breast cancer indication. GSK hopes to position Tykerb as the first dual kinase inhibitor targeting both ErbB1 (EGFR) and ErbB2 (HER-2), Paoletti said.

GSK will then seek a first-line indication for the treatment of advanced breast cancer before integrating it into adjuvant therapy, he said.

GSK has bounced back and forth on whether to initially focus lapatinib's development in first-line or refractory breast cancer.

In May, after more positive clinical trial results were seen in the front-line setting and less favorable data were demonstrated in a refractory setting, the company said it would delay filing until 2006-2007 to await new trial results (² Also see "GSK Lapatinib Breast Cancer Development Shifts To Front-Line Setting" - Pink Sheet, 23 May, 2005., p. 13).

The announcement marked the second delay in GSK's timeline for filing the drug. The company had originally anticipated submitting an NDA in 2004, then postponed plans until 2005.

Paoletti said development in both front-line and refractory breast cancer will be rapid and aggressive. Based on evidence to date combining studies in 3,500 patients, Tykerb has demonstrated a 26% response rate with Genentech's Herceptin (trastuzumab) in refractory breast cancer and a 33% response rate in first-line Herceptin-naive patients.

Tykerb also could potentially be an "ideal" therapy for the adjuvant setting, Paoletti said. He cited research showing activity in first-line metastatic breast cancer similar to that of Herceptin, with low incidence of cardiotoxicity, a possible effect on brain metastases and the convenience of an oral dosage form.

Based on its potential as an adjuvant treatment, GSK and the Breast Cancer International Group signed an agreement in November to collaborate on an adjuvant trial. The multi-arm study, expected to begin in 2006, will enroll 8,000 women.

In research efforts on pazopanib, GSK plans to start a Phase III study evaluating the oral VEGF inhibitor as a single agent for the treatment of renal cancer early next year. The company is also studying the drug for the treatment of solid tumors, breast and lung cancer, including combinations with chemotherapy and lapatinib.

In the supportive care setting, GSK is pursuing the NK-1 agonist casopitant to address a "significant unmet medical need" in the treatment of chemotherapy-induced nausea and vomiting and post-operative nausea and vomiting, the company said.

"GSK has been a leader in this field," Paoletti said, and "we want to continue to be a leader." The firm markets the anti-emetic Zofran (ondansetron).

Data from Phase II trials in chemotherapy patients showed that those treated with 100 mg casopitant combined with Zofran and dexamethasone experienced a 26% improvement compared to patients treated with Zofran and dexamethasone alone.

In a trial of post-operative patients, those treated with 150 mg casopitant, Zofran and dexamethasone experienced a 15% improvement versus the control, GSK reported.

The company will initiate Phase III trials evaluating casopitant for PONV and CINV in 2006, with the post-op studies slated to begin first. Regulatory filings are anticipated in 2007.

The company also is moving the thrombocytopenia treatment eltrombopag into Phase III following positive Phase II results.

In a Phase II study in patients with idiopathic thrombocytopenic purpura who had failed at least one prior therapy and had a platelet count below 30,000, 87% of those treated with 75 mg eltrombopag achieved the primary endpoint of a platelet count of 50,000 or higher after six weeks.

The company is studying eltrombopag in an ongoing Phase II trial in hepatitis C patients. GSK expects to initiate Phase III trials in both ITP and hepatitis C patients in 2006.

The company hopes to submit an application for a short-term treatment indication in ITP patients next year, with a filing for long-term treatment expected in 2008. A filing in hepatitis C is also targeted for 2008.

GSK also is investigating the benign prostatic hyperplasia therapy Avodart (dutasteride) for prostate cancer risk reduction, which would be a first-of-its-kind indication.

The company completed enrollment of 8,000 patients in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial in January and expects an interim data analysis in 2007. A full analysis is slated for early 2009.

Paoletti said the company decided to pursue a prevention indication for Avodart after two Phase III studies supporting the BPH filing demonstrated a 50% reduction in prostate cancer risk in patients treated with Avodart compared to placebo.

"This trial was not designed for this reason, but the signal was very important," Paoletti said.

The company also was propelled by results from the National Cancer Institute's Prostate Cancer Prevention Trial, which demonstrated a reduction in prevalence of prostate cancer in patients treated with Merck's Proscar (finasteride) versus placebo (³ Also see "Merck To Seek Prostate Cancer Claim For Proscar Despite Short Patent Life" - Pink Sheet, 28 July, 2003., p. 23).

GSK Oncology Pipeline Expansion Means Healthy Phase III Program In ’06

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