Amgen To Re-Launch AMG 706 Phase II Enrollment, Phase III Still Delayed

Amgen will re-launch enrollment of head-to-head Phase II studies for its oncologic AMG 706 after concerns were raised about the potential development of cholecystitis, although the Phase III trials remain indefinitely delayed.

"We had concerns about potential safety signals with respect to cholecystitis, and we're still investigating that, but we've become confidant enough in where we stand that we are re-launching enrollment," Amgen Exec VP-Research & Development Roger Perlmutter said during the company's third quarter earnings call Oct. 24.

Amgen's Phase II head-to-head trials comparing the multi-targeted vascular endothelial growth factor agent to Genentech's Avastin (bevacizumab) in first-line HER2 negative metastatic breast cancer and in first-line non-small cell lung cancer will re-launch with protocol amendments during the fourth quarter.

"This reflects...a lot of review of data and discussion with experts in oncology and gallbladder physiology, and we feel like we have an understanding of where we are with respect to AMG 706," Perlmutter said. "We're going to be performing some studies in '07 that will help illuminate the effect of AMG 706 on gall bladder function, if any," he added.

Two "mega-site" Phase III clinical trials in first-line breast cancer and first-line non-small cell lung cancer, previously expected to begin in the fourth quarter, remain delayed. Amgen has planned 11 "mega-trials" for the year, nine have been initiated.

The increased frequency of cholecystitis (inflammation of the gall bladder) was first reported in the firm's second-line gastrointestinal stromal tumor study, which Amgen announced during its second quarter earnings call. Interim GIST data showed that between 2% and 3% of AMG 706 patients had developed the condition.

At the time, Perlmutter assured analysts that Amgen was not going to halt ongoing studies. In retrospect, it appears Amgen did temporarily halt enrollment of the Phase II studies.

The GIST data is expected to be presented at the Connective Tissue Oncology Society meeting in the first week of November, which "will give a sense of the efficacy profile of AMG 706," Perlmutter said.

In addition, "we do expect fairly soon to be able to see the behavior of AMG 706 in metastatic thyroid cancer refractory to previous treatment, a Phase II study with 184 subjects for which enrollment has been complete for some time." Data from that study is expected to be published in the first half of 2007.

Amgen has been ramping up spending on R&D due to the number of clinical trials planned or ongoing. The company reported that R&D expenses increased 49% during the third quarter to $835 mil., in part because of the increased funding needed to support the company's late-stage clinical program (¹ (Also see "Amgen Struggles To Spark Enbrel Growth, Faces Increased Competition" - Pink Sheet, 30 Oct, 2006.), p. 10).

However, AMG 706 is not the only clinical program where Amgen is having trouble. The firm is also facing enrollment delays in clinical trials for its epidermal growth factor receptor inhibitor Vectibix . Panitumumab cleared FDA Sept. 27 with accelerated approval for treatment of metastatic colorectal cancer following fluoropyrimidine, oxaliplatin and irinotecan containing regimens (² (Also see "Amgen Vectibix Cap Cuts Patient Cost, But Will Payers Balk At High Price?" - Pink Sheet, 2 Oct, 2006.), p. 3).

The company's randomized, open-label, Phase IIIb Panitumumab Advanced Colorectal Cancer Evaluation study is evaluating whether panitumumab, administered concomitantly with chemotherapy and Avastin, improves progression-free survival compared to chemotherapy and Avastin alone.

PACCE "enrollment was slower than we had hoped for," Perlmutter said. "But it picked up smartly, and indeed, we enrolled 824 patients in [the] oxaliplatin-containing arm and 229 patients in the irinotecan arm."

Amgen had hoped the release of initial results from PACCE, which began in April 2005, would coincide with the initial approval. However, during the third quarter Amgen was still completing enrollment of all 1,000 patients.

"There's a lot of interesting information that will come out of this [trial], beginning with response rate data which we'll make available in January of '07," Perlmutter said. "And thereafter we'll begin to talk about progression data and survival data as these data roll out."

The company is currently enrolling its Phase II second-line and first-line registrational colorectal studies and Phase II third-line colorectal cancer study in Japan. Amgen's adjuvant CRC study, a cooperative group study with the National Surgical Adjuvant Breast & Bowel Project, is expected to start in Q2 or Q3 of 2007; the NSABP study was originally slated to begin in Q1 or Q2 of 2007. Perlmutter explained that the timeframe reflects "ongoing discussions with NSABP about study design."

"In head and neck cancer, our first-line study for locally advanced squamous cell carcinoma [SCCHN]....We now expect study initiation probably in Q2 or Q3 '07, with a slightly larger number of patients, again, based on our consideration of data that have become available in other contexts and discussions with regulatory agencies."

The first-line locally advanced SCCHN Phase III study was slated to begin in Q1 2007. During its second quarter earnings call, Amgen reported that the Phase III trial in first-line recurrent or metastatic SCCHN had been delayed in response to changes in the competitive marketplace in the head and neck setting. Bristol/ImClone's Erbitux was approved for head and neck cancer in March, and Sanofi-Aventis' Taxotere received approval for SCCHN Oct. 18. Other agents, such as GSK's Tykerb , are in SCCHN studies.

Perlmutter said that "we still are expecting to engage in our study on recurrent/metastatic [SCCHN] beginning in the first quarter of 2007."

Amgen's Phase III trials for its subcutaneous injection immune thrombocytopenic purpura therapy AMG 531 in pre- and post-splenectomy will conclude at the end of 2006, with database locks in early 2007.

An open label Phase II study of AMG 531 was published in the New England Journal of Medicine Oct. 19. The double-blind, placebo-controlled evaluation of 21 patients with ITP found that weekly doses of AMG 531 at 1 and 3 µg/kg increased the platelet count "in most patients," and that it caused no major adverse events.

The median time from the first dose to peak count was 18 days for 1 µg/kg and 19 days for 3 µg/kg, compared to 63 days for placebo. Seven out of eight patients receiving 1 µg/kg and three out of eight patients receiving 3µg/kg reached the targeted platelet range. The targeted range was exceeded by an additional two patients receiving the 3µg/kg dose. An open label extension of the trial is ongoing.

Amgen also has Phase II AMG 531 studies in chemotherapy-induced thrombocytopenia and in patients with low or intermediate risk myelodysplastic syndrome, which are currently enrolling.

Amgen's Phase III trial in post-menopausal osteoporosis for its RANK ligand agent denosumab with nearly 8,000 patients is ongoing and scheduled to be completed in 2008. Data will be published in 2009. The company announced in April that it would be waiting for three-year data before submitting denosumab for treatment of PMO, after previously suggesting it may file for the indication based on a two-year interim analysis of the trial.

Amgen is also conducting several head-to-head trials for denosumab with bisphosphonates: one versus Merck's Fosamax (alendronate) and three versus Novartis' Zometa (zoledronic acid) (³ (Also see "Amgen Head-To-Head R&D Strategy Speaks To Growing Importance Of Payers" - Pink Sheet, 6 Feb, 2006.), p. 21).

The company is enrolling for the head-to-head Phase III study versus Fosamax, as well as for a Phase III study evaluating patients who are already being treated with Fosamax and then switched to denosumab. The Phase III head-to-head studies comparing denosumab to Zometa in treating bone metastases in prostate cancer, breast cancer and solid tumors are ongoing. "Those studies are all enrolling, they're very large studies, and we're completely focused on the execution of these studies," Perlmutter said.

The company will be presenting six-month Phase II data from a denosumab trial in rheumatoid arthritis, aimed at prevention of bone erosion and cartilage degradation, at the American College of Rheumatology meeting in November.

Amgen is also enrolling for large Phase III trials of two of its marketed products, the anemia therapy Aranesp and the hyperparathyroidism therapy Sensipar , looking at their effects on cardiovascular outcomes.

The company is seeking to confirm results from two Phase II studies of Aranesp in heart failure patients with its large scale RED-HF trial. A pooled analysis of the two randomized Phase II trials in heart failure was presented at the European Society of Cardiology Heart Failure conference in June. The data showed a trend towards benefit with Aranesp, but "require confirmation from a large, Phase III randomized controlled clinical trial," Amgen said.

Another Phase III Sensipar study in chronic renal insufficiency has completed enrollment; data will be released in the fourth quarter of 2007.

- Kathryn Phelps