On the heels of a new warning label for its erythropoietin drugs Aranesp and Epogen, shares of Amgen Inc. dipped a little lower on more bad news. The company stopped a Phase III trial of its colorectal cancer drug Vectibix in a dual-biologic, first-line treatment regimen due to a lack of efficacy and toxicity concerns.

While not designed as a registrational study, Amgen had hoped results from the PACCE Phase IIIb trial would demonstrate improved progression-free survival in patients receiving both Vectibix (panitumumab) and the VEGF inhibitor Avastin in addition to chemotherapy. However, data from the interim analysis - conducted after the first 231 events of death or disease progression - showed that the addition of Vectibix had the opposite effect. Patients receiving both biologics and chemotherapy demonstrated a lower progression-free survival rate than patients receiving only Avastin and chemotherapy. The Vectibix treatment group also showed a statistically significant lower rate of overall survival compared to the control group.

Amgen's stock (NASDAQ:AMGN) lost $2.45 Friday to close at $58.02, though analyst Christopher Raymond, with Robert Baird & Co. in New York, maintained an "outperform" rating. He wrote in a research note that Vectibix "has potential for strong uptake" in second- and third-line settings," though the PACCE data might delay the drug's off-label use in first-line therapy. That setback prompted him to adjust revenue estimates for Vectibix, now projecting that sales won't hit $1 billion until 2010.

For Amgen, the trial results should not affect any ongoing registrational trials of Vectibix in combination with chemotherapy in first- and second-line treatments, said Amgen spokeswoman Trish Hawkins. The PACCE study - or Panitumumab Advanced Colorectal Cancer Evaluation - was intended "to explore a dual biologics approach" and it marked the first time Amgen tested both a VEGF (vascular endothelial growth factor) inhibitor and an EGFr (epidermal growth factor receptor) in combination with chemotherapy in colorectal cancer.

South San Francisco-based Genentech inc.'s Avastin (bevacizumab) is approved for first-line metastatic colorectal cancer patients in combination with chemotherapy.

The randomized, open-label trial tested chemotherapy (oxaliplatin and irinotecan) plus Avastin, with or without Vectibix, as a first-line therapy in 1,054 patients with metastatic colorectal cancer. The primary endpoint was defined as a 30 percent improvement in progression-free survival with the addition of Vectibix.

Instead, "we saw statistical significance favoring the control arm," Hawkins told BioWorld Today.

The company reported hints of the trial's toxicity issues in its fourth-quarter earnings call in January. At that time, interim 12-week data showed an increased incidence of adverse events, such as diarrhea, dehydration and infection in the Vectibix arm, as well as an increased occurrence of pulmonary embolism. (See BioWorld Today, Jan. 29, 2007.)

While the trial results were disappointing for the Thousand Oaks, Calif.-based company, the news was a shot in the arm for ImClone Systems Inc., which, along with partner Bristol-Myers Squibb Co., markets its competing colorectal cancer drug, Erbitux (cetuximab). Shares of ImClone (NASDAQ:IMCL) jumped $4.62 Friday to close at $38.50.

Though Erbitux, which gained approval in 2004, is ahead in development, it's been widely thought that Vectibix would prove to be a better EGFr inhibitor, with a slightly safer profile and more convenient dosing. Worldwide sales of Erbitux totaled $1.1 billion in 2006.

Both products are moving forward in additional late-stage trials for expanded uses in colorectal cancer. In January, ImClone and BMS, both of New York, reported positive top-line Phase III data from Erbitux in first-line metastatic colorectal cancer. In combination with an irinotecan-based chemotherapy, the drug met its primary endpoint of increasing median duration of progression-free survival over chemotherapy alone. (See BioWorld Today, Jan. 11, 2007.)

Meanwhile, Amgen is conducting two Phase III studies: one as a first-line treatment in 900 patients, and one as a second-line treatment in 1,100 patients. Those studies are expected to be completed around 2009-2010, Hawkins said.

Vectibix pulled in revenues of about $39 million in the fourth quarter. "It's been doing well since we launched, and we still think it's going to offer a significant benefit to patients," she said. "So we're going to follow the science where it takes us."

The company is conducting early stage testing of Vectibix in combination with AMG 706, a multi-kinase inhibitor, though it's not clear yet whether the PACCE data would have any impact on that program.

The largest biotech firm in terms of revenues - the company reported $3.8 billion in revenue for the fourth quarter of 2006 - Amgen's had a run of bad news so far this year. In January, it told investors it would not file for an expanded indication of Sensipar (cinacalcet HCl) in secondary hypertension after Phase III data showed an increase in asymptomatic hypocalcemia. And, earlier this month, the company's top-selling EPO drugs were slapped with a "black box" warning, citing risks of death and cardiovascular events and tumor growth when used in off-label dose regimens or populations. Amgen countered that most problems stem from the drugs being administered at higher-than-approved levels, and the company will take part in an FDA panel to discuss EPO drug issues. The new warnings affected Aranesp (darbepoetin alfa), Epogen (epoetin alfa) and Epogen's counterpart, Procrit, which is marketed by New Brunswick, N.J.-based Johnson & Johnson. (See BioWorld Today, March 12, 2007.)

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