Amgen/Takeda VEGF Inhibitor Motesanib Faces Setback In NSCLC

Enrollment in a Phase III trial in NSCLC patients is suspended after early mortality rates were seen in the treatment arm.

Partners Amgen and Takeda have pinned near-term oncology growth prospects on motesanib, a vascular endothelial growth factor inhibitor for the treatment of non-small cell lung cancer. Now motesanib is facing a setback; Amgen announced Nov. 19 that the Phase III MONET-1 study has been temporarily suspended after a planned safety review showed earlier mortality rates in the treatment group.

An independent data monitoring committee found a higher incidence of hemoptysis (severe bleeding at the site of the tumor) in squamous NSCLC patients taking motesanib.

It made the decision after reviewing data from the first 600 patients enrolled in a trial comparing treatment with carboplatin and paclitaxel administered every three weeks with or without 125 mg of motesanib daily. The study had enrolled 1,100 patients of the targeted 1,240, including both squamous and non-squamous NSCLC patients.

In addition to temporarily suspending enrollment, the DMC also recommended that patients with squamous NSCLC immediately discontinue motesanib. Non-squamous NSCLC patients were not directed to discontinue therapy, however. About one-third of the patients enrolled in the study had squamous cell carcinoma, Amgen said, reflective of the overall patient population.

Partners hoped to show superiority to Avastin

The company had expected the study to complete enrollment in 2009, with data available in 2010. Now it's unclear how the suspension could impact the timing of collecting data in non-squamous patients continuing with treatment.

Amgen has been hoping to position motesanib as superior to Genentech's Avastin (bevacizumab) -the only VEGF inhibitor approved for treatment of NSCLC. During the company's analyst day Nov. 7, management highlighted motesanib as a potential best-in-class multi-kinase inhibitor.

Amgen partnered with Japanese drug maker Takeda earlier this year on rights for motesanib, offering an upfront payment of $100 million and $175 million in milestones to share 50 percent of global, ex-Japan profits. The deal was part of a larger partnership in which Takeda acquired Japanese development and commercialization rights to 13 of Amgen's clinical candidates (¹ (Also see "Takeda Makes $1 Billion Move For Amgen Development Rights" - Pink Sheet, 4 Feb, 2008.)).

Amgen and Takeda are conducting two ongoing Phase II studies in breast and lung cancer, excluding squamous cell patients, pitting motesanib against Avastin. Enrollment in those studies has completed, and data is anticipated in 2009.

Safety issues reflect class effect, Amgen says

Several VEGF inhibitors have faced similar challenges in the NSCLC patient population. Avastin is not approved for patients with the squamous form of the disease.

Avastin labeling includes a "black box" warning on the risk of fatal pulmonary hemorrhage in patients with NSCLC, and points to incidence of severe or fatal hemoptysis of 31 percent in patients with squamous histology versus 2.3 percent in patients with NSCLC excluding predominant squamous histology.

"While we are disappointed in this outcome, it is consistent with data seen with some other anti-VEGF therapies and appears to constitute a class effect of these types of agents," Amgen Exec VP R&D Roger Perlmutter said in a statement.

Bayer/Onyx experienced a similar setback with their multi-kinase inhibitor Nexavar (sorafenib) in lung cancer, when investigators halted a Phase III trial earlier this year after a panel concluded it would not meet its primary endpoint of overall survival and that higher mortality was observed in patients with squamous cell carcinoma (² (Also see "Bayer/Onyx’s Nexavar Falters In Lung-Cancer Phase III" - Pink Sheet, 19 Feb, 2008.)).

AstraZeneca announced a Phase II/III study evaluating its anti-VEGF candidate Recentin (cediranib) in NSCLC patients would not move forward into Phase III due to an imbalance in toxicity; trials in colorectal cancer are continuing (³ (Also see "AstraZeneca’s Recentin Will Move Into Phase III For Colorectal Cancer, But Not NSCLC" - Pink Sheet, 27 Feb, 2008.)).

Amgen's Phase II oncology pipeline is full

For Amgen, motesanib is the nearest term opportunity for a new drug approval after the osteoporosis candidate denosumab, which is also in studies for bone metastases.

However, the biotech has several targeted oncology candidates in Phase II development, including the monoclonal antibody AMG 655 in pancreatic cancer, colorectal cancer and lung cancer; the angiogenesis inhibitor AMG 386 in ovarian cancer, breast cancer and gastric cancer; and an Apo2 ligand/TRAIL in NSCLC.

"This news is clearly disappointing as motesanib is immediately behind denosumab as Amgen's next Phase III asset and future growth driver in oncology," Rodman & Renshaw analyst Christopher James said in a Nov. 20 research note. "That being said, we believe Amgen's pipeline remains full with compounds the company can leverage and provide future growth for the oncology franchise."

The setback for motesanib is the second oncology disappointment for Takeda in as many months, both involving pricey partnerships. In October, Cell Genesys/Takeda's cancer immunotherapy GVAX failed a second Phase III clinical trial in prostate cancer patients, and development of the drug was placed on hold (⁴ (Also see "Cancer Immunotherapy Sees Setback With Failure Of Cell Genesys’ GVAX" - Pink Sheet, 16 Oct, 2008.)).

That development came about six months after Takeda signed a partnering deal with Cell Genesys for GVAX, paying $50 million upfront.

Disappointments with motesanib and GVAX put more pressure on Millennium to drive Takeda's oncology growth. Takeda announced the acquisition of the Velcade marketer in April for $8.8 billion, as part of a goal of becoming a top three oncology company (⁵ (Also see "Takeda’s Millennium Buy Brings In Potential Cancer Blockbuster Velcade" - Pink Sheet, 14 Apr, 2008.), p. 8).

-Jessica Merrill ([email protected])