Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Serious side effects like skin infections requiring hospitalization could limit market penetration.

An FDA advisory committee will convene on August 13 to discuss, what is considered by some, Amgen’s fate as a biotech giant. The panel will vote on recommending approval of the firm’s osteoporosis drug, denosumab. With product sales taking a hit due to labeling constraints and the entrance of biosimilars, denosumab is pegged as Amgen’s nearest shot on goal to bolster its position as a leader in the biopharmaceutical industry.

Phase III trial results, however, showed side effects such as serious infections requiring hospitalization. Despite its clear superiority in preventing fractures, relatively convenient dosing regimen of bi-annual subcuteanous injections, and concerns about long-term side effects of bisphosphonates, this side-effect profile could hinder physician acceptance and the drug’s market penetration.

Roger Perlmutter, M.D., Ph.D., head of Amgen’s R&D, commented in a webcast during the Goldman Sachs healthcare conference on June 10 that while he does not expect the drug’s efficacy to be questioned, safety issues with the antibody would come under scrutiny during FDA review.

Amgen reports that the denosumab program is “the largest ever initiated by Amgen” with nearly 20,000 patients participating in clinical trials for multiple indications worldwide. The company is seeking approval to market denosumab under the proposed brand name Prolia to treat or prevent osteoporosis in postmenopausal women as well as treat or prevent bone loss in patients undergoing hormone therapy for breast or prostate cancer. The scheduled PDUFA date for this humanized mAb is October 19.

Slowed Growth for Amgen

Amgen’s key product sales from Aranesp and Epogen have slowed due to safety-related labeling updates and reimbursement changes. Also the specter of biosimilar versions for Neuopogen and Neulasta (a longer-lasting Neupogen) looms; these drugs stimulate production of white blood cells in chemotherapy patients and lose patent protection in 2013 and 2015, respectively. In February Sandoz’ version of Amgen’s Neupogen obtained EU approval.

Insmed has geared up to produce alternate versions of Neupogen and Neulasta. The company has already faced competition in Europe for Epogen from Hospira’s biosimilar epoetin, Retacrit™. In March 2009 Merck & Co. purchased all Insmed’s biosimilars-related assets for $130 million. Merck has its own osteoporosis bisphosphonate drug called Fosamex, which now has generic versions sold by Teva Pharmaceuticals, Barr Pharmaceuticals, and Watson Pharmaceuticals.

Amgen CEO, Kevin Sharer, previously commented that he does not believe biosimilars will have the impact that generics have had on branded chemical drugs. Traditional small molecules can quickly lose 80% or more of their sales when faced with less expensive alternatives.

All Eyes on Denosumab

All this puts denosumab under huge pressure and at the same time has created great expectations; the antibody has the potential to deliver on part of the $7 billion osteoporosis market. J. P. Morgan analyst Geoffrey Meacham upgraded Amgen shares to overweight from neutral because of denosumab’s potential to become the market-leading osteoporosis drug, saying that “while Amgen’s revenue growth hit a trough in 2008, up only 1.6%, denosumab data was the driver of share performance.”

A June 1 study from Decision Resources says that denosumab along with Eli Lilly’s parathyroid hormone (PTH) analogue Forteo/Forsteo will drive the 4.3% annual growth in the U.S. osteoporosis drug market from 2013 to 2018. Denosumab could reach blockbuster sales of $2 billion by 2018, according to the report.

Amgen’s pivotal Phase III study consisted of approximately 7,800 women with osteoporosis, and patients received either denosumab or placebo. Treatment with denosumab resulted in a statistically significant reduction in the incidence of new vertebral fractures compared with placebo treatment. Women receiving denosumab also experienced a statistically significant reduction in the incidence of new nonvertebral and hip fractures (each secondary endpoints) compared with those receiving placebo.

Side-Effect Profile

The incidence and types of both adverse and serious adverse events observed in this study, including serious infections and neoplasms, were similar between the denosumab and placebo groups. A previous late-stage study in 332 participants, however, showed that some serious adverse events occurred in 18 women in the denosumab group and nine women in the placebo group. Overall, Dr. Perlmutter says that, although clinical trials had indicated similar side effect rates for both denosumab and placebo patients, denosumab patients had a higher rate of serious skin infections that required hospitalization.

The question remains whether, in a chronic disease setting such as osteoporosis in otherwise reasonably healthy individuals, this constitutes acceptable risk. Donny Wong, Ph.D., director of metabolic diseases at Decision Resources and author of the report previously mentioned, worries more about the risk of infection with denosumab use in immunocompromised cancer patients with already weakened immunity due to both disease and chemotherapy.

In that case he says, “The risk of infection may result in a black box warning and can potentially restrict the drug’s use in oncology. Right now the standard of care to slow bone metastases in cancer patients is relatively high-dose bisphosphonate drugs. But with higher bisphosphonate doses, osteonecrosis of the jaw is a complication. Denosumab’s premise is that it has a significant safety advantage over high-dose bisphsphonates.”

Patricia F. Dimond, Ph.D. ([email protected]), is a principal at BioInsight Consulting.

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