Bone builders

Dr. David Lacey, who today serves as Amgen’s Senior Vice President of Discovery Research, joined the company’s pathology group in 1994. One year later, he began research on a discovery that eventuated in denosumab, a fully human monoclonal antibody, which is receiving significant attention from the scientific and medical community as a potentially promising novel treatment for bone loss and destruction across a range of conditions, including osteoporosis, treatment-induced bone loss, bone metastases and rheumatoid arthritis.

The project initially started as a component project of what was termed the ‘Amgen Genome Program’. “The guiding strategy of the project was to determine the function of novel genes using mouse functional genomics. Our scientists would identify novel, predominantly secreted molecules through analysis of cDNA libraries from different cells and tissues. And based on criteria derived from informatics, using sequence analysis, homology assessments and so on, the genes would be selected to be functionated using transgenic mice as the test tube as opposed to cell culture systems,” Lacey relates.

One of the first genes that were selected in this program was what looked to be a novel tumor necrosis factor (TNF) receptor superfamily member – a secreted protein as opposed to one anchored on the cell surface. Lacey and his team noted that when levels of the protein – ultimately called osteoprotegerin (OPG) – were increased in mice, it resulted in denser bones.

An exciting observation, OPG appeared to impact on osteoclast biology. “Pretty much right away we were trying to figure out whether OPG itself could be made into a product to be investigated, at least in the clinical sense, in human clinical trials.”

Novel TNF receptor

Two forms of the molecule were taken into clinical trials, which proved that the exposure of humans to recombinant OPG oppressed markers that indicated that there was a suppression of osteoclast activity. “But for reasons that we discovered, we weren’t satisfied with the drug-like properties of either molecule. So we were back to the drawing board stage.”

In the meantime, investigators in the academic world as well as Amgen’s biotech rivals were also interested in novel TNF family members. In 1997, Immunex (acquired by Amgen in 2001) published a report on what had been termed RANK ligand – the protein that OPG inhibited. “RANK ligand is an essential factor for osteoclast formation, maturation and activation. Withdrawal of RANK ligand from either animals in vivo or from tissue culture settings in vitro leads to osteoclast – they undergo apoptosis or programmed cell death. So RANK ligand is essential for osteoclast activity,” summarizes Lacey.

“With that discovery in hand, we proceeded in the later 1990s to work with a company called Abgenix, who had a specially made mouse, called the ‘XenoMouse’, engineered to express the human immunoglobin repertoire. When exposed to foreign proteins, these mice develop not mouse antibodies but human antibodies. We were using that XenoMouse technology through a collaboration with Abgenix – and developed the antibody that, today, is known as denosumab.” In 2006, Amgen acquired Abgenix.

Preventing bone loss

Since its discovery, denosumab has been studied for its potential to prevent bone loss caused by osteoporosis and other diseases. Being a neutralizing fully human monoclonal antibody directed against human RANK ligand, it antagonizes osteoclast formation, maturation, activation and survival by interdicting RANK ligand.

Currently in phase III testing, denosumab is being studied in a range of bone loss conditions including postmenopausal osteoporosis, rheumatoid arthritis, cancer treatment-induced bone loss in breast cancer and prostate cancer patients, as well as for its potential to delay bone metastases and inhibit and treat bone destruction across many stages of cancer.“It’s pretty clear that a development program for antagonists of RANK ligand would look at a spectrum of diseases that were characterized by excess bone resorption.”

A recent head-to-head study designed to compare denosumab treatment twice yearly with weekly oral alendronate Fosamax, the industry-leading bisphosphonate, looked at the change in bone mineral density at the total hip. “In that endpoint, we achieved a magnitude of BMD increase that was about 40 percent greater in the denosumab group compared to the Fosamax or alendronate group,” Lacey points out.

Secondary endpoints measuring bone mineral density at other sites also showed a statistically significant benefit compared to Fosamax, while the type of adverse events (AE) were similar between the two treatment groups; the most common AEs included arthralgia, back pain, constipation and dyspepsia.

Competition

How does denosumab differ from other drugs available on the $7 billion osteoporosis market, like Fosamax, Actonel and Reclast? Denosumab is not a bisphosphonate-like therapy and thus it works in a different way. Unlike denosumab, bisphosphonates attach to the bone matrix and are absorbed by mature osteoclasts, which then are inhibited, explains Lacey.

In contrast, denosumab specifically targets RANK Ligand, an essential mediator of osteoclast formation, function, and survival, in all bone throughout the skeleton. Denosumab is not dependent on the bone surface or osteoclast absorption to exert an effect.

There is no evidence that suggests that bisphosphonates interact with or block RANK ligand the way denosumab does, Lacey adds. “Also, bisphosphonates are small molecule drugs, while denosumab is a fully human monoclonal antibody. So the modality is different as well.”

Analysts believe that denosumab could achieve sales of up to $2 billion a year if and when approved for osteoporosis and cancer patients. Being the only potential blockbuster nearing FDA approval, the drug is even more important to Amgen. However, says Lacey, there are other projects that are interesting in the portfolio. “One program in the area of bones is a collaboration that we have with UCB Celltech. And that’s around a target called ‘sclerostin’. We reported very interesting phase I single-dose data at last year’s American Society for Bone and Mineral Research meeting.”

Promising treatments

Amgen focuses on four therapeutic areas: oncology, inflammation, metabolic disorders and neuroscience programs. Most advanced is Amgen’s hematology/oncology portfolio. Recently, the company announced data from two phase III studies which evaluated the administration of the protein therapeutic romiplostim on increasing and sustaining platelet counts in both splenectomized and non-splenectomized patients with chronic Immune Thrombocytopenic Purpura (ITP).

“The molecule is under review currently at the FDA. It may not be the size of denosumab, but it represents a novel way to simulate platelet formation. And in a disease that’s complicated by bleeding episodes, this is a promising new treatment.”
Last year, Amgen introduced thirteen molecules into development. In 2008, the biotech company is expecting to advance 10 of its molecules into mid-stage trials. In addition, Amgen entered into an arrangement with Takeda Pharmaceutical Company Ltd, the leading pharmaceutical company in Japan. “The development programs included in this collaboration represent the growth engine for Amgen in the next decade,” Lacey says. “Takeda’s confidence in these programs validates their potential to become innovative therapies for patients in Japan and worldwide.”

About Dr. David Lacey

Dr. David Lacey, SVP of Discovery Research at Amgen, joined Amgen in 1994. He is responsible for Amgen’s discovery research programs across all therapeutic areas.