The new gold standard

Bone metastases have been a constant and major clinical concern for the healthcare and life sciences sectors for decades. For the patient it can translate into severe pain, bone fractures, spinal cord compressions and a general, rapid degradation in quality of life; for the industry and its experts it has meant a head-scratching journey trying to assess how to push the envelope of treatment once more towards combating mortality and securing a future with next generation treatments.

In an effort to do precisely that, Amgen has recently taken the torch as the owner of the first bone-targeted therapy for cancer patients in nearly a decade. Approved by the US Food and Drug Administration (FDA) back in November 2010, Amgen's Xgeva (denosumab) is the first and only RANK Ligand inhibitor for the prevention of skeletal-related events in patients with bone metastases from solid tumors. And how did they achieve Xgeva? Through the largest clinical programme ever conducted in patients with bone metastases, with the drug being approved following a six-month priority review by the FDA - a designation usually reserved for drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists.

Developing Xgeva from the outset, Roy Baynes, Vice President of Global Development and lead for Denosumab in the Oncology setting for Amgen, has been pivotal in the birth and subsequent upbringing of Xgeva. "The area of bone metabolism in cancer patients has really been dominated in the past few years by the bisphosphonates," he begins. "They've gone through various generations of development aimed at producing increasingly more potent molecules. The contrast between Xgeva and bisphosphonates is that the Xgeva molecule is exquisitely targeted. Basically, this is directed at RANK Ligant, which is the final common pathway for the activation of the osteoclast."

Indeed, by contrast bisphosphonates are relatively non-specific; instead being taken in by the body and absorbed into the bone. From here, the bone becomes semi-impregnated with bisphosphonate. The osteoclast - in the action of reabsorbing bone -ingests the bisphosphonate before being killed from within by a toxic effect of the bisphosphonate. So where the former therapy was a non-specific and non-targeted mechanism, Xgeva represents the emergence of an elegant and specifically targeted mechanism to switch off the osteoclast.

But whilst it's easy to sit back and describe how the therapy works, it's only the tip of the proverbial iceberg. As Baynes asserts, the Xgeva programme is completely organic - from axis and specific target discovery through to development and the full clinical programme. And, quite frankly, it represents the culmination of 15 years of cumulative work of scientists and clinicians at Amgen, proving how important innovation in the context of organic development truly is for their patients.

Kevin Sharer, Chairman and CEO of Amgen, said at the initial announcement of the FDA's approval of Xgeva: "Today's approval illustrates what is possible when scientific innovation, commitment and investment come together to advance medicine, A diagnosis of bone metastases is a major event for patients living with cancer and the consequences can be devastating. We are pleased to offer this new advance to patients and their healthcare providers."

"The development of Xgeva, which is primarily in the cancer setting, has focused on two major opportunities," continues Baynes off the back of Sharer's statement. "The first was to look at patients who had boney metastases who were at risk of developing skeletal-related events. These events complicate a metastases and normally include one of four events that in turn cause morbidity and the significant impairment of patients' quality of life: a pathologic fracture where the metastases leads to the bone breaking; surgery, which is usually required to prevent a fracture; and radiation therapy to irradiate the bone that's had to be replaced surgically. The final, and most feared complication, is an oncologic emergency, which is what happens when a metastases in a vertebrae ruptures through into the spinal canal and compresses the spinal cord, causing nerve compression that could take the form of paraplegia.

"All of these are grievous and serious, so as you can imagine there's a desire to address these. So, what we did was say 'Okay, we've got a drug that's exquisitely-targeted and we're very impressed with its actions'. We'd done a Phase II programme, which established that we could suppress a bone turnover market, which is essentially a surrogate for the bone benefit. We also started to see a benefit in skeletal-related events, so we were confident about the molecule."

The next step for Baynes and his team was to set up a programme that compared their findings with the Gold Standard of Treatment at the time - a potent bisphosphonate known as Zometa that primarily contains zoledronic acid - and study it in a head-to-head fashion in the context of various cancers, from breast to prostate, and with a mixture of solid tumours. Using a selection of randomized patients to either receive Xgeva or Zometa on the backbone of the standard of care they were already receiving, Baynes' team then monitored the patients for any sign of the development of skeletal-related events. According to Baynes, these were set as "non-inferiority trials" that aimed to highlight that, at the very least, Xgeva was no worse than Zometa in terms of effect.

Once that had been established, Baynes and his team went on to test, in accordance with FDA guidance, whether Xgeva was superior to Zometa. "What we found," details Baynes, "was that we were superior in the breast cancer study; we were superior in the prostate cancer study and we were very close to superior in the solitary trial. So, in those three trials we were clearly extremely favourable for Xgeva - not only for the first event but also for subsequent events. In the solid tumour, it was close to superior but didn't quite make it. When we looked at pre-specified integrated analysis of all three studies it was strikingly superior - so if you think about this for patients, we have a treatment that certainly surpasses the Gold Standard in terms of efficacy.

"In terms of safety, we were very comparable. We had two major side effects that showed up: hypocalcemia and osteonecrosis of the jaw. These are both well-recognised complications of bisphosphonates. In terms of low calcium, we produced more frequently than Zometa, which speaks to the increased efficacy of the molecule because the mechanism here is on target. In other words, you're switching off the osteoclast, which is one of the sources of calcium for the body, so the osteonecrosis jaw occurs at a similar rate with the two agents. Encouragingly, a significant number of those on Xgeva were reversible, so a very favourable risk and efficacy profile."

Further backing this, David Henry, clinical professor of medicine and vice chair for the Department of Medicine at the University of Pennsylvania Healthcare System, said: "As many as three out of four patients with advanced prostate, lung and breast cancer will experience a spread to their bones. Despite the availability of current treatments, a significant proportion of these patients still experience bone complications or are not candidates for existing treatments.

"Based on the compelling science and robust clinical evidence seen with Xgeva, I expect this new option to quickly become a mainstay of cancer care and to play an important role in reducing the incidence of debilitating bone complications in patients with advanced cancer."

But whilst Amgen, Baynes - and indeed his team's - efforts have proved pioneering in breaking through to producing a world leading treatment, as we all know it's far harder to stay at the top than it is to get there in the first place. So what is Baynes doing to ensure Xgeva and Amgen maintain their position as top dogs? Well, naturally they're now focused on patients who have not yet developed boney metastases but who are at risk of doing so. More specifically, Baynes has identified two major tumour types to begin work on.

"One is prostate cancer, the other is breast cancer. In the prostate caner arena, we have conducted a randomised control trial versus placebo where men who are at high risk of developing metastatic prostate cancer are randomised to either get a placebo of Xgeva along with whatever prostate standard of care they're getting for their prostate cancer. These are the patients who are castrate resistant - that is to say they are no longer responding to hormone deprivation - so what we're looking at is the time to the first metastases or death: an endpoint known as Bone Metastases Free Survival. At the moment, we're looking to see whether Xgeva will be able to delay that and improve the outcome."

To date, the trial has completed enrolment, with its subsequent data release managing to be squeezed into the tail end of 2010. In announcing the top-line results from their Phase III trial, conducted with 1432 male patients with castrate-resistant prostate cancer, Amgen concluded that: "Xgeva significantly improved median bone metastasis-free survival by 4.2 months compared to placebo (primary endpoint), and significantly improved time to first occurrence of bone metastases.

"Our data demonstrates that Xgeva, which antagonizes the RANK Ligand axis, limits the ability of tumours to colonise bone, an important finding for men at risk for bone metastases and their healthcare providers. We look forward to presenting these landmark data at an upcoming medical conference."

Further confirming the importance of the prostate trial, Neal Shore, Medical Director at Carolina Urologic Research Centre, said back in 2010: "As many as 70 percent of patients with prostate cancer that have metastasized to the bone are not currently receiving therapy to prevent complications from these bone metastases. This may be secondary to urologists lacking comfort or facilities to provide infusion treatment. Xgeva could provide increased treatment care options and accessibility for urologists who treat advanced prostate cancer; as Xgeva is administered as a subcutaneous injection on a monthly basis. Also, Xgeva does not require dose adjustment for changes in renal function."

Amgen also has another large trial ongoing with women patients with breast cancer. Known as the DK Study, women with high-risk, primary breast cancer who are getting adjuvant treatment are being randomised in very much the same way as the male trial population - being given either Xgeva or a complete placebo. Ultimately it's the same idea, but with the prostate trial in its final stages, having started in early 2006, it'll be some time before the data sets for the breast cancer trial are collated, analysed and released.

Whilst Xgeva is a breakthrough in every sense of the word for Amgen, it's ever more important for its customers. The total economic burden of patients with bone metastases in the US alone is already estimated to be US$12.6 billion annually. Patients who experience skeletal-related events (SRE) as a result of bone metastases incur significantly higher medical costs compared with those who don't go through the pain of such events. Moreover, once patients experience an SRE, the risk of a subsequent SRE is increased. The costs of SREs vary by type and severity - ranging from relatively low costs for minor fractures to high cost events like spinal cord compression associated with hospitalisation.

When it comes to the crunch, Xgeva is more than just "an innovative therapy that significantly reduces debilitating and costly SREs". It's more than just a pioneering breakthrough for the Californian-based human therapeutics company. And it's more than just years of work for Roy Baynes and his team. Xgeva is the key to changing lives for patients with bone metastases from solid tumours - not just in terms of physiological and financial improvements, but in pushing the envelope of success for future patients. For Amgen, it seems that the Gold Standard will never be enough - a sentiment that has got them to where they stand today.