Amgen's osteoporosis and bone-related cancer drug denosumab may be one of the most eagerly-anticipated approvals of the year - not least by Amgen itself, whose future growth depends almost entirely on an FDA nod. But in another sense this antibody marks an ending, not a beginning.

D-mab may yet be among the last of the anti-resorptive treatments for osteoporosis - that is to say, drugs that block the natural process in which bone is broken down as part of an ongoing regeneration cycle. Most marketed osteoporosis drugs, broadly speaking, are bisphosphonates, which do the same thing, although none with the same mechanism as D-mab.

Ultimately, the real future of this lucrative yet tricky primary care market, affecting more than 75 million people in the developed world, lies with anabolic drugs, which help build new bone, rather than prevent breakdown of the old. One biotech chief executive said: "You'd be crazy to try and develop anything else."

Amgen's entry will certainly heat up competition in an already cut-throat field; D-mab's PDUFA date is in October (¹ Also see "Likely Sales Slump Puts (Still More) Heat On Amgen’s Denosumab To Win" - Pink Sheet, 16 April, 2009.). Amgen argues that D-mab is a more potent anti-resorptive than what's currently available and, as a twice-yearly subcutaneous injection, will be more convenient. Incremental data on use of the product to prevent bone fractures in prostate cancer patients was just presented at the American Society of Clinical Oncology (see ² Also see "Xarelto Action Letter No Surprise; But Does FDA Want Data, REMS Or Both?" - Pink Sheet, 1 June, 2009. ).

Currently marketed bisphosphonates include Merck's now-generic Fosamax (alendronate). Novartis is busy defending its territory around its once-yearly infusion, Reclast (zoledronic acid) which on June 1 received FDA approval to prevent (rather than simply treat) osteoporosis in post-menopausal women with low bone mass. In this additional indication it will require an even less invasive once-every-two-year infusion.

Look Out, Forteo

But coming up through the ranks are a group of drugs that challenge the one significant anabolic agent out there: Eli Lilly's Forteo (teriparatide). In 2008, sales of Forteo were just short of $800 million. While that's not quite blockbuster status, it's not bad considering the drug - recombinant human parathyroid hormone (PTH) - carries a black box warning due to osteosarcomas found in rats during pre-clinical trials and requires a daily injection over a long period. And what's more, Forteo sales are growing, at least outside of the U.S., which is more than can be said of bisposphonates, which are facing increasing generic competition.

So an obvious starting point for the host of smaller players trying to elbow into the market is improving Forteo - all the more so given the high development and regulatory risk surrounding any novel compound targeting a chronic, primary care condition like osteoporosis.

Zosano Pharma, for example, has a Phase II transdermal formulation it hopes to register using the 505(b)(2) pathway, the short cut that relies on data from previously approved drugs. In doing so, Zosano looks to be as lucky in finding a partner as TransPharma Medical was last year, when Lilly signed rights to that biotech's own transdermal PTH formulation (³ Also see "Lilly Licenses Hormone Patch For Osteoporosis" - Pink Sheet, 12 June, 2008.). Altea Therapeutics has also chosen PTH as a candidate for its transdermal technology, validated recently by Lilly and its partner Amylin Pharmaceuticals in a deal for a patch version of Byetta .

Others, like Pennsylvania-based Zelos, believe intra-nasal delivery of PTH is the answer, but its drug is only in pre-clinical and, what's more, it's using an alternative PTH analog, made up of a slightly shorter string of amino acids than Forteo. That means large fracture outcomes trials - involving several thousand patients - and therefore money, and/or a partner. Zelos hasn't yet found either.

Meanwhile, according to John Santini, CEO of MicroCHIPS, anything requiring daily administration, whether transdermal or nasal, is going to lead to poor compliance. His solution: an implant containing one year's worth of daily PTH doses (each within a sealed reservoir), programmed to release a dose each day. Santini hopes to begin clinical trials in 2010.

Variations On The PTH Theme

Like Zelos, Radius Health, based in Cambridge, Mass., has moved beyond simply seeking improved delivery of Forteo. It has already completed one Phase II trial of BA058, an analog of human parathyroid hormone-related protein (hPTHrP) licensed from Ipsen in 2005. PTHrP is a "more direct bone-forming agent" than PTH, according to Radius Chief Financial Officer Nick Harvey, but scientists aren't sure exactly how it works.

Six-month data from BA058 shows a significant improvement over Forteo in hip bone density in particular, and the drug is stable at room temperature (unlike Forteo, which must be refrigerated). Radius is hoping that will be enough to convince Novartis to exercise the option it took on BA058 back in 2007, alongside an equity investment via the MPM Bio IV NVS Strategic Fund, a joint program between MPM Capital and Novartis' pharmaceutical business unit. Novartis' decision is expected shortly.

Even if Novartis doesn't exercise its option, MPM managing director Ansbert Gadicke says the VC is 100 percent dedicated to supporting Radius anyway. That financial support is unusual in a field that more than a few VCs view as a no-go zone - rather like cardiovascular disease. Trial costs, regulatory risk and the existing competition - many of the Big Pharma heavyweights have osteoporosis drugs, and Amgen will add its marketing muscle shortly - mean several smaller firms like Zelos are struggling to raise funds.

Much of the innovative work on the next-generation of anabolic blockbusters is very early stage. Scientists know a lot less about bone-building pathways - what they are, how they converge - than they do about those involved with bone-resorption.

One anabolic pathway getting some attention, however, if not yet from VCs, is the sclerostin pathway. This protein was identified ten years ago after scientists observed that a group of Afrikaner people with a disorder in the gene coding for sclerostin had very thick bones and an unusually low fracture incidence. Amgen's anti-sclerostin antibody is about to enter Phase II, Lilly has some related IP (but won't comment), and three-year old OsteoGeneX is going after small molecule sclerostin inhibitors.

OsteoGeneX's problem is familiar, though: a lack of funds and reliance on a deep-pocketed pharma partner to pursue the osteoporosis indication. Indeed, for all the promising early-stage work on anabolic pathways, VCs and Big Pharma can by and large afford to sit and wait until novel targets and mechanisms are better validated.

That's a problem for the many start-ups who need money, and deals, right now. But whether or not denosumab's splash triggers a new round of investment, research efforts across both biotech and Big Pharma in osteoporosis presage a future with more anabolic treatments. They won't displace cheaper, well-established anti-resorptives but they may provide the potential for combination treatments and, ultimately, more meaningful fracture-rate reductions - and the associated costs that follow.

- Melanie Senior (m.senior @elsevier.com)

After D-mab: Next-Generation Osteoporosis Drugs Focus On Building Bone

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