Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘osteonecrosis of Jaw’

The February 2011 issue of Nature Reviews Drug Discovery has an interesting review by Kawai, Mödder and colleagues on “Emerging therapeutic opportunities for skeletal restoration.”

Some of the new products they discuss include:

  1. Parathyroid Hormone-Related protein (PTHRP)
  2. Cathepsin K Inhibitors: odanacatib
  3. Wnt-ß-catenin pathway targets: sclerostin, DKK1 antagonists, lithium.

The market opportunity for osteoporosis remains significant, affecting 44 million people in the United States over the age of 50, resulting in healthcare costs in excess of $15 billion a year; numbers that are set to increase with the ageing population of baby boomers.  The low bone mineral density (BMD) associated with osteoporosis results in increased risk of hip fracture, from which the mortality rate is 20-30% in the first year.

The current competitive landscape for osteoporosis includes antiresorptive agents such as the bisphosponates (alendronate, risedronate, ibandronate, zoledronic acid) that inhibit bone resorption.  These compounds reduce fracture-risk by 20-30%, but long-term safety issues remain a concern.  High doses of zoledronic acid (Zometa) has been linked to osteonecrosis of the jaw (see previous blog post).

Amgen’s new monoclonal antibody, denosumab, binds to RANK-L, thereby inhibiting its action, with the result that osteoclasts (the cells responsible for bone resorption) cannot form, function or survive.  The result of this mechanism of action is a reduction in bone loss and bone destruction.

Like zoledronic acid, denosumab also has a risk of osteonecrosis of the jaw developing.  However, one additional long-term safety issue for denosumab is the fact it suppresses TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) that is not only produced by osteoblasts (the cells responsible for bone formation), but also by immune cells.  This raises the possibility of skin and immune adverse events, which were seen in the clinical trial data.

Kawai & Mödder in their review article conclude that:

“There is still a need for therapies that reduce fracture risk beyond the level achievable with bone-resorbing agents, particularly as virtually all of the currently available drugs do not eliminate the possibility of future fractures.”

However in addition to having a market opportunity and scientific rationale, any biotechnology company looking at osteoporosis as part of their marketing strategy, must face up to the increasing ethical concerns over placebo-controlled clinical trials.  This topic was highlighted last year in the New England Journal of Medicine.

In the future there is likely to be increased pressure not to recruit subjects at high-risk of osteoporosis (T score less than -2.5) into placebo-controlled trials, thus increasing the costs, number of patients and time to bring new products to market.  In addition, the regulatory barriers to entry are becoming higher, given that regulatory agencies require a reduction in fractures over 3 years to establish the efficacy of a new drug.  This ultimately results in the need for large, expensive, and long phase III clinical trials.

In forthcoming posts, I will discuss the opportunities for market entry by new osteoporosis drugs targeting the Wnt- ß-catenin pathway, Cathepsin K inhibitors and Parathyroid hormone-related protein.

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This week’s New England Journal of Medicine (NEJM) has an interesting paper (Teriparatide and Osseous Regeneration in the Oral Cavity) that caught my attention on the use of teriparatide (Eli Lilly, Forteo®) in patients with chronic peridontitis, a disease that affects one in five American adults.  The total market for periodontitis services and products is estimated to grow at 6.4% to 2016, when it will be worth $1,937 m.

Teriparatide is a recombinant form of parathyroid hormone (PTH) consisting of amino acids 1-34, and is used for the treatment of osteoporosis.  In the body, PTH is the hormone that regulates the level of calcium in the blood.  Low blood calcium causes increased PTH release. The use of teriparatide has been limited by the FDA due to the risk of osteosarcoma from long-term exposure.  However, what makes it an interesting compound is its ability to stimulate osteoblasts to build bone, which is why the results from the NEJM on peridontitis are perhaps not that surprising.

As Andrew Gray in his NEJM editorial comments, because teriparatide activates bone remodelling it may have a role to play in the management of osteonecrosis of the jaw (ONJ). ONJ is a particularly nasty side effect that many breast, multiple myeloma and prostate cancer patients experience following any dental work.

Badros et al, point out in their Journal of Clinical Oncology (JCO) paper, that bone disease effects 70% of multiple myeloma patients, many of whom take a bisphosphonate such as zoledronic acid (Novartis, Zometa®) to reduce the risk of skeletal related events (SRE). Unfortunately, a few patients subsequently end up with ONJ as a serious side effect! Clinical trial results showed that ONJ occurred with a similar frequency in breast cancer patients taking denosumab (Amgen, Prolia®) as compared to zoledronic acid.

One only has to read the patient commentary available on online forums such as to realize the debilitating effect that ONJ has, not to mention the severe morbidity because of lack of delayed diagnosis and lack of effective treatments.

It is unclear whether the positive results from the NEJM in peridontitis will lead to clinical trials for the treatment of ONJ in cancer patients.  Although there is an unmet need, the market is small. In the meantime, I expect that doctors will be using teriparatide off-label to treat severe ONJ, which is less than ideal.

One biotech company banking on continued interest in Forteo® is Zelos Therapeutics, whose CEO, Dr Brian MacDonald is a fellow alumni of the University of Sheffield.  Zelos have a nasal spray formulation of teriparatide (ZT-034), which they hope will be equivalent to Ely Lilly’s product (that requires a daily injection).

Source: Zelos Therapeutics. In a press release earlier this year, Dr MacDonald commented:

“We believe that formulation of teriparatide as a nasal spray with comparable efficacy and safety to Forteo represents a simple, convenient approach to dosing that will make PTH therapy a better option for many more patients.”

Zelos’ product is currently in early stage clinical trials, so it will be interesting to see how this develops. The NDA is planned for 2012.  It is certainly a valid strategy for emerging biotechnology companies to take an existing marketed product and use a new drug delivery mechanism such as Aegis Therapeutics’ Intravail® drug delivery technology to expand the market.

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