Biotech Strategy Blog

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

Posts tagged ‘Wnt-ß-catenin pathway’

And we’re off!

Rays of hope during dark days

No, no, not to the races – and certainly not to Cheltenham – but rather it’s that time of the year when the first of our annual AACR Preview series drops.  While some cancer conferences have been postponed and even cancelled, others such as AACR and ASCO are proceeding with virtual meetings, proving that even dark times can offer hints of hope.

This is good news for both young researchers and companies alike in getting data out there and shared because life goes on as time and tide wait for no man.

The actual abstracts themselves won’t be revealed until later in the month on April 27th, but for now we get a taster of this year’s truncated event since the titles available for the first virtual meeting.

Often time, this glimpse is sufficient to garner some useful clues, so what does this year hold in store for us all?

This Preview series will be in multiple parts – a review of some of the key oral sessions from the first virtual program (targeted agents, immunotherapies, cell therapies, novel targets, translational studies etc) followed by a review of the posters in the final part.

To get started, let’s take a look at some of the important presentations we can expect to hear on the first day…

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Hitching a ride on the Powell and Mason tram

Gastrointestinal (GI) cancers comprise quite a wide variety of different tumour types, including those of the oesophagus and stomach, pancreas, small bowel and hepatobiliary tract, as well as the colon, rectum and anus.

With the possible exception of oesophagus and gastric/stomach cancers, this bunch of tumour types are generally colld rather than hot tumours for various reasons.

Aside from some recent forays by immune checkpoint blockade in gastric cancer, this field hasn’t had a lot of startling new developments to get excited about of late.

Are things finally changing?

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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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