Biotech Strategy Blog

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

Posts tagged ‘Osteoblasts’

Continuing my previous post about emerging drugs for osteoporosis, one of the new classes in development are those that target sclerostin.

Sclerostin is a protein produced by osteocytes within bone that inhibits bone formation. It is thought to pass through the surface of bone where it acts on osteoblasts (cells responsible for bone formation).  There it binds to low-density lipoprotein receptors and inhibits the Wnt/beta-catenin signaling involved in bone mass regulation.

There is some uncertainty in the scientific literature as to the precise method by which sclerostin acts on bone. However, the Wnt/beta-catenin osteocytic signaling does play a role in bone homeostasis.

Preclinical animal work using an antibody to sclerostin led to increased bone formation, bone mineral density and bone mineral strength. This supports the concept that inhibition of sclerostin has potential as a treatment for osteoporosis.

Interest in sclerostin has grown enormously, with over 50 abstracts presented on its measurement at the 2010 American Society of Bone and Mineral Research (ASBMR) annual meeting.  Also last year, Biomedica and its distribution partner ALPCO Diagnostics launched the first commercial immunoassay kit for the measurement of circulating sclerostin.

Not surprisingly companies have started to look at sclerostin inhibition as a drug development target.  The leader in the pack is Amgen with AMG 785, a sclerostin monoclonal antibody.

The phase 1 trial results published by Padhi et al in the January issue of the Journal of Bone and Mineral Research (JBMR) show that it was well tolerated in 72 healthy subjects that received AMG 785 or placebo.

AMG 785 is now in phase 2 clinical trials that will look more closely at dosing and efficacy.  A 330 patient study to assess fracture healing is currently recruiting (NCT01081678).  The study will look at three doses of AMG 785 (70mg, 140mg, 210mg ) given by injection subcutaneously (under the skin).

The study hypothesis is that giving AMG 785 to those with a new hip fracture will increase their healing. The functional healing will be measured using the timed-up-and-go (TUG) test i.e. the time to stand up on one’s own, walk three meters, turn around, walk back and sit down.

The estimated primary completion date for this trial is December 2012, so I don’t expect we will see some data till 2013 at the earliest.

Amgen already has a major osteoporosis franchise with denosumab, it’s RANKL inhibitor for postmenopausal women at high risk for fracture. It’s a smart new products strategy to build on this, although its too early to tell whether AMG 785 will make it to market.

One unknown challenge for those targeting sclerostin’s action is whether disruption of Wnt/beta-catenin signaling in bone could lead to the stimulation of cancers elsewhere in the body, since this pathway is also involved in a wide range of cellular signaling in the body, including cancer.

While this may not be a problem in healthy individuals, it could raise the issue of the use of sclerostin inhibitors in those patients with low bone mineral density (BMD) or fractures who are being treated for cancer at the same time. Since skeletal related events (SRE) are seen in many advanced breast and prostate cancer patients, this may be a cause for concern.

Further information on Pharma Strategy Blog where Sally Church has written an excellent post on “Wnt Signaling and Cancer.”

Update Jan 2, 2014 Phase 2 Data for Romosozumab published in NEJM

New Year’s day is not when you might expect the New England Journal of Medicine to publish an online first article. However, that’s what happened yesterday when the phase 2 trial data for romosozumab (AMG 785) in postmenopausal women with osteoporosis was published. The joy of Twitter is that interesting news is rapidly shared:

The trial data published in the NEJM by McClung et al shows that romosozumab, a sclerostin inhibitor being developed by Amgen/UCB Pharma provides increased bone mineral density and bone formation:

“All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide”

In the accompanying NEJM editorial, Carolyn B. Becker MD from Brigham and Women’s Hospital in Boston describes the results as “impressive” and outlines many of the questions that remain unanswered that hopefully the results of the phase 3 trial under way (NCT01631214) will provide.

Whether it is a potential blockbuster as some on Twitter questioned yesterday evening, I think we will have to wait and see what the phase 3 trial data shows in a larger study.

However, based on the phase 2 data published in the NEJM it looks like romosozumab will be a future addition to Amgen’s osteoporosis franchise unless something untoward is seen in the phase 3 trial results.

References

ResearchBlogging.orgPadhi, D., Jang, G., Stouch, B., Fang, L., & Posvar, E. (2011). Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody Journal of Bone and Mineral Research, 26 (1), 19-26 DOI: 10.1002/jbmr.173

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 breastcancer.org 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.

error: Content is protected !!