Biotech Strategy Blog

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

Posts from the ‘Osteoporosis & Bone Disease’ category

Contrary to popular opinion, innovation is not dead in the biomedical industry, as evidenced by news of a novel drug-delivery system published as a Rapid Publication in Science Translational Medicine (STM) on February 16, 2012.

The paper from Robert Farra of MicroCHIPS, Inc. and research collaborators, describes a first-in-human testing of a wirelessly controlled drug delivery microchip.

Farra et al., report the results of a clinical trial with 8 women in whom microchips were implanted for 103 days. The data showed that the pharmacokinetic profile of microgram-quantities of the anti-osteoporosis drug, teriparatide (FORSTEO), delivered by the microchip was similar to subcutaneous injections.  However, the device did fail in one of the 8 women, so data is only reported for 7 patients, a very small patient sample.

Picture Credit: MicroCHIPS, Inc.

The drug delivery device is an array of 600-nL micro reservoirs in which the drug is stored, that is associated with a 13.0 mm x 5.4mm x 0.5mm silicon chip.

The microchip was implanted beneath the skin (subcutaneously) in the abdomen by creating a 2.5cm incision, performed during an outpatient visit.

This paper is also interesting for its use of telemedicine. A remote operator was able to establish a wireless link and send instructions directly to the implant on dosing schedule as well as receive information back on operation of the chip.

John T. Watson, Professor of Bioengineering at the University of California San Diego  commented in the accompanying editorial that:

“The microchip represents more than 10 years of engineering design and development efforts to arrive at a programmable, implantable device for subcutaneous release of a therapeutic agent in discrete doses.”

Multiple engineering design advances were made along the way.

He also noted the results from the quality-of-life surveys administered during the trial; the majority of women stating they often forgot they had the device implanted and would readily consent to a fresh implant if needed.

Innovations in drug delivery offer hope of an improved quality of life to patients with chronic disease who require daily injections.  In 2010, there were approximately 50,000 teriparatide users, not an insignificant market opportunity.  People with diabetes who require daily injection of insulin is another potential market that springs to mind.

The first-in-human results reported in Science Translational Medicine show promise and the potential of a novel implanted wireless drug delivery system.

However, many questions remain unanswered by this research including the reliability & durability of the microchip device, given that it failed in 1 out of 8 women implanted.

Further work on validating the technology, and confirming its safety, reliability and efficacy in a larger sample size will be needed before it can obtain regulatory approval.

References

ResearchBlogging.orgFarra, R., Sheppard, N., McCabe, L., Neer, R., Anderson, J., Santini, J., Cima, M., & Langer, R. (2012). First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip Science Translational Medicine DOI: 10.1126/scitranslmed.3003276

Watson, J. (2012). Re-Engineering Device Translation Timelines Science Translational Medicine DOI: 10.1126/scitranslmed.3003687

San-Francisco-Golden-Gate-Bridge-view-from-Coit-Tower-copyright-Pieter-DroppertAfter the recent JP Morgan Healthcare conference, San Francisco remains the destination of choice for forthcoming medical meetings.

Yesterday, saw the start of the 2012 ASCO Gastrointestinal Cancers Symposium (ASCO GI) at Moscone West from Jan 19-21.

In a few weeks time, the 2012 ASCO Genitourinary Cancers Symposium (ASCO GU) will be held at the San Franciso Marriott Marquis from Feb 2-4.

If you are based in San Francisco, you are at the heart of the action. It’s less optimal if you are East Coast based, unless you need the frequent flyer miles and have a good travel budget!

According to the ASCO GU preliminary program there are eight oral abstracts on prostate cancer that will be presented at the meeting on Thursday, February 2. Here’s my preview of a few that caught my attention:

ASCO GU Abstract #1:

MDV3100 Phase 3 AFFIRM trial results

The first presentation of the MDV3100 AFFIRM phase 3 trial results are a late-breaking abstract and my prediction for the highlight of the prostate cancer session at ASCO GU.

So far, all that is known from the November 3, 2011 press release from Medivation/Astellas is that MDV3100 produced a 4.8 month advantage in median overall survival compared to placebo in men with advanced prostate cancer.

This met the primary endpoint of the phase 3 AFFIRM trial, and the study was stopped early as a result.  As the press release notes, MDV3100 provided a 37% reduction in risk of death compared to placebo (hazard ratio = 0.631).

Howard Scher (MSKCC) will present the AFFIRM trial results at ASCO GU, and a closer look at the MDV3100 data is eagerly awaited.

ASCO GU Abstract #6:

Effect of denosumab on prolonging bone-metastasis-free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics.

Amgen are seeking a new indication for denosumab (Xgeva) in prostate cancer on the grounds that it prolongs bone metastasis-free survival in men with non-metastatic CRPC.  The supplemental Biologics Application (sBLA) for denosumab will be discussed at the Oncologic Drugs Advisory Committee (ODAC) meeting on February 8, 2012.

The results from the phase 3, 147 trial were published in The Lancet last November and showed that use of denosumab delayed time to first bone metastasis by 3.7 months and improved bone-metastasis free survival.

Sally Church on Pharma Strategy Blog wrote about the denosumab 147 data presented at the annual meeting of the American Urological Association (AUA 2011) last year.

However, the challenge that Amgen faces is that they have yet to show that use of denosumab in men with prostate cancer results in an improvement in overall survival.  While it may delay the spread of prostate cancer to the bone, the gold standard for all the prostate cancer drugs approved to date has been overall survival.

The 147 trial showed that overall survival was similar between those taking placebo and those receiving denosumab (HR 1.01; 95 percent CI: 0.85, 1.20; p=0.91). Hypernatremia and osteonecrosis of the jaw were also reported with a higher frequency in the denosumab group

It is possible that there may be updated data at ASCO GU, but most likely it will be a review of The Lancet data with some subset analysis.

The FDA Center for Drug Evaluation & Research (CDER) plans to provide a free of charge, live webcast of the February 8, 2012 meeting of the Oncologic Drugs Advisory Committee, so I am looking forward to what the committee makes of Amgen’s filing.

ASCO GU Abstract #7:

Vitamin E & the Risk of Prostate Cancer – updated results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT)

Eric Klein will be presenting updated results from the SELECT trial that were previously reported in the October 12, 2011 issue of the Journal of the American Medical Association (JAMA).

The data showed a 17% increase in prostate cancer risk with Vitamin E supplements. Although the program abstract advertises updated data, I’m not expecting the data to differ dramatically from last year’s JAMA paper.

ASCO GU Abstract #8:

Overall survival benefit and safety profile of radium-223 chloride (Alpharadin), a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases.

The ALSYMPCA trial data is being presented for the benefit of attendees who did not hear Oliver Sartor’s presentation on radium-223 (Alpharadin) at the NY Chemotherapy Foundation or hear Chris Parker present the trial data at ECCO/ESMO in Stockholm. This makes strong commercial sense, especially as it’s a product that physicians in the United States may know little about.

I blogged extensively about the ALSYMPCA trial results presented last year, and had the privilege to do an interview with Chris Parker from the Royal Marsden Hospital at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO/ESTRO) in Stockholm.

I am not expecting new data to be presented at ASCO GU on radium-223, but it will be interesting to see how the audience views a bone targeted radio-pharmaceutical that unlike denosumab, does provide an overall survival benefit.

The ALSYMPCA trial showed a significant delay in time to first skeletal-related event (SRE) of 13.6 months vs 8.4 months:

radium-223-Alpharadin-time-to-first-skeletal-related-event-ALSYMPCA-trialAND a median overall survival of 14 months compared to 11.2 months for placebo group:

radium-223-Alpharadin-overall-survival-benefit-ALSYMPCA-trialAlpharadin is on the fast track to FDA approval this year.

My conclusion:  If you plan to be at ASCO GU 2012, the prostate cancer data to watch is the first presentation of the MDV3100 AFFIRM trial results.

 

Bone is a tissue in constant state of remodeling by osteoclasts (cells responsible for bone resorption) and osteoblasts (cells responsible for new bone formation).

Osteoporosis is a disease of progressive bone loss that is associated with increase risk of fractures.  Particularly debilitating are hip fractures in the elderly that are costly to treat and also lead to increased death and reduction in quality of life.  It’s estimated that osteoporosis affects 44 million people in the United States over the age of 50.

Most treatments for osteoporosis inhibit bone resorption e.g. bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid).  By inhibiting or reducing bone resorption, there is a lower amount of bone loss.

Recent research published in the November 2011 issue of the journal Nature Medicine has highlighted a new potential target for osteoporosis drug development that acts on osteoblasts and promotes bone formation.

In a series of elegant experiments, Takako Negishi-Koga and colleagues found that osteoclast-derived Semaphorin 4D (Sema4D) inhibits bone formation.

They found that the transmembrane protein Sema4D is expressed by osteoclasts and inhibits osteoblastic bone formation. In other words, Sema4D is a critical mediator of osteclast-osteoblast communication. 

They reported that:

In osteoblastic cells, Sema4D stimulation decreased the expression of cadherin-11 at the cell-cell contact region suggesting that Sema4D stimulates cell motility through an impairment of cell-cell adhesion, which in turn results in the reduction in bone-forming activity.

Osteoclast-derived Sema4D inhibits bone formation: 

The binding of Sema4D to its receptor Plexin-B1 on osteoblasts resulted in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 (IGF-1) signaling and by modulating osteoblast motility. 

The implication of these findings is that blocking Sema4D could promote osteoblastic bone formation without affecting osteoclastic bone resorption.  The researchers successfully tested this hypothesis using an antibody to Sema4D.

They concluded that:

These results suggest that the blocking Sema4D–Plexin-B1 interaction is a new and potentially effective strategy for increasing bone formation in humans.

This preclinical work using an animal model is highly promising and suggests that as we learn more about the bone microenvironment, new therapeutic and molecular targets for drug development may emerge.

ResearchBlogging.orgNegishi-Koga, T., Shinohara, M., Komatsu, N., Bito, H., Kodama, T., Friedel, R., & Takayanagi, H. (2011). Suppression of bone formation by osteoclastic expression of semaphorin 4D Nature Medicine, 17 (11), 1473-1480 DOI: 10.1038/nm.2489

The Oncologist Journal of the Society for Translational Oncology (STO) has published a video recording on prostate cancer that is well worth watching for those with an interest in this area.

At their Sept 8, 2011 CME symposium held in Belfast, a roundtable was held entitled “Prostate Cancer: Progress & Promise.”

Moderated by Bruce A. Chabner (Mass General/Harvard), the panelists were Joe O’Sullivan (Queen’s University, Belfast), Johann De Bono (The Institute for Cancer Research) and David Waugh (Queen’s University, Belfast).

Professor de Bono in the video comments that”

“with regards to our dream of eventually treating men with prostate cancer without castrating them, which must be our ultimate goal and curing them of cancer. I think we will have to focus on for example drugs targeting ERG or ERG signaling.”

Chabner then asks the good question of whether ERG is a druggable target?

To which De Bono replies that you can drug ERG by inhibiting PARP and references a paper by the Chinnaiyan group published in the May 2011 issue of Cancer Cell.

PARP inhibition represents an interesting area of prostate cancer research.

If you would like to know more, Sally Church, PhD has written about this on Pharma Strategy Blog.  See posts on “TMPRSS2: ERG may be a more useful marker than PSA in prostate cancer” and “Personalized Therapy for Prostate Cancer – is it possible?

In the STO video, De Bono discusses why he would like to replace bone scans in prostate cancer with another imaging modality that more accurately reflects the activity of the disease. Future possibilities include use of diffusion weighted magnetic resonance imaging and novel PET tracers.

There’s also a good discussion about Alpharadin for those interested in some anecdotal commentary on experiences with it.

Another notable comment by De Bono is his belief that “taxanes work in prostate cancer primarily by targeting androgen receptor signaling.” Taxanes have typically been thought to target mitosis.

De Bono goes on to say that clinical trial data being submitted for publication shows that patients who are refractory to abiraterone, are also refractory to docetaxel when they progress on it.  The suggestion is that there may be cross resistance between abiraterone and taxanes with a subgroup of patients who just don’t do well on androgen receptor (AR) targeting drugs.  The reason for this isn’t yet clear.

A new phase 2 clinical trial is starting soon that will look at the sequencing of abiraterone and cabazitaxel.  One group will receive abiraterone followed by cabazitaxel, the other cabazitaxel followed by abiraterone.

The Belfast STO symposium was the second in a three part series. The next one will be held during ASCO GU in San Francisco next year.

Another potentially useful meeting in this area is the February 2012 AACR workshop on “Advances in Prostate Cancer Research” chaired by Arul Chinnaiyan & Charles Sawyers.

Prostate cancer remains an exciting therapeutic area to watch with tremendous progress and promise of late.

Biotech Strategy Blog is 1 today!  I can’t believe that a year has gone by so quickly!  Before moving on to year 2, I thought a brief review might be interesting.

What have been the top posts on Biotech Strategy Blog this past year?

In terms of total visitors per post:

  1. Results from NEJM Lucentis v Avastin AMD CATT clinical trial
  2. AUA Results from PIVOT study show no benefit from radical prostatectomy in low risk early stage patients
  3. ASCO 2011 Cabozantinib (XL184) may be an exciting new prostate cancer drug
  4. Merck’s capthepsin-K inhibitor odanacatib in osteoporosis
  5. Update from AACR on new prostate cancer drugs to watch

For those who like metrics:

  • Highest number of reads per month was in May (19,927)
  • Year to date there have been 79,179 visitors
  • Most visited day was September 22, 2011 (2136 reads)

What have been some of the other posts that I enjoyed writing about?

My top 5 (not in rank order) would be:

  1. Alpharadin will be new treatment option for prostate cancer
  2. Patient advocacy session at European Hematology Assocation EHA Congress shows impact of drug adherence on outcome
  3. How nanotechnology may revolutionize the detection of traumatic brain injury using a sensor that changes color
  4. Innovation in Nanotechnology will lead to improved drug delivery, diagnostics & imaging
  5. Insights of the decade

Finally, I have produced 4 videos that you can watch on the biotechstrategy channel on YouTube.


It’s been a busy but enjoyable year. Biotech Strategy Blog is still a work in progress.  If you have enjoyed a particular series of posts or would like me explore a topic or theme in the future, do email me or post a comment.

One piece of hot news at the 2011 European Multidisciplinary Cancer Congress (twitter #EMCC2011) taking place in Stockholm this weekend is the data on radium-223 chloride (Alpharadin) in metastatic castration resistant prostate cancer. The phase 3 ALSYMPCA trial results were presented in yesterday’s presidential symposia by Dr Chris Parker, Consultant Clinical Oncologist at The Royal Marsden Hospital.

Dr-Chris-Parker-Alpharadin-Presentation-Stockholm-Cancer-Congress-2011

The Scandinavian location for the presentation could not have been better, given that Alpharadin was developed by the Norwegian company Algeta. Bayer Schering Pharma AG have the worldwide commercial rights, but Algeta maintains a co-promotion option in the United States.

I first picked up on Alpharadin in a presentation given at the American Urological Association (AUA) annual meeting by Oliver Sartor (Tulane) earlier this year when he reviewed new prostate cancer products in development.

Algeta-Radium-223-Chloride-ASCO 2011-Abstract-4620At the ASCO 2011 meeting in Chicago there was a poster on the Alpharadin Phase 2 trial data (see the figure on the right) that caught my attention given that it showed an overall survival (OS) advantage.  This news was, however, largely drowned by the interest in cabozantinib (XL184).

The result is that Alpharadin has to many come out of left field. It is a promising compound for the treatment of prostate cancer that will provide new treatment options for patients with metastatic disease. In particular, use in combination with other therapies such as abiraterone acetate (Zytiga) may prolong survival to a greater extent than either does individually.

Currently, radium-223 chloride (Alpharadin) is only in investigational use and is not approved in Europe or the United States. It is, however, on the fast track towards FDA approval in 2012.

ALSYMPCA phase 3 prostate cancer data presentation ESMO ECCO 2011What makes Alpharadin exciting as a new treatment option for castration resistant prostate cancer (CRPC) is that the ALSYMPCA trial data shows that it not only provides a significant median overall survival (OS) benefit of 2.8 months compared to placebo (14 months versus 11.2 months, p=0.00185, HR 0.695), but significantly delays the time to first skeletal event by 5.2 months (13.6 months versus 8.4 months, p=0.00046, HR 0.610).

The overal survival (OS) benefit seen in the ALYSMPCA phase 3 trial is comparable to other approved agents in the post-docetaxel setting for CRPC. However, where it is unique is in the additional effect it has on skeletal related events (SRE), a common occurrence in metastatic prostate cancer.  Bone metastases are painful and have a significant impact on quality of life.

Other compounds that target the bone microenviroment such as denosumab (Xgeva), provide a delay in the time to first skeletal event in prostate cancer patients but to-date have not been shown to confer an overall survival advantage. This means that Alphardin is the first bone targeted agent to confer both an overall survival and a delay in time to first skeletal event.

After Dr Parker’s presentation of the ALSYMPCA phase 3 trial data yesterday here in Stockholm,  Professor Wim Oyen of the Department of Nuclear Medicine in Nijmegen discussed the data.

What he noted was the high tolerability of Ra-223 chloride (Alpharadin) as compared to other radiopharmaceuticals for treatment of patients with bone metastases.  He discussed how the emission of alpha particles allows for a short range effect (a few cell diameters) that is very localized, but with a large biological effect.

Oyen highlighted the “opportunity for improving patient outcome by adding Ra-223 in regimens of combination therapy,” something that Dr Parker speculated about in his media briefing.

Professor Oyen also saw “an opportunity for improving patient outcome by using Ra-223 in an adjuvant setting.”  His conclusion based on the phase 3 ALSYMPCA trial data presented was that radium-223 chloride (Alpharadin) is an “effective, very well tolerated and convenient treatment modality.

 

Dr Parker mentioned to me, while waiting for a train back to Stockholm, that the ALSYMPCA trial data he presented had not yet been submitted for publication. He said he would be disappointed if it did not appear in the New England Journal of Medicine. Given that it is groundbreaking and “practice changing,” I would be surprised if it is not published in the NEJM in due course.

I am sure that we will be hearing more about radium-223 chloride (Alpharadin) in the forthcoming months, especially now it is on fast track to FDA approval in 2012.

Although not a cure for prostate cancer, the ALSYMPCA trial data presented here in Stockholm is further good news for patients, and will provide a potential new treatment option for urologists and oncologists.

1 Comment

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

Following on from my recent blog post on emerging treatments in osteoporosis, one of new approaches in development is the inhibition of cathepsin-K.

Cathepsin-K inhibition is a novel approach to osteoporosis treatment and Merck’s odanacatib is leading the way in this new class of drugs. It is currently in phase III development, with 16,716 subjects enrolled (NCT00529373).

Cathepsins are lysosomal proteases. Cathepsin K (Cat-K) is a cysteine protease that plays an important role in the function of osteoclasts (the cells responsible for bone destruction). Cat-K acts to degrade bone collagen. By inhibiting it, the removal of bone matrix proteins by osteoclasts is reduced.

However, Cat-K inhibitors such as odanacatib do not kill off the osteoclast, but allow it to still produce chemokines and growth factors such as WNT that are responsible for the effective function of osteoblasts (the cells responsible for bone formation).

The net result is that Cat-K inhibitors reduce bone resorption.

Phase II clinical trial results for odanacatib presented at the American Society of Bone and Mineral Research (ASBMR) annual meeting last year (abstract #1247),  showed an increase in spine and hip bone mineral density (BMD) after four years of follow-up, suggesting that odanacatib use leads to increased bone strength. As reported by Merck in their press release:

In postmenopausal women who received odanacatib 50 mg weekly for four years (N=13), an increase in BMD of 2.8 percent at the lumbar, and 2.7 percent at the hip were demonstrated between years three and four of treatment. Over four years of treatment, these women had increases in lumbar spine (10.7 percent) and hip (8.3 percent) BMD from baseline.

If you are looking for further information on the science, the February 2011 issue of “The Journal of Bone and Mineral Research” has several papers on odanacatib, osteocytes and cathepsin K inhibitors.

Merck has 16,716 subjects enrolled in their phase III trial for odanacatib, and July 2012 is indicated as the date when data will be available for the primary end-point of reduction in fracture risk over the three year treatment period.  We can expect the phase III results shortly after that, and if positive, an FDA approval could be expected in 2013.

The development of odanacatib by Merck is clearly a strategy to combat generic alendronate, which has eroded Merck’s market share and profits for Fosamax.  Both odanacatib and generic alendronate, are once weekly doses. The timeline for a product launch for odanacatib appears to be in the late 2013/2014 period, and I am sure further clarity on this will appear from Merck nearer the time.

The challenge for odanacatib is that by 2015, analysts estimate that Amgen’s RANKL inhibitor denosumab will be a blockbuster (more than $1 billion in sales) and sales of parathyroid hormone analogues will have tripled to $1.4 billion.

Although the market opportunity in osteoporosis is likely to grow given the aging population around the world, it remains to be seen how the cost/benefit of odanacatib will stack up against the competition, and whether Merck can capitalize on this.

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.

1 Comment

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 !!