Biotech Strategy Blog

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

Posts tagged ‘Targeted Therapies’

We have selected five key strategic trends that are emerging that will be critical to follow, understand, and even implement if you are on the coal-face of clinical research and new product development.

ASCO16 Chicago 5We aren’t talking about financial things such as cost toxicity, or even how doctors should be paid, but meaty scientific aspects that we need to watch out for. If we are going to improve on cancer research and R&D in the future, these issues will be important.

For companies and academic researchers alike, there is much to learn from the tsunami of data that hit this week if you have a keen interest in the field and a bent for making sense of patterns out of an amorphous mass of data.

Not paying attention to evolution in clinical development can mean the difference between being in the winners circle, on the outside looking in, or falling way behind your competitors. Playing catch up is never anyone’s idea of fun in this market – oncology moves at a lightning fast pace compared to many other therapy areas.

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If you had told me several weeks ago that we would write over 28 posts on #AACR16 and become very interested in mouse models, then most likely I would have laughed out loud and told you not to be so ridiculous!  Here we are with the 29th one and, another, on the bromododomain landscape yet to go.  Such was the vast richness of data and concepts being discussed or presented in New Orleans for those who chose to look.

Today, I want to start the segue from AACR to ASCO coverage.

Nawlins MGRAS FIOne way to do that is through the second part of the Gems from the Post Hall series. This latest one looks at a range of intriguing new targeted therapies and novel targets that are emerging, including a pharma company with a particularly interesting early pipeline.

Several pharma companies presented interesting data on their very early compounds currently in development, plus I noticed a trend for a new class of targeted therapies to emerge, MNK inhibitors, which we will also discuss.

Companies mentioned: Bayer, Orion Pharma, Lilly, Novartis, Pfizer, Agios.

Targets mentioned: PI3K, CDK, Akt, TWEAK, FGFR, BUB1, IDH1, SMYD2, MNK

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San Francisco – the AACR-NCI-EORTC international conference on Molecular Targets and Cancer Therapeutics kicked off last Saturday with two educational sessions, including one that I attended on “Clinical Trial Paradigms in the Era of Novel Therapies.

The session had an impressive line-up of speakers:

  • New paradigms for early-phase trials (James Doroshaw)
  • Phasing out phase III trials: How much evidence do we need if the target is clearly hit? (Jaap Verweij)
  • Development of clinical trials incorporating genomic signatures: Lessons learned? (Lisa McShane)
  • Clinical trial designs for targeted therapies (John Crowley)

James H. Doroshow, deputy director for clinical and translational research at the National Cancer Institute, started his presentation by reviewing the causes of phase II trial failure:

  • 19% Safety
  • 51% Efficacy
  • 29% Strategic

He stated that the overall success rate of recent phase II trials was 18%.

As the debate continues about whether more cancer clinical trials should be done in Phase 2, the key issue according to Doroshow remains lack of a demonstrable proof of mechanism (POM) in many drug trials. That goes hand-in-hand with a lack of molecular markers which can be used to select trial subjects.

“Lack of molecular markers with proven clinical utility follows lack of clinically-demonstrable proof of mechanism”

He provocatively asked:

Should we perform early phase trials without generating evidence supporting POM patient by patient?

His view was that to obtain POM, you need to demonstrate drug action on intended tumor target early in development, prior to expectation of efficacy.

Jaap Verweij in his presentation used the examples of crizotinib, vismodegib, vemurafenib and imatinib in GIST as examples of drugs that had:

  • functionality for a target
  • aimed at a specific population
  • availability of a selection marker.

They are the poster children of targeted therapy, and he convincingly showed that the phase 1 trials of those compounds were largely predictive of the phase 3 results.

His conclusion was that phase I trial can be considered predictive of a phase III study so long as there is a large enough sample size.

We may need to look for bigger increments which should allow us to perform smaller trials,” he said. This would allow trials that are quicker and cheaper. However, he acknowledged that it was not likely we can completely eliminate phase 3 trials particularly for combination therapies or chemotherapies.

John Crowley reviewed the different phase III trial designs, including my least favorite, the “all comer” design.  The ridaforolimus sarcoma phase 3 trial presented at ASCO this year is a good example of how an “all comer” design yielded less than stellar results, and failed to identify the subset of sarcoma patients that optimally respond.  This is the type of phase 3 trial that runs the risk of failure if there are too many non-responders in the heterogeneous patient population.  This problem can often be avoided by more rigour in phase 2 trials to identify the optimal treatment period, relevant biomarkers and subsets of patients most likely to respond.

There is a lot of interest in how to design cancer clinical trials better, bring drugs to market more quickly and more efficiently.  While I enjoyed the content of this session, I did wonder whether it would have been better presented as a roundtable with more audience interaction and engagement rather than the perspective of a few.

A webcast of this session will be available on December 8 from the American Association for Cancer Research (AACR).

At the recent ARVO meeting, one of the symposia that I live tweeted from was on “Nanotechnology for Drug and Gene Delivery.”  During his presentation on “Nanomedicines: From Bench to Bedside” Vladimir Torchilin from Northeastern described how nanotechnology can use methods from other scientific disciplines including layer-by-layer (LbL) polymer chemistry.

Which leads me into an interesting paper that came across my desk from Zhiyong Poon and colleagues at the Koch Institute for Integrative Cancer Research at MIT.

In their paper published online on April 23, 2011 in ACS Nano. they describe how nanoparticles with a pH-sheddable layer can be used to target tumor hypoxia.

In other words, the nanoparticle can travel in the blood to the tumor, then in the changed acidity and pH of the tumor microenvironment, the outer stealth layer is eroded and shedded, exposing another layer of the nanoparticle that delivers drug to the target hypoxic tumor region.

Image Source:  ACS Nano. The author’s conclusion is that “this concept for tumor targeting is potentially valid for a broad range of cancers, with applicability for therapies that target hypoxic tumor tissue.”

This proof of principle research is further progress towards the development of nanomedicines in oncology.

ResearchBlogging.orgPoon, Z., Chang, D., Zhao, X., & Hammond, P. (2011). Layer-by-Layer Nanoparticles with a pH-Sheddable Layer for Targeting of Tumor Hypoxia ACS Nano DOI: 10.1021/nn200876f

This month is Parkinson’s awareness month.  Following on from my recent interview (that you can read here & here) with Dr Todd Sherer of The Michael J. Fox Foundation for Parkinson’s Research, I was interested to read about progress being made on the road to towards targeted therapies.

The April 2011 issue of Nature Chemical Biology reports the development of a selective inhibitor of leucine-rich repeat kinase 2 (LRRK2), a gene that is mutated in some patients with Parkinson’s disease.

The team of researchers from Dana-Farber Cancer Institute, Harvard Medical School, University of Dundee, Scripps Research Institute and ActivX Biosciences applied a novel, screening strategy focused on selectively inhibiting LRRK2.

The result was the identification of LRRK2-IN-1, a novel analog that inhibits both wild-type and mutant LRRK2 kinase activity. The team confirmed the activity of LRRK2-IN-1 using human lymphoblastoid cells from a Parkinson’s disease patient with the LRRK2 mutation.

Unfortunately, LRRK2-IN-1 was unable to cross the blood-brain barrier, which means that it is not suitable for Parkinson’s disease.  However, this research is progress on the road to LRRK2 inhibition and the development of a targeted therapy in the future.

Moving forwards Parkinsons’ researchers may wish to consider combining new small molecules with nanoparticles that are able to cross the blood-brain barrier; this may be the way to deliver targeted therapies to the brain.


ResearchBlogging.orgDeng, X., Dzamko, N., Prescott, A., Davies, P., Liu, Q., Yang, Q., Lee, J., Patricelli, M., Nomanbhoy, T., Alessi, D., & Gray, N. (2011). Characterization of a selective inhibitor of the Parkinson’s disease kinase LRRK2 Nature Chemical Biology, 7 (4), 203-205 DOI: 10.1038/nCHeMBIO.538

One of the themes of this blog is innovation in biopharmaceutical new product development. Innovation can take many forms ranging from nanotechnology based drug delivery to a novel scientific mechanism of action.  The March 17, 2011 edition of Nature, highlights how innovative preclinical animal models are having an impact on drug development.

In their article on translational medicine, “Cancer lessons from mice to humans”, David Tuveson and Douglas Hanahan, describe how preclinical mouse models helped predict the recent phase III clinical trial results for sunitinib and everolimus in pancreatic neuorendocrine tumor (PNET).

The data was a major breakthrough for this disease. As Sally Church noted on Pharma Strategy Blog, sunitinib doubled the progression free survival (PFS) time and improved OS.

Tuveson and Hanahan in Nature note that “a vast number of potential anticancer drugs are currently in the pipelines of biopharmaceutical companies.” The challenge is not one of a shortage of candidates nor of potential targets, but in deciding which have most promise and where to spend valuable clinical development resources.

The authors conclude that there’s now optimism that genetically engineered mouse models may be able to mimic the progression of human cancer at the cellular and tissue levels. The mouse model of PNET (RIP-Tag2) successfully predicted that sunitinib and everolimus would be effective in treating humans.

Of course, not all human cancers can be modeled and adaptive resistance can subsequently occur in clinical trials, suggesting that preclinical models do have their limitations.

I hope we will see further innovation in mouse models of human cancer as translational medicine develops.

ResearchBlogging.orgTuveson, D., & Hanahan, D. (2011). Translational medicine: Cancer lessons from mice to humans Nature, 471 (7338), 316-317 DOI: 10.1038/471316a

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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Uveal melanoma is a common cancer of the eye that involves the iris, ciliary body and choroid.  It is a disease that hits 2000 people per year in the United States and is common in those over 50.  Standard treatment involves removal of the eye or radiotherapy. There is an unmet need for systemic drug therapy.

Mutations in the BRAF gene (a member of the Raf family that encodes a serine/threonine protein kinase) have been found in many skin melanomas.  In 80% of the cases, a single point mutation in exon 15 (T1799A) has been shown to occur.  Some new agents in development such as PLX4032, ipilumumab, GSK2118436 have shown promise in advanced skin melanoma, but research suggests that BRAF may not be the key to Uveal melanoma.

Henriquez et al, in a paper published in Investigative Ophthalmology & Visual Science showed that the T1799A BRAF mutation was only present in 9 of 19 iris melanoma tissue samples, but only in one case of uveal melanoma, suggesting differences in the genetic and clinical differences between the two.

Recently, two papers have been published that provide new insight into this intraocular cancer. In the December 2, 2010 issue of the New England Journal of Medicine, Van Raamsdonk et al, found mutations of either the GNAQ or GNA11 gene to be present in 83% of uveal melanomas that were sequenced (n=713).

Harbour et al, in the December 3, 2010 issue of Science reported findings of a frequent mutation of BAP1 in metastasizing uveal melanomas. They found that in 26 of 31 (84%) of uveal melanoma tumors they examined, there was a mutation of BAP1, the gene encoding BRCA1 associated protein 1 (BAP1) on chromose 3p21.1. The results published in Science, “implicate loss of BAP1 in uveal melanoma metastasis and suggest that BAP1 pathway may be a valuable therapeutic target.”

The data suggests that there may be multiple pathways involved in uveal melanoma.  It is promising to see translational medicine in action, with scientists seeking to understand the molecular basis of a disease so that targeted therapies can be developed.  Uveal melanoma only strikes a relatively small number of patients, but if a highly effective drug can be developed, this could be a market opportunity worth pursuing.

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