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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

New mechanisms of drug resistance to BRAF inhibitors in melanoma

By on February 23, 2011

Many of you will have been following the ongoing story of the discovery of activating V600E mutations in BRAF in greater than 50% of melanomas. As a result, BRAF inhibitors such as PLX4032 have emerged in melanoma but ultimately, we have also seen how resistance unfortunately sets in after 6 to 9 months of therapy despite some impressive initial results.  In addition, approximately 20% of patients don’t respond at all – the key question is why?

Previously, we have discussed several mechanism of resistance, namely AKT and MEK, which has lead to new clinical trial combinations of BRAF plus an AKT or MEK inhibitor (e.g. see this trial) to see if this approach can delay the development of resistance and thus improve the time to progression further.   A background on MEK inhibition can also be found here.

A new article published this month in Cancer Research from Paraiso et al., (2011) suggests another possible mechanism of resistance with BRAF inhibition may also be involved, namely loss of PTEN function (see references below).  They looked at what might happen with a new second generation BRAF inhibitor, PLX4720.

In this new research, some interesting findings emerged:

“We identify loss of PTEN expression, observed in >10% of melanoma specimens, as being responsible for increased PI3K/AKT signaling when BRAF is inhibited.

We further show that PTEN loss contributes to the intrinsic resistance of BRAF V600E-mutated melanoma cell lines to PLX4720 by suppressing the expression of the pro-apoptotic protein BIM.”

They essentially found that increased AKT signaling occurs with PTEN loss:

“Treatment of the PTEN+/- cell line panels with PLX4720 increased pPDK1 and pAKT signaling only in the melanoma cell lines lacking PTEN expression.”

They also observed that:

“Loss of PTEN contributes to intrinsic BRAF inhibitor resistance via the suppression of BIM-mediated apoptosis.”

Some of you may be wondering how these findings can be used to design new therapeutic strategies.  However, loss of PTEN function and heightened BIM expression isn’t something that can be changed directly, but rather, indirectly:

“Dual treatment of PTEN- cells with PLX4720 and a PI3K inhibitor enhanced BIM expression at both the mRNA and protein level and increased the level of apoptosis through a mechanism involving AKT3 and the activation of FOXO3a.”

There are some new trials open with either single agents or combination trials in this area, such as the following selection (by no means exhaustive):

  1. GSK2118436 (A BRAF and MEK/ERK inhibitor) – single agent trial interim data was previously presented at ASCO and ESMO last year.  The initial data in melanoma related brain mets presented at ESMO was stunning.
  2. BKM120 (PI3K) and GSK1120212 (MEK) – combination trial in advanced solid tumours with RAS/RAF mutations.
  3. GDC-0941 (PI3K) plus GDC-0973 (MEK) – combination trial in advanced solid tumours.
  4. GSK1120212 and GSK2141795 phase I safety and PK trial.

I think this is one area in oncology where the research into the underlying biology and mechanism of resistance is almost keeping pace with the clinical research, which is great news for patients!   More vibrant data may begin to emerge soon at ASCO in June and ESMO in September, so hopefully we won’t have long to wait for a new update on progress.

A big question that remains to be answered though, is figuring out which patients should get what combination and in what sequence?  Time will tell, but we have a while to go before we understand things better.

References:

ResearchBlogging.orgParaiso, K., Xiang, Y., Rebecca, V., Abel, E., Chen, A., Munko, A., Wood, E., Fedorenko, I., Sondak, V., Anderson, A., Ribas, A., Dalla Palma, M., Nathanson, K., Koomen, J., Messina, J., & Smalley, K. (2011). PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression Cancer Research DOI: 10.1158/0008-5472.CAN-10-2954

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NFKBIA Deletion in Glioblastomas

By on February 22, 2011

In simple terms, glioblastoma multiforme (GBM) is the most common form of brain cancer, but also the most deadly.  Part of the reasons behind this lie in several factors:

  1. It’s a highly complex disease with multiple things going on
  2. It’s heterogeneous – many of the subsets have yet to be identified
  3. Crossing the blood brain barrier is a challenge for therapeutics

You only have to read a couple of papers from Vogelstein’s group and others (see references) to grasp how complex the underlying biology of this disease is.  From IDH1 deletions to EGFR.   Other targets have included PDGFR-alpha, ERBB2 and MET, with limited success.

A few definitions first to make things easier for people to follow:

Amplifications: An increase in the copy number of a particular gene, which can be either inherited or somatic.  Amplification of oncogenes is a preeminent event in the pathogenesis of many types of human cancer.

Deletions: The absence of one (heterozygous deletion) or both (homozygous deletion) copies of a gene in a diploid cell.  Heterozygous deletions may or may not disrupt gene or protein function and cell function as a result.

The current research looked at Nuclear factor of κ-light polypeptide gene enhancer in B-cells (NF-κB), which is a transcription factor activated by the EGFR pathway. Constitutive activation of NF-κB has previously been observed in glioblastomas.   NF-κB inhibitor-α (NFKBIA) represses NF-κB and signaling in the NF-κB and EGFR pathways.

In addition, mutations of NFKBIA have been found in a variety of tumour types, including Hodgkin’s lymphoma, colorectal cancer, melanoma, hepatocellular carcinoma, breast cancer, and multiple myeloma, which suggests that NFKBIA is a tumour suppressor. In other words, it can prevent drive tumourigenesis and prevent existing therapies such as EGFR inhibitors from working well.

To test this idea out, they analyzed human glioblastomas (n=790) for deletions, mutations, or expression of NFKBIA and EGFR and studied the tumour-suppressor activity of NFKBIA in cell culture. They then compared the molecular results with the outcome of glioblastoma in 570 people.

What they found was interesting:

“NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity.”

The emphasis above is mine.  Unsurprisingly, deletion and low expression of NFKBIA were associated with more unfavourable outcomes:

“Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification.”

The researchers concluded that:

“Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.”

What these results mean is that because NFKBIA plays such a big role downstream and essentially induces cross-talk signalling with EGFR, future therapeutic strategies may need to take this tumour suppressor into consideration.

References:

ResearchBlogging.orgParsons, D., Jones, S., Zhang, X., Lin, J., Leary, R., Angenendt, P., Mankoo, P., Carter, H., Siu, I., Gallia, G., Olivi, A., McLendon, R., Rasheed, B., Keir, S., Nikolskaya, T., Nikolsky, Y., Busam, D., Tekleab, H., Diaz, L., Hartigan, J., Smith, D., Strausberg, R., Marie, S., Shinjo, S., Yan, H., Riggins, G., Bigner, D., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V., & Kinzler, K. (2008). An Integrated Genomic Analysis of Human Glioblastoma Multiforme Science, 321 (5897), 1807-1812 DOI: 10.1126/science.1164382

Phillips, H., Kharbanda, S., Chen, R., Forrest, W., Soriano, R., Wu, T., Misra, A., Nigro, J., Colman, H., & Soroceanu, L. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis Cancer Cell, 9 (3), 157-173 DOI: 10.1016/j.ccr.2006.02.019

Bredel M, Scholtens DM, Harsh GR, Bredel C, Chandler JP, Renfrow JJ, Yadav AK, Vogel H, Scheck AC, Tibshirani R, & Sikic BI (2009).  A network model of a cooperative genetic landscape in brain tumors. JAMA : the journal of the American Medical Association, 302 (3), 261-75 PMID: 19602686

Bredel, M., Scholtens, D., Yadav, A., Alvarez, A., Renfrow, J., Chandler, J., Yu, I., Carro, M., Dai, F., Tagge, M., Ferrarese, R., Bredel, C., Phillips, H., Lukac, P., Robe, P., Weyerbrock, A., Vogel, H., Dubner, S., Mobley, B., He, X., Scheck, A., Sikic, B., Aldape, K., Chakravarti, A., & Harsh, G. (2011). NFKBIA Deletion in Glioblastomas.  New England Journal of Medicine, 364 (7), 627-637 DOI: 10.1056/NEJMoa1006312

On oncogenes in Luminal B breast cancer

By on February 21, 2011

Last week while I was away at the ASCO GenitoUrinary (GU) symposium in Florida, two interesting findings in cancer science hit the journals, one in breast cancer and the other in glioblastoma, a form of brain cancer.  I thought it would be a good idea to take a quick look at those new publications (see reference links below) over the next couple of days.

Today, we begin with the ZNF703 oncogene in Luminal B breast cancer.

This research is important because it’s the first oncogene to be found in the last 5 years and could be active in up to 1 in 12 breast cancers.   The last active oncogene to be discovered in breast cancer was HER2 and we all know how that worked out!

I always remember Harold Varmus’s pithy keynote lecture at AACR a few ago, where he described how oncogenes work in a very simple to understand way, namely:

“Oncogenes are normal genes that control growth in every living cell, but which, under certain conditions can turn renegade and cancerous.”

The latest research, jointly led by Cancer Research UK Cambridge Research Institute and the British Columbia Cancer Agency in Vancouver, Canada, reports how they looked at gene activity in breast tumour samples (n=1172), as well as looking at breast cancer cells grown in the laboratory.

It’s a elegant study that by a painstaking process of detective work, they were able to sort through the enormous mass of data and eliminate genes, until there was only the ZNF703 gene left within a region on chromosome 8, that was overactive in all the samples tested. Wow.

What is particularly interesting, is that that region of DNA was suspected of harbouring mutant genes twenty years ago, but it is only with modern data gathering and processing tools (ie high-resolution copy number profiling) that the oncogene could be actually be isolated.

Here’s what the scientists concluded:

“Overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors.  Taken together, these data strongly point to ZNF703 as a novel oncogene in Luminal B breast cancer.”

Luminal B histology is common in estrogen receptor-positive (ER+) breast cancers.

Keep an eye on this oncogene, because in the next few years we may well see new targeted drugs emerge from Pharma and Biotech pipelines to target the aberrant activity and by inhibiting the oncogene, switch off the signalling activity driving the cancer.  If that happens, this could well be an important and exciting finding:

“Clinical correlation: ZNF703 amplification is associated with a distinct subtype (Luminal B breast cancer) and with worse clinical outcome in ER+ cancers.  ZNF703 amplification is associated with higher grade and more aggressive tumours, explaining the worse clinical prognosis.”

It’s much easier to design a drug or therapeutic once you have a valid target to aim for and with more specific targeting, comes improved patient outcomes.

Reference:

ResearchBlogging.orgHolland, D., Burleigh, A., Git, A., Goldgraben, M., Perez-Mancera, P., Chin, S., Hurtado, A., Bruna, A., Ali, H., Greenwood, W., Dunning, M., Samarajiwa, S., Menon, S., Rueda, O., Lynch, A., McKinney, S., Ellis, I., Eaves, C., Carroll, J., Curtis, C., Aparicio, S., & Caldas, C. (2011).  ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium EMBO Molecular Medicine DOI: 10.1002/emmm.201100122

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ASCO GU Symposium 2011

By on February 16, 2011

Today, I’ll be heading off to Orlando to the Genito-Urinary Cancer meeting co-hosted by ASCO, ASTRO and SUO and runs through Saturday. This year promises to have some interesting data coming out on a variety of cancers, including renal cell and prostate cancers.

The official hashtag is #gusymposium, which is unfortunately rather long, when you consider there are only 140 characters for a tweet and medical meetings tend to contain a lot of complex information to parse on the fly. Like many, I’ll be using #ascoGU, which is much simpler and shorter when tweeting in a hurry. The widget below captures both to make following remotely easier.

If you have any questions, do tweet me @maverickny and I’ll do my best to answer them. ASCO also have a Twitter handle (@asco) if anyone has any logistics queries.

Do allergies lower the risk of low and high grade Glioma?

By on February 15, 2011

It’s not often that having multiple allergies is a good thing, but that certainly seems to be the case if a recent study published in Cancer, Epidemiology, Biomarkers and Prevention is accurate.  I was tempted to create a new category for ‘wacky findings’ but managed to resist the temptation, at least for now.

Study Details

Self-reported data on medically diagnosed allergies and antihistamine use for patients with glioma (n=419) and cancer-free patients (n=692) was studied by researchers at the University of Chicago.  The controls had no prior history of brain tumours or any other cancers, and did not have a history of neurodegenerative disease.

Respondents completed a web-based or telephone survey and were asked if they were medically diagnosed with allergies or asthma at least two years prior to the survey, and if so, the age of diagnosis.   In addition, they were also asked to indicate the number of individual allergies within each of the following categories:

  • Seasonal
  • Pets
  • Medications
  • Food
  • Others

Details on regular medication usage two years or more prior to the survey, and information on specific medication brands, frequency and duration of usage were also collected.

What did they find?

In short:

  1. Allergies appeared to be protective, providing a reduced risk for those with who have a higher number and more types of allergies.
  2. Age of allergy diagnosis and years since diagnosis were not associated with glioma risk.
  3. Antihistamine use, including diphenhydramine hydrochloride (a possible neurocarcinogen), did not appear to affect glioma risk separately from the effects of allergies.

In essence, the study suggests that there is a relationship between the immune system of allergy sufferers and glioma risk.

However, if you look at the literature, the answer is not as clear cut as the researchers themselves point out:

“Allergies and/or atopic disease, on the other hand, have been associated with a significantly decreased risk of glioma in many, but not all, studies.  The decreased risk associated with glioma has been hypothesized to be the result of an increase in immune surveillance related to atopic disease; this hyperactive immune surveillance may limit abnormal cell growth. However, the specific mechanism through which atopic disease may influence glioma risk has not been identified and noncausal associations with glioma risk have not been ruled out.”

They also went on to suggest that:

“A comprehensive study of allergies and antihistamine use using standardized questions and biological markers will be essential to further delineate the biological mechanism that may be involved in brain tumor development.”

To circle back to the original question…

Many of you will be very aware that discovering a relationship occurs between two variables does not imply causality, so until the mechanism of action for this phenomenon is delineated one way or the other, I would treat the results with a rather large pinch of salt.

References:

ResearchBlogging.orgMcCarthy, B., Rankin, K., Il’yasova, D., Erdal, S., Vick, N., Ali-Osman, F., Bigner, D., & Davis, F. (2011). Assessment of Type of Allergy and Antihistamine Use in the Development of Glioma Cancer Epidemiology Biomarkers & Prevention, 20 (2), 370-378 DOI: 10.1158/1055-9965.EPI-10-0948

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Science and data

By on February 14, 2011

One of the things you can never escape from in modern science is the sheer volume of data that needs to parsed, processed and presented.  One of the things I particularly love about many of our smart clients is that they specifically request “no data dumps” preferring instead to receive relevant strategic insights.  Of course, these take longer to generate, more experience in the subject area and more brain power to produce, but ultimately they also have more value to customers.

Science and data processing

Word Cloud courtesy of Science Magazine

This morning, I was pleased to see that Science magazine are running a very timely overview of data in science in their current issue.  It’s free (with registration to non-subscribers) for those interested in a broad look across multiple science disciplines.

Included in the edition, is an overview of data in climate change, ecology, neuroscience, social science, stem cells and other topics.

Oddly, they haven’t included an article on cancer specifically, although bioinformatics in this area would be particularly fascinating since it is probably far advanced compared to many other life science disciplines in data processing.

Still, there is one on genomics and next generation sequencing that many of you may be interested in, since the article raises some interesting questions, such as:

“The availability of deep (and large) genomic data sets raises concerns over information access, data security, and subject/patient privacy that must be addressed for the field to continue its rapid advances.”

Personally, I love reading Science magazine, and its sister publication, Science and Translational Medicine, as they are usually both chock full of good articles to read on a weekly basis to pass the spare time on trains and planes while travelling to conferences.  I often Instapaper the PDFs for later reading on my iPhone, but you can also read them in the paper magazine or online, depending upon your preference.

Check out the current Science Special Edition on Data and see what you think for yourselves.  By chance, it is virtually a year, almost to that day, that Phil Baumann and a bunch of us Pharma types on Twitter were debating the value of content and process that led to Phil’s excellent summary of the topic on his blog.  Check it out, it’s well worth a read.

References:

ResearchBlogging.orgKahn, S. (2011). On the Future of Genomic Data Science, 331 (6018), 728-729 DOI: 10.1126/science.1197891

NYAS: The pathogenesis of cancer

By on February 10, 2011

After recovering from a sore throat yesterday, I’m heading off to the New York Academy of Science this afternoon, where I’m a member, to listen to a lecture of the pathogenesis of cancer.  The actual long-winded version of the title is:

“Oxidative Stress in Cancer and Exploitation of Negative Regulators as Therapeutics.”

Oof, I wonder how many people were put off by that technical description, rather than the simpler and more digestible ‘pathogenesis of cancer’?  I do hope not.

The speakers come from some prestigious cancer institutions around the country including Dana Farber, MD Anderson and Moffitt in Tampa, so it will be interesting to see where this field of research is going.

If you’re in the NY area and are interested, there is probably still time to sign up – it doesn’t start until 1pm.

{UPDATE:

A few people have contacted me asking me about the link between oxidative stress and cancer.  Put simply, reactive oxygen species (ROS) promotes tumour cell proliferation and survival.   This often occurs by directly modulating growth regulatory molecules and key transcription factors.

In addition, several chemotherapy agents such as doxorubicin increase ROS production, inducing apoptosis but it may also be responsible for it’s cardiotoxicity.  The conundrum with ROS is that while excessive oxidative stress induces apoptosis, moderate oxidative stress promotes proliferation, metastasis, and avoidance of apoptosis, imparting a survival advantage to tumour cells, so getting the balance right is critical!}

Do stromal endothelial cells directly influence cancer progression?

By on February 9, 2011

Years ago, while doing my Ph.D research in respiratory medicine, I was fascinated by one of my friends chosen area of study.   She was looking at the role of endothelial cells and nitric oxide in controlling blood vessels.   At the time, it was particularly relevant to cardiovascular disease and most of the focus was in that area. However, at one of the University of London seminars where she was presenting, the conversation spilled into related areas such as where else the concepts could be applied.   One of the students was doing related area in cancer research and was interested in how the learnings were relevant to his research.  A fairly spirited debate ensued.

Fast forward a decade or two and I was amused to see a paper pop up last month in Science and Translational Medicine, although I only just got round to reading it in my huge pile of what I call ‘interestingness’.

We’ve covered angiogenesis extensively here on this blog, but not in the context of endothelial cells in the tumour microenvironment.  Folkman’s seminal 1971 paper is well worth reading (or re-reading) on the topic:

“Tumor cells appear to stimulate endothelial-cell proliferation, and endothelial cells may have an indirect effect over the rate of tumor growth.”

In other words, tumour vessels were originally thought to control tumor growth through perfusion of metabolically active cancer cells.   For those of you interested in a more recent review based on progress with angiogenic therapy, Kerbel (2008) published a thorough update on angiogenesis.

Meanwhile, the latest research from Franses et al., (2011) is crucial, because they realised that instead of the long held belief that endothelial cells providing support, they actually do something far more important i.e. secrete molecules that dynamically regulate cancer cell proliferation and invasiveness:

“Secretions from quiescent ECs muted the proliferative and invasive phenotype of lung and breast cancer cells in vitro and reduced cancer cell protumorigenic and proinflammatory signaling.”

The mechanism isn’t yet fully clear, but reducing signaling through intracellular pro-tumor and pro-inflammatory pathways was suspected.

From this study it looks as though endothelial cells (such as fibroblasts and immune cells) are therefore active participants in regulating the tumour microenvironment, and thereby potential targets for therapeutic intervention. Stromal-cancer crosstalk is rapidly becoming a hot topic and realising that the endothelial cells may be more important than originally thought may be a useful advance in our understanding of angiogenesis and how tumours proliferate.

So, to answer the question of whether stromal endothelial cells directly influence cancer progression, the answer would appear to be a surprising yes, which may have implications for future combination trials.

References:

ResearchBlogging.orgFranses, J., Baker, A., Chitalia, V., & Edelman, E. (2011). Stromal Endothelial Cells Directly Influence Cancer Progression Science Translational Medicine, 3 (66), 66-66 DOI: 10.1126/scitranslmed.3001542

Sherwood, L., Parris, E., & Folkman, J. (1971). Tumor Angiogenesis: Therapeutic Implications New England Journal of Medicine, 285 (21), 1182-1186 DOI: 10.1056/NEJM197111182852108

Kerbel, R. (2008). Tumor Angiogenesis New England Journal of Medicine, 358 (19), 2039-2049 DOI: 10.1056/NEJMra0706596

Molecular subsets in lung cancer

By on February 7, 2011

Over the last couple of years, our knowledge and understanding of non-small cell lung cancer (NSCLC) has improved as mutations and translocations that drive tumour growth and survival have been identified.

Unfortunately, while we have many new targeted agents in the clinic, few have so far made it to market for broader use in every day clinical practice.  EGFR inhibitors such as erlotinib (Tarceva) and gefitinib (Iressa) were probably the first to gain people’s attention and soon we will hopefully have crizotinib for ALK translocations, since Pfizer have begun the rolling NDA submission to the FDA.

Lowly and Carbonne (2011) discussed the progress with lung cancer subsets in a short piece in Nature Reviews Clinical Oncology that is well worth checking out (see reference below).   They point out that identifying these groups based on their molecular peculiarities is important because patients can be identified and better response rates obtained in a more targeted population:

“Patients with lung cancers harboring EGFR mutations have dramatically greater clinical responses when treated with the oral EGFR tyrosine kinase inhibitors (TKIs) erlotinib or gefitinib, compared with patients without these mutations. In 2009, two seminal trials (the Iressa Pan-Asia Study [IPASS] and the Spanish Lung Cancer Group) demonstrated response rates of around 70% to EGFR TKIs in this cohort of patients, compared to a response rate of 30–40% with traditional platinum-based chemotherapy.”

They went onto describe the molecular subsets found to date:

Molecular Subsets in Lung Cancer

Note that approx. half of the aberrant mutations have yet to be found and about one-eighth have been identified, but clinical trials are still ongoing with various inhibitors, so there is more hope for the future if any of these pan out with positive data.

Of course, what everyone wants to know is what is the next target that may emerge after crizotinib and ALK.  I think PI3-kinase inhibitors look the most promising and there are a few being evaluated in trials right now.  However, my suspicion is that we will be very lucky to get it right first time and it may well take some more creative combinations than at present before we figure it out.  We may see a few failures before someone cracks the optimal solution based on biomarker and research into resistance mechanisms.

I’ll be off to San Francisco later this month to attend the AACR meeting on the PI3-kinase/mTor pathway in cancer to see what progress is being made.  Watch this space for updates on what the key opinion leaders think.

References:

ResearchBlogging.orgLovly, C., & Carbone, D. (2011). Lung cancer in 2010: One size does not fit all Nature Reviews Clinical Oncology, 8 (2), 68-70 DOI: 10.1038/nrclinonc.2010.224

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Phase III submission and failures in Pharma R&D

By on February 4, 2011

Following on from yesterday’s post about FDA approvals, here’s another short Nature Reviews Drug Discovery synopsis, this time on Phase III drug submissions and failures trends between 2007 and 2010.

This caught my eye:

“The Centre for Medicines Research International has noted that the average for the combined success rate at Phase III and submission has fallen to ~50% in recent years.”

Ouch.  Bold highlight mine.

The overall picture looks like this, based on n=83 submission failures:

Source: Nature Reviews Drug Discovery

I was astonished to see that oncology contributes over a quarter of the filings, but much less surprised that lack of efficacy was the reason of the failure:

“Of the drugs that failed to show an improvement in efficacy as an add-on therapy, 58% were anticancer drugs, and of those that failed to show an improvement in efficacy versus placebo, 33% were nervous system drugs.”

The author suggested that perhaps the challenging environment has led to unwise or hasty filings:

“… but is perhaps also a result of the pressure on companies to replenish pipelines with drugs that have high potential for approval and reimbursement, particularly in a period during which patent expiries for major products are threatening future revenues.

Owing to this urgency, it seems that companies have progressed drugs into Phase III trials even though they only displayed marginal statistically significant efficacy in Phase II proof-of-concept studies; consequently, these drugs carry a greater than average risk of failure.”

Sometimes that may well be true, but quite frankly, cancer trials are a bit of a crapshoot at the best of times so I’m not sure I agree with the sweeping perspective.

Promising phase II data can often lead to spectacular and unexpected phase III flops as sanofi-aventis discovered with their PARP inhibitor, iniparib, in triple negative breast cancer only last week.   The phase II data was hardly marginal and was worthy of publication in the New England Journal of Medicine.

In the long run though, we learn more from failures than successes, so that others following in the wake can improve on the trial design and combination therapies used. Still, that’s not much comfort for those who blazed the path initially.

References:

ResearchBlogging.orgArrowsmith, J. (2011). Trial watch: Phase III and submission failures: 2007–2010 Nature Reviews Drug Discovery, 10 (2), 87-87 DOI: 10.1038/nrd3375

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