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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

2010 FDA drug approvals

By on February 3, 2011

The current Nature Reviews Drug Discovery has a short analysis of last year’s FDA approvals for new molecular entities (NME) and biologics:

“The US Food and Drug Administration’s (FDA’s) Center for Drug Evaluation and Research (CDER) approved 15 new molecular entities and 6 new biologics in 2010. The total of 21 new products falls below the 25 approved in 2009 and the 24 in 2008.”

Here’s a graphic of the overall trend since 1996:

2010 FDA drug approvals

Source: Nature Reviews Drug Discovery

You can see that for drugs, the trend has been downwards since 1996, although the last few years have been fairly stable. The biologics, while only a small proportion of the total have been steady.

What you can’t see in the chart above is:

  1. Ratio of submissions to approvals
  2. Impact of generic approvals
  3. Shift from mass market primary care drugs to specialty and orphan drugs.

Over the next few years within the oncology sector, for example, I think we will see more targeted drugs emerging that affect smaller patient populations.   A good example of this is Pfizer’s crizotinib, which was filed last month for ALK translocations in non-small cell lung cancer (NSCLC).  The target population is only ~5% of NSCLC.

The other trend that hasn’t yet made a huge impact, but will likely do so in future, is biosimilars and biobetters. That’s a whole different ball game entirely.

What do you think will happen this year? Hopefully there won’t be as many complete response letters (CRL) in 2011 as there were in 2010!

References:

ResearchBlogging.orgMullard, A. (2011). 2010 FDA drug approvals Nature Reviews Drug Discovery, 10 (2), 82-85 DOI: 10.1038/nrd3370

Can we predict when cancer will spread?

By on February 2, 2011

Early this morning I saw a headline float by my Twitter stream from yesterday with a link to an article or paper suggesting that yes, we can indeed predict metastasis. I can’t remember who shared it, or what was the exact news article but a quick Google search for latest news found some noise around a potential biomarker, CPE-ΔN. The paper (open access) in the references link below, is from the Journal of Clinical Investigation.

Now, the idea that a biomarker might be able to predict metastasis is important because it signals the need for more aggressive treatment as the disease is advancing. Equally, if someone is doing well, you don’t want to intensify therapy needlessly but resection may be more appropriate.   Clearly, the earlier you detect the cancer, the better, but conversely, figuring out when to change treatment and prevent or slow metastasis is also important.

Reading the paper carefully, the authors stated:

“We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-ΔN) that drives metastasis.”

In the research, they used a liver cancer model (or hepatocellular cancer, HCC) to see what was happening with the protein.  Interestingly, CPE-ΔN tended to be present and have high levels in tumours that have metastasised.

They followed a group of patients with HCC (n=99) and looked to determine whether high or low levels of CPE-ΔN was associated with prognosis, with interesting results:

Can cancer metastasis be predicted?

They also looked at patients with stage 2 disease that had only spread within the liver, as well as patients with a rare adrenal disease and colon cancer.  The patients with stage II HCC have a low chance of recurrence, but it can happen, so the question was could the biomarker be used to predict those most at risk?

The answer was yes.

Of the patients with early HCC (n=18):

  • Thirteen had low levels of CPE-ΔN and 10 of those were still cancer-free three years after surgery.   However, three with low CPE-delta N levels did have recurrence, giving an accuracy level of 77% in predicting metastasis.
  • Five had high levels of CPE-ΔN and in four of them recurrence occurred, giving an accuracy level of 90%.

All in all, it’s a good piece of solid research that may have important implications for future research.  Be warned, the paper is a little heavy to read though!

The next steps for the group are:

  1. Find a therapeutic method of blocking CPE-ΔN, preferably with a small molecule
  2. Determine the mechanism by which CPE-ΔN is activated, thereby figuring out how the switching on of metastasis works

All in all, although this research, while still at the very early stage, looks promising and worth following to see how the idea pans out.  I can’t help wondering how this research will impact the Norton and Massagué cancer seeding theory – it should add to it.  Now, if only we can find out what activates the CPE-ΔN protein, thereby triggering the metastasis, that could well be a key piece in the puzzle.

References:

ResearchBlogging.orgLee, T., Murthy, S., Cawley, N., Dhanvantari, S., Hewitt, S., Lou, H., Lau, T., Ma, S., Huynh, T., Wesley, R., Ng, I., Pacak, K., Poon, R., & Loh, Y. (2011). An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers Journal of Clinical Investigation DOI: 10.1172/JCI40433

Introducing Google Search on Pharma Strategy Blog

By on February 1, 2011

One of the nice things about 800 posts is that it becomes a useful database of cancer meetings, clinical papers and general observations.  Sometimes, I remember snippets of things covered at meetings from a year or two ago and find it helpful for jogging my memory about the data or any implications that may have emerged.

The challenge though, has been finding a way to search those posts and find relevant information rather than an unhelpful zero on the return string.

Lijit search worked beautifully on the old host but did not settle down well on the new one, so we tried several others with mixed results.  It drove me potty that searching for scientific terms was so tricky, especially with dashes in words.

Finally, success!  We tried a Google search plugin, it just searches the blog but not the web, for relevant things, like this one on PI3-kinase, which the last two search widgets failed miserably at:

PI3-kinase in cancer

It’s located on the top right hand side of the blog if you ever need to search for various cancer drugs, conferences or pathways.  Let me know what you think.

Update on PARP inhibitors including olaparib, iniparib and veliparib

By on January 28, 2011

Now that the dust has settled on the news from sanofi-aventis yesterday that iniparib did not achieve it’s primary survival endpoints in the phase III trial in newly diagnosed triple negative breast cancer (TNBC), it’s time to take stock of this class.

Yesterday was another major snow shovelling day in New Jersey so I missed the AstraZeneca year end conference call.  A Pharma Strategy Blog reader kindly filled me in with some relevant information – the company discontinued the development of their PARP inhibitor, olaparib, in BRCA breast cancer – scroll down to the discontinued section to see the note.

Our source also listened to the Q+A and in response to questions on olaparib from the analysts, Martin Mackay, the Head of R&D observed that:

“We decided to focus on serious ovarian cancer, and really focus our attention to that in the first instance and wait to see how those results play out in Phase III. Then we’ll revisit… breast cancer.”

This raises some interesting questions about PARP inhibitors in general.

Yesterday, we noted the fine line that needs to be trod between potency/efficacy and tolerability.  Last ASCO we saw how challenging it was to manage the toxicities with olaparib in combination with chemotherapy.  Iniparib doesn’t appear to add to the adverse event profile in combination, but missed its efficacy endpoints.

Meanwhile, Abbott’s PARP inhibitor, veliparib, is being tested in the I-SPY breast cancer trial, so while it will be a while before we see any data, it will be interesting to see how it pans out given that it is also more potent than iniparib.  Pfizer, BMS and Merck are also potential players in the PARP class, but their inhibitors are in earlier stage development. Based on the latest news with iniparib and olaparib it will be fascinating to see what they decide to do.

The latest developments in triple negative breast cancer also raise other critical issues:

  1. Was the olaparib decision based on toxicities, lack of efficacy or being behind iniparib, since they recently announced their phase II results?
  2. How will neliparib fare in the neoadjuvant setting and what toxicities might be expected?
  3. TNBC are mainly basal cell histology so many will also be BRCA1 or 2 positive – did these women do better in the olaparib trial?
  4. Will the Pfizer and Merck compounds have a better risk:benefit profile?
  5. What biomarkers will emerge to indicate subsets or predict response to therapy?
  6. If (5) does evolve, how will this develop from a diagnostics perspective?
  7. What will happen in ovarian, lung and prostate cancers, all of which have a very small proportion of people who have the BRCA1 or 2 mutation.

The current situation with iniparib and olaparib raises more questions than answers, so it will be interesting to see what learnings emerge from the data and whether the once promising class is salvageable or dead.

All in all, 2011 is turning out to be an interesting year and we have yet to get past January.

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Sanofi's iniparib misses primary endpoints in newly diagnosed triple negative breast cancer

By on January 27, 2011

BREAKING NEWS

That was the essence of an email alert that landed in my inbox from sanofi-aventis just now:

“A randomized Phase III trial evaluating BSI-201 (iniparib*) in patients with metastatic triple-negative breast cancer (mTNBC) did not meet the pre-specified criteria for significance for co-primary endpoints of overall survival and progression-free survival.”

After the brouhaha of the positive phase II data published in the NEJM the other week, this is another example of we should be careful getting over-excited by early data until confirmatory larger scale study results are available.

However, while the agent flopped in newly diagnosed disease, in the relapsed/refractory setting there was a silver lining of hope:

“The results of a pre-specified analysis in patients treated in the second- and third-line setting demonstrate an improvement in overall survival and progression-free survival, consistent with what was seen in the Phase II study.

The overall safety analysis indicates that the addition of BSI-201 did not significantly add to the toxicity profile of gemcitabine and carboplatin.”

Iniparib was thought to offer the best chance of success with PARP inhibitors because the others have so far been shown to be

  1. more potent
  2. more challenging to combine given the toxicities involved.

Clearly it is a fine line between potency and toxicities with this particular class.

Trials are ongoing with other tumour types including lung cancer, but there may still be an opportunity for approval in triple negative breast cancer in the 2nd and 3rd line settings.

It will be interesting to see how the subset analysis pans out and whether those women who had the BRCA1 or 2 mutation fared better than those who did not.

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Genomics and cancer research

By on January 27, 2011

Since the human genome was sequenced in 2000, much progress has been made with cancer research.  In a review article published this week in the New England Journal of Medicine, McDermott et al., (2011) stated that:

“The identification of an essentially complete set of protein-coding genes, coupled with the discovery of novel transcribed elements such as microRNAs, has fostered an explosion of investigation using array-based approaches into patterns of gene expression in most cancer types.”

In most cancers, histology still drives diagnosis, which I always thought of as a rather crude method of differentiation.  The ones that have begun to advance beyond this?

  • Breast cancer: where expression profiling has led to the identification of different molecular subtypes of basallike, positive for human epidermal growth factor receptor 2 (HER2), normal breastlike, luminal A, and luminal B.
  • Acute and chronic myeloid leukemias, where molecular subtyping helps in diagnosis and also to determine outcomes and in some cases, when to change therapy as new mutations are acquired.

In CML, basic and clinical research may be far advanced in Academic practice on both sides of the pond, but sadly often community clinical practice in the US is lagging in basic routine monitoring of patients with CML in terms of regular cytogenetic and molecular testing to evaluate responses to treatment or acquired resistance developing.  In AML, many molecular subsets have been identified, but we still don’t know which are key drivers or mere passengers.  There is a long way to yet in practical day to day terms.

The impact of the research in breast cancer has demonstrated that different subtypes exhibit very different clinical and biologic features, including patient survival.  Essentially this means taking a very heterogeneous disease and identifying more homogenous subgroups that behave more consistently.  That said, the authors note:

“In routine clinical practice, however, classification is still based on conventional histologic analysis, coupled with immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), and HER2, which when combined can reconstruct most of the subclasses defined by mRNA expression.”

Gradually, though, new treatments are evolving for each subtype as well and this will continue to develop as new, more targeted therapies emerge based on a deeper understanding of the biology and how it all fits together.  Systems biology is very much at the heart of breast cancer research.

The review highlighted several areas where advances may emerge:

  1. Prognostic indicators
  2. Optimising use of therapeutics
  3. Development of new therapeutics
  4. Acquired resistance to therapy
  5. Monitoring of disease burden and early recurrence
  6. Genomics in the design of early clinical trials
  7. Susceptibility to cancer

Of course, as the article notes,

“The technologies that are research tools today are primed to become the diagnostics of tomorrow.”

One of the cool things about this article was an interactive graphic looking at the assay of tumor DNA to detect recurrence and early after resection using non-small cell lung cancer (NSCLC) as an example.   Unfortunately, the article appears to be subscriber only, not open access, so if your institution takes this journal I highly recommend checking it out  {HT to Edward Winstead of the NCI Cancer Bulletin, this article is indeed open access for anyone to read}.

I’ll leave you with the final observation from the review to ponder and debate:

“The rapid development of next-generation sequencing technologies seems likely to be transformative. Within a few years, a complete cancer genome sequence will be obtainable for a few hundred dollars or less. As the number of informative genetic abnormalities to be searched for in an individual cancer continues to increase, it may ultimately be more parsimonious to sequence the whole genome rather than do a large battery of directed tests.

However, in order to exploit the full clinical potential of information within the cancer genome, it will first be necessary to incorporate analysis of the genome and transcriptome more widely into clinical trials, generating new and unexpected predictors of drug responsiveness and prognosis.”

References:

ResearchBlogging.orgFeero, W., Guttmacher, A., McDermott, U., Downing, J., & Stratton, M. (2011). Genomics and the Continuum of Cancer Care New England Journal of Medicine, 364 (4), 340-350 DOI: 10.1056/NEJMra0907178

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Role of Smads and WWP2 in potentially blocking some cancers

By on January 26, 2011

“Ubiquitin-dependent mechanisms have emerged as essential regulatory elements controlling cellular levels of Smads and TGFβ-dependent biological outputs such as epithelial–mesenchymal transition (EMT).

In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners. We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFβ pathway.

Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFβ-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3.

Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFβ-dependent transcription and EMT.

Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilise Smad7 protein levels and prevent TGFβ-induced EMT.

Collectively, our data suggest that WWP2-N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFβ stimulation.

Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads.”

Source: Oncogene

That was an abstract I was browsing over coffee in my oncology RSS feeds and while it was a bit heavy for early in the day, I was intrigued because Smads have been cropping up in GI sessions at meetings over the last six months or so.  Smads are signal transducers for members of the transforming growth factor-beta (TGF-beta) superfamily, so they occupy a key role in transcription of proteins:

The biology of TGF-beta and Smads

In addition, I’ve included a link to an open access article on the biology of Smads in the references below.

Essentially, the translational research from Soond and Chantry (2011) is suggesting that blocking the WWP2 gene could prevent metastasis, ie cancers from spreading to other organs of the body.  Many of you will remember the post on Norton and Massague’s cancer cell seeding theory and this new finding could well have implications for that research too.

Overall, the latest findings mean that if we have a valid target, we can design a drug to target the rogue gene sending signals.

Of course, these are still very early days yet, but it will be interesting to see if the basic science can be translated into R&D and eventually, a real clinical impact in the long run.

For those of you wanting a simpler version of the abstract, BBC Health did a nice job of putting the research into plain English.  Do check out their short report with pretty pictures here.

References:

ResearchBlogging.orgSoond, S., & Chantry, A. (2011). Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT Oncogene DOI: 10.1038/onc.2010.617

Attisano, L., & Tuen Lee-Hoeflich, S. (2001). The Smads Genome Biology, 2 (8) DOI: 10.1186/gb-2001-2-8-reviews3010

Izzi, L., & Attisano, L. (2004). Regulation of the TGFβ signalling pathway by ubiquitin-mediated degradation Oncogene, 23 (11), 2071-2078 DOI: 10.1038/sj.onc.1207412

Why does sorafenib work in HCC but sunitinib does not?

By on January 24, 2011

That was the question from a reader that greeted me in my inbox recently, it’s a good point.   Sorafenib has received FDA approval in this indication, while Pfizer terminated their phase III trial of sunitinib in HCC for futility last year.

At first, I couldn’t remember the subtle differences between them, since they both inhibit VEGF and PDGF, although sunitinib also inhibits KIT, until a friend reminded that sorafenib also targets RAF.  On checking out the IC50 values of several multi-kinase TKIs, it turned out to be true, good catch:

Why does sorafenib work in HCC but sunitinib doesn't

In addition, there was a paper just published from Nagai et al., (2011) in Molecular Cancer Therapeutics, which demonstrated sorafenib inhibits the hepatocyte growth factor (HGF) mediated epithelial mesenchymal transition (EMT) in hepatocellular carcinoma (HCC).  EMT is a key developmental program that is often activated during cancer invasion and metastasis.  It is a highly complex area that is receiving a lot of research attention at the moment.

Nagai et al., essentially demonstrated that:

“Sorafenib and the MEK inhibitor U0126 markedly inhibited the HGF-induced morphologic changes, SNAI1 upregulation, and cadherin switching, whereas the PI3 kinase inhibitor wortmannin did not.

Collectively, these findings indicate that sorafenib downregulates SNAI1 expression by inhibiting mitogen-activated protein kinase (MAPK) signaling, thereby inhibiting the EMT in HCC cells.”

If we look at the potential pathway, it would look like this:

HGF-RAF-EMT pathway

Based on these findings, it would be interesting to find out whether adding a MEK inhibitor to sorafenib would improve efficacy further to cut off feedback loops.

On checking out the clinical trials database, I found two trials either ongoing or about to begin enrolling with sorafenib and AZD6244 (ARRY 142886), a MEK inhibitor from AstraZeneca/Array Pharma.  The former should have data emerging soon, if it hasn’t already done so.  I think EMT is a fertile area of research where we may see more science and emerging this year.

References:

ResearchBlogging.org Nagai, T., Arao, T., Furuta, K., Sakai, K., Kudo, K., Kaneda, H., Tamura, D., Aomatsu, K., Kimura, H., Fujita, Y., Matsumoto, K., Saijo, N., Kudo, M., & Nishio, K. (2011). Sorafenib Inhibits the Hepatocyte Growth Factor-Mediated Epithelial Mesenchymal Transition in Hepatocellular Carcinoma Molecular Cancer Therapeutics, 10 (1), 169-177 DOI: 10.1158/1535-7163.MCT-10-0544

Today is my 801st post…

By on January 20, 2011

Writing this many articles certainly wasn’t one of my goals when I first started blogging about the science behind cancer, 100 seemed like the north face of the Eiger at the time! I’m not sure how many of you have been with me since the first few posts, but this seems a great opportunity to thank everyone for dropping by and reading, whether it’s your first time or you’ve been a regular for a while. All the comments and emails received have been very much appreciated.

Earlier this month, I put up a one question poll asking what sort of content you wanted to read more about and here are the results (accessed on Jan 18th):

The most popular requests were for more reviews of companies (27%), interviews with thought leaders (20%), with a fifth of those voting saying the mix was about right.  The poll is still running for those of you who missed and want your vote to count.  I’ll be re-running it later in the year to keep tabs on what readers want to see here on the blog.

The conference meeting insights will be rolling out in the newsletter, which will go out to subscribers by email occasionally.  If you haven’t signed up yet, you can add your name and email in the signup box in the right hand margin.

Over the next few days I plan on posting an interview with Dr Michael Kastan of St Judes who did a lot of stellar work on p53 and a review of Mirna Therapeutics, who have an interesting microRNA platform.

If anyone would like to suggest thought leaders or companies they would like to hear more about, please do add them in the comments below.

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PLX4032 phase III data in metastatic melanoma announced by Roche

By on January 19, 2011

Some of the most frequently searched words on this blog or those that arrive via organic Google searches centre around:

  • Melanoma
  • Ipilimumab
  • PLX4032

Interestingly, few are searching for RG7204, the Roche code for their compound being developed in partnership with Plexxikon or BRAF, the actual kinase target involved.

As background, you can read up on the past developments with BRAF V600 mutated melanoma here, here and here, including the phase II NEJM data, mechanisms of resistance (MEK or AKT) and how targeting CRAF as well as BRAF can lead to the development of squamous cell lesions in some patients.

This morning, Roche and Plexxikon announced the long awaited results of the phase III study (BRIM3) in newly diagnosed patients with metastatic melanoma:

“RG7204 (PLX4032) met its co-primary endpoints showing a significant survival benefit in people with previously untreated BRAF V600 mutation-positive metastatic melanoma.

Study participants who received RG7204 lived longer (overall survival) and also lived longer without their disease getting worse (progression-free survival) compared to participants who received dacarbazine, the current standard of care.”

The good news is that the survival benefit observed in the Phase II trials appears to be confirmed although the press release was rather short on specifics, presumably because the actual data will be presented at a cancer meeting later this year. However, given the current timing, I’m thinking this may augur well for an ASCO data submission. If so, ASCO is going to be interesting in metastatic melanoma this year with data anticipated from PLX4032 and ipilimumab (BMS).

Clearly, Roche intend filing the positive data with the Health Authorities, and in the meantime, they have announced plans to expand the access to PLX4032:

“Roche is now working closely with global health authorities to expand the recently announced RG7204 Early Access Program (EAP). The global EAP will be extended to include people with previously untreated, BRAF V600 mutation-positive metastatic melanoma.”

Now that we know more about the mechanisms of BRAF V600 resistance in metastatic melanoma, I’m also wondering when we might see some logical new trials evolve with PLX4032 in combination with a MEK or AKT inhibitor or perhaps sequenced, but to me it would make more sense to combine them.  It will be very interesting to see:

  • What the final survival advantage for PLX4032 is over dacarbazine
  • If a BRAF-MEK combination would further improve the OS

Fortunately, Genentech actually have two MEK inhibitors in development, GDC-0623 and GDC-0973 in solid tumours, so this approach is certainly feasible for them.

We’ll have to wait and see, but to put things in context, the phase II trial reported by Flaherty et al., (2010) in the NEJM demonstrated an approx. 6 month survival advantage in favour of PLX4032 before resistance set in.

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