Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

FDA conducting safety review of commonly used prostate cancer drugs

By on May 3, 2010

This morning I received the usual hodge podge of alert emails, which I only just got round to checking and nearly fell off my chair when clicking through to one from the FDA that brought me up with a start:

Picture 1
There's been a lot of news out there lately about obesity and diabetes, as well as the excitement of Dendreon's new vaccine for prostate cancer, Provenge, which was approved last Thursday to much fanfare. 

It's therefore a little shocking to see the FDA's initial safety analysis of hormone therapies, which have been pretty much the bedrock of treatment for early stage prostate cancer for many years, including several are now available as generics:

"Preliminary review suggests an increase in the risk of diabetes and certain cardiovascular diseases in men treated with GnRH agonists."

You can find out more here.  Yikes.

It will be interesting to see how the FDA separated out the effects of natural aging and a sedentary lifestyle from real long term drug effects.

Who knows, but Provenge may well turn out to have other hidden benefits such as less risk for diabetes or stroke, but we won't know until we see more data in the earlier, non-metastatic setting.

Perhaps I'm being cynical, but I can just see some ambulance chasers starting another class action lawsuit…

What makes a great Pharma marketer?

By on May 3, 2010

A bunch of friends and I have been debating offline about what separates a great from a good brand marketer.  In our case, we've been focusing on oncology, but really it could be any pharma category from asthma to Zellweger syndrome.

To date, the answers and ideas have been stimulating and interesting, but we all agreed that none have really captured the very essence we were seeking to describe.

Until I read Brad Feld's superb post this morning.  He was actually talking about what makes a great entrepreneur:

“A complete and total obsession with the product”

And I realised that's exactly what we were trying to describe for Pharma marketing.

If you're not absolutely obsessed with everything about your drug or brand, from scientific preclinical and clinical data to understanding market research on how your customers feel about it or indeed how anything impacts your product, then you're missing something vital.

Life is too short to just go through the motions.

Thoughts?

3 Comments

#ASCO10

By on April 30, 2010

I've been getting a lot of enquiries lately about what I think will be interesting at ASCO this year, so next week will see a couple of posts on this topic after some research has been completed with the crystal ball this weekend.

The American Society of Clinical Oncology (ASCO) will be in Chicago rather than Orlando in June for the next 10 years and have announced that this year's hashtag is #ASCO10.  You can follow all the chatter around the topic on Twitter for the next 2 months, no doubt.  

AACR_SM

It will be interesting to see what they are doing with social media after the success their cousins at the American Association of Cancer Research (AACR) have been having, particularly with the warmth with which they (AACR) have encouraged and embraced science bloggers and Tweeters.

What I liked about AACR's approach is that they did a great job sharing and rolling out the science for those who were following via podcasts and webcasts both on their site and also in iTunes. When EU presenters were unable to attend key presentations due to the Volcano, they didn't miss a beat and improvised with teleconferences to live slides.  Great job!

In comparison, I confess that I was a little disappointed to see ASCO are charging $100 a pop for podcasts and $75 for the virtual meeting with no audio. Clearly a much more commercial organisation.

Still, it's usually an interesting meeting packed with data and a great opportunity to see what's coming through in early phase I trials from preclinical research.

In the meantime, if you have any specific requests, please add them to the comments below and I'll do my best to include them in the pre-meeting analysis.

Watch this space!

2 Comments

The lull before the Dendreon storm?

By on April 29, 2010

Today's post is going to be relatively short as I'm knee deep (literally) reviewing poster handouts from the recent AACR meeting, but while reading translational medicine data I came across a poster on sipuleucel-T basically explaining that it engages the immune system and activates or stimulates priming of T-cells in asymptomatic disease.  

Like many out there I'm quietly wondering what will happen tomorrow with Dendreon's PDUFA date due on Saturday May 1st.  We can reasonably assume a response on sipuleucel-T (Provenge) might be forthcoming on either Friday or Monday.

Given the gap in available treatments between castration resistance (CRPC) and stage IV metastatic disease, I'm hoping Provenge receives approval on the basis of the four month survival advantage after a somewhat rocky path along the journey.  Approval could well kick off what may well turn out to be a new era, with other therapies also in late stage development, namely OrthoBiotech/Cougar's abiraterone and Medivation/Astellas' MDV3100, which are both seeking to test their efficacy and safety and in phase III trials for CRPC.

Non-approval could well be a disaster for a company who has invested so much into immunotherapy as their lead product, investors will likely be very unhappy and Monday could turn into a blood bath.  I'm more inclined to be positive though, and my educated guess is that approval will be forthcoming given Dendreon met the pre-defined FDA targets.

We shall see.

{UPDATE: The FDA officially approved Dendreon's Provenge today 29-4-10, see comments below for FDA links and materials including the PI.}

4 Comments

The biology of pancreatic cancer

By on April 28, 2010

The cause of pancreatic cancer is still unknown, although there are risk factors involved, such as increased exposure to tobacco smoke and a family history of the disease.  It is usually detected late when advanced stage disease has set in because most patients are asymptomatic for a long period and then it is too late.  This raises the question of how can we learn and understand more about the biology of the disease as well as develop early warning signs via biomarkers used in screening?

It was therefore fascinating to be browsing through the latest edition of the New England Journal of Medicine over coffee this morning to discover an article on the medical progress in pancreatic cancer while simultaneously noticing an item on a new potential biomarker for the disease in Twitter!  The NEJM review hasn’t been published online yet, so I’ll add the reference later.

Essentially, the NEJM article reviewed the biology of what we know of pancreatic cancer so far:

  1. Results from successive accumulation of gene mutations (average of 23 per tumour)
  2. Most patients with malignant disease carry 4 or more mutations (eg KRAS, CDKN2A, TP53, DPC4)
  3. It’s extremely heterogeneous (more difficult to treat)
  4. Formation of dense tumour stroma (dermoplastic reaction)
  5. It is poorly vascularised (due to stellate cells and activation of TGFβ1, PDGF and FGFR)
  6. Poor prognosis and treatment resistance has been conferred by the presence of cyclooxegenase-2 and PGFR, VEGF, SPARC and Hedgehog overexpression to name a few

The poor vascularisation of the tumour may well explain why anti-angiogenic therapies have not yielded promising results in the clinic to date.

Treating advanced cancer is always more difficult than earlier cancers in the neoadjuvant and adjuvant settings.  The big challenge with pancreatic cancer to date, though, has been finding useful biomarkers for earlier detection, which would most likely impact outcomes for the disease.  According to the NEJM article:

“The overall 5-year survival rate among patients with pancreatic cancer is <5%.”

That’s a pitiful number that needs to change.

image from www.genwaybio.com There are a number of agents in the clinic for the treatment of advanced pancreatic cancer including inhibitors of SPARC, MEK, Mucin-1, IGF-1R, Hedgehog, PDGF and FGFR, Src, RAS, JAK-STAT and TNFα, for example.

Many of these agents are looking at single agent studies or in combination with the current standard of care, gemcitabine, itself with limited effectiveness. It is, therefore, quite hard to imagine that blocking one pathway alone is likely to be the panacea for such a hard to treat and highly complex cancer, as the graphic to the left shows (click to see the detail).

Source: Genway Bio

Meanwhile, progress may be possible on the detection front.  Goicoechea et al. reported in PLoSONE that a type of protein called “palladin” is produced in large amounts in groups of cells in the stroma surrounding pancreatic tumours, known as the ‘tumour nest’.   By measuring the levels of palladin in patient samples, doctors could have an improved way to screen for the disease, potentially detecting it earlier than current tests.

However, I say potentially, because these findings while interesting, need to be validated in large scale phase III clinical trials before we can really be certain of their long term validity.  Nevertheless, it is a promising start for a devastating disease.   

If there was one cancer that would hugely benefit from better earlier detection and diagnosis, it’s pancreatic cancer.  We need more cowbell.  That is all.

AACR Clinical Cancer Research Journal CoverUpdate October 12, 2012

Another interesting paper on the biology of pancreatic cancer that is worth looking at if you are interested in this area is by Manuel Hidalgo and Daniel Van Hoff and was published earlier this year in the August 15, 2012 issue of the AACR journal Clinical Cancer Research.

Entitled, “Translational Therapeutic Opportunities in Ductal Adenocarcinoma of the Pancreas“, the full paper is currently available for free!

ResearchBlogging.org
Goicoechea, S., Bednarski, B., Stack, C., Cowan, D., Volmar, K., Thorne, L., Cukierman, E., Rustgi, A., Brentnall, T., Hwang, R., McCulloch, C., Yeh, J., Bentrem, D., Hochwald, S., Hingorani, S., Kim, H., & Otey, C. (2010). Isoform-Specific Upregulation of Palladin in Human and Murine Pancreas Tumors PLoS ONE, 5 (4) DOI: 10.1371/journal.pone.0010347

New Product Marketing

By on April 27, 2010

One of the things about oncology or any other therapeutic are new product development and marketing is that you get to spend a LOT of time at scientific congresses like AACR in DC the other week, which means early to rise and late to sleep:

Photo
Source: Personal iPhone – view of over the Potamac and Georgetown, DC from Arlington, VA. 

Anyone who thinks these meetings are junkets or jollies should join me on my schedule next trip;sometimes there isn't time to eat or by the time you do have a free slot it's too late.  Often, it means 18 hour days and a day back in the office is a relative rest.  There's always thought leaders to talk to, sessions to attend, media briefings, poster sessions (you can walk miles at those alone), plenaries etc, not to mention clients as well.  Fitting it all in makes for jam packed days.

The interesting thing about new data though, is that while trends may be obvious to those following the specific disease area, they are not to others.  I always find it amusing watching the teams of young things running around with their crib sheets frantically collecting poster handouts, rudely barging past people and trying to discreetly snap the posters without security catching them.  

In DC, I asked one what they did with all the data they amassed.  It turns out they just dump it all in a report for their client by whatever category seems apt.  No strategic analysis, what it all means or even trend spotting, just a data dump.  Ugh.

Sometimes less really is more.

1 Comment

#AACR10: The Kinase Dilemma

By on April 26, 2010

There are a lot of clinical trials out there right with tyrosine kinase inhibitors; unfortunately many will fail because they were rushed into phase II or III trials without thinking through all the options.  There are, however, some smart companies out there who do think.

What was noticeable at AACR this year, was the surfeit of posters and presentations regarding logical combinations designed to eliminate escape routes and hence resistance.  For example, cross-talk is a common problem between ligands, eg IGF-1R and EGFR, so combining the two may reduce the problem but that isn't the whole story.

Feedback loops also exist, so targeting PI3-kinase alone is less likely to be effective than targeting both PI3-kinase and mTOR.  Neal Rosen from MSKCC showed some interesting data to this effect and argued cogently that oncogenes tend to lead to constitutive negative feedback.  He also noted that the BRAF mutation predicts for sensitivity to MEKi, for example.  Michael Korn also discussed the feedback activation loop between the RAS-ERK and PI3K pathways and how the inhibition of autophagy (where cells self digest themselves) can enhance apoptosis and the anti-tumour effect with smart combinations.

Targeting both MEK and AKT may therefore also have more effect than either alone, as you can see in the chart below: 

Picture 10Source: Array Biopharma

In a recent trial reported at the the ASCO GI meeting in January, Merck described an elegant design where IGF-1R, EGFR and AKT inhibitors were all combined to target advanced pancreatic cancer, with promising early results.  I thought this was a prescient approach at the time, since it clearly sought to eliminate both cross-talk and feedback, so it was interesting to see numerous researchers advocating similar approaches in different tumour types based on the overexpression profiles at AACR last week. The design is based on rational biochemistry, which regular PSB readers will know I'm a big fan of, rather than randomly adding a kinase inhibitor to whatever is the standard chemotherapy of the day in a haphazard blunderbuss approach.

There are a number of MEKi and AKTi inhibitors out there (I counted nearly a dozen last time I checked), as well as a plethora of PI3-kinase and mTOR inhibitors, either alone or in combination.  Merck and AstraZeneca announced an interesting deal earlier this year to jointly pursue research with their AKT (MK-2206) and MEK (AZD6244) inhibitors.  This collaboration makes a lot of sense biochemically.  Novartis (a client) have one of a broadest kinase pipelines in the industry and just added to it prior to AACR in a deal with Array BioPharma to license their MEK inhibitors, of which ARRY-162 is the lead candidate. 

The compounds that ultimately win the race may not necessarily be the ones furthest ahead in clinical trials right now, but the ones with the smartest clinical trial designs to eliminate some of the issues associated with kinase inhibition – cross-talk, feedback, feed-forward loops and additional mutations. 

MEKi and AKTi are two of my favourite kinase approaches right now because they offer the flexibility to add to existing TKI's such as erlotinib, sorafenib or everolimus, for example, potentially improving the outcomes further in a variety of different cancers, never mind the future combination possibilities.  It's going to be a very interesting and hot area to watch in the near future, that's for sure.

If you have any thoughts or questions on this fascinating topic, please do add them in the comments below.

 

4 Comments

#AACR10: The Cancer Genome

By on April 23, 2010

One of the challenges of scientific conferences, at least the ones I attend, is that the investigators have a tendency to rush through a high volume of highly interesting slides at a fast pace, meaning ones notes end up looking like a chicken scratched them out and then a spider with wet feet ambled over them for good measure.  Teasing out the nuggets is sometimes a challenge, "what was I thinking when I scrawled that?"

AACR And so it was with the plenaries at the American Association of Clinical Research meeting in DC this week. Looking at the notes from Charles Sawyers and Bert Vogelstein's plenary talks on the prostate cancer and the cancer genome, respectively, is particularly apt as you can see in the photo on the right!

Every time I listen to one of Prof Vogelstein's talks I learn something new and the last lecture makes more sense too.  He noted that 78 cancer exomes have been published to date.  The exome is the 1% of the human genome that is functionally relevant for phenotypic changes.  Exomes are comprised of short segments of DNA called exons, and provide the genetic blueprint for proteins.

The question is how many genes are altered in a typical solid tumour?Vogelstein showed that this varies by tumour type.  For example, in pancreatic cancer, there are an average of 44 non-silent mutations, while for more complex cancers such as melanoma and lung cancer, there are 100-200, 30-80 in breast, colon and brain cancers.  The lowest are seen in leukemias and medulloblastomas, at around 10.

Most mutations in a cancer are actually passengers though, so the big needle in the haystack question is working out which are the drivers? 

The other interesting fact I learned was that approx. 90% (263) of drivers are actually suppressors, as in tumour suppressor genes, and virtually all are found in 12 key pathways (eg NOTCH, PI3K/mTOR, RAS/RAF etc) and only 10% (33) are actually oncogenes.

However, the elephant in the room, as Vogelstein accurately alluded to is tumour heterogeneity.  It is the very diversity that makes it difficult to understand, describe and target appropriately with therapeutics to improve outcomes in humans.  After all, with respect to tumour suppressors, Vogelstein's pithy statement:

"You can't target something that isn't there!"

Rings very true, which is frustrating to say the least.  Much progress has been made in cancer research to date, but we still have a long way to go.  

The confluence of basic research, applied research, clinical trials, and therapeutics at this AACR meeting at least reassured me that the time from bench to bedside is improving, as are the technologies and strategic thinking based on a deeper understanding of the underlying biology. There was an urgency here in DC that I hadn't noticed before.  Long may it continue.

2 Comments

Zen and the art of Cancer Research at #AACR10

By on April 22, 2010

Yesterday afternoon I returned from DC and the annual American Association of Cancer Research (AACR) meeting tired but exhilarated.

image from ecx.images-amazon.com

Despite the Europeans unfortunately stranded by the Icelandic volcano, business continued as usual with many presenters doing their talks by teleconference to live slides in the room.  Quite a few researchers also FedExed their posters, so people could still peruse them and an envelope was provided for business cards or questions.

As we Brits say, "Keep calm and carry on."

There were approximately 18,000 delegates and 6,000 accepted posters this year, a sign of the times that the meeting is getting much bigger and cancer research is an active area of research.

The AACR staff did a fantastic job behind the scenes, were very responsive in whatever help or support was needed and also very active in social media, which was encouraged between delegates in order to share science and learnings with others in different sessions, those who were stranded and others who could not attend, but had an interest in the area.  

In general, I think most of us used common sense and tweeted interesting and general highlight points made, but did not tweet material that was clearly labelled as unpublished, in press or from private discussions in poster sessions.  If you want to find out more than the headlines, that's the point of travelling to the live meetings in person.

All this activity was very encouraging to see, because webcasts from key oral sessions and plenaries went up very quickly online for others to see.  The missing Europeans possibly speeded this up, but AACR have a history of sharing science, as past meeting podcasts and interviews will demonstrate on the website.  It also fosters comradeship and open science in the face of a common goal – curing cancer.  

Here are the webcasts to date and also the link to podcasts and media teleconferences.  Dr Ed Kim from MD Anderson did a superb job explaining the complexities of the BATTLE trial in simple, easy to understand language.  I'm actually going to be listening to some of the webcasts and podcasts myself over the weekend because there were so many sessions one couldn't attend those in parallel, so it's really useful to see them up there. 

If you are interested in cancer facts and figures, this short video from the AACR team may well surprise you: 

It's always easy to criticise what organisations are doing if things are not exactly to our liking, but in this case, I genuinely want to say publicly, "Nice job, AACR!"

Twitter had several impacts for me at the meeting.  I must confess that I dashed over to another session because Dr Naoto Ueno, an inflammatory breast cancer specialist at MD Anderson and a translational researcher, Dr Wafik El Deiry, at Hersey were both tweeting what looked to be a more interesting session than the one I was in (shhhh)!  Such is the power of persuasive tweets.  Twitter was also great for finding and meeting up with people one had been tweeting with, but not yet met.  Chatting in the cloud is great, but meeting in real life also solidifies those relationships for the future and I was honoured to meet many really awesome people at AACR.  I sincerely hope to catch those I missed at ASCO in June as it was a hectic meeting and trying to see everyone as well as attend sessions and posters was near nigh impossible.

It seemed particularly apt that a new Moleskine was christened at the beginning of the meeting for Dr Charles Sawyers opening plenary talk on prostate cancer and now the notebook is nearly a third full of chicken scratch notes already!

Still, many of you will be waiting with baited breath to hear what were the big picture emerging trends I noticed at this year's AACR? 

Here are some quick thoughts of the top of my head:

  1. The cancer genome is now dominant and understanding the biology is very much a focus, even from manufacturers.
  2. Free plasma DNA is going to be critical for biomarker research.
  3. RNA seems appear in almost every other abstract (more later).
  4. GWAS is becoming more relevant, highlighting distinct subsets of patients who can then be evaluated for prognosis, biomarkers, efficacy and tolerability differences.
  5. Combination targeted therapy is the smart way to go to eliminate cross-talk, feedback and feedforward loops.  They may also reduce some acquired resistance, at least for a time.
  6. Dr Bert Vogelstein noted that there are currently 12 critical pathways that impact cancer cell survival. Understanding these more will lead to new and better therapies.
  7. Despite all the above, cancer is a heterogeneous disease and much work still needs to be done in unravelling the mysteries behind it.

Over the next few days, I'll be posting more in-depth thoughts about some of the key new TKI classes that are in the clinic, as well as some of the hot research topics that are emerging.  I have a lot of notes and over 500 poster handouts to condense in a Zen-like fashion before that can be done, not to mention some glorious blisters from miles of walking!  

Do feel free to add any thoughts, questions or immediate observations you may have from the meeting in the comments below in the meantime, it's always good to hear from others.

Photo Credit: Amazon

2 Comments

Capturing the big picture of the 2010 Annual AACR tweets

By on April 18, 2010

After being here in DC a day, it didn't take me long to realise that everyone is using a hodge podge of hashtags including #AACR, #AACR10 and even AACR or AACR 2010.  Some researchers are tweeting without hashtags, so do check out others commentary such as Prof W Eldeiry too as everyone is attending different sessions.  The poster sessions are huge here, three different sections, twice a day as well as a multitude of education sessions, mini symposia and plenty of preclinical, genomic and biomarker research.

I've therefore captured them in the Cover It Live widget below for easy tracking of everyone's tweets.  The event will until Wednesday, when the meeting finishes.

The big focus this year seems to be on relating translational medicine to clinical research, which is a great thing.  The big event today is the plenary at 9.45am when some famous names in translational research will be talking.  I can't wait!

For those following in the backchannel, do feel free to join in and follow the event remotely.

1 Comment
error: Content is protected !!