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By MaverickNY on March 15, 2010

There is a lot going on in the world of Pharmaceuticals. Drugs are being discovered, being marketed, and, far too often it seems, being recalled.

How much will a new medication sell? Will it make through the clinical trials without being thrown out for lack of efficacy, toxicity, or other issues?

via healthlifeandstuff.com

Well, I had a nice surprise this morning – it seems that Pharma Strategy Blog is #7 out of the top Pharma Analysis blogs. The leaders are Ed Silverman’s Pharmalot, Jack Friday’s Pharma Gossip and Derek Lowe’s In the Pipeline.

I was delighted and honoured to even be in a list with such company, but was most amused to see that a sex change appears to have occurred in the process :-).

Posted via web from sally church’s posterous

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Tumour associated macrophages and survival in Hodgkins Lymphoma

By MaverickNY on March 15, 2010

While reading my pile of mail on Friday, I realised that an interesting paper on Hodgkins Lymphoma (HL) appeared in the current edition of the New England Journal of Medicine (full reference below).

The basics of the paper are that despite advances in HL, including curative radiation in the early stages if the disease, one third of patients with advanced disease and about 15% of those with early disease have a relapse after treatment. 20% of people still die from the disease.

The question is why?

Well, unfortunately, current prognostic models have not been shown to be very accurate and so far, no biomarker has been found to be particularly useful.

The authors set out to use gene-expression profiling obtained from people with HL during diagnostic lymph node biopsy to determine which signatures were correlated with treatment. They confirmed their findings with an independent cohort of 166 patients using standard immunohistochemical analysis.

What they found was fascinating:

A gene signature of of tumour associated macrophages was associated with primary treatment failure.
An increased number of CD68 macrophages correlated with likelihood of relapse after autologous stem cell transplantation.
The adverse prognostic factor (macrophages) outperformed the current International Prognostic Score for disease-specific survival.
The absence of an elevated number of CD68+ cells in patients with limited stage disease defined a sub-group of patients with long-term disease specific survival of 100% with the current therapies.

When I was at school, we learned that macrophages were associated with an immune response to invasion. According to the NEJM Editorial, by DeVita and Costa, this may not be the case:

"Most of the evidence, however, now links the presence of tumor-associated macrophages with a poor prognosis."

In short, the data shows that increased number of tumour associated macrophages was strongly associated with shortened survival in HL and provides a biomarker for prognosis and risk stratification. What does this all mean though, for clinical practice?

DeVita and Costa noted that:

"If at the time of diagnosis we could identify patients who are destined to have a poor response to treatment, most patients could be spared a combination of therapies or radiotherapy with its attendant long-term toxic effects."

This is an important observation alone.

For the future, though, the data suggests some new directions that clinical research could go in, such as an anti-CD68 monoclonal antibody perhaps. There are some that have been identified for rheumatoid arthritis (RA) as the Kunisch paper shows below, but I don't think any are currently in commercial development at the moment.

For the moment, though, I'm left wondering more than there are answers.

Why do people with macrophages do worse, what is the mechanism for this? How can we best target the macrophages or the CD68 cells? If people are screened and are found to have a poorer prognosis and are spared the exposure to chemotherapy or radiation as DeVita and Costa suggest, how should they be treated instead?

Perhaps more research will be galvanised by Steidl et al's findings. Time will tell.

Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, & Gascoyne RD (2010). Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. The New England journal of medicine, 362 (10), 875-85 PMID: 20220182

DeVita, V., & Costa, J. (2010). Toward a Personalized Treatment of Hodgkin's Disease New England Journal of Medicine, 362 (10), 942-943 DOI: 10.1056/NEJMe0912481

Kunisch, E. (2004). Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and PGM1) widely used for immunohistochemistry and flow cytometry Annals of the Rheumatic Diseases, 63 (7), 774-784 DOI: 10.1136/ard.2003.013029

More phase III cancer trials flop: Pfizer (Sutent) and Roche (Avastin)

By MaverickNY on March 12, 2010

The last 18 months have seen a lot of failed cancer studies in phase III development after early promising phase II results, teaching us that sometimes rushing full steam ahead without fully understanding the issues is not always the smartest strategy.

Let's start with Pfizer's figitumumab, an IGF-1R antibody, which we have previously discussed in non-small cell lung cancer (NSCLC) (here and here). There was one phase II trial at MD Anderson that led to what many of us thought was a rather cavalier, aggressive and hasty phase III program, without really seeking to understand the underlying biology behind the pathway first. Interestingly, other competitors have taken a much slower and more methodical approach to thinking through the various issues and may well come out ahead as a result.

Given the front-line trial produced a negative response, I think many of us were expecting the 2nd line study to eventually go the same way. The endocrine and biochemical interactions happening around IGF-1R will need more careful reflection before the concept has a real chance of working. There are various things happening around cross-talk between receptors, interaction with the insulin receptor and AKT may well turn out to have an important role to play. All in all, manipulating the biochemistry of the pathways needs a little more sophistication than a mere sledgehammer to crush a grape approach.

Pfizer also announced that two phase III trials with sunitinib (Sutent) also failed to meet their primary endpoint. Sutent is approved for the treatment of renal cell cancer and gastrointestinal stromal tumours (GIST) and as an oral VEGF/KIT inhibitor that was originally developed by Sugen before it was snapped up by Pharmacia, I think it has done pretty well. It is unrealistic to expect every drug to work in every indication and there may be differences between how monoclonal antibodies such as bevacizumab (Avastin) work compared to small molecules such as Sutent and Bayer's sorafenib (Nexavar).

Like Pfizer, Bayer recently announced promising phase II results in breast cancer. Given that Pfizer previously announced last year that a Sutent trial in breast cancer was negative (see previous post), I wasn't expecting the two current trials to be positive. Had they done so, it would have been akin to a miracle.

Roche's Avastin has had a string of good results and also a few setbacks. The original program focused on breast cancer rather than colorectal cancer before the trial was negative. To give Genentech credit though, they went back to the drawing board to figure out what worked and where the issues were before eventually having another success in breast cancer much later. This is probably what Pfizer need to do now too, scientific and clinical reflection is sometimes a necessary part of the pain on the journey.

Avastin has been now approved in colorectal, lung, breast, renal and brain cancers, so a setback in prostate cancer, as Genentech announced this morning, is probably not going to matter too much. This is unfortunate because there really aren't that many options for advanced stage patients who have become hormone resistant. All is not completely lost for men with prostate cancer though, as sanofi-aventis (a client) have reported that their next generation taxane, cabazitaxel, increased survival in this population, so hopefully we will see more of the data at this year's ASCO meeting in June.

One thought we should perhaps reflect on. 'Oncogenic addition' is a phrase bandied around quite a bit these days, and for sure, some approaches have been very successful. We need to remember though, that targeting kinases and enzymes is only going to work if the enzyme is actually critical to the survival of the tumour, which will rarely happen in isolation. The way forward is most likely going to need a more sophisticated approach that combines multiple inhibitors in a logical fashion. To achieve that approach though, will require more iterative phase II trials to really determine exactly what is going on.

Pfizer and Roche/Genentech both have smart scientists and clinicians in their organisations, so my feeling is that they will go back to the drawing board and evaluate these trials and the data very carefully. You can't have a home run every time, but you can sometimes figure out ways to see if an agent can be made to work by tweaking things. Often, we're limited by our knowledge of the biology and sometimes negative trials can actually help us understand things better.

Photo Credit: Stuck in Customs

BioSante announce positive data from GVAX leukemia vaccine in CML

By MaverickNY on March 11, 2010

This morning the newswires (HT Mike Huckman) are full of the BioSante (formerly Cell Genesys) news on their leukemia vaccine, GVAX, which is being tested to see whether it is a viable approach for eradication of minimal residual disease. Accordingly, BioSante announced:

"Positive results of a human clinical study that show that its GVAX Leukemia vaccine may be able to reduce or eliminate the last remaining cancer cells in some chronic myeloid leukemia (CML) patients taking the drug Gleevec (imatinib mesylate). All patients enrolled in the trial used Gleevec for at least one year and still had cancer cells present. The study was conducted by researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, led by Hyam Levitsky, M.D., professor of oncology, medicine and urology at the Cancer Center. The research was funded by the National Institutes of Health."

Currently standard of care for CML is daily treatment with an oral tyrosine kinase inhibitor (TKI), imatinib (Gleevec), with the option of two second generation TKI's nilotinib (Tasigna) and dasatinib (Sprycel) being available if the imatinib fails. All three of these drugs are effective at inhibiting the enzyme associated with the gene BCR-ABL, which occurs in every CML patient and essentially shut off production of the excess white blood cells so that the cells stop growing and eventually die.

There are various degrees of response with TKIs and at the American Society of Hematology meeting in December, Tim Hughes from Adelaide presented the concept of a safe haven as you can see from the chart below:

Source: Dr Tim Hughes, Adelaide, Australia

Obviously, the deeper the response, the more likely a patient would attain a major molecular response (MMR) and provide a safe haven from treatment relapse.

The important question then becomes one of how low should one go in order to

Optimise treatment response and
Provide enough protection without increasing side effects?

Going back to the quote at the top of the post about GVAX, we can see that the researchers goal was to eliminate minimal residual disease (MRD) and kill all detectable cancer cells below what is currently possible with TKI therapy.

In the article published in Cancer Clinical Research (free PDF download courtesy of AACR), it seems that according to the researchers

"Thirteen patients had a progressive decline in disease burden, 8 of whom had increasing disease burden before vaccination. Twelve patients achieved their lowest tumor burden measurements to date following vaccine, including seven subjects who became PCR-undetectable."

Now while this is very good news to hear that it can be accomplished, the numbers are very small and we don't have any data whatsoever yet to prove that achieving the nirvana of MMR is actually necessary for the majority of CML patients. None, nada, zilch. We also do not have any idea from the article how durable the vaccine results will be yet as there may be an attenuation of response over time.

We do know from the IRIS updates that newly diagnosed people with CML now have a much longer life expectancy of around 7+ years on average when treated with imatinib. Stem cell transplants are curative in some patients, but that decision is fraught with a risk-benefit trade-off of 20% procedure related mortality and the risk of graft-versus-host disease and other long term complications afterwards.

In conclusion:

It will be interesting to see what impact this vaccine will have in the long term in terms of improved survival for people living with CML and whether future research will demonstrate a clear need to eliminate minimal residual disease below what is currently possible. These are promising results and I look forward to seeing more data over the next few years as the answers evolve. The ultimate goal is always to find a cure but whether this approach will help achieve that remains to be seen.

Smith, B., Kasamon, Y., Kowalski, J., Gocke, C., Murphy, K., Miller, C., Garrett-Mayer, E., Tsai, H., Qin, L., Chia, C., Biedrzycki, B., Harding, T., Tu, G., Jones, R., Hege, K., & Levitsky, H. (2010). K562/GM-CSF Immunotherapy Reduces Tumor Burden in Chronic Myeloid Leukemia Patients with Residual Disease on Imatinib Mesylate Clinical Cancer Research, 16 (1), 338-347 DOI: 10.1158/1078-0432.CCR-09-2046

Abbott makes some waves in Pharma

By MaverickNY on March 10, 2010

While listening to last week's presentation by BMS on their pipeline, one slide in particular caught my attention:

Source: BMS

Now, it wasn't the fact that BMS were second in their table of Total Shareholder Return (TSR) that was interesting to me, but that Abbott were first, and by a long way, according to the chart above. Of course, shareholder return is only one measure of performance and says nothing at all about putting customers and patients first, but that is another story/blog.

Recently, Abbott has been in the news with the acquisition of Solvay, a generics company, which added $3B to their revenues and last night it was announced that the company are also acquiring Facet Biotech, which was being pursued by Biogen Idec. The Biogen deal clearly fell apart after the company declined to raise their offer beyond $17.50/share. Abbott offered $27/share and thus a white knight was found. Interestingly, the Facet CEO, Faheem Hasnain, is a former employee of Biogen Idec.

The acquisition is a hot one, so to speak, and many of us in the industry have been speculating in vain on who the partner might be, so you would think that going on CNBC's Pharma's Market with Mike Huckman would be a nice coup for a small company. I thought it was odd though, to see that they seem a little publicity shy, as this tweet shows the company's rather gauche immaturity:

What do Abbott get from acquiring Facet?

Well, first we need to think about where Abbott is coming from. Most companies with either build on existing platforms and franchises or add new products in areas where they want to expand. Abbott is probably best known for it's immunology franchise, with adalimumab (Humira), its TNF inhibitor for rheumatoid arthritis and psoriasis.

Several companies, including Abbott and BMS, have embarked on a race to develop the next generation of Hepatitic C drugs and vaccines. Infectious diseases are not something that are going away fast, so this is seen as an attractive market segment by many.

Looking at the Facet acquisition, the pipeline is thus interesting because they have also been developing monoclonal antibodies but in different diseases including immunology and cancer. The lead compound is daclizumab, which is in phase II development for multiple sclerosis in partnership with… Biogen Idec. Facet own the exclusive rights to the asthma indication though.

There are also several anticancer antibodies such as volocizumab (solid tumours) and elotuzumab (multiple myeloma) in Facet's R&D. Oncology is an area where Abbott has been relatively weak, although they have some interesting compounds in development for liquid and solid malignancies. In 2009, a joint venture with TAP was concluded, adding Lupron, one of the best selling drugs for hormone-sensitive prostate cancer to the portfolio of currently marketed products.

Abbott may well see topline growth from it's cancer franchise in the future… if the pipeline products from their own labs or Facet's deliver. If those from Facet fail, Biogen Idec will be breathing a sigh of relief that their offer was turned down.

Such is life on the Pharma roller coaster.

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Data dumps are information overload, not insights

By MaverickNY on March 9, 2010

“I made this letter longer than usual because I lack the time to make
it shorter.”

Pascal, Provincial Letters XVI, 1660

One of the things that used to drive me absolutely potty as a marketing director was reports masquerading as doorstops, as if more was better than less. 300+ pages of data… blah, blah, blah and no insights or analysis, leaving the hapless reader to try and figure out exactly what it all means and some seek some context for how it might actually be useful.

Sadly, I see the same thing happening a lot even now in competitive intelligence at scientific congresses. Gangs and posses of people marching round grabbing as many poster handouts as they can and illegally snapping as many photos as possible without getting thrown out by security.

Talking to some of those folk was really interesting; what do they do with all the data they gather? The blithe answer was, “Oh, we reproduce it all for our client and recreate the abstracts for them in a big report after the meeting.”

Uh? Right, and exactly was does the poor client do with the report? Use it as a doorstop probably.

And therein is the rub.

Information isn’t always power. Data is useless without context. Ultimately, it’s all about insights – what does this all mean to YOU given that your particular situation is unique? To process such a huge volume of information and give it contextual meaning requires a modicum of intelligence and some knowledge of the disease and therapeutic area in order to sort out the wheat from the chaff.

Some of my best client reports have been relatively short (30-40 pages or even less) from a conference with a clear focus on relevant insights, trends and learnings, what the implications are and what could be considered next. Short, sharp and snappy. No blah, but plenty of insights. Data with meaning.

Of course, sometimes the hardest part is accomplished up front in pinning the client down; “what exactly do you need to know?” The distracted stressed client doesn’t know what they don’t know and takes solace in volume, which adds to the problem.

My smart clients, the partner ones I really enjoy working with, are usually very precise when asked what they really need and are relieved to be asked because oddly, they know they can immediately stop fretting about the answer. It will come. This applies to conference coverage or ongoing market surveillance.

Insights analysis is a craft; making data sing is part art, part science.

It also, as Pascal noted, takes longer to be succinct and precise than it does to merely reproduce what is out there in copious quantities. Writing shorter, more impactful, reports based on data analysis takes more time too.

Once you’ve done a marketing or new products job in Pharma you know that deep down what matters is to keep moving, preferably faster than the competition, but with a clear strategic sense of what’s going on around you in the landscape and how market changes can impact you so that you can execute flawlessly.

Anything else is just irrelevant noise. Or doorstops.

What are you doing to filter the signals from the noise?

Roche's ocrelizumab and AstraZeneca's cediranib bite the dust

By MaverickNY on March 8, 2010

This week kicked off with some interesting emails and alerts in my inbox.

You may well be wondering what on earth rheumatoid arthritis and colorectal cancer have in common. The answer is that yet more agents in development have bitten the dust.

Firstly, it seems that Roche and Biogen Idec have announced that they are suspending the development of their humanised anti-CD20 monoclonal antibody, ocrelizumab, for treatment of rheumatoid arthritis (RA) and Lupus.

This follows a recommendation of the independent Data and Safety Monitoring Board (DSMB) based on their assessment of the studies in RA. The review detected an infection related safety signal which included serious and opportunistic infections, some of which were fatal.

According to the Roche press release:

"As previously announced, the FILM study in MTX-naïve RA patients was placed on clinical hold following an assessment of benefit to risk in this specific RA patient population. In addition, the BELONG study in lupus nephritis patients was previously halted due to serious and opportunistic infection signals."

The trials in multiple sclerosis appear to be ongoing. Their other CD20 antibody, rituximab, has been on the market for several years for the treatment of cancers such as non-Hodgkins Lymphoma (NHL) and more recently, chronic lymphocytic leukemia (CLL). There have been no safety issues with this product.

Oddly, the second agent that flopped today went up against Roche's Avastin and was found to fall short of the required hurdle in a large phase III trial. AstraZeneca's cediranib (Recentin), is a oral small molecule VEGF inhibitor that was being evaluated for the treatment of colorectal cancer (CRC).

According to AstraZeneca's press release this morning:

"This study, HORIZON III, assessed the efficacy of cediranib compared with bevacizumab, both in combination with chemotherapy. Clinical activity was observed in the cediranib arm of the study and there was no statistically significant difference between treatment arms on the efficacy endpoints examined. However, the efficacy did not meet the pre-specified criteria for the primary endpoint of non-inferiority in progression-free survival."

Ouch!

However, these results are not entirely surprising given the previous failure of Novartis' vatalanib in CRC, another small molecule inhibitor, in phase III trials for colorectal cancer. There may well be some quirk in the mechanism of action in colorectal cancer that preferentially allows monoclonal antibodies to work more effectively than small molecules. The half life, dosing schedules or inhibiting the ligand differently could all play a crucial part in the process.

For AstraZeneca, though, their run of bad luck in oncology continues with Iressa, Zactima and now Recentin all struggling to make a major impact.

Photo Credit: Kiragon

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What can we learn from the Oscars?

By MaverickNY on March 8, 2010

Last night many people in the NY-NJ-CT region missed the Oscars beamed from the Academy Awards after an argument over money between CableVision and ABC. If a Biotech company and their big Pharma partner has a spat, it is rarely as public or has as much impact as TV deals do, but the shock waves can certainly be felt through the investor community every time a high profile predatory shareholder such as Carl Icahn gets their teeth into a biotech such as Genzyme or Biogen IDEC.

It was interesting that the year’s biggest grossing, most expensive and stunning film, ‘Avatar’, lost out to a smaller, niche film about the Iraqi war, ‘The Hurt Locker’, with a stronger plot, storyline and superb acting.

It’s a bit like a baby Biotech producing a string of new products with solid efficacy doing well, much as Genentech did with Herceptin, Tarceva and Avastin or Amgen did in their early days with Neupogen and Epogen. Eventually, of course, the new kid on the block becomes household name and new companies rise behind them with new science and a solid underpinning.

After the austerity of last year’s Awards ceremony, this year’s Oscars were a little more lavish by comparison. I wonder if that is a metaphor for the economy in general, with less doom and gloom and some signs that things are picking up?

Art ultimately reflects life.

The big question is, who are the next generation of big Biotech's in the making?

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Sharpen the saw!

By MaverickNY on March 7, 2010

Today I took some time out for rest and relaxation as it was a gorgeous Spring afternoon in New York City.

Walking from the World Trade Center, up the West Side Highway and then along the Highline between W12th and 23rd Streets was great fun.

On the way back, you could feel the energy of a city awakening from hibernation and the frozen tundra of winter. Joggers, cyclists, walkers and bladers all sharing the mixed use space in harmony.

Sitting on a park bench watching the tennis players shake of rust while feeling the sun’s gentle rays made me realise what a beautiful world it is.

Sometimes, just thinking about nothing quietens the mind and sharpens focus.

How many people actually stop to think and reflect on their marketing efforts rather than rush pell mell into getting things done?

When in the corporate world, some of the best customers insights I ever gained came at odd moments of reflection, while sitting in Starbucks watching the slanted patterns of light through the window or when sitting on a park bench watching the world go by. Obtuse thoughts sudden come to you in a moment of inspiration.

Perhaps this is a reflection of those precious Zen moments when you manage to quieten the soul and voice within.

Taking time out to sharpen the mental saw is also a good idea, whether you’re a marketer or whatever cool job you do. When did you last have fun?

Ipilimumab from BMS looks like an interesting new melanoma drug

By MaverickNY on March 5, 2010

It's been a frantic week on the work front and today was no different, but I wanted to highlight a really interesting slide from the BMS pipeline presentation yesterday afternoon.

Here's one of the slides Elliot Sigal, President of R&D, showed from one of the ipilimumab trials. More data may be available at ASCO if the submitted abstract is accepted, but for now, even though it's only an n of 1, a picture tells a thousand words:

Source: BMS

After all the recent good news about malignant melanoma, hopefully at least one of these promising agents will make it to market in the not too distant future, offering people suffering with the condition a glimmer of hope. I sincerely hope the CTLA4 results turn out to be durable.

In the meantime, we can all wonder until June, when the annual ASCO meeting will held.

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Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

The Very Best Pharma Blogs & Resources « Health and Life

Tumour associated macrophages and survival in Hodgkins Lymphoma

More phase III cancer trials flop: Pfizer (Sutent) and Roche (Avastin)

BioSante announce positive data from GVAX leukemia vaccine in CML

Abbott makes some waves in Pharma

Data dumps are information overload, not insights

Roche's ocrelizumab and AstraZeneca's cediranib bite the dust

What can we learn from the Oscars?

Sharpen the saw!

Ipilimumab from BMS looks like an interesting new melanoma drug