MaverickNY | Pharma Strategy Blog

Betterness is Good Business even for Pharma

By MaverickNY on May 17, 2010

"Good Businesses" are not judged solely by better sales, profits, equity returns and sharholder value – these becoming old measures on their own. Investors are increasingly asking "So you made a profit – yawn – but did you also make an impact?" This is what it takes to outperform today and tommorrow.

What about Big Pharma? Or little Pharma for that matter.

Aren't these companies founded on the ideals of delivering novel life-changing treatments to patients, transforming science into therapies, to serve patients, to deliver meaningful benefits to consumers, and to improve the quality of life?

How does this square with off-label marketing, physician payola schemes, manufacturing failures resulting in product shortages, contaminated or adulterated product, massive corporate lay-offs and outsourcing jobs elsewhere?"

via thebigredbiotechblog.typepad.com

Bruce Lehr of The Big Red Biotech Blog wrote a nice blog this morning that made me sit up and take notice. He's right; some areas of the industry could do well to clean up their act and focus on the important things that matter rather than skimping on quality or indulging in fluff n puff marketing. And some people wonder why Pharma is held in such distain akin to oil or tobacco companies?

Meanwhile, in the oncology arena, we're always running head to head trials, figuring out how to beat the standard of care and improve overall survival. In other words, finding the compounds that give an edge and make an impact.

It's easy to forget that many other areas of the Pharma business live in fear of not winning, not making blockbuster revenues and thus run an inordinate number of placebo controlled rather than head to head trials. After wading through a mass of non-oncology data at the weekend, I was left wondering, "How on earth do you prove your product is better in that situation?"

If you can't beat the competition, why bother?

Which takes us back to the original review article from Umair Hague in the HBR on why Betterness is Good Business and how great companies focus on the stuff that matters, rather than just profitability and increased shareholder value.

So, I think I'll stick with the dog eat dog mentality in oncology, where we focus more on people and trying to make a difference to the lives of people with cancer. If your compound doesn't beat the standard of care it effectively dies in that indication. My firm belief is if you focus on bettering the competition, the rest will follow naturally and organically. That doesn't mean that some don't fall off the wagon and transgress into the dreaded off-label promotion though.

Still, maybe the rest of Pharma could learn a thing or two from oncology?

The cool side of Science and Technology: DNA robots

By MaverickNY on May 13, 2010

My buddy Bill Scully kindly sent me the link to a superb WSJ article on DNA Robots:

Source: WSJ

"For the first time, microscopic robots made from DNA molecules can walk, follow instructions and work together to assemble simple products on an atomic-scale assembly line, mimicking the machinery of living cells, two independent research teams announced Wednesday."

Nanobots, FTW!

For the technically minded, you can read more about one of the team's research in their letter to Nature and some commentary on robots here. Two other letters were also published from Gu et al., and Lund et al. (subscription required for Nature).

Maybe just sometimes Science Fiction springs to life decades after the original imaginative creation in movies. Awesome.

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ASCO 2010 Preview #2: PI3K and mTOR inhibitors

By MaverickNY on May 12, 2010

One of the interesting things about scientific conferences such as AACR and ASCO is that everyone looks at the same data differently as if it were through a kaleidoscope.

Brand marketers focus on their competition by tumour type or disease, scientists look at specific mechanisms or pathways, investors look at particular companies and so on.

Someone asked me the other day how I analyse the data. I hadn't really thought about it much until then, but on reflection what I'm interested in is trends and how research evolves from a big picture science view so that means I look at pathways like a true biochemist. This also teaches us where the gaps are and what opportunities may arise in the future. It's not exactly rocket science, but it is a useful approach sometimes.

Image via Wikipedia

One of the clear trends emerging at AACR the other week is that dual inhibition of both the PI3K-mTOR and RAS-ERK pathways may be necessary in some cancers such as melanoma to reduce cross-talk, feedback and feedforward loops, drug resistance and loss of PTEN gain of function, just as one might also target IGF-1R and EGFR to reduce cross-talk and add in another inhibitor, eg MEK or AKT.

Given the increasingly critical role of MEK and AKT in various combinations in the future to reduce the potential for drug resistance occurring, this bodes well for a host of companies. I wasn't, therefore, surprised to see Novartis snap up Array's MEK inhibitor (ARRY-162) given they already have an mTOR on the market (everolimus, Afinitor), two PI3-kinases in development and others including a RAS inhibitor. Having a MEK inhibitor as well may therefore give them a lot of flexibility with different combinations in multiple cancer types if this approach pans out.

Merck are also following a similar approach with their mTOR inhibitor, ridaforolimus, which they have finally grabbed commercial control of from their partner, Ariad. Let's not forget they also have an AKT inhibitor, dalotuzumab and a MEKi through their partnership with AstraZeneca to play with too.

This is all good news for several biotech companies though, if some big Pharma companies start catching onto the trend and realise they need may a PI3K-mTOR inhibitor and a MEK or AKT inhibitor to stock up in their pipeline before the field gets too crowded.

Which companies might have new and interesting data in this area?

Well, Keryx and Aeterna Zentaris, Semafore, Calistoga, Intellikine and a few others all have PI3K inhibitors in development, while Exelixis have a deal in place with sanofi-aventis for XL147 and XL765 and Roche/Genentech have a pan-PI3K inhibitor, GDC-0941. Novartis have two (BEZ235 and BKM120). Some of these compounds are single PI3K inhibitors and some are dual inhibitors of PI3K-mTOR.

Looking at the ASCO abstract titles, Exelixis appear to have the most abstracts in this area this year, so it will be interesting to see what sort of data they have across a range of different tumour models and early phase I results in solid and hematologic malignancies, with a variety of different combinations.

One session I'm really looking forward to at this year's ASCO is a Clinical Science Symposium entitled, "Paths for Clinical Development of PI3K Inhibition" with some of the heavyweights in the field such as Neil Rosen (MSKCC), Skip Burris (Sarah Cannon), Jose Baselga (Spain) and Carlos Arteaga (Vanderbilt). Arteaga is presenting a talk in that session entitled, "Next steps in clinical development of PI3K inhibitors?"

More later on this blog after the posters and the data become available at the meeting.

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Are we becoming immune to daily gene announcements?

By MaverickNY on May 11, 2010

The other day I clicked on a link someone shared on Twitter about new findings in breast cancer genes, which sounded really cool and interesting. On clicking through it turned out to be a rather disappointing Reuters release on several fronts:

Where's the link to the original article (in these days of social sharing leaving it out is plain lazy)?
What/where are the "five common genetic factors" exactly? No mention is made of them.
What does this finding actually mean?
What's the 'wow' factor here rather than the 'so what' factor?

I don't know about anyone else, but daily press releases and assaults in the media about identification of yet more gene blah blah that may or may not be relevant becomes anaesthetising after a while.

After a while, I finally tracked down the actual article in Nature Genetics myself to see what the data actually said (reference below with link to the paper for those interested).

What the researchers did was interesting; they conducted a large genome-wide study (GWAS) in around 8,000 people, approx. half of whom had a family history of breast cancer and half did not (controls). They then studied the DNA of another 24,000 women, with and without breast cancer. By analysing over half a million SNP's, they were able to identify new 5 loci on chromosomes 9, 10 and 11 which if present, represent an increased risk of developing breast cancer. This is in addition to 13 gene variations already identified in previous research.

Many of you will be aware of two high risk genes which are more likely to be defective in someone with breast cancer, known as BRCA1 and BRCA2. These genes often confer higher risk of breast or ovarian cancers and can be tracked in families to try and pick up the cancer earlier. More recently, they have become targets for therapeutic intervention with PARP inhibitors such as AstraZeneca's olaparib in BRCA-positive breast and ovarian cancers. More on this in another post.

But what if these 5 new gene variations are also important and early identifiers of increased risk?

The reason that these findings are important is that as Prof Bert Vogelstein of Johns Hopkins never tires of pointing out at AACR meetings, most cancers, including breast cancer, are often diagnosed relatively late in their development and people die from the last 3 years of metastatic disease because the cancer went undetected for 20 odd years.

GWAS as a field is also becoming more relevant, highlighting distinct subsets of
patients who can then be evaluated for prognosis, biomarkers, efficacy
and tolerability differences.

We still have very few methods of efficient and effective early detection, but what GWAS may allow us to do in future when we have more complete information (and gene testing is cheap, reliable and more widely available) is to potentially run screens to identify those most at risk for cancer. These people could then be monitored more closely and watched diligently for early signs of cancer appearing. Early stage cancer is potentially curable with surgery. Inevitably, preventative studies could also be considered for high risk groups in future.

So these findings will have little immediate impact now, but in future if replicated, they could form the backbone of a comprehensive strategy to identify those people most at risk from developing cancer. If we think about it, the enormous cost of end of life medical care massively dwarfs what the cost of earlier intervention and potential cure via surgery with or without neoadjuvant therapy would be. Ultimately, we need this kind of data to move to a wellness model rather than a palliative model.

I would like to acknowledge my buddy Scott Hensley at NPR Health for prodding me into explaining the rationale behind my grump on Twitter about the flood of 'so what' rather than 'oh wow' gene data that constantly abounds daily. If you're not following him on Twitter or listening to his awesome NPR Health podcasts on iTunes or the web, you should consider it!

Turnbull, C., Ahmed, S., Morrison, J., Pernet, D., Renwick, A., Maranian, M., Seal, S., Ghoussaini, M., Hines, S., Healey, C., Hughes, D., Warren-Perry, M., Tapper, W., Eccles, D., Evans, D., Hooning, M., Schutte, M., van den Ouweland, A., Houlston, R., Ross, G., Langford, C., Pharoah, P., Stratton, M., Dunning, A., Rahman, N., & Easton, D. (2010). Genome-wide association study identifies five new breast cancer susceptibility loci Nature Genetics DOI: 10.1038/ng.586

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ASCO 2010 Preview #1

By MaverickNY on May 11, 2010

It's only 3 weeks to go to the Annual ASCO meeting in Chicago so I thought it would be a good time to kick off the annual preview of key data. One of the things that sets the tone of the meeting is which abstracts are in the plenary session. Sometimes I don't attend the session if it looks arcane, but this year looks really interesting and worthwhile attending.

The selected abstracts comprise the following:

#LBA1: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or Fallopian tube cancer (FTC): A Gynecologic Oncology Group study.

#2: Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC).

#3: Clinical activity of the oral ALK inhibitor, PF-02341066, in ALK-positive patients with non-small cell lung cancer (NSCLC).

#4: A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma.

Now, three of these trials promise some excitement. The one I'm surprised about is the French Intergroup study looking at a taxane plus platinum in lung cancer. In case anyone is wondering, the trial (link) states that:

"It thus seemed to us justified to compare a standard arm, the vinorelbine or the gemcitabine (with the choice of the center) in monotherapy with an experimental arm, association carboplatine + paclitaxel."

Carboplatin plus paclitaxel (with or without bevacizumab) is pretty much standard as first-line treatment for non-small cell lung cancer (NSCLC), so now we know that the doublet is likely more effective than single agent gemcitabine or navelbine in the elderly too, but for me all four are old drugs, likely available as generics and it's all an iteration of what we mostly know already. I'm particularly interested in new and exciting agents that are coming through or new indications or more recent drugs as we see them expand their utility.

The results are no doubt important, but plenary important? It could
have well led off an oral lung cancer session and received attention at
Best of ASCO perhaps, but for me, the plenary sessions should be
about groundbreaking new therapies or indications, which the other three
clearly are.

Still, the Korean study in ALK-positive people with NSCLC really gets my attention because we've only heard about a US study in the past, so seeing how this evolves Globally is vitally important. Pfizer have done a nice job speeding this agent, PF-02341066 (crizotinib), through development having recognised the significance of the rearrangements and then invested significant resources to moving it forward. They should be commended for that and I sincerely hope the results continue to be positive.

What is also nice is that I've come across a few new ALK inhibitors at AACR and elsewhere that may work in patients where crivotinib stopped working, perhaps as a reult of new mutations. This is an exciting area of research, even if it just affects a small subset of patients. Cancer is a heterogeneous disease so researching and identifying different subtypes that can be then targeted with new therapeutics is critical.

After excitedly listening to the BMS R&D Day, I was expecting that ipilimumab might have a chance of a plenary with the melanoma data because the example they gave just took your breath away – this is what we all live for in cancer research – something that really makes a difference to the disease and makes you go, "oh wow!" You can read more about that commentary here. Roche and Plexxikon also have a promising compound in development (PLX4032) that targets BRAF. At Roche's R&D Day, they noted that they planned to present the phase II data later this year at a melanoma meeting. That's how the timing rolls sometimes.

The bevacizumab (Avastin) data in ovarian cancer was previously announced by Roche earlier this year to be positive, so this is excellent news for women with ovarian cancer. I really look forward to seeing the results in full. What's particularly important about this trial is that it is the first positive phase III study of an anti-angiogenic therapy in advanced ovarian cancer. I think Judah Folkman would be mightily pleased with the progress of angiogenesis inhibitors such as Avastin so far, if he could see them. It's all too easy to forget the visionaries in research and focus on the results.

For some reason, ovarian cancer always seems to be the poor cousin to breast and lung cancers and regimens that work in either tend to dribble down to ovarian cancer years later, but all three share many similar regimens.

From tomorrow, I'll start an ASCO series taking a look at some of the bionic biotechs with interesting data and a review of some of the big cancers and the potentially interesting data that may be worth highlighting and checking out.

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Malcolm Gladwell on cancer research

By MaverickNY on May 10, 2010

I was reading an article from the New Yorker this morning by Malcolm Gladwell on the Annals of Innovation. You can read the abstract here.

The article centres around the story of Synta/GSK's elesclomol in melanoma in 2007. The drug, like many others, started off promisingly but the final results showed that the patients did more poorly in the treatment arm. What the researchers didn't know at the time was that the target in melanoma was actually different from the one they were aiming at. The understanding of the biology had yet to evolve beyond chemotherapies at that time and our understanding of biomarkers in melanoma was sketchy at best.

Essentially, the author concluded:

“When will we find a cure for cancer?” Gladwell writes, “implies that there is some kind of master code behind the disease waiting to be cracked. But, so far as we can see, there isn’t a master code. There is only what can be uncovered, one step at a time, through trial and error.”

In some sense Gladwell's right, the process of finding new cancer drugs based on the biology of the disease goes one step at a time, science and research is necessarily iterative, after all. But he missed the reason why.

It's because cancers are heterogeneous.

Photo Credit: Cnet

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ASCO 2010

By MaverickNY on May 7, 2010

To answer all the emails and requests I've been getting for the pre-ASCO blogs: the series is rolling out next week with a different topic each day for consideration.

This week has been a tad busy with various client projects, so I'll have time over the weekend to finish the ASCO research and analysis. I will also provide some links to other commentators posts I've come across as well for extra delectation and mind broadening :-).

I'll be doing a 3 week road trip from AUA in San Francisco to ASCO in Chicago to EHA in Barcelona, so will cover AUA and EHA at the meetings.

Happy Friday, everyone!

Is there a better model for health care?

By MaverickNY on May 7, 2010

Recently, I've been doing so much research and analysis of advanced cancers, it struck me that we spend millions of dollars on healthcare at the end of life when it likely won't have much impact, yet the real change happens when we catch and treat, or preferably prevent, diseases such as cancer earlier. This is not exactly rocket science.

Maybe we need a change in approach?

By that, I mean a greater focus on prevention, health and wellness rather than medicate and palliate end of life care.

How much of illness is as a result of poor body management, for want of a better term? Obesity, cardiovascular disease, sedentary lifestyles and lack of exercise all take their toll.

Most people don't do anything until a major wake-up call comes, but by then, it may well be too late do much.

What we need is a wellness model and people educating themselves to take better care of things earlier and having more responsibility for their choices. After all, we can't expect an unlimited pot to be available at the end of the rainbow to cover the inexorable rising cost of treatment. That's totally unrealistic and impractical.

Eventually, the pot runs out and there is no more.

What then?

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BIO 2010: A place for new biotech deals emerging?

By MaverickNY on May 6, 2010

I've been following the annual Biotechnology Industry Organisation (BIO) Conference being held in Chicago remotely on Twitter (check out the hashtag #BIO2010) while busy with client work this week and secretly thanking my lucky stars that I'm office bound and not whinging about sore feet myself as McCormick Place has hard floors and miles of corridors! Much of the lifestream seems to be a lot of moaning about the limited/almost non media access to the keynotes and grumbling about the general lack of social media savvy of the organisation. No surprises there.

Still, in a world where life seems to be increasingly on 24/7, this interesting little snippet from the San Francisco Business Times was much more revealing:

"Big drug makers are ready to make a deal.

With some facing a multibillion-dollar patent cliff and others just trying to expand their focus, big biotech and pharmaceutical companies are reaching out to capture potential products from other companies.

That played out at the recent Biotechnology Industry Organization convention in Chicago. While smaller, privately held companies continued to dominate the number of 15-minute pitches, South San Francisco-based biotech biggie Genentech Inc. and German goliath Bayer Schering Pharma AG also spun out appeals to smaller companies to sell out or partner up.
The list of big companies taking time slots to make similar pitches included the likes of Pfizer, Merck AstraZeneca, Eli Lilly and GlaxoSmithKline."

It's a few weeks post AACR and a month before the run-up to ASCO, also oddly in Chicago, and thus companies interested in oncology will have been evaluating the latest AACR data and thinking about whether or not to make a move before the competition do.

Of course, with many companies facing a potential perfect storm of patent cliffs and a shortfall in the in-house pipelines over the next few years, everyone is desperately hunting for 'breakthroughs'. These are never a sure fire thing and are very hard to predict.

Increased activity and competition for licensing deals also means good news for the little companies as supply and demand may well drive prices up. It will certainly be interesting to see who pounces over the next few weeks and many investors will be scanning their crystal balls hard for clues.

Who do you think will be snapped up?

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Clinical trials for cancer patients

By MaverickNY on May 5, 2010

Earlier this week I was reading Fierce Biotech's excellent article about the human face of the drug industry and was surprised to learn about one of the requests from the women with breast cancer who were featured in the post:

"All three women were frustrated by the lack of available clinical trials for Stage IV patients."

Given that most cancer drugs are tested in the advanced stage first, I would have expected more there than earlier stage disease.

It's interesting first to look at how many trials there are for common conditions. In the NIH database, I searched for some common diseases and came up with the following:

Cancer is by far the most active category in the clinical trials I searched for; in fact, all the others added up to 32,260, a bit more together than cancer alone.

So I decided to check the databases out further, but along the way I came across some frustrations. Firstly, if you go to the NIH site, you can't actually search by stage of cancer type easily. You can search by Phase (ie phase of clinical trial) but that's not the same thing as disease stage:

Ugh. Ok, off to the more cancer specific forum at the NCI, which accesses the same trial database but has a different front end for search, surely that would be more useful?

Again, you can search for all sorts of things (hidden for space reason) except stage of disease!

To find the actual list of trials you want out of 25,885 available for all CANCER as a condition, you have to click on the search box for CONDITION and type in words like 'metastatic', 'advanced', 'stage IV' for example. But how many people would know or actually think of that?

Using breast cancer as an example, we can find all trials involved with the disease and how many studies are for advanced stage disease:

Breast Cancer

– All: 3,618

– Metastatic OR Advanced OR Stage IV: 1,267

Thus 45% of breast cancer studies, or nearly half, are in later stage disease.

There is a nifty little feature that maps out the location of those studies as well for great context under the Map button:

Inevitably, most of those studies are run in the USA, but it's good to see improved access for women with breast cancer in other parts around the world too.

Of course, many of those trials may have completed, been suspended or finished enrolling. Fortunately, you can hide non-active trials, so this brings the 1,267 number down further to 576 studies globally open for advanced breast cancer, and from the map tab, 380 are open in the US, 167 in the EU and only a paltry 29 in the ROW:

That's a far cry from the massive 25,000 global cancer studies we started off with!