Pharma Strategy Blog

Pathwork Diagnostics and Novartis to pursue a research partnership

It was interesting to see my Diagnostics alert feed full of the news that Pathwork Diagnostics and the new Novartis molecular diagnostics group are entering a research partnership.

I first came across Pathwork Dx at ASCO last month when they presented an interesting poster on their tissue of origin gene based expression test to help in the diagnosis of poorly differentiated and metastatic tumours.  Clearly, an accurate diagnosis will lead to better optimisation of appropriate therapy and risk assessment/management.  The tissue based test has since received approval from the FDA.

According to Pathwork:

"The Tissue of Origin LDT uses a combination of microarray technology and advanced analytics to measure the gene expression patterns (comprising more than 1500 genes) of challenging tumors, including poorly differentiated, undifferentiated, and metastatic cancer. These data are compared with the gene expression patterns of a panel of 15 known tissue types—representing 58 morphologies and covering 90% of solid tumors—in order to identify the tumor."

The tissue test is based on gene arrays using DNA and RNA technology used in research, but with its approval, we will start to see more commercial applications evolve for diagnostic purposes.

More details about the deal and the financial background can be found in the WSJ.

What's interesting here is that:

1) We are seeing more sophisticated technology emerge for both tissue and blood biomarkers, which will hopefully help us improve not only diagnosis but also treatment and monitoring of drug responses over time.

2) More integration and collaborations between manufacturers and diagnostic companies means that the information and knowledge can be shared more easily and quickly rather than being bogged down in silos.

3) The companies that do well with integrating diagnostics into their cancer programs will not only have a huge commercial edge, but it will continue to raise the bar for new competitors and smaller companies in terms of funding and resources.

It's going to be fascinating watching this area of oncology develop.

The ravages of smoking and cancer...

We all know that long term exposure to chemical insults and carcinogens from smoking and alcohol can act as irritants, leading to biochemical changes that can induce the development of hyperplasia, and potentially, carcinomas.

Over the weekend I was shocked to learn that Alex "Hurricane" Higgins, former World Snooker Champion, had passed away aged 61 from throat cancer.  He was an incredible talent who will be sadly missed and remembered for many years to come.

I wrote a bit more about it here: be warned though, the before and after photos are rather distressing :(

The Long Tail of Cancer Research

"What's really amazing about the Long Tail is the sheer size of it. Combine enough nonhits on the Long Tail and you've got a market bigger than the hits." 

Source: Chris Anderson, Wired

The other other day, while barely lucid in the early hours of the morning, I was thinking about the herd instinct, the tendency to follow the masses and the counterpoint to that, i.e. the long tail.

If you're wondering what the long tail is, think of those statistical distribution plots where everything is bunched around the median, creating 50% on one side and 50% on the other.  At either end the plots tail off into infinity.  That's the long tail.  

The long tail looks small at first, but creative marketers realise that added up (as Chris Anderson's quote above shows), you can in effect still have quite a large niche market while every one else focuses on minute shares in the middle.

I first realised the long tail effect as a sales rep in the tough anti-cholesterol market.  You can spend fruitless hours chasing the majority of the primary care doctors who see reps but don't remember you when the relevant patient appears, or you can carefully invest time in the ones who don't see reps but are busy with appropriate patients and eventually crack if you try enough times. Once convinced, they often switch wholesale and your job is done with a smaller group of physicians who others can't see :-).

If we apply the principle of the long tail to cancer research, we can see things more clearly.  In the old days, the majority of patients got treated pretty much the same with various chemo doublets, irrespective of whether they might work or not.  In fact, in many cases, there wasn't even biomarkers such as ERCC1 to determine which patient should get platinum or not, but things are changing and now it's much easier to make these decisions and start segmenting patients according to their biochemical profile and make decisions based on the profile.

Today, we can take this niche idea to treatment a lot further.  

In colon cancer, for example, we now know that patients with wild type KRAS are more likely to respond to an EGFR therapy than those with mutant KRAS. However, in lung cancer, the old adage was that erlotinib (Tarceva) was best suited for patients who were female, asian, non-smokers with adenocarcinoma is giving way to a more precise definition, i.e. do they have the EGFR mutation or not? If they do, they're more likely to respond, irrespective of smoking status. Offering these patients maintenance treatment may also be an effective treatment strategy that impacts outcomes.  

We can see this effect in other cancer types too.  Trastuzumab (Herceptin) is approved for women with Her-2 breast cancer, imatinib (Gleevec) and other TKIs such as dasatinib (Sprycel) and nilotinib (Tasigna) for Philadelphia-chromosome positive chromic myeloid leukemia (CML).

Histology is a very crude way to select patients, but looking at the aberrant mutations essentially creates niche long tail opportunities to treatment for pharma and biotech companies.  Patients who are more likely to respond to a given therapeutic get appropriate treatment, without having to expose others who would not to unnecessary systemic effects. This is a win-win solution all around.  

Why?  

Well, it's good news for patients as you increase the chances of successful outcomes rather than relying on hope alone.  It's also good news for manufacturers because smaller patient populations ultimately involve fewer patients in clinical trials, thereby making clinical development more cost effective and as cancer therapy moves from an acute to chronic disease, so longer term revenues are generated despite a small patient base.

As more oncology companies start looking at their pipelines, we can see many asking the critical questions - which patients are more likely to respond to a given treatment and why?  As we learn more about the underlying biology of the disease, so companion diagnostics are also evolving in sophistication and sensitivity.

The other marketing advantage of developing niche targeted therapies and diagnostics is that often, you see less competition for smaller subsets of disease because it creates a high barrier to entry. Diagnostics also create barriers to entry because of the extra costs involved in their development.  For smaller biotechs this can be prohibitive, and many are more actively seeking Pharma and Biotech partners to fund late stage research and clinical trials.  Overall, the long tail opportunities offer big and small hurdles, depending on the circumstances.  

Roche's VEGF monoclonal antibody bevacizumab (Avastin) has a very high barrier to entry in colon cancer, for example, as other VEGF inhibitors have fallen by the wayside, unable to beat the results already obtained by the first to market drug.  

At the other end of the scale, the barrier to entry is much lower in renal cell cancer with numerous targeted therapies now approved for a relatively small niche indication, including sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), everolimus (Afinitor), pazopanib (Votrient) and bevacizumab (Avastin), probably reflecting the improvement over IL2, without completely reducing unwanted side effects or dramatically improving efficacy.

Some of the marketed therapies mentioned in this post are now billion dollar blockbusters despite cancer being a relatively niche market opportunity compared to the much bigger primary care markets such as metabolic or cardiovascular disease, proving that there are valuable nuggets to be found, even in the long tail.  

The future in cancer research is not in broad acting systemic chemotherapies that target normal cells as well as cancer cells, but in the niche development of better and less toxic targeted therapies based on the underlying biological abnormalities with easy to use diagnostic technology based on fluid-based biomarkers.  To achieve this though, will take a lot of bright smart people with expertise in oncology who dare to think differently and boldly, whether they be scientists, marketers or clinical research professionals.

Watch this space!

Fluid-based early detection biomarkers in cancer

A really interesting idea that seems to be growing in popularity is the concept of fluid-based biomarkers from blood, urine, saliva etc, as opposed to invasive tumour biopsies. A recent paper in Cancer Research took a look at this novel and much needed concept (reference below). 

One of the biggest challenges in oncology at the moment is finding easier and more convenient ways of identifying appropriate patients who might be best suited for a given therapy.  In clinical trials, often tests are developed as useful biomarkers based on tumour biopsies.  However, once a drug is approved, Community Oncologists often find their patients older, frailer and with a poorer performance status or more advanced disease and thus unresectable. Earlier detection of asymptomatic patients would also be useful, since in general, the earlier the patient is diagnosed, the better their long term chances are.

There is a lot of potential value, therefore, in developing fluid-based biomarkers and tests since the majority of cancer patients are treated in the Community, rather than Academic, setting.

In leukemias, FISH and QT-PCR testing have become standard, largely because it is easy to compare a blood sample with that of a bone marrow sample to validate test results.  In solid tumours though, that has generally been less easy. Even the FISH test for HER-2 positive women with breast cancer has not been without it's controversies over the years.  

At recent cancer meetings such as ASCO and AACR, I have noticed an increasing number of early surrogate markers being explored in solid tumours such as circulating tumour cells (CTCs) in prostate cancer as a more viable marker than PSA, as the authors also discussed:

"Fluid sampling has advantages over imaging as it is widely accepted, readily repeated, convenient, noninvasive, and low cost. Biomarkers in body fluids have the potential to detect a wide variety of primary tumors and metastases located throughout the body. Fluid biomarkers include a variety of components in blood, urine, or other fluids that reflect the presence of a tumor in the body. These include circulating tumor cells (CTC) and macromolecules such as lipids, proteins, RNA, microRNA, and DNA that originate from tumor cells."

Source: Martin et al.,

It was interesting to see the development of Pfizer's crizotinib in non-small cell lung cancer (NSCLC) with ALK mutations emerge recently.  While Pfizer should be applauded for the speed with which they have developed the drug after the mutation was discovered, the development of the mutation test has clearly not been without its challenges. 

A number of patient blogs complained about the time taken to produce the results from the tumour biopsies (several weeks to a month compared to say, 48 hrs for blood tests) and also in some cases, that their own physician ordered tests were not accepted, requiring another test validated by a central laboratory, sometimes with differing results. This does not augur well for an easy to use commercial diagnostic test for ALK if there are variations in the results. 

Patients with advanced lung cancer often don't have a lot of time so this will be an issue to them and their physicians. Part of the reason for the delay is that tumour biopsy tests often require DNA sequencing to be performed, which inevitably takes time. A validated blood test would have a huge advantage in terms of time and convenience, but whether it is practically possible in an example like this, I don't know. 

Whether a validated blood test is being developed in parallel isn't yet clear, but lung biopsies in the community setting are not routine in the way they are for breast cancer, for example.  Finding suitable patients will therefore be akin to looking for needles in a haystack as the data so far suggests that the number of patients who were ALK positive in the NSCLC trials that looked for the mutation was around 5%.  I'm not sure if this will extrapolate to the broader lung cancer universe though, as patients in a clinical trial are typically different from those in the general cancer population.

Meanwhile, another other interesting trend that is emerging is microRNA:

"In addition to proteins, mRNAs are promising biomarkers, and microarrays represent a powerful approach for their discovery in blood.  A study using custom spotted arrays published in 2001 identified a signature of 12 genes whose mRNA expression was elevated in peripheral blood mononuclear cells (PBMC) of breast cancer patients." 

Source: Martin et al.,

The number of articles, papers, abstracts and presentations on microRNA has increased at a tremendous rate over the last 2 years.  At the AACR Molecular Targets meeting last November, it seemed as though 1 in 3 abstracts mentioned the subject in a variety of different ways from prognosis to early resistance. This is one area I'll be following to see what interesting new concepts emerge. I've had a few requests for more information on microRNA, so this will be the topic of a forthcoming blog post.

The ultimate question as always, though, is what does this all mean?

Clearly, earlier detection of disease is useful for prognosis, but predicting the impact of therapeutic intervention is also important. If we can develop biomarkers for determining which drug might work optimally for a given patient or subset, that would alleviate a lot of the pressure on healthcare systems and reducing patient exposure to drugs that would not work. At present, there are probably more tests developed than actually used in practice, but incorporating them into large scale clinical trials as part of a battery of tests may well provide more useful information in the near future across a variety of different cancer types. 

Time will tell, but it makes a lot of sense to incorporate a vast battery of surrogate biomarker tests upfront and then track what happens over time, as the Medivation trial with MDV3100 has shown with PSA and CTC's in prostate cancer, to offer a practical example.  You never know which of the biomarkers tested will emerge as useful in any given tumour type, so testing more rather than fewer may have a higher chance of hitting the bullseye.

Martin, K., Fournier, M., Reddy, G., & Pardee, A. (2010). A Need for Basic Research on Fluid-Based Early Detection Biomarkers Cancer Research, 70 (13), 5203-5206 DOI: 10.1158/0008-5472.CAN-10-0987

On clinical trials, creativity and patient adherence in cancer

"Let us honour if we can

The vertical man

Though we value none

But the horizonatal one."

WH Auden 

Over the last few months, I've been having some interesting conversations with various people involved with cancer research and have been impressed with how many are going about looking at the clinical trial conundrum with a new and fresher lens.  Sometimes doing the same thing repeatedly isn't always in the best interests of everyone, the researchers, doctors, patients, manufacturers, regulatory authorities.

The good news is that there are some new initiatives being discussed that break the mould from just looking at either first-line metastatic or relapsed, refractory disease as the first port of call in a isolationist nihilistic approach.  This is good news and I'm hoping that more people taking on a broader, more holistic perspective will change the kaleidoscope of collective thinking.  

Think about it.  

What happens when patients stop adhering to therapy?  How does that affect outcomes?  What education is needed to help address this?  Who should provide the education?  Giving out pills boxes and chips in lids isn't going to change much without a link to why it matters. 

At the recent EHA meeting, Jan Geissler gave an excellent overview of the broader factors affecting patients in two different sessions from the patient perspective.  I hope it opened many physicians eyes to some of the underlying issues.  This issue is nowhere near as simple as many may think.  In a different session, David Mahon gave a fascinating talk on the impact of patient adherence on outcomes in CML based on some serious research.  As one might expect, they were affected negatively, but the shocking piece of information was how many physicians encouraged dose holidays or skipping a dose, saying it wouldn't matter.  This creates the wrong impression to start with.

More recently, the news that compliance with chronic tamoxifen therapy for treatment of hormone sensitive breast cancer is often poor, is not a surprise given the tolerability issues associated with the drug, but what is surprising is how little take-up this made in the medical news (HT Jody Schoger).  How many women had a poorer outcome from their hormone treatment as a result of less than 90% compliance?  What can be done about it?  Very little comment or analysis in the medical press or advocacy world ensued.

In the end, we need more creative leaders working on this problem, a greater synergy between translational and biology research with clinical practice, cross functional working groups that involve multiple stakeholders, including patient advocacy, working towards a common goal for the greater good. 

It is only when all of these factors come together in multi-functional teams that faster and better progress in cancer outcomes, in terms of both survival and quality of life, will ultimately be made. Where's that Cowbell when you need it?

What are you doing to help change things?

Advancing the Use of Biomarkers in Cancer Drug Development

This was the title of a fascinating article I saw on Twitter a few minutes ago, courtesy of the American Association of Cancer Research (AACR).  They are providing access to the paper free of charge to the public using this link.  If you are on Twitter and interested in cancer related research, do follow them and keep track of the hot news items as they share quite a few important articles on translational research.  Of all the medical associations I've come across in social media, they are also very helpful and responsive to enquiries.

So, what of the Consensus Report?  Well, it's a collaborative effort from the AACR, FDA and NCI to create a position statement of the state of play so far:

"There is a growing imperative to modernize the drug development process by incorporating new techniques that can predict the safety and effectiveness of new drugs faster, with more certainty, and at lower cost."

As always, though, things are never as easy or simple as one might like.

Developing novel and useful biomarkers is an expensive and time consuming process driven largely by translational research and bioinformatics, often with a lot of diverse stakeholders involved in the process. 

The Cancer Biomarkers Collaboration covered recommendations in eight key areas:

1. Biospecimens
2. Analytical performance
3. Standardisation and harmonisation
4. Bioinformatics
5. Collaboration and data sharing
6. Regulatory issues
7. Stakeholder education and communication
8. Science policy

Ultimately, the goal of the collaboration is to:

"The AACR-FDA-NCI Cancer Biomarkers Collaborative is a stakeholder-driven effort to inform and accelerate the FDA Critical Path Initiative and the work of the broader cancer community."

The paper is well worth reading for those interested in the area, so check it out.

Meanwhile, on a practical note, a new potential biomarker has emerged in small cell lung cancer (SCLC) - see link to the Journal of Thoracic Oncology below (subscription required).  The problem here is that while the majority of people with SCLC initially respond well to chemotherapy, resistance develops leading to relapse. The big question is why?

To answer this question, the researchers hypothesised that:

"... tumor microRNAs (miRNAs) could serve as predictive biomarkers for chemoresistance and prognostic biomarkers for survival of patients with SCLC treated with systemic chemotherapy."

The initial microRNA research on tumour samples (n=34) showed that:

"Higher tumor miR-92a-2* levels are associated with chemoresistance and with decreased survival in patients with SCLC. Tumor miR-92a-2* may have application in screening patients with SCLC at risk for de novo chemoresistance in an effort to design more tailored clinical trials for this subpopulation."

In other words, microRNA (miR-92a-2*) could potentially be used as both a predictive and prognostic marker in SCLC.  These results will need to be validated in larger scale trials, but they offer a promising glimpse of what might be possible for future therapeutic interventions.

Khleif, S., Doroshow, J., Hait, W., et al., (2010). AACR-FDA-NCI Cancer Biomarkers Collaborative Consensus Report: Advancing the Use of Biomarkers in Cancer Drug Development Clinical Cancer Research, 16 (13), 3299-3318 DOI: 10.1158/1078-0432.CCR-10-0880 

Ranade, A., Cherba, D., Sridhar, S., Richardson, P., Webb, C., Paripati, A., Bowles, B., & Weiss, G. (2010). MicroRNA 92a-2* Journal of Thoracic Oncology DOI: 10.1097/JTO.0b013e3181dea6be

Should use of CT scans be reduced?

Last night I was reading about the latest Iressa (gefinitib) data in lung cancer published in the NEJM, but unfortunately the DOI code isn't yet available for easy tagging and linking of the article in Research Blogging, so it will have to wait until it's out.

There was, however, a pair of interesting articles on computerised tomography (CT) scans (see references and links below).  While the use of such scans has clearly improved diagnosis, it has come at a cost - both in terms of expenditure and also with respect to increased risk of radiation exposure:

"We found that the risk of cancer from a single CT scan could be as high as 1 in 80 — unacceptably high, given the capacity to reduce these doses."

Source: Smith-Bindham, NEJM

"Changing the culture of medical practice to encourage more thoughtful use of imaging today will help to ensure that future patients will benefit from continued imaging innovation." 

Source: Hillman and Goldsmith, NEJM

Good points both, but little is likely to change unless the payers and insurers force them economically. Physicians are typically cautious and conservative by nature and would rather check to see if any cancer might be present than risk missing it or be hit with a law suit for negligence.  Given that radiation has not been shown conclusively to be cancer-causing, most would probably rather be safe than sorry.

Smith-Bindman, R. (2010). Is Computed Tomography Safe? New England Journal of Medicine DOI: 10.1056/NEJMp1002530 

Hillman, B., & Goldsmith, J. (2010). The Uncritical Use of High-Tech Medical Imaging New England Journal of Medicine DOI: 10.1056/NEJMp1003173

Pharma R&D is a rollercoaster - Mylotarg withdrawn and Ziopharm stumbles

Interesting news in Pharmaland today as we hear that Pfizer has decided to voluntarily withdraw gemtuzumab ozogamicin (Mylotarg) from the market and the FDA declined to grant Ziopharm an SPA for their phase III trial with palifosphamide (palifosfamide for those reading in American English) in soft tissue sarcoma.

The first is unexpected, the second interesting.

Mylotarg

In 2000, Wyeth (now part of Pfizer) were granted accelerated (fast track) approval in AML for Mylotarg, an anti-CD33 monoclonal antibody, on the basis of response rates, with the intent that survival data would provide evidence for full approval. Unfortunately, like Iressa's situation in lung cancer, that did not happen so polite withdrawal is the only option in this situation. Perhaps the only surprise is that it took a decade for it to happen.

It's not a big loss for elderly AML patients, given the drug never showed any major efficacy benefit and the side effect profile of fevers, chills, nausea and vomiting severely impacted quality of life for many frail people. Many AML patients are over 60 and in much less robust health compared to younger, fitter patients who might be candidates for high dose chemotherapy and a transplant. This is where Mylotarg was supposed to offer hope, given the limited options. In this setting, the ideal drug would be a targeted therapy without too many debilitating adverse events. Early toxicities with Mylotarg, however, were not pleasant:

"... among all patients evaluable for early toxicity the fatal induction toxicity rate was significantly higher in subjects given the combination of standard induction chemotherapy and Mylotarg than in those treated with chemotherapy alone."

Source: Pfizer

I always look at sales as a good indicator of whether physicians like a drug or not.  At around $35M annually, Mylotarg clearly wasn't a popular option. Sometimes we need to focus on what matters - response rates per se (around 10-13% complete responses) don't mean much in isolation, but extending lives does, hopefully without too much collateral damage. In this situation, Pfizer made a good call.

Palifosfamide

Ziopharm's management team have been very bullish and brimming with confidence lately, however, such sentiments can sometimes turn out to be irrational exuberance.  The phase II PICASSO trial with palifosfamide and doxorubicin versus doxorubicin alone has completed enrollment with initial promising interim results in metastatic or unresectable soft tissue sarcoma and the company were clearly hoping to negotiate an SPA with the FDA for the phase III trials, but it seems negotiations have broken down on that front, with concomitant fall in the share price.

The trial design is interesting for several reasons.  

Firstly, the current standard of care for treatment of soft tissue sarcoma is ifosfamide plus doxorubicin but there's no comparator arm with ifosfamide, an old chemotherapy now available generically.

According to the company:

"Palifosfamide (ZIO-201) is a proprietary stabilized metabolite of ifosfamide."

Meaning it's a second generation version of the generic, but is it any better than ifosfamide?  We won't know with the proposed design. Of course, the current reimbursement structure means that oncologists will make more revenue from a branded drug (6% of $1000 is more than 6% of $100), whereas in the old scheme, there was more usage of generics because the spread was greater than for newer, more expensive therapies.

Secondly, the big sticking point for the FDA was the proposed primary endpoint, ie PFS rather than overall survival (OS).  One does not always follow the other, but seriously, accepting OS as the goal may well have been an easy win-win for Ziopharm. It seems a little odd that they chose not to go there in the initial discussions with the FDA:

"In a recent communication, FDA has indicated that the Company could conduct the pivotal trial as designed without SPA and that approvability would be determined by the data, balanced with risks and benefits. FDA presently considers the endpoints as designated for the proposed pivotal trial as not supportive of SPA in this disease setting, although they would grant SPA with modified endpoints."

If changing the endpoint from PFS to OS is all that is needed for garnering an SPA, I think I would grab it and go. It's much easier to gain approval if you meet the criteria for a pre-negotiated SPA, as Roche/Genentech have shown with Tarceva several times, even with marginal, yet significant improvements, based on well powered studies. Going it alone without agreement with FDA is a recipe for disaster down the road, as many small biotechs have discovered to their dismay over the last 18 months.

Aggregating the EHA 2010 tweets

After the success of the American Society of Clinical Oncology (ASCO) Twitter aggregation, with over 250 readers over the course of the weekend, I thought it would be fun to repeat the experiment for the European Hematology Association (EHA) meeting in Barcelona this weekend.  The tweet volume is likely to be significantly less tough, with fewer people tweeting from the event.

Most of the topics I'm interested in will be on leukemias, lymphomas and myeloma, so if you are interested in these cancers, you can follow the feed below.  I've aggregated two hashtags, #EHA10 and #EHA2010. 

Additionally, Dr Anas Younes from MD Anderson Cancer Center will also be attending and following his tweet stream may also be instructive, especially if you are interested in his specialty, lymphomas.

Do feel free to join in remotely in the back channel and add links, comments or ask questions if you feel so inclined. The more the merrier!

I'm particularly looking forward to the Patient Advocacy symposium chaired by Jan Geissler, an awesome guy who just happens to have CML.  While the science and clinical data are important, it's also critical to hear and learn from the advocacy viewpoint.  

On the healthcare (#hcsmeu) front, I'm also hoping to meet fellow Twitter buddies, Miguel and Angel for an impromptu tweetup of #hcsmeuES.  If you're on Twitter and interested in healthcare, check them all out, all three are great gentlemen I would highly recommend!

Aggregating the ASCO 2010 tweets

As with previous meetings, I'm aggregating the ASCO tweets using three key hashtags: 

#asco10 (the official twitter hashtag) 

#asco2010 (some people are using this) 

#ascopress (for press alerts)

The stream should be live as of 3pm CST and will run for the duration of the meeting until COB on Tuesday:

Ready, Steady, Go!

The big day for ASCO 2010 abstracts

Tonight at 6pm, the ASCO abstracts of live online with the exception of the plenaries, late breakers and clinical review abstracts, which will published at the meeting.  7 policy exceptions were granted under SEC guidelines, meaning that limited information to be made publicly available in advance of the meeting:

Abstract 8010: Lenalidomide maintenance after transplantation for myeloma. 

Abstract LBA4007: The AVAGAST trial: A randomized, double-blind, placebo-controlled, multicenter phase III study of capecitabine and cisplatin plus bevacizumab or placebo as first-line therapy in patients with advanced gastric cancer. 

Abstract LBA4507: Denosumab versus zoledronic acid for treatment of bone metastases in patients with castration-resistant prostate cancer. 

Abstract 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. 

Abstract LBA4511: A randomized, double-blind, placebo controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castrate-resistant prostate cancer (metCRPC): Survival results of CALGB 90401. 

Abstract LBA7502: Results from ARQ 197-209: a global randomized placebo-controlled phase 2 clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGPR-inhibitor naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). 

Abstract LBA8512: A phase III random assignment trial comparing percutaneous hepatic perfusion with melphalan (PHP-mel) to standard of care for patients with hepatic metastases from metastatic ocular or cutaneous melanoma.

Of these 7, no doubt keen investors will be interested in the first ($CELG) and last ($DCTH), and analysts will be anxious to see the denosumab data ($AMGN), but the ones that I will be most interested in are ARQ197 ($ARQL) and bevacizumab (Avastin) ($RHHYG).  We already know that the Avastin data was negative in gastric and prostate cancers, but positive in ovarian cancer from Roche's previous press announcements.  Ovarian cancer badly needs new options that improve outcomes for women suffering with the disease.

Sometimes though, the best data is not always in the plenary session, witness the Herceptin trial in adjuvant HER2+ breast cancer a few years ago when everyone stood up in a packed session and clapped because the data was simply stunning and groundbreaking. 

Tonight's peek at the available abstracts should give us some clues about what might be interesting. I'll try and schedule some quick posts this evening as I'll be out at client meetings all day tomorrow, great timing, not.

The interesting dichotomy of oncology research vs clinical medicine

Over the past few years it has been interesting to watch AACR organise and group it's sessions by pathways, so you end up with a higgledy piggledy collection of different inhibitors, therapeutics, chemotherapies etc as well as a mix of different tumour types.  This works well for the scientist, less so for the clinician who may specialise in only a few cancer types.  

Meanwhile, at ASCO, everything is organised by cancer track, so if you want to search for data on say, MEK, AKT or c-MET inhibitors for example, then the data is now all over the place and trying to get round and find it all is much more difficult.  The chances of missing something, or worse, having clashes in interesting sessions is much higher.  I'm already looking a potential schedule with too many clashes and periods of nothing.  That's not a very efficient way to organise the data, yet this was not something I experienced at AACR to the same extent.

Personally, I find myself much preferring the AACR approach because it's ultimately logical and allows you to see patterns and trends more strategically, providing you approach it sensibly. You do need to think in 3D though, much like that 3 level chess board beloved by Spock in the original Star Trek. This way allows you to see potential connections and future approaches more easily rather than being hemmed in by tumour siloes.

In the long run, I confidently predict that the future trend of personalised medicine is going to be more based on a pathways approach allied with mutational analysis based on constitutive activation, rather than simply thinking in terms of cancer type by line of therapy.  Once you start understanding which subsets exist and which inhibitors can be combined together, it is not hard to see a new world evolving out there that may lead to better outcomes and improved quality of life.

Who knows, we might even be able to get rid of toxic chemotherapies altogether and prescribe a cocktail of more targeted agents based on the patients characteristics.

Now that would be a fine thing indeed.  Thoughts?

Photo Credit: GiftsforyouBiz

Betterness is Good Business even for Pharma

"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?

ASCO 2010 Preview #2: PI3K and mTOR inhibitors

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.

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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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• Aeterna Zentaris Presents a Poster on its Dual Inhibitors for PI3K and Erk, as well as an Oral Presentation Reporting Data on Selective Erk Inhibitors, at AACR Annual Meeting (newswire.ca)

Are we becoming immune to daily gene announcements?

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:

1. Where's the link to the original article (in these days of social sharing leaving it out is plain lazy)?
2. What/where are the "five common genetic factors" exactly?  No mention is made of them.
3. What does this finding actually mean?
4. 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