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My take on the crizotinib Xalkori FDA approval

By on August 26, 2011

Pfizer’s Crizotinib (Xalkori) approved in ALK-positive lung cancer!

The FDA just announced that they have approved Pfizer’s crizotinib (Xalkori):

The U.S. Food and Drug Administration today approved Xalkori (crizotinib) to treat certain patients with late-stage (locally advanced or metastatic), non-small cell lung cancers (NSCLC) who express the abnormal anaplastic lymphoma kinase (ALK) gene.

Xalkori is being approved with a companion diagnostic test that will help determine if a patient has the abnormal ALK gene, a first-of-a-kind genetic test called the Vysis ALK Break Apart FISH Probe Kit. It is the second such targeted therapy approved by the FDA this year.

Source FDA

This is wonderful news for those unfortunately affected by this debilitating disease and those yet to be diagnosed with the aberration who will be able to be treated with a new highly specific and targeted drug.

ALK aberrations typically occur in the order of 4-7% of NSCLC patients, depending on sources. No doubt the companion FISH diagnostic test from Abbott will make it easier to screen and identity patients. In turn this will help determine which patients with lung cancer are eligible for treatment.

Pfizer began the rolling NDA submission in January and completed it in May, giving a PDUFA date around November 17th. This rapid approval in approx. three months continues the 2-3 month trend seen with cabazitaxel (Jevtana) and abiraterone (Zytiga) in castration-resistant prostate cancer (CRPC), and vemurafenib (Zelboraf) in metastatic melanoma.

The Xalkori story has been nothing short of amazing and represents another major advance for targeted therapy in a clearly identified subset of patients. There are several patient stories that I’ve come across on the internet, most are heart warming – take a look at this snippet I have curated from ‘feel good’ anecdotes from a caregiver this month alone:

View “Does crizotinib work in ALK+ lung cancer?” on Storify

It’s amazing to follow their story of courage and grace under pressure; it is also very hard to have a bad hair day when the very fragility of human life stares at you in the face. It could be any of us under 50, even non-smokers.

The response rates to crizotinib have been incredible, as witnessed by Dr Jack West’s story about one of his patients at Swedish:

{Update 1: Dr West tells me that the young gentleman he referred to in his TED story has now been on crizotinib 2+ years and is doing well enough to coach soccer!}

In the final PI, the overall response rates for Xalkori in two single arm studies (n=136 and 119) in patients who had mostly received prior systemic therapy. They differed in that:

“In Study A, ALK-positive NSCLC was identified using the Vysis ALK Break-Apart FISH Probe Kit. In Study B, ALK-positive NSCLC was identified using a number of local clinical trial assays.”

The ORR was 50% and 61% for each respectively. This is pretty impressive, in my opinion. According to the PI, the adverse event profile is quite tolerable:

“The most common adverse reactions (≥25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation.
Grade 3-4 adverse reactions in at least 4% of patients in both studies included ALT increased and neutropenia.”

These are fairly normal and commonplace for cancer therapy, although there are potential vision disturbances that may need to be watched (from the PI):

“Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical trials.
These events generally started within two weeks of drug administration.
Ophthalmological evaluation should be considered, particularly if patients experience photopsia or experience new or increased vitreous floaters.
Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment.”

The good news is that Xalkori is now available – according to the Pfizer press release:

XALKORI is available immediately through a number of specialty pharmacies.
Patients prescribed XALKORI can call 1-877-744-5675 for assistance accessing the medication.

For more information about the FDA-approved ALK test, call (855) TEST-ALK (837-8255).

The big question many will be asking, though, is what’s the price?

Answer: Price: $9,600/month, putting it in line with similar pricing to Roche’s Zelboraf in metastatic melanoma.

{Update 2: Abbott has also received approved for the ALK test although no information on the cost of the test was provided}.

 

13 Comments

The spiralling costs of cancer research and treatment

By on August 23, 2011

“The problem at the moment is that it takes $1bn [£600m] to get a drug to market and 15 years or more. That is the justification for the pharmaceutical industry charging high prices.

If on the other hand by the time you get to phase 2 you know exactly which patients it is going to work on, you only put those patients through and instead of 10% you get an 80% response rate.

You get a licence on the basis of the data and don’t have to go to phase 3 (a trial involving thousands of people). That saves vast sums of money and years of development. What that does to the business model is it means you can justify charging lower prices because it cost a lot less in the first place.

If we get this right, it changes the entire dynamics of the business model of the pharmaceutical industry.”

Source Harpal Kumar, the chief executive of Cancer Research UK (CRUK) via The Guardian

A UK friend kindly sent me this article today and provocatively asked me what I thought. Hmmm, a very interesting, meaty and relevant topic indeed.  Here goes…

Will this change the way we do business in cancer research?

The theory behind this statement by CRUK is that if we develop more targeted drugs to fewer patients and generate higher response rates e.g. 70-80% in a specific biologic subset, instead of say, 10% in a broader population, then the costs of development will come down and thus the treatment cost of the disease will ultimately lower.

Not so fast!

The reality might actually be different, and here’s why:

  1. For this to happen you need more translational research, biomarkers and companion diagnostics.
  2. The cost of researching and developing the targets is quite high.
  3. While clinical development costs might be lower with fewer large scale trials, the costs of iterative phase II trials will go up and the available pool of patients for commercialization is now much lower e.g. 5% of patients with the ALK translocation in lung cancer not 100% of all available relapsed patients.
  4. In order to maintain revenues, it is basic economics 101 that smaller patient niches will equal higher costs.

If you are not convinced of the last point, take a look at the costs of treating rare diseases or small subsets of patients.

Some good examples exist in the hematology space include:

  1. Alexion’s Soliris (eculizumab),which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This is a rare hematologic disorder that affects approx. 8,000 to 10,000 people in North America and Europe. The cost is something like $400K per annum.
  2. Genzyme’s Fabrazyme (agalsidase beta) for the treatment of Fabry Disease, another rare hematologic condition, this time an inherited metabolic defect that affects 1 in every 40-50,000 people in the US. Fabrazyme lowers the amount of a substance called globotriaosylceramide (GL-3), which builds up in cells lining the blood vessels of the kidney and certain other cells. It’s very effective, but certainly not inexpensive at around $160K per annum.

What is the likely impact of the changing research paradigm?

Both of the above patient pool sizes are not out of the realm of reality for a comparison with oncology.

In the old model, clinical trials tended to involve more allcomer trials, i.e. patients with a particular tumor type (e.g. non-small cell lung cancer), stage of disease (metastatic) and line of therapy (frontline, relapsed or refractory).

In the new world order, things are changing in clinical trials already:

  1. Roche’s Zelboraf (vemurafenib) was recently approved in metastatic melanoma in patients with the BRAF V600E mutation, reducing the available pool who might respond by 50%. It was launched last week with a price tag of around $56.4K for an average of 6 months treatment.
  2. Crizotinib (Xalkori) is being evaluated in patients with NSCLC who have the ALK translocation and have failed prior therapy. That’s a tiny subset of patients. Patients with this aberration make up maybe 4-7% of the total NSCLC pool. Imagine how small the target population will be for other ALK inhibitors in crizotinib refractory disease?!
  3. The cost of funding and finding biomarkers that predict response is a huge undertaking.  Genentech have no doubt spent many millions looking for a predictive biomarker for Avastin, so far to little avail.

Of course, there are plenty of other exciting targets with small subsets being evaluated in the clinic, but there are several factors to consider:

  1. Small subsets = fewer patients = higher cost.
  2. Will combination strategies be affected by the cumulative costs that will inevitably result? e.g. Yervoy + Zelboraf in metastatic melanoma potential treatment cost = $170-180K if the studies are successful in showing that survival is improved.
  3. Since Dendreon’s Provenge ($93K) was recently given the green light by the CMS, the costs of new targeted entrants is creeping up over the $100K watershed marknot down, viz Yervoy ($120K) and Adcetris (~108K), for example.

In conclusion…

I admire the chutzpah of CRUK, but disagree with some of their conclusions, which I think are rather naive.

Today, I will go on record here and declare that I believe specialised treatment based on the underlying biology will ultimately cost more, not less, in the long run in terms of research and development, diagnostics/biomarkers and treatment costs of ever smaller subsets.

However, I have no doubt we will ultimately see better results clinically with this more scientific approach but this will come at a cost.  While that’s great news for patients and caregivers, it is not so great for the payers, Government or investors, because higher risks and R&D costs will inevitably equate to more failures and this drives higher costs in a spiral fashion.  Ultimately, those costs will trickle down to all of us in the form of higher co-pays and more expensive medical plans to cover the payers margins.  Success has to be paid for somewhere down the line.

And the constant refrain from everyone in Pharma of “let’s do more with less” will increase.

It’s a vicious cycle of unsustainability, with no end in sight.

9 Comments

On T cells and chronic lymphocytic leukemia

By on August 15, 2011

Late last week saw an incredible amount of noise in the media over the startling news that three patients with chronic lymphocytic leukemia (CLL) had responded well to an experimental gene therapy that aimed to boost T cells to fight a particular type of leukemia, some of it, unfortunately, bordering on near hysterical hype, such as MSNBC’s article entitled:

“New leukemia treatment exceeds ‘wildest expectations'”

Ugh.  There were others in similar vein, mostly derived from the AP and Reuters press releases.  Quite frankly, with a headline like that I was expecting something more substantial and robust than three patients.

The most measured story I saw came from NPR Shots, who took a more rational and thoughtful approach to the publications in New England Journal of Medicine and Science and Translational Medicine.

Gary Schwitzer also did a nice review of some of the commentary that emanated from the health media outlets as well as a well thought out longer piece.

It was clear though, that some of my medical and science friends were rather disappointed by the rather breathless nature of the general media reporting.  There is something really icky about raising peoples hopes based on very minimal data.  Part of this is due to journalists and editors with attention grabbing headlines, presumably because that’s what drives traffic, but also a noticeable lack of rigour or critical thinking in reviewing the situation in depth.

Let’s take a look at the disease in more detail first.

CLL is well known to be a disease of the elderly, with a median age around 63-65 years. It’s an indolent immune-sensitive cancer and treatment is largely based on a series of immunotherapies, either alone or in combination, such as fludarabine, rituximab, bendamustine, pentostatin and alemtuzumab, for example.  Not one of the media reports I read looked at how refractory these patients (only a small sample of n=3) really were or what their prognosis was.  It is well known that patients can live normal lives between treatments until relapse, when another treatment is initiated.  This process can go on for several years but eventually, they run out of options as these patients did.

What do we know about the patients?

Looking at the actual data reported from the two journals, we find some interesting nuggets about their prior immunotherapy treatment and karyotypes:

  1. The NEJM article is a single case report on one patient who had previously received FR (twice, for 2 and 4 cycles), BR (1 cycle), B (3 cycles) and alemtuzumab. He was found to have a 17p del with TP53 involvement, which has a known poor prognosis.
  2. All three patients had received both bendamustine and alemtuzumab (in different lines of treatment).
  3. Not all of the patients appear to have received prior fludarabine, which is surprising given that it is largely considered to be the standard of care, either as fludarabine-cytoxan-ritiximab (FCR) or fludarabine-rituximab (FR).  (Note: The patient who achieved a PR rather than CR did not apear to receive prior fludarabine).
  4. Two of the patients had a 17p deletion (with p53 involvement), the other had a normal karyotype.  The latter generally has a better prognosis.
  5. No indication of what might be expected without treatment in terms of the time elapsed after the last therapy is feasible without a comparative trial, so evaluating the effects of the gene therapy versus a control group will be needed going forward.
  6. None of the patients appear to have received a prior bone marrow transplant, which while potentially curative in about half of patients, is not without its complications such as a 20% chance of mortality from the procedure itself.
  7. All of the patients experienced some degree of tumour lysis with fevers, chills, nausea and fever, which occurs when many cancer cells die at once.

The tumour lysis reported in the patients is the most encouraging signal that the gene therapy was working effectively.

What did the researchers do?

Porter et al., (2011) described the idea behind the gene therapy in the NEJM article:

“In most cancers, tumor-specific antigens for targeting are not well defined, but in B-cell neoplasms, CD19 is an attractive target. Expression of CD19 is restricted to normal and malignant B cells and B-cell precursors”

This knowledge provided an opportunity to create a targeted gene therapy and test it in a pilot proof of concept study in a small sample size (n=3).  Patients cells were removed and then a personalised gene therapy was created:

“We designed a self-inactivating lentiviral vector (GeMCRIS 0607-793), which was subjected to preclinical safety testing, as reported previously.”

In plain English, the lentivirus vector encodes an antibody-like protein known as a chimeric antigen receptor (CAR), which is expressed on the surface of T cells and was designed to bind to the CD19 protein used as the target.

The U. Penn press release described the rationale behind the targeted therapy further:

“Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes CLL tumor cells and normal B cells.

All of the other cells in the patient that do not express CD19 are ignored by the modified T cells, which limits side effects typically experienced during standard therapies.” 

What results were seen?

Two patients (one normal karyotype, one with a 17p TP53 del) were seen to have a complete response (CR) of 10 and 11 months each.

A third patient with a 17p TP53 del was adjudged to have a partial response (PR) of 7 months.

These results were fairly encouraging and offer a good proof of concept that the gene therapy is viable in CLL patients.  They also justify pursuing the gene therapy approach in larger scale clinical trials.

What do these data really mean?

Very little, other than an initial proof of concept, based on such a small sample size, but it does give some encouragement to move forward with a broader program to validate the findings.  At present, there is no doubt that people who have CLL with 17p and TP53 deletions tend to experience shorter remissions after standard therapies, so a new option that can be evaluated in clinical trials is an encouraging and welcome sign of some progress in this area.

Overall, while encouraging, these results are best described as ‘promising, but very early indeed’ – a lot more data will need to collected from randomised controlled trials before we see whether we really have a viable new therapy for people with CLL.  To suggest anything else is hype over hope at this stage and that does a great disservice to people with the disease.

Far too many agents fail between initial proof of concept to actually filing for Health Authority approval based on phase II or III data to raise hopes unnecessarily.  In fact, given more therapies fail in R&D than make it market, we would best remember that before we call anything the new ‘breakthrough’ or ‘killer therapy.’

I’m looking forward to seeing the gene therapy program develop further in larger randomised clinical trials, hopefully without excessive hype.

In an editorial in the NEJM, Urba and Longo (2011) urged some caution:

“Only with the more widespread clinical use of chimeric antigen–receptor T cells will we learn whether the results reported by Porter et al. reflect an authentic advance toward a clinically applicable and effective therapy or yet another promising lead that runs into a barrier that cannot be easily overcome.”

I couldn’t agree more with those sentiments.

Still, on a much lighter note, XKCD came to the rescue with this awesome cartoon to brighten up a dull grey morning:

Source: XKCD

References:

ResearchBlogging.orgPorter, D., Levine, B., Kalos, M., Bagg, A., & June, C. (2011). Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia New England Journal of Medicine DOI: 10.1056/NEJMoa1103849

Kalos, M., Levine, B., Porter, D., Katz, S., Grupp, S., Bagg, A., & June, C. (2011). T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia Science Translational Medicine, 3 (95), 95-95 DOI: 10.1126/scitranslmed.3002842

Urba, W., & Longo, D. (2011). Redirecting T Cells New England Journal of Medicine DOI: 10.1056/NEJMe1106965

12 Comments

Nuclear factor I/B is an oncogene in small cell lung cancer

By on August 11, 2011

Last month, a critical paper was published in Genes and Development by researchers at MIT, The Broad Institute and Dana Farber, highlighting the discovery of Nuclear Factor I/B (NFIB), which may play a key role in small cell lung cancer (SCLC).  I thought I had reviewed the NFIB oncogene already, but it never made it out of Drafts.  Time to fix that omission!

Regular readers will remember the recent discussions of other findings by some of the same researchers (Nathanael Gray and Matthew Myerson) in squamous cell carcinoma, a subset of non-small cell lung cancer (NSCLC), such as the DDR2 and FGFR1 mutations. The group, along with Levi Garraway and Tyler Jacks, are very active in lung cancer research.

Small cell carcinoma is a different disease though, affecting approximately 15% of all lung cancer cases.  Sadly though, 95% of people who are diagnosed with the disease are no longer with us at five years, so the overall survival rate is fairly poor.  This happens partly because it is a very aggressive disease, and partly because it tends to be diagnosed late.

We don’t know what the driver genes in SCLC are, so chemotherapy has been very much the bedrock of treatment for many years and as far as I know, there are no approved targeted agents for SCLC.

In the current research, Dooley et al., (2011) described how they used whole gene profiling to find a new oncogene that was present in both the mouse model (with two key tumor-suppressor genes, p53 and Rb, deleted) and in patients with SCLC:

“Using a genetically engineered mouse model of SCLC driven by conditional deletion of Trp53 and Rb1 in the lung, we identified several frequent, high-magnitude focal DNA copy number alterations in SCLC.

We uncovered amplification of a novel, oncogenic transcription factor, Nuclear factor I/B (Nfib), in the mouse SCLC model and in human SCLC.”

This is the first time NFIB has been reported in SCLC, but it has been observed in mouse studies in prostate cancer.  It is a significant finding, because as the authors note:

“This model provided a platform with which to identify genetic alterations that occur during tumor progression.”

The NFIB gene codes for a transcription factor, which means it controls the expression of other genes, so researchers in Jacks’ lab are now looking for the genes controlled by NFIB.  As Dooley observed:

“If we find what genes NFIB is regulating, that could provide new targets for small cell lung cancer therapy.”

Overall, this is thorough and very promising research in SCLC that matches activity in animals with patients.  I’m looking forward to the next installment when we will hopefully learn what the potential targets are.  Once we have that information, there will either be currently approved agents that can be tested, others in clinical development, or even new compounds that will need to be designed for the purpose.

The good news is that progress is being made – that’s always heartening to hear.

References:

ResearchBlogging.orgDooley, A., Winslow, M., Chiang, D., Banerji, S., Stransky, N., Dayton, T., Snyder, E., Senna, S., Whittaker, C., Bronson, R., Crowley, D., Barretina, J., Garraway, L., Meyerson, M., & Jacks, T. (2011). Nuclear factor I/B is an oncogene in small cell lung cancer Genes & Development, 25 (14), 1470-1475 DOI: 10.1101/gad.2046711

Corporate culture in Pharma and Biotechs

By on August 10, 2011

Today a tweet from the GoToMeeting team caught my eye – they were tweeting about how companies can influence employees and customers under the #deliveringhappiness hashtag:

Twitter via @gotomeeting

The list of Zappos core values they were referring to was as follows:

Source: Zappos

It amused me because while #8 is something I increasingly hear from pharma and biotech companies over the last 12-18 months, none of the others are things that seem very much to the forefront or the hearts and minds of Pharmaland.  I would even go to so far as to say that #1 on the Zappos list is probably one of the last in Pharma.  It shouldn’t be, but it certainly seems that way.  Sadly, even biotechs seem to be coming more corporate and Pharma-like these days as more people move from one to the other and vague buzzword bingo becomes the norm.

Perhaps these kind of ideas should resonate more with Pharma, maybe a more cheerful work environment would make a difference to people’s lives, but it struck me how different the retail and drug industries really are – they’re a world apart, and not just in terms of regulations.

Thoughts?

4 Comments

PTEN is an important tumor suppressor gene in breast cancer

By on August 5, 2011

An interesting new paper has just appeared in the latest online first edition of Cancer Discovery, and discusses a functional classification for evaluating the alterations in breast cancer to ultimately determine which are drivers and passengers.

Functional Variability in Breast Cancer

The researchers are essentially using an integrated approach of combining genomics and gene expression profiles overlaid with functional data to create a systematic map.

The goal was to determine if it will help identify key vulnerabilities in genetic mutations and the breast cancer genome as part of a joint Stand Up To Cancer (SU2C) and American Association for Cancer Research (AACR) initiative.

“We have carried out a functional genetic screen in >30 commonly used models of breast cancer to identify genes critical to the growth of specific breast cancer subtypes. In particular, we describe potential new therapeutic targets for PTEN-mutated cancers and for estrogen receptor–positive breast cancers.

We also show that large-scale functional profiling allows the classification of breast cancers into subgroups distinct from established subtypes.”

Should such an approach be successful, it is easy to see how it could be replicated in other tumour types.

The beauty of this methodology, while complex, is we know that not all mutations and aberrations that appear are critical to the tumour’s survival, so creating a road map will enable clinicians to better design trials in a more personalised medicine approach to treatment.  Once we know a patients particular molecular make up and which aberrations are important, then treatment can be more selective and appropriate based on the profile and biomarkers.

Although conceptually, this article was about the idea of figuring out the critical driver oncogenes, they also focus on PTEN mutations and PIK3CA mutations as potential targets, since loss of PTEN is associated with many cancers, including breast cancer. Unravelling the heterogeneity and key targets amy well lead to new therapeutic approaches.

I first heard of PTEN inhibitors a while back in relation to a small private start-up biotech called Pintex, although they were subsequently sold to a UK company, Vernalis.  Vernalis is developing several interesting compounds including Heat-shock proteins (Hsp) and has partnerships with several large pharma companies.  I don’t think any of the PTEN inhibitors survived though and it appears to be a transfer of assets that was more valuable than the compounds they had in development.

Since then, the lead PTEN inhibitor appears to be Semafore’s SF1670, which had a recent preclinical publication in Blood magazine (see references below) and may be hitting clinical trials in the next year or two.  One interesting approach that might evolve is a ‘set-up-knock-down’ approach in tumours that have loss of PTEN and follow this with, say, a PI3K inhibitor.  Semafore also have one of those too, in SF1126, making such a dual strategy in sequencing potentially feasible:

Dual PTEN/PI3K inhibition

As Michel Becker, Semafore’s acting CEO succinctly described it to me:

“The PTEN inhibitor’s role would be to stimulate quiescent cells into a treatable/PI3K addicted state.”

Check out Wicha et al., (2006) for more details on this concept.  Given that PI3K inhibitors have, at best, resulted in stable disease in the tumour types tested to date (including breast cancer), it would be interesting to see if this would lead to better response rates and ultimately, outcomes.

Brough et al’s., (2011) research into loss of PTEN and PIK3CA mutations (mutant not wild type or point mutations) in breast cancer is most interesting, but there is still a long way to go. We need to know more of the underlying biology and the impact of inhibition of targets and the consequences. We should then be able to figure out the optimal targets and logical combination strategies that will lead to responses that are both superior and more durable than currently seen in patients with breast cancer and other tumour types.

The good news is that the basic research is looking fairly promising to date.  I can say without hesitation that combination strategies are more likely to lead to better results than targeting either PTEN or PI3K alone.

 

References:

ResearchBlogging.orgBrough, R, Frankum, JR, Sims, D, Mackay, A, Mendes-Pereira, AM, Bajrami, I, Costa-Cabral, S, Rafiq, R, Ahmad, AS, Cerone, MA, Natrajan, R, Sharpe, R, Shiu, K-K, Wetterskog, D, Dedes, KJ, Lambros, MB, Rawjee, T, Linardopoulos, S, Reis-Filho, JS, Turner, NC, Lord, CJ, & Ashworth, A (2011). Functional Viability Profiles of Breast Cancer. Cancer Discovery : 10.1158/2159-8290.CD-11-0107

Li, Y., Prasad, A., Jia, Y., Roy, S., Loison, F., Mondal, S., Kocjan, P., Silberstein, L., Ding, S., & Luo, H. (2011). Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model. Blood, 117 (24), 6702-6713 DOI: 10.1182/blood-2010-09-309864

Wicha, M. (2006). Cancer Stem Cells: An Old Idea–A Paradigm Shift Cancer Research, 66 (4), 1883-1890 DOI: 10.1158/0008-5472.CAN-05-3153

How picking up prostate cancer earlier may improve outcomes

By on August 4, 2011

Prostate cancer is very much in the news this morning, not all for good reasons though.

Dendreon’s Provenge launch to community oncologists did not go well

Dendreon’s stock is in free fall after the company missed it’s earnings and revenue expectations rather badly yesterday.  Adam Feuerstein of The Street has a nice overview of the 2Q earnings call for those of you interested.

There are a couple of things that come to mind though:

  1. The reimbursement may well have a broader impact on the landscape than many realise – CMS may pay for a drug or vaccine, but it doesn’t always pay for the surrounding expenses associated with it*
  2. The “cost dense” issue is offset by ipilimumab (Yervoy) doing better than expected in their metastatic melanoma launch despite a higher overall price (execution matters!)
  3. The root of Dendreon’s problem may well be lack of demand and healthy scepticism from medical oncologists over the value of Provenge relative to the cost:benefit (no impact on tumour shrinkage, bone pain, etc; patients just live a little longer)
  4. Strategy and execution are key in cancer launches to community oncologists

* There are some excellent reimbursement experts out there such as my good friend Bobbi Buell at Covad who steer companies through this kind of minefield.  In fair disclosure, I know I appreciated and valued her solid advice when I was at Novartis and we launched Gleevec in CML.  Having such expertise is a necessity, not a luxury, these days.

Medivation’s MDV3100 may have new opportunities

There was good news from Medivation that caught my interest.  Medivation are developing their androgen receptor (AR) antagonist, MDV3100, in castrate resistant prostate cancer pre and post chemotherapy, with interim results from the latter possibly expected by the year end.  Today, the company announced some positive preclinical data in breast cancer:

“Researchers at the University of Colorado Denver… provide evidence that MDV3100 inhibits proliferation of breast cancer cells.

In different cell-based assays, MDV3100 was able to inhibit both androgen- and estrogen-mediated breast cancer cell proliferation.”

What are the significance of these findings?  Well, the company quoted one of the study authors, Dr Jennifer Richter:

“Our findings are exciting because they challenge the existing idea that androgens are protective in breast cancer by demonstrating that androgens can stimulate proliferation of breast cancer.

These preclinical data show that MDV3100 suppresses androgen-driven breast cancer cell growth and, surprisingly, also suppresses estrogen-driven breast cancer cell growth.”

I think it would be reasonable to expect a phase I clinical trial to evolve soon to test the hypothesis in women with hormone-sensitive breast cancer.

TMPRSS2:ERG may be a more useful marker than PSA in prostate cancer

The big news that really cheered me most this morning, though, was new  data from Science Translational Medicine showing the feasibility of a simple urine test to pick up signs of prostate cancer potentially earlier than we do now. Having had a father who was suddenly diagnosed with stage IV disease, hearing about a test that may help diagnose it earlier than currently feasible with biopsies or PSA is a most welcome advance.

Back in 2005, Arul Chinnaiyan’s lab reported a fusion between two genes present in around half of all prostate cancers called TMPRSS2:ERG.  When the two genes, TMPRSS2 and ERG, combine, they cause aberrant activity and drive prostate cells to grow out of control, leading to cancer.  This is in much in the same way BCR-ABL drives aberrant activity in chronic myeloid leukemia (CML).  The next step after the discovery was to evaluate the reliability and faithfulness of the gene in indicating whether men had prostate cancer.

In the latest report, the researchers measured the level of the fused gene in the urine of men (n=1312) with high PSA levels in their blood, then looked at TMPRSS2:ERG levels, tumour volume and clinically significant prostate cancer, and PCA levels.  They analysed the data to see if the two markers were a good indication of prostate cancer or not.

Half of the men sampled were found to have the TMPRSS2:ERG gene, confirming previous research by the group.

The results also demonstrated:

 “TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy.”

Essentially, this means that by combining the TMPRSS2:ERG results with PCA data, the group have found a way to stratify men with prostate cancer in terms of risk – in other words, they have a larger and more invasive tumour that requires aggressive treatment.

The diagnostic technology was developed by Gen-Probe, so I think it would be reasonable to assume the company will submit the data to the FDA for approval once further tests have been completed to evaluate accuracy and specificity of the test.  If those are successful, we may well have a new diagnostic test for prostate cancer in the not too distant future.

It goes without saying that picking up aggressive disease earlier and treating it effectively will likely lead to better outcomes for men with prostate cancer.

 

References:

ResearchBlogging.orgTomlins, S., Aubin, S., Siddiqui, J., Lonigro, R., Sefton-Miller, L., Miick, S., Williamsen, S., Hodge, P., Meinke, J., Blase, A., Penabella, Y., Day, J., Varambally, R., Han, B., Wood, D., Wang, L., Sanda, M., Rubin, M., Rhodes, D., Hollenbeck, B., Sakamoto, K., Silberstein, J., Fradet, Y., Amberson, J., Meyers, S., Palanisamy, N., Rittenhouse, H., Wei, J., Groskopf, J., & Chinnaiyan, A. (2011). Urine TMPRSS2:ERG Fusion Transcript Stratifies Prostate Cancer Risk in Men with Elevated Serum PSA Science Translational Medicine, 3 (94), 94-94 DOI: 10.1126/scitranslmed.3001970

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AACR has free journal access online until end of August

By on July 14, 2011

Gotta love Twitter for finding useful and helpful things that make a difference to scientific research… Last night I saw a tweet from the delightful Tara Yates of AACR:

Tara G Yates, AACR

Yes please!

Whether you are a subscriber or interested in the offer like I was, you can download the AACR app on iTunes.

I couldn’t resist – did it immediately on my iPad and discovered the AACR app was beautiful – well designed UI, nicely integrated and intuitive features, easy to use. The sharp interface looks like this:

AACR iPad App

You can scroll through, choose a journal, read Online first, Current Issue or the previous three issues. Very neat. You can also favourite articles for later reading:

AACR iPhone App Abstract

Note the “Download the PDF” button at the top right. This is where the app really shines. In the iPad, you can download the PDF and save it to any readers you have such as iBooks, Goodreads, Stanza or whatever you have installed. The app let’s you choose your preferred option. I like iBooks and save PDFs to there for easy reading while travelling or even while working or writing blog posts.

The other option I use is to save PDFs to Evernote as well. The reason for this is that the readers all search on title alone, whereas Evernote is OCR based and will find words in an article, not just the title. This is very handy if you need to find something quickly and only have a vague idea of what you remember.  The other day I needed an article on VEGF biomarkers but only remembered vaguely reading it was about ‘myeloid’ factors and couldn’t remember the journal, authors, the institution, the drug or anything else other than VEGF and myeloid.  Evernote found it in seconds after searching for ‘myeloid’. Very cool.

Evernote also syncs seamlessly across my iPad, iPhone, laptop and Desktop computers making it the ultimate database and search tool for scientific data and papers.  It has certainly saved my bacon more than a few times when doing consulting projects!

I highly recommend this app from AACR – even if you’re not a member, it’s well worth checking out the free access offer and reading a lot of high quality articles on a range of topics from basic and translational research, to biomarkers, clinical research and even cancer prevention.  It’s really very easy to get engrossed reading the interesting journal articles on a iPad and forgetting to download or save them…  I’m going to be very sad when the free trial runs out next month 🙁

Nice job, AACR!

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Should Pharma and Biotech be engaging in social media?

By on July 1, 2011

Today several people have reminded me that it’s Canada Day and also the Independence Day weekend in the US.   Although I’m British and celebrate neither, there will be a short hiatus from blogging in honour of my Canuck and American friends.

We’ll be working unfortunately, such is the life as a consultant, with deadlines galore due next week!

For those of you anxious not to miss anything hot on the social media front, check out this article from BioWorld on Biotechs and Social Media, kindly sent in by Drs Brian Orelli and Al Lalani.

Here’s an interesting quote from the research:

In an informal BioWorld Today survey, more than 44 percent (95) of the 215 respondents said their firms are not engaging in social media.  The No. 1 reason, listed by 42 percent, was that social media “was not the place for us.”

I can understand that approach completely – social media is about engagement and sharing; dealing with the challenges of unhappy patients complaining publicly online via social media puts Pharma in an awkward spot regarding how to handle issues that may arise:

The biggest concern the companies had with social media was how to balance the risks and benefits. That balance was cited by nearly half the respondents.  Other top concerns were dealing with third-party comments and opening themselves to liability.

The short article is well worth reading.  It reminds me of the dilemma a client recently expressed:

“Do we continue to focus strategically on research & development, trying to find cures for cancer, or do we allow ourselves to be distracted by other issues like shiny new tools and tactics?  I only have so much time in a day.”

Fair point indeed and a dilemma that many of you will already be discussing offline. There is no right or wrong answer – you can only do the best you can with the time and resources you have available.

In the meantime, Pharma Strategy Blog will resume as usual on Tuesday.

Happy Holidays to all!

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Biotechnology, Genomics and Personalized Medicine

By on June 29, 2011

Ruby (@divabiotech) talking at Singularity U

My friend Ruby Gadelrab is the very dynamic and vivacious Head of Marketing and Clinical Development for International Markets at Affymetrix.

She was recently invited to give a talk at the prestigious Singularity University meeting.

I was thrilled to see that Ruby has generously posted her talk online on her blog, Diva Biotech, which I’m a big fan of, and check out regularly in my RSS feeds.   The excellent presentation well worth reading if you want to come up to speed on the basics, as well as see her personal view on where the field is going in the near future.

I learned a lot from her synopsis and thought it was a nice thing to share here with PSB readers who may be interested in the topic, as this is a subject that will be very much to the fore in the next 5-10 years.

You can read all about it and download Ruby’s slides on Biotechnology, Genomics and Personalized Medicine.

Check it out!

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