After yesterday's post about the I-SPY trials in neoadjuvant therapy for breast cancer and how they may speed up the process of bringing new innovative cancer drugs to the clinic faster, I was reflecting on my own experiences with imatinib (Gleevec).
The Philadelphia Chromosome was first identified in 1960 by Nowell and Hungerford. Gleevec was finally approved by the FDA in May 2001, 41 years later.
Between 1999, when I arrived in the US and working in New Product Development at Novartis until 2001 when Gleevec was launched, I attended scientific meetings including AACR, ASH and ASCO. Often, Dr Judah Folkman, a scientific researcher from Harvard, would talk about angiogenesis and hypothesised that was the principal mechanism by which tumours grew. I listened to his ideas many times because I was curious and found the concept both fascinating and intuitive. There was a long line of drugs that failed to work though, and every meeting seemed to bring yet more negative results.
Now, Folkman first advanced the angiogenesis theory in 1971 in the New England Journal of Medicine, but it wasn't until 2002, when bevacizumab (Avastin), a VEGF inhibitor that prevented angiogenesis from happening, was finally approved for the treatment of colon cancer. At that point you go, 'oh wow' and realise that Folkman's theory was indeed proven correct.
Thus a tale of two incredible cancer drugs that both took a relatively long time to evolve from scientific idea to effective treatment in people with cancer. Or perhaps they were actually relatively 'quick' compared to others, but why it takes this long is something we can surely do better at.
Last night I was researching ideas for drug development and innovation since the concept of bench to bedside fascinates me and came across this enlightening video from a lunchtime talk that Dr Susan Desmond-Hellmann gave last year at UCSF. Oddly, she seems to have trodden similar thought processes and asked why and how can we speed things up as well.
The short lecture is well worth listening to for those interested in drug development - the good doctor explains the bench to bedside concept far better than I:
Sources for scholars and clinical scientists:
The NEJM doesn't appear to go back beyond 1993 online, but the original reference to Folkman's article is at:
Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.
A more recent one from 1995, which provides an update is available online at: NEJM
A short while ago on this blog we began a series on Making a Difference about people in the cancer field who have a real passion and excitement for lasting and impactful change. The first one was an interview with Alain Moussy of AB Science in Paris.
Today, I had the pleasure of chatting with the admirable Dr. Susan Desmond-Hellmann, formerly Head of R&D at Genentech and now Chancellor at UCSF. It's a strange business sometimes as we were both working in industry at the same time on different targeted cancer drugs in liquid and solid tumours but our paths never crossed, although it seems we share similar views on cancer drug development, ie purer targeted agents and finding faster ways to market for effective therapies that impact the lives of people with cancer.
Which brings me to the main topic of today's discussion.
There are many challenges in cancer drug development, not least of which are regulatory hurdles, time consuming, risky and expensive clinical trials (we've seen a lot of phase III failures lately), basic research, biomarker development and many others. Traditionally, cancer trials take two main strategies to market:
Head to head comparison with standard care or a with and without approach if adding a new agent to the combination
As a single agent in the relapsed, refractory setting
Both of these approaches are typically tested in the advanced or metastatic setting when the disease burden is relatively high and the risk of a drug failing in phase III trials is also high. In solid tumour cancers, once a drug has been shown to be effective, studies tend to move into the earlier, adjuvant setting after surgery has taken place but these trials can take a very long time to reach fruition, typically 5-10 years in some cases.
For many of us, the challenges of how to think outside the box and speed up development while treating earlier stage of disease more effectively has occupied many thoughts. Sometimes the bureaucracy across so many functions is just mind boggling.
No more.
Dr Desmond-Hellmann was telling me about the Investigation of Serial Studies to Predict your Therapeutic Response with Imaging and Molecular Analysis (I-SPY) project, which was launched in DC this morning and aims to change the way we think about cancer drug development.
"What's really neat about the I-SPY trial is that Laura Esserman, the PI of the trial, is a breast cancer surgeon here at UCSF and has added so much value to the project because she sees patients early and has a unique opportunity to offer neoadjuvant therapy.
Patients are getting their primary therapy before they get surgery, so for imaging and biomarkers - either established or exploratory - it is a fantastic opportunity. The endpoint is pathological complete response, so you can see if the tumour has disappeared or not."
Treatment with therapeutics prior to surgery is known as neoadjuvant therapy and has a much shorter time span (around a year) for collecting results than adjuvant trials. Furthermore, Dr. Hellmann elaborated what is exciting about this new approach:
"It's a fantastic rapid readout model so you can get answers much more quickly in a year, including pathological specimens, along with the answers from biomarkers and imaging, which are important.
The FDA has allowed a master IND agreement for this study, so it will be possible to move agents in and out of the trial quickly.
So if agent A looks promising it can be advanced quickly and more patients put on it, but if agent B looks toxic, it can be discarded quickly. It's not just a clinical trial but a experimental trial process that gives you a rapid readout of whether the agent works or not.
The hope is that you won't wasting time and money in phase III trials, but most importantly, patients experience on that molecule. If the answer is yes on I-SPY, you then have a biomarker hypothesis for that agent and can then do a more traditional phase III trial having increased your chances of success."
In this way, we will also learn more about the biology of the cancer and effectiveness of the treatments earlier in the course of the disease, which may lead to better long term survival than if treatment is delayed to the later stage of disease, when the cancer has spread and metastasised.
You can find out more about the clinical trial process here and here.
For breast cancer, the standard of care is paclitaxel followed by four cycles of anthracycline therapy. In this model, women with breast cancer can also receive other therapies, either marketed or investigational, to see if their outcome can be improved. For this I-SPY2 project, the five initial investigational agents are provided by Pfizer, Abbott and Amgen:
ABT-888 (veliparib) from Abbott, is a PARP inhibitor
AMG 655 (conatumumab) from Amgen is an APO/TRAIL protein that causes apoptosis
AMG 386 from Amgen is a VEGF angiogenesis inhibitor similar to Genentech's Avastin
CP-751,871 (figitumumab) from Pfizer is an IGF-1R inhibitor that targets the insulin receptor
HKI-272 (neratinib) from Pfizer is a Pan ErbB inhibitor similar to Herceptin
None of the I-SPY-2 breast cancer project would have been possible without the passion, energy and enthusiasm of women such as Drs Sue Desmond-Hellmann, Laura Esserman or Janet Woodcock of the FDA, who has been pressing for more creative solutions to fast track better cancer drugs for some time. This consortium is particularly fascinating to watch because it brings together the major players - academia, industry and the FDA, in a way that has never been done before. We should salute their originality and endeavour to think, and more importantly, do things differently.
If the basic concept proves successful, such a revolutionary clinical trial process may well become the new model for early and more effective drug testing, not only in cancer, but also for other diseases such as alzheimers, diabetes and other chronic diseases. In the long run, this approach may also lead to lower healthcare costs by improving efficiencies.
While Dr Hellmann was excitedly describing the process, I was thinking how much intuitive sense it makes and wished that the bureaucratic hurdles to more collaborative academia-industry-FDA clinical trials had fallen long ago.
The important thing though, is that's it's actually happening right here, right now and for people with cancer, that is good news indeed.
The future of Oncology... is in neoadjuvant and biomarker led trials.
It's been a frantic week on the work front and today was no different, but I wanted to highlight a really interesting slide from the BMS pipeline presentation yesterday afternoon.
Here's one of the slides Elliot Sigal, President of R&D, showed from one of the ipilimumab trials. More data may be available at ASCO if the submitted abstract is accepted, but for now, even though it's only an n of 1, a picture tells a thousand words:
Source: BMS
After all the recent good news about malignant melanoma, hopefully at least one of these promising agents will make it to market in the not too distant future, offering people suffering with the condition a glimmer of hope. I sincerely hope the CTLA4 results turn out to be durable.
In the meantime, we can all wonder until June, when the annual ASCO meeting will held.
With Medicare reimbursement rates to physicians set to drop by more than 20 percent Monday, Vicksburg physician Randy Easterling, president of the Mississippi State Medical Association, is warning that elderly patients could find themselves with no doctor able to afford to treat them.
Easterling said the 21.2 percent decrease in Medicare reimbursements to doctors will automatically go into effect Monday unless Congress votes to stop it.
“They didn’t vote to stop it last night (Thursday night),” Easterling said Friday. “Maybe they’ll do it this weekend, but if they don’t, doctors won’t be able to see these patients.”
The U.S. House passed H.R. 4691, a “Temporary Extension Act,” Thursday, postponing the reimbursement cuts until the end of the month, but the measure, tied to other legislation, did not pass in the Senate. The Senate adjourned just before noon Friday and wasn’t expected to reconvene until Monday afternoon, according to a floor schedule on the Senate’s Web page. The site indicated no votes had been cast.
A domino-effect could also impact the state’s low-income patients on Medicaid, because Mississippi Medicaid reimbursement is a percentage of Medicare, Easterling said. If one goes down, so does the other.
In the past, AMA surveys have shown that the threat of reducing the reimbursement for Medicare can have several impacts:
Physicians have seen their profits from treating Medicare patients fall to just covering their costs, and in some cases where treatment or required tests are expensive, it would mean treating those patients at a loss.
Some physicians have limited the number of Medicare patients they would be willing to treat and this may increase.
Other physicians stopped taking Medicare patients altogether and referred them to other doctors or clinics able to take them. This too, may also increase, unless the reimbursement system is fixed rather than patched.
Of course, the AMA always threaten these actions annually and thus significant lobbying takes place to pressure lawmakers to provide a solution, yet the system remains flawed and broken. The current Government appears to recognise this, but has been unable to broker a solution and is mired in partisan bickering.
Ultimately, a new plan may emerge in 2010 as part of the ongoing health care reform, but so far, a bipartisan agreement has not been possible to attain. Any proposals being reviewed now may not be the final form that is eventually enacted as law.
The next 10 days may well determine what happens with Medicare reimbursement this year and are likely to have a significant impact on areas such as cardiology and oncology.
If the news from Roche about Avastin failing in a phase III trial for gastric cancer wasn't enough this week, hot on it's heels was another alert today that Novelos Therapeutics just announced (pdf) that their phase III trial with NOV-002 in non-small cell lung cancer (NSCLC) was negative.
NOV-002 is a chemopotentiator and a chemoprotectant that works to try and enhance the effect of chemotherapy. It has been approved for use in Russia for the last decade and the early trial centres were Russian. Many of us were waiting to see what would happen in the larger scale phase III trial expected to be presented at AACR in April. It is only relatively recently that US centres have become involved, so anticipation in the product and company was beginning to build.
However, in a stunning press release, Novelos revealed this morning:
"The primary endpoint of improvement in overall survival was not met in Novelos’ pivotal Phase 3 trial in advanced non-small cell lung cancer (NSCLC) studying its lead product, NOV-002, in combination with first-line chemotherapy."
The trial involved 12 countries and enrolled 903 people with NSCLC. They were randomised to receive either standard chemotherapy (carboplatin plus paclitaxel) or chemotherapy plus NOV-002 with overall survival as the primary endpoint.
This endpoint was not met.
Data in breast cancer is due later this year, but it's probably not something to raise one's hopes about if the lung cancer data is anything to go by.
Promising phase II data does not always translate into positive phase III results in oncology; it's a big minefield fraught with as many failures as there are successes of late.
"At a time when cancer still kills one in four Americans, it is a job that requires as much hubris as heart. To chronicle the trial of the drug known as PLX4032 is to ride a roller coaster of breakthroughs and setbacks at what many oncologists see as a watershed moment in understanding the genetic changes that cause cancer."
The NY Times is running a three-part series on PLX4032, a B-Raf inhibitor being developed for the treatment of malignant melanoma by Plexxikon and Roche/Genentech. Hat tip to my buddy Bill Scully of the HCA Group for sending the link. Today, was the first installment in the series. The article, although a little breathless and hypey for my taste, is well worth reading.
A few years ago, I interviewed the physician, Dr Keith Flaherty involved in the trials at the American Society of Clinical Oncology (ASCO) meeting, after he presented the initial phase I results of the trial. Most interviews usually take about 5-10 mins, because the researcher is busy and rushing between sessions. Dr Flaherty stopped and chatted about the disease, treatments, the new data and it's implications for 40 minutes. His energy and enthusiasm for finding a better treatment for his patients was both palpable and admirable. He reminded me vividly of Dr Brian Druker from OHSU, who I worked with at Novartis (a former employer and a client) on the drug Gleevec in CML.
The reality of phase I cancer trials is that many patients will sadly die and most drugs fail to offer any sign of efficacy or have toxic side effects that prevent pursuing further development. I sincerely hope the Plexxikon/Roche agent actually amounts to something; the companies announced the commencement of phase III trials last month, which is a promising sign.
Every once in a while, something comes along where the science, biology and clinical development totally gel, offering new hope and promise for everyone involved from patients to physicians to Pharma company. That's what you all live for and work countless long hours to make happen.
Last night and this morning brought some topical news on the leukemia front.
Just before 5pm EST yesterday, the FDA announced they had approved Roche/Genentech'srituximab (Rituxan) in chronic lymphocytic leukemia (CLL). Rituxan is already approved for non-Hodgkins Lymphoma (NHL) and rapidly the standard of care when combined with CHOP chemotherapy in this disease. CLL is the most common adult leukemia and tends to affect older patients.
According to the Roche press release this morning, the FDA approval was for:
"Rituximab plus fludarabine and cyclophosphamide (FC) chemotherapy for people with either previously untreated (first-line) or previously treated (relapsed or refractory) CD20-positive chronic lymphocytic leukemia (CLL)."
The CLL data was presented last year at ASH, showing that FCR led to improved survival compared to FC alone. FDA's press release highlighted the results:
"The safety and effectiveness of Rituxan was evaluated in two studies that measured progression-free survival, defined as the time a patient in the study lived without the cancer progressing.
In one study of 817 patients who had not received any prior chemotherapy, progression-free survival was eight months longer for those receiving Rituxan plus chemotherapy than for those who received chemotherapy alone. In another study of 522 persons whose cancer had progressed following other chemotherapy drugs, progression-free survival was five months longer for those who received Rituxan plus chemotherapy.
The FDA analyzed the data on patients 70 years of age and older who had received Rituxan and found no evidence that adding the drug to chemotherapy benefitted elderly patients compared to receiving chemotherapy alone. However, there was also no evidence that Rituxan was harmful to elderly patients."
This approval affects several companies in the CLL space.
Late last year, GSK received approval for their CD20 antibody, ofatumumab (Arzerra) in CLL in the refractory setting but are likely to be impacted by rituximab's approval in both first and second line CLL. My guess would be that physicians will be very comfortable and experienced using the Roche/Genentech monoclonal antibody and therefore using it in CLL as well as NHL will not be a difficult stretch.
Bendamustine (Treanda), from Cephalon, is an old drug that has been making a comeback in NHL and after the success of the bendamustine-rituximab (BR) combination in NHL that was presented at ASH, it may well become the new standard of care there instead of R-CHOP. Trials are ongoing with BR in CLL and if positive, I can see that becoming a solid option in CLL in the not too distant future. For now, FCR looks like being the most efficacious first-line option in CLL, replacing FC. It may not be long before BR offers similar or better efficacy than FCR with fewer side effects. We will have to wait and see.
The other news that was interesting in my inbox is that Novartis (a client), announced that nilotinib (Tasigna) received FDA priority review for newly diagnosed patients with early-stage chronic myeloid leukemia (CML):
"FDA priority review status is granted to therapies that offer major advances in treatment or provide a treatment where no adequate therapy exists. This status accelerates the standard review time from 10 to six months. Tasigna demonstrated that significantly fewer patients progressed to more advanced stages of the disease than the standard of care Glivec® (imatinib)* at 12 months. Tasigna also showed a statistically significant improvement over Glivec in every other measure of efficacy in the trial, including major molecular response (MMR) and complete cytogenetic response (CCyR) at 12 months."
Novartis and BMS were in a race to file for the front-line indication for their second generation tyrosine kinase inhibitors (TKIs) with comparative trials versus the standard of care, imatinib (Gleevec/Glivec). Novartis presented the initial Tasigna results at ASH in December in a late breaking abstract that pointed to earlier and deeper responses with nilotinib compared with imatinib.
BMS didn't presented any data from their randomised registration trial at the meeting, but recently announced at the JP Morgan Healthcare conference last month, that they expected data to be available at ASCO. I'm not sure whether they submitted a regular abstract or a late breaker, but it will be interesting to see what the data looks like and the big question now is when will they be filing Sprycel with the FDA for the front-line indication?
It going to be an interesting few months ahead in leukemia, that's for sure!
It's been a while since I took a look at what's happening in the prostate cancer arena, but it seems a good time after the recent flurry on lung and colorectal cancers, especially as it's Groundhog Day :-).
There are three particular agents that I'm interested in:
I'm going to spend most of this post talking about the first two, as much has been said on Dendreon already.
Dendreon filed their amended BLA on November, and the FDA have given a PDUFA date of 1 May 2010. The data from 512 patients showed an improvement of 4 months survival for Provenge over placebo, meeting the FDA's threshold.
We have, however, no idea how the vaccine would have done compared to standard chemotherapy such as docetaxel plus prednisone, and therein lies the rub. Normally, in oncology trials we compare the standard of care with and without the new agent or compare the standard therapy to a different regimen. Placebo controlled trials have not done well with ODAC and the FDA, as J&J, Vion and Genzyme all learned with placebo controlled trials in elderly AML patients.
Regular readers of Pharma Strategy Blog will know I'm not a big fan of either placebo trials in cancer or vaccines, so we'll wait and see what the FDA decide. My expectation is that it will receive approval this time round having jumped through the extra hoops.
Cougar Biotech and J&J are developing abiraterone in advanced prostate cancer. A phase III trial in asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer began enrolling this month.
It's estimated to complete in April 2014 and the primary endpoint is overall survival, but initial results should be available in April 2011 for progression free survival at 12 months from what I can see, so perhaps there will be some data around ASCO in 2011. Based on that data I can't see a filing much before the 2nd half of 2011 at the very earliest, possibly not until 2014.
Looking at J&J's analyst presentations, I found the following timeline for their pipeline:
Now, many drugs are lumped together in the 2011 timeframe across 3 columns. It isn't clear whether each column represents 2011, 2012 and 2013 or it's a random list of drugs that will be filed in that period. Either way, it's hard to see abiraterone getting accelerated approval so my assumption for now is abiraterone will be filed in 2013, with approval in 2014.
It's not going to be a fast development: Cougar is very inexperienced and J&J are relatively weak and slow in oncology.
The asymptomatic nature of the patients will also complicate things because it's a high risk study that may not show much in the end. If it works, great! That said, I'm not sure how well the results will fare in what looks like a fluffy trial design comparing abiraterone plus prednisone to placebo plus prednisone. Patients are specifically excluded if they have received prior chemotherapy. Well then, why not compare abiraterone to docetaxel, which is the current standard of care in castration-resistant disease, given that this is a front-line trial?
Recently, at the AACR Molecular Targets meeting in Boston, I had the pleasure of listening to a most excellent talk from Dr Charles Sawyers (MSKCC), one of may favourite researchers. He covered a lot of ground on the lessons learned in targeted agents, principally in CML and prostate cancer.
With regards to prostate cancer, he showed a graphic similar to this one (from Medivation):
Clearly, there are a number of opportunities to explore for the development of new drugs for the disease after hormome therapy ceases to work. This is where traditional drug development for chemotherapies typically starts.
What was interesting about Sawyers talk is his discussion about the androgen receptor (AR) and whether or not it is important in castration resistant disease.
Previously, AR was thought to be irrelevant in this situation because it is not expressed in 2 common prostate cancer cell lines, but Sawyers argued cogently that this shows a failure to appreciate the potency of inhibition because AR is restored through PSA production. Several reasons have been evaluated for this, including AR amplification, mutation and alternative pathways among others. AR is also overexpressed in castration resistant xenograph models, and can confer castration resistance.
What followed was an elegant discourse showing that MDV3100 is distinct from bicalutamide, whereby it has a greater affinity, binds AR selectively, without displaying agonism in AR overexpressing cells and has more potent antagonistic activity.
In the end, Sawyers argued that what was important was not AR overexpression per se, but AR amplification because prostate cancer cells with natural AR amplification are more sensitive to AR knockdown than AR single copy prostate cancer. Minor AR knockdown is sufficient to inhibit growth of AR amplified disease. All of this leads us logically to an important question:
Are AR amplified prostate cancers a different (and important) patient subtype?
Clinical trials with MDV3100 have demonstrated that at least half of prostate cancer patients remain AR dependent, suggesting that this is indeed the case. Clearly, if you can keep patients hormone sensitive or at least responding to therapies using different approaches, then the opportunity to delay time to metastasis and late stage disease may well exist with these novel approaches.
Updated Survival Analysis of a Randomized Study of Lapatinib Alone or in Combination with Trastuzumab in Women with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab Therapy.
Background: The synergistic interaction of lapatinib combined with trastuzumab was established in HER2-positive preclinical models, hence providing the rationale to evaluate this combination in a clinical setting. Progression-free survival (PFS) from study EGF104900 revealed the combination of lapatinib plus trastuzumab was superior to lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) that progressed on multiple lines of trastuzumab-based therapy. Preliminary data showed a trend in overall survival (OS) favoring the combination therapy; however, data were not mature. Updated OS analyses are reported.
Methods: Women with HER2-positive MBC progressing on prior trastuzumab-containing regimens were randomized to receive either lapatinib 1500 mg once daily or lapatinib 1000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose). If objective disease progression occurred on or after 4 weeks of lapatinib alone, crossover to the combination arm was permitted. OS was summarized using Kaplan-Meier curves and compared between treatment arms using stratified log-rank tests. Analyses adjusting for baseline prognostic factors and crossover were also performed.
Results: 296 women were randomized (148 per arm). The median number of prior trastuzumab-containing regimens for MBC treatment was 3. Of the women randomized to lapatinib alone, 52% (77/148) crossed over to the combination arm. At data cut-off for updated OS, 218 deaths (74%) had occurred. Median OS following treatment with lapatinib plus trastuzumab was 60.7 weeks compared with 41.4 weeks for lapatinib alone. A significant improvement in OS was demonstrated with combination therapy compared with lapatinib monotherapy (HR: 0.74; 95% CI: 0.57, 0.97; P=.026). The survival benefit was maintained after adjusting for baseline prognostic factors (HR: 0.71; 95% CI: 0.54, 0.93; P=.012). A trend toward a clinically relevant 25% reduction in risk of death (P=.080) was also observed after adjusting for crossover.
Conclusion: A statistically significant OS benefit was observed in women with heavily pretreated, HER2-positive MBC treated with lapatinib in combination with trastuzumab compared with those treated with lapatinib alone. The actual survival benefit of the combination therapy may be underestimated due to the high frequency of crossover.
This data from the Sam Antonio Breast Cancer Symposium last month showed that heavily pre-treated patients including prior trastuzumab (Herceptin) who received a combination of two HER-2 inhibitors, trastuzumab and lapatinib (Tykerb) improved their survival by 4.5 months over lapatinib alone:
The EGF104900 study included 296 women and resulted in an overall survival rate of 56% in patients randomized to lapatinib (1,000mg/day) plus trastuzumab compared to 41% in those assigned to lapatinib (1,500mg/day) alone.
Presently, trastuzumab is approved for first treatment of HER-2 positive breast cancer and lapatinib is given in second line once Herceptin fails. It is interesting that there wasn't a Herceptin only arm, only a lapatinib only arm, but then the patients had previously progressed on trastuzumab therapy.
Previous studies with Herceptin and anthracyclines have shown an increase in cardiotoxicity associated with mainly with doxorubicin. There was no suggestion of a cardiac safety issue with the HER-2 combination therapy in this study.
Lapatinib and trastuzumab target HER-2 through different mechanisms, which may account for the apparent additive effect in combination. Previous preclinical and animal studies have suggested synergistic benefits for the combination, including enhanced apoptosis, anti-proliferative effects and downregulation of survivin.
This is the first study to show a survival improvement for any anti-HER2 agent taken beyond first line therapy. It validates the concept that trastuzumab is an important drug to maintain through disease progression beyond initial therapy in patients who have previously done well on combined chemotherapy and HER-2 regimens before developing disease progression.
"The other travelers came walking down the track And they never went further, no, they never went back Then came the churches then came the schools Then came the lawyers then came the rules"
Dire Straits, Telegraph Road
As a European in the USA over the last ten years it never ceases to amaze me how expensive everything is in healthcare compared to back home. That goes for dentistry too, but that's a whole 'nother story.
What is both interesting and tragically sad is comparing the US with other countries in terms of various healthcare costs and finding it number one in just about every category, it isn't just the drug companies charging higher prices, physician fees, hospital costs etc are also much higher than in other Western nations including Canada and European countries.
a common procedure (childbirth without complications)
a widely used drug (Lipitor)
And found the USA stood out every single time:
They downloaded the data, and plenty other examples, from here (warning PDF file).
Strategically, the data makes you realise that healthcare reform is more than just reducing drug costs and blaming the Pharma and Biotechnology industry, because the hospitals and doctors are also charging premium prices too. The whole economic system is completely out of whack and with the constant upward pressure on wages and costs over the last 10 years, everyone wants a piece of the pie.
The sad thing is that the ones left holding the baby are the patients, because they sure don't get 4 times the value of their European or Canadian counterparts. When you couple the data above with data on the number of uninsured people as noted by the Health Populi blog:
"Between 2007 and 2008, 18% of American women between 18 and 64 years of age were
uninsured. 1 in 10 women in this age group were enrolled in Medicaid."
"In 14 states, at least 1 in 5 women was uninsured."
You can see more key information in the statistics provided in the table below:
The end result is often tragic stories, where people lose their job, their ability to pay for insurance and risk dropping into a very big hole of debt or worse, they sadly die. What kind of decent civilised system can even allow such stories to be imagined, let alone happen?
As the recession bites deeper and more redundancies and layoffs occur, so the situation may well get worse before it gets better. These sort of stories can happen to anyone who has the misfortune to lose a job and get sick.
There has to be a better way and fairer to provide more affordable healthcare for all Americans, otherwise bankruptcy on an unimaginable scale will surely ensue. The European and Canadian systems aren't perfect since they may offer more limited choices, but they do offer healthcare for all and everyone has the right to be treated.
In America, you're on your own and no one really cares unless they get paid. Money talks.
I rarely write about politics on this blog but it goes without saying that I will NOT be voting for Chris Christie for NJ Governor today; his idea of making people pay even more for healthcare such as the cost of mammograms for the early detection of breast cancer was just a ludicrous bridge too far. Where are the fresh ideas and inspiration for getting small, medium and large companies back on track in this State?
As I look around me, it is 3 old school candidates with boring old school ideas that don't work anymore; patronage reigns supreme here, do your time, look after your own. Who really cares about the We The People of the United States or even New Jersey? In a few years, we might get some bright young things with fresh ideas and energy like Newark's Cory Booker or hey, Mayor Bloomberg, if NYC doesn't want you come over the Hudson and shake things up here! NJ desperately needs shaking up and the corruption cleaned out once and for all.
To paraphrase Britain's The Sun newspaper:
Will the last person leaving New Jersey please turn out the light.
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Earlier this year I posted about the interim results in non-small cell lung cancer (NSCLC) for AstraZeneca's Zactima (vandetanib) at the ASCO meeting, as part of a review about VEGF inhibitors. Of the 3 trials available for review, one showed some responses and the other two 'had not yet reached significance'.
Unfortunately, it now seems that the final survival data was indifferent at best and AstraZeneca announced the sudden withdrawal of the marketing applications to the regulatory authorities this morning:
"The decision to withdraw these submissions was based on an updated analysis that demonstrated no overall survival advantage when vandetanib was added to chemotherapy as well as preliminary feedback from regulatory agencies that the current package with progression-free survival (PFS) as the primary endpoint may not be sufficient for approval."
Granted that oncology is a difficult area to develop new drugs, but the woes in this category have made for a sad and sorry 2009 for R&D this year so far.
With 2 months to go, perhaps we might see a stunning winner yet...
This week is going to be a busy one in the Icarus office with several client strategy reports to finish and many Pharma companies reporting 3Q earnings and plans for making year end targets.
Meanwhile, on the Biotech front, Genentech and Amgen are reviewing their letters from the FDA on rituximab in moderate to severe rheumatoid arthritis (RA) who no longer respond to methotrexate (and other DMARDs) and denosumab for the treatment and prevention of postmenopausal osteoporosis, respectively.
Neither letters are a big surprise. The FDA has declined to support the approval of rituximab in rheumatoid arthritis owing to the incidence of a rare, but fatal adverse event, known as progessive multifocal leukeoencephalopathy (PML). According to Genentech:
"PML is a usually fatal brain disease caused by the reactivation of a common virus called the JC virus. Although the incidence of PML in RA patients treated with Rituxan is rare (as of today, three reports out of approximately 100,000 patients), there are no known reliable PML treatments."
Amgen have an entirely different kettle of fish on their hands, however. The FDA were expected to get back to the company this month and last week there were rumours circulating about potential delays in the approval due to the FDA's backlog and other reasons. However, they have indeed sent a complete response letter, requesting further information be provided, including:
"The Complete Response Letter related to the Prolia applications requested several items, including further information on the design of Amgen's previously submitted post-marketing surveillance program. This letter does not require additional pre-marketing clinical trials to complete the review of the treatment indication. The FDA has requested a new clinical program to support approval of Prolia for the prevention of postmenopausal osteoporosis indication.
The FDA has determined that a Risk Evaluation and Mitigation Strategy (REMS) is necessary for Prolia and must include a medication guide, a communication plan, and a timetable for submission of assessments of the REMS. The FDA acknowledged receipt of Amgen's previously submitted proposed REMS materials. The FDA has also requested all updated safety data related to Prolia."
Amgen had clearly anticipated the need for a REMS in pre-submitting some materials, so this application will likely lead to full approval in the near future. Whether the company has the sales muscle to compete in a highly competitive mass market segment with primary care doctors instead of specialists such as medical oncologists is a whole different ball game though.
At the other end of the spectrum, GSK have received approval to market their HPV vaccine for prevention of cervical cancer, Cervarix, a competitor to Merck'sGardasil, which ironically, just received approval for the treatment of genital warts in boys, a new indication in addition to the one already held for the prevention of cervical cancer in girls. The Merck vaccine inhibits several additional HPV types compared to the GSK one, but whether this is significant or not is unclear. Either way, physicians and patients now have a choice and this can only be a good thing, although there will likely not be any difference in the manufacturer's prices of the two vaccines.
{UPDATE:}
Amgen announced that they have also received a complete response letter for the BLA for Prolia in the treatment and prevention of bone loss due to
hormone ablation therapy (HALT) in breast and prostate cancer patients. In a press release, the company stated:
"The Complete Response Letter on the Prolia HALT applications requested
additional information regarding the safety of Prolia in patients with
breast cancer receiving aromatase inhibitor therapy and patients with
prostate cancer receiving androgen deprivation therapy. Specifically,
the FDA has requested results from additional adequate and
well-controlled clinical trials demonstrating that Prolia has no
detrimental effects on either time-to-disease progression or overall
survival."
This second letter requesting data from additional clinical trials will likely significantly delay approval for the cancer indication.
Germ cells are sensitive to genotoxins, and ovarian failure and infertility are major side effects of chemotherapy in young patients with cancer. Here we describe the c-Abl–TAp63 pathway activated by chemotherapeutic DNA-damaging drugs in model human cell lines and in mouse oocytes and its role in cell death. In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters.
For many individuals with cancer, protecting fertility from the damaging effects of radiation and chemotherapy is complicated by factors such as age, marital status, the time they have to delay treatment, even the uncertainty of surviving their disease.
Recent research and access to information about the fertility threats of treatment and the options for fertility preservation have improved significantly.
This can only be a good thing.
While this research is preclinical, it does offer hope for cancer patients because the findings could lead to new ways to protect germ cells from the damaging effects of toxic cancer treatments such as cisplatin, which is commonly used for treating breast and gynaecologic cancers.
The other day I was browsing the pharmacy shelves for anti-inflammatories and debating whether to purchase a branded product or a generic. Of course, the pharmacy own label brand was suitably placed most conveniently at eyeline, whereas the competitors were housed above and the branded products awkwardly placed at the floor level.
There was inevitably difference in the prices and a wide range of formulation choices (soft gel capsules, hard pills, capsules, caplets etc). None were dispersible, which was what I was ideally looking for.
In the time I spent thoroughly investigating the options, 3 or 4 people walked past, paused briefly and grabbed the cheapest (and most lurid) box on display, and marched off with their selection.
Back in the office, I did some research on generics. In the last few years we've all become accustomed to news about pipeline failures in phase III, a dearth of new products coming to market and various market pressures on patents, prices etc.
But what of generics, what's the trend there? I'm particularly interested in this because a number of blockbuster cancer drugs have either just gone off patent (eg sanofi-aventis's Eloxatin) or are about to within the next 12-18 months (Taxotere, Doxil, the aromatase inhibitors etc).
Taking a look at the industry PhRMA site, I found some interesting data in several places about the growth of generics, which you can see consolidated graphically below:
Now, this data only applies to full years already reported, so with a number of blockbusters going off patent, we can expect the share of generics in the market to increase. Is it any wonder that prices of new therapies are rising as the market pressures on profit margins increase?
It's going to be an interesting 18 months ahead as we watch the industry adapt and try to do more with less. Ultimately, those who are smart and creative will more likely to be successful.
The convergence of Pfizer and AB Science in the tyrosine kinase inhibitor market is an interesting conundrum.
The market for tyrosine kinase inhibitors (TKI) is one that I keep an active interest in having worked in new product development and marketing at Novartis Oncology bringing Gleevec to market in CML and GIST.
I was, therefore, fascinated to read that AB Science, a fifty person, privately held company based in Paris, launched the first targeted cancer therapy for dogs in June this year. Masivet (masitinib) is a TKI with approval by the European Medicines Agency (EMEA) for the treatment of non-resectable grade 2 or 3 mast cell tumors (mastocytoma) in dogs. Up to 20 to 25 percent of skin tumors in dogs and cats are mast cell tumors
In clinical trials, Masivet increased the survival time of dogs by 300 days compared to placebo, and after two years the survival rate was 2.5 times that of dogs receiving placebo. The drug also demonstrated increased progression free survival. Masitinib is currently under review by the FDA veterinary division for approval in the U.S..
Animal health is big business and a growing market, particularly in the United States were pet owners are willing to pay for drugs and treatments that will maintain the life of their pets. There are over 130 million dogs and cats in the United States, and 4 out of every ten households own a dog.
It should come as no surprise that major pharmaceutical companies are players in this field. In 2008, Pfizer’s animal health division had $2.89B of revenue compared to $2.41B from human oncology drug sales. In June 2009, AB Science did a pan-European launch of Masivet in Europe, but at the same time Pfizer obtained approval in the U.S. for their TKI, Palladia (toceranib), for same indication i.e. the treatment of mast cell cancer in dogs. AB Science are still waiting on FDA approval for their drug.
Whether AB Science, who have publicly stated that they don’t wish to partner with other pharmaceutical companies, will be successful in the U.S. animal health market when their product is approved by the FDA remains to be seen. In the U.S., Pfizer Animal Health have first mover advantage, started selling product in July and have the infrastructure, sales force and marketing to capture market share. It is hard to see how a small company can compete with an industry behemoth.
At Icarus Consultants, amongst other things, we work with pharmaceutical, biotechnology and healthcare companies on developing market entry strategies into the U.S.. What we see are many examples of business plans that are destined to fail. As John Mullins of London Business School describes in his new book on “Getting to Plan B: Breaking Through to a Better Business Model”, many companies have flawed business plans that are the equivalent of selling Coke to kids in China. It sounds attractive on paper given the market size - "all we need is 1% of such a large market", but without the resources to distribute or market the product or a deep understanding of which segments to target (and how to reach them), it is a fundamentally flawed business plan. The same could be perhaps said for AB Science seeking to compete against Pfizer in selling animal health drugs for dog cancer in the United States.
What makes the convergence between Pfizer and AB Science even more fascinating, is that AB Science are developing masitinib for human use as well. They are currently in phase 3 clinical trials of masitinib in Gastrointestinal Stromal Tumor (GIST) going head to head against Novartis’ Glivec/Gleevec for first line use. Not only is this market already dominated by Novartis, the leading second-line treatment for patients who eventually develop imatinib resistance is Pfizer’s Sutent (sunitinib). Other major pharmaceutical companies that have drugs for this indication include BMS with Sprycel (dasatinib).
It will be interesting to watch what happens to AB Science over the forthcoming months as they go it alone against major Pharma companies with very limited resources.
Will they make a success of it or will they end up going to the dogs?
This blog is published by: Sally Church, PhD of Icarus Consultants, Inc. The contents of this blog are the intellectual property of the author and all rights are reserved. No commercial use, copying or distribution is permitted without the author's express permission.
What we do
Icarus Consultants is a management consulting company focusing on marketing strategy and new product development to the Pharma and Biotech industry. We focus on specialist areas such as oncology, hematology, immunology, respiratory and HIV.
Our particular areas of interest include social media monitoring, key opinion leader research, competitive intelligence and landscape opportunity assessments. We use primary qualitative market research and buzz metrics to support our strategic analyses.
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