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.
While reading my pile of mail on Friday, I realised that an interesting paper on Hodgkins Lymphoma (HL) appeared in the current edition of the New England Journal of Medicine (full reference below).
The basics of the paper are that despite advances in HL, including curative radiation in the early stages if the disease, one third of patients with advanced disease and about 15% of those with early disease have a relapse after treatment. 20% of people still die from the disease.
The question is why?
Well, unfortunately, current prognostic models have not been shown to be very accurate and so far, no biomarker has been found to be particularly useful.
The authors set out to use gene-expression profiling obtained from people with HL during diagnostic lymph node biopsy to determine which signatures were correlated with treatment. They confirmed their findings with an independent cohort of 166 patients using standard immunohistochemical analysis.
What they found was fascinating:
A gene signature of of tumour associated macrophages was associated with primary treatment failure.
An increased number of CD68 macrophages correlated with likelihood of relapse after autologous stem cell transplantation.
The adverse prognostic factor (macrophages) outperformed the current International Prognostic Score for disease-specific survival.
The absence of an elevated number of CD68+ cells in patients with limited stage disease defined a sub-group of patients with long-term disease specific survival of 100% with the current therapies.
When I was at school, we learned that macrophages were associated with an immune response to invasion. According to the NEJM Editorial, by DeVita and Costa, this may not be the case:
"Most of the evidence, however, now links the presence of tumor-associated macrophages with a poor prognosis."
In short, the data shows that increased number of tumour associated macrophages was strongly associated with shortened survival in HL and provides a biomarker for prognosis and risk stratification. What does this all mean though, for clinical practice?
DeVita and Costa noted that:
"If at the time of diagnosis we could identify patients who are destined to have a poor response to treatment, most patients could be spared a combination of therapies or radiotherapy with its attendant long-term toxic effects."
This is an important observation alone.
For the future, though, the data suggests some new directions that clinical research could go in, such as an anti-CD68 monoclonal antibody perhaps. There are some that have been identified for rheumatoid arthritis (RA) as the Kunisch paper shows below, but I don't think any are currently in commercial development at the moment.
For the moment, though, I'm left wondering more than there are answers.
Why do people with macrophages do worse, what is the mechanism for this? How can we best target the macrophages or the CD68 cells? If people are screened and are found to have a poorer prognosis and are spared the exposure to chemotherapy or radiation as DeVita and Costa suggest, how should they be treated instead?
Perhaps more research will be galvanised by Steidl et al's findings. Time will tell.
Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, Bast MA, Rosenwald A, Muller-Hermelink HK, Rimsza LM, Campo E, Delabie J, Braziel RM, Cook JR, Tubbs RR, Jaffe ES, Lenz G, Connors JM, Staudt LM, Chan WC, & Gascoyne RD (2010). Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. The New England journal of medicine, 362 (10), 875-85 PMID: 20220182
DeVita, V., & Costa, J. (2010). Toward a Personalized Treatment of Hodgkin's Disease New England Journal of Medicine, 362 (10), 942-943 DOI: 10.1056/NEJMe0912481
Kunisch, E. (2004). Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and PGM1) widely used for immunohistochemistry and flow cytometry Annals of the Rheumatic Diseases, 63 (7), 774-784 DOI: 10.1136/ard.2003.013029
The last 18 months have seen a lot of failed cancer studies in phase III development after early promising phase II results, teaching us that sometimes rushing full steam ahead without fully understanding the issues is not always the smartest strategy.
Let's start with Pfizer's figitumumab, an IGF-1R antibody, which we have previously discussed in non-small cell lung cancer (NSCLC) (here and here). There was one phase II trial at MD Anderson that led to what many of us thought was a rather cavalier, aggressive and hasty phase III program, without really seeking to understand the underlying biology behind the pathway first. Interestingly, other competitors have taken a much slower and more methodical approach to thinking through the various issues and may well come out ahead as a result.
Given the front-line trial produced a negative response, I think many of us were expecting the 2nd line study to eventually go the same way. The endocrine and biochemical interactions happening around IGF-1R will need more careful reflection before the concept has a real chance of working. There are various things happening around cross-talk between receptors, interaction with the insulin receptor and AKT may well turn out to have an important role to play. All in all, manipulating the biochemistry of the pathways needs a little more sophistication than a mere sledgehammer to crush a grape approach.
Pfizer also announced that two phase III trials with sunitinib (Sutent) also failed to meet their primary endpoint. Sutent is approved for the treatment of renal cell cancer and gastrointestinal stromal tumours (GIST) and as an oral VEGF/KIT inhibitor that was originally developed by Sugen before it was snapped up by Pharmacia, I think it has done pretty well. It is unrealistic to expect every drug to work in every indication and there may be differences between how monoclonal antibodies such as bevacizumab (Avastin) work compared to small molecules such as Sutent and Bayer's sorafenib (Nexavar).
Like Pfizer, Bayer recently announced promising phase II results in breast cancer. Given that Pfizer previously announced last year that a Sutent trial in breast cancer was negative (see previous post), I wasn't expecting the two current trials to be positive. Had they done so, it would have been akin to a miracle.
Roche's Avastin has had a string of good results and also a few setbacks. The original program focused on breast cancer rather than colorectal cancer before the trial was negative. To give Genentech credit though, they went back to the drawing board to figure out what worked and where the issues were before eventually having another success in breast cancer much later. This is probably what Pfizer need to do now too, scientific and clinical reflection is sometimes a necessary part of the pain on the journey.
Avastin has been now approved in colorectal, lung, breast, renal and brain cancers, so a setback in prostate cancer, as Genentech announced this morning, is probably not going to matter too much. This is unfortunate because there really aren't that many options for advanced stage patients who have become hormone resistant. All is not completely lost for men with prostate cancer though, as sanofi-aventis (a client) have reported that their next generation taxane, cabazitaxel, increased survival in this population, so hopefully we will see more of the data at this year's ASCO meeting in June.
One thought we should perhaps reflect on. 'Oncogenic addition' is a phrase bandied around quite a bit these days, and for sure, some approaches have been very successful. We need to remember though, that targeting kinases and enzymes is only going to work if the enzyme is actually critical to the survival of the tumour, which will rarely happen in isolation. The way forward is most likely going to need a more sophisticated approach that combines multiple inhibitors in a logical fashion. To achieve that approach though, will require more iterative phase II trials to really determine exactly what is going on.
Pfizer and Roche/Genentech both have smart scientists and clinicians in their organisations, so my feeling is that they will go back to the drawing board and evaluate these trials and the data very carefully. You can't have a home run every time, but you can sometimes figure out ways to see if an agent can be made to work by tweaking things. Often, we're limited by our knowledge of the biology and sometimes negative trials can actually help us understand things better.
While listening to last week's presentation by BMS on their pipeline, one slide in particular caught my attention:
Source: BMS
Now, it wasn't the fact that BMS were second in their table of Total Shareholder Return (TSR) that was interesting to me, but that Abbott were first, and by a long way, according to the chart above. Of course, shareholder return is only one measure of performance and says nothing at all about putting customers and patients first, but that is another story/blog.
Recently, Abbott has been in the news with the acquisition of Solvay, a generics company, which added $3B to their revenues and last night it was announced that the company are also acquiringFacet Biotech, which was being pursued by Biogen Idec. The Biogen deal clearly fell apart after the company declined to raise their offer beyond $17.50/share. Abbott offered $27/share and thus a white knight was found. Interestingly, the Facet CEO, Faheem Hasnain, is a former employee of Biogen Idec.
The acquisition is a hot one, so to speak, and many of us in the industry have been speculating in vain on who the partner might be, so you would think that going on CNBC's Pharma's Market with Mike Huckman would be a nice coup for a small company. I thought it was odd though, to see that they seem a little publicity shy, as this tweet shows the company's rather gauche immaturity:
What do Abbott get from acquiring Facet?
Well, first we need to think about where Abbott is coming from. Most companies with either build on existing platforms and franchises or add new products in areas where they want to expand. Abbott is probably best known for it's immunology franchise, with adalimumab (Humira), its TNF inhibitor for rheumatoid arthritis and psoriasis.
Several companies, including Abbott and BMS, have embarked on a race to develop the next generation of Hepatitic C drugs and vaccines. Infectious diseases are not something that are going away fast, so this is seen as an attractive market segment by many.
Looking at the Facet acquisition, the pipeline is thus interesting because they have also been developing monoclonal antibodies but in different diseases including immunology and cancer. The lead compound is daclizumab, which is in phase II development for multiple sclerosis in partnership with... Biogen Idec. Facet own the exclusive rights to the asthma indication though.
There are also several anticancer antibodies such as volocizumab (solid tumours) and elotuzumab (multiple myeloma) in Facet's R&D. Oncology is an area where Abbott has been relatively weak, although they have some interesting compounds in development for liquid and solid malignancies. In 2009, a joint venture with TAP was concluded, adding Lupron, one of the best selling drugs for hormone-sensitive prostate cancer to the portfolio of currently marketed products.
Abbott may well see topline growth from it's cancer franchise in the future... if the pipeline products from their own labs or Facet's deliver. If those from Facet fail, Biogen Idec will be breathing a sigh of relief that their offer was turned down.
"Astellas announced Monday that it has made an unsolicited offer to acquire all outstanding shares of OSI Pharmaceuticals in a deal worth $3.5 billion. The Japanese company's CEO Masafumi Nogimori said that the "offer follows attempts over the past 13 months to engage OSI in meaningful discussions," adding that "as recently as February 12" OSI rejected an offer from Astellas, saying it "very significantly undervalues" the company."
Whoa! Interesting news to start the month of March in Pharmaland.
On Astellas' website, the press release further stated that:
"The all-cash offer, set forth in Astellas’ letter to OSI delivered this morning, represents a significant premium of over 40% on the closing price of OSI’s common stock of $37.02 per share on February 26, 2010, a 53% premium to its three-month average of $34.01 per share, and a 31% premium to its 52-week high of $39.66 per share. Astellas’ offer is not subject to any financing conditions."
My guess is that the bid will be turned down again and a higher bid will need to be made.
Astellas is clearly keen to expand beyond their urology and immunology focus and build its oncology franchise. It has already completed a deal with Medivation to develop MDV3100 in prostate cancer, so OSI's Tarceva (erlotinib) franchise and an interesting small molecule pipeline, including an IGF-1R inhibitor would be attractive to Astellas. Roche license erlotinib from OSI, which will make the bid all the more fascinating - how will Roche/Genentech and OSI react to the hostile bid?
Beyond an improved offer, who knows what will happen. There are no guarantees, as the previous offer for CV Therapeutics fell through. It could get very interesting in the next few weeks and no doubt a lot of Pharma business development and licensing people are watching the situation closely to see what happens!
We spend a lot of time researching biotechs in the oncology space and thus it occurred to me that many of them are located around the San Francisco bay area as a hub, in a landscape dominated by Genentech, now part of the Roche empire. San Francisco has good logistic connections, a lot of roomy office space, active research in several universities and provides a pleasant haven for science, academia, research and industry to all flourish.
There are far to many to mention in one blog post, but here is a quick update on some of the companies we've been following over the last couple of years in the cancer market (in no particular order):
Sunesis ($SNSS): Got off to a rocky start with the early development of voreloxin, but have refocused the clinical trial designs with some interesting phase I and II results to date in AML. The compound, a quinolone derivative that acts as DNA damaging agent, is also being developed in platinum resistant ovarian cancer. I'd like to see some comparative data in AML at some point, or at least a study with just a standard chemo in it compared to the standard + voreloxin, otherwise it will be hard to see exactly what the agent actually adds.
Poniard ($PARD): Poniard are developing a new generation platinum agent, picoplatin, that seeks to offer equivalent efficacy as existing platinums, but with less neuropathy that is common to existing treatments such as oxaliplatin.
Picoplatin got off to a good start with trials starting in small-call lung cancer (SCLC) and colorectal cancer (CRC). Early results looked promising. However, results from the pivotal Phase 3 SPEAR (Study of Picoplatin Efficacy After Relapse) trial of in the second-line treatment of SCLC did not meet its primary endpoint of overall survival. The analysis, based on 320 evaluable events (patient deaths), showed a hazard ratio of 0.82 with a p value of 0.089. The company felt that the main reason for the discrepancy lay in pateints in the placebo arm receiving more chemotherapy than the picoplatin arm after relapse occurred.
A randomised, controlled Phase 2 trial of picoplatin in metastatic CRC patients is ongoing. The study recently met its primary objective. Picoplatin, in combination with 5-fluorouracil and leucovorin (FOLPI regimen), was associated with a statistically significant reduction in neurotoxicity (p <0.004) compared to oxaliplatin given in combination with 5-fluorouracil and leucovorin (FOLFOX regimen). The results also suggested that FOLPI had similar efficacy to FOLFOX. More data is expected at ASCO in June.
Nodality: Is an interesting technology company that is developing next generation diagnostics by characterising cell signalling pathways. The concept is based upon proprietary flow cytometry technology, originally developed in the laboratory of Professor Garry Nolan and licensed from Stanford University.
Flow cytometry has been widely used to characterise cell surface markers on hematologic cells. Nodality are now utilising advanced quantitative flow cytometry to define the signalling networks within individual cancer cells, in order to enable biologically-driven clinical decision making for cancer treatment. Essentially, this technology can be used to determine changes before and after cancer treatment, eventually leading to the identification of appropriate biomarkers for treatments.
BiPar Sciences: Are developing BSI-201, a PARP inhibitor for the treatment of triple negative breast cancer and ovarian cancer. They signed a deal with sanofi-aventis last year and are now a wholly owned subsidiary. It looks to be a promising agent, albeit with a short patent life. The race to market against KuDos/AstraZeneca will be an interesting one to watch over the next couple of years. How will the two PARP inhibitors stack up? Time will tell. They also have a follow on PARP inhibitor (BSI-401) in development, and an anti-tubulin compound.
Exelixis ($EXEL): Have been in the news frequently over the last few years as they license out their in-house compounds to companies such as BMS, GSK, sanofi-aventis and Genentech. Their stated goal is to develop first in class or best in class compounds through their own discovery and clinical programs. The pipeline runs an interesting gamut of targeted agents to various pathways, including MET, VEGF, PI3-kinase, IGF-1R, MEK, RAF and others.
The most advanced agent (XL184) is in phase III development for metastatic medullary thyroid cancer (MTC) with BMS (aka BMS-907351). This is a very slow growing cancer, so a rapid development is unlikely. The compound is a multi-kinase inhibitor of VEGFR, MET and RET. It is also being tested in phase I/II trials for recurrent glioblastoma (GBM), non-small cell lung cancer (NSCLC) in combination with erlotinib and a phase I trial in advanced malignancies is also ongoing.
BMS probably have the biggest investment in Exelixis, having licensed at least 5 of their compounds in cancer. Time will tell if this proves to be a smart decision or not.
Plexxikon: Are a private Berkeley based company who focus on the discovery and development of small molecules in several therapeutic areas including cardio-renal disease, CNS, inflammation, metabolic disease and oncology. They are most known for their BRAF inhibitor, PLX4032, which is being developed for the treatment of malignant melanoma. BRAF is thought to be mutated in approximately half of melanomas and may be one of the drivers of the disease.
Plexxikon signed a deal to develop the agent with Genentech, now Roche, and phase III trials in melanoma were announced last month. This is definitely a promising agent to watch out for.
Facet Biotech ($FACT): have been in the news recently after Biogen Idec tried to purchase the company, but offers have been repeatedly rebuffed and dismissed as inadequate. The company was launched as a spin-off from PDL BioPharma, Inc in December 2008.
Facet are developing several compounds in the multiple sclerosis and cancer markets, including volociximab (solid tumours) and elotuzumab (myeloma). The MS agent in phase II, daclizumab, has received most attention but the oncologic agents are too immature to determine how effective they might be yet. Definitely one to watch out for though, if a white knight in the form of a big pharma with cash descends in the near future. The most obvious companies with cash and a declared growth by acquisition strategy are BMS and Celgene, but I'm not sure Facet would be a good fit for either. On paper, Biogen Idec was probably a better option.
There are plenty of other interesting cancer companies in the Bay Area, but these are a few that I've been watching. More will be covered in the next update of the cancer market in the area. New data will no doubt be presented at the forthcoming American Society of Clinical Oncology (ASCO) meeting in June.
Recently, I noticed that oncology companies are in the news for raising new financing or even announcing IPO's, and wondered if that was an anomaly after the credit shutdown following the Wall St crisis. In general, my perception was that they seemed to be down overall. To find out more, I checked out the VC funding statistics at OnBioVC:
Surprisingly, oncology dominates the market at the moment, with the latest data being available from 3Q09: nearly one-third were from oncology alone during that period. According to the report, they represented:
"... a diverse therapeutic approach; from small molecules targeting the inhibition of receptor tyrosine kinase to HDAC to metallo-enzymes to PI3K and mTOR, as well as a variety of mAb’s and therapeutic vaccines."
In more terms, though, the aggregated dollars raised per sector is significantly down over the same period in 2008:
But overall, the total number of financings for Biotech are up, thanks to a strong growth in the medical device sector, although the biopharma sector is down slightly:
Last October, Auxilium received proceeds, net of offering expenses and underwriting discounts and commissions, of approximately $115.7 million. The company closed its previously announced public offering of 3,000,000 shares of common stock at a price of $34.50 per share.
Meanwhile, last week was a busy one.
Firstly, Ironwood raised $188M from their IPO in one of the biggest deals of the decade (more than Eyetech's $150M in 2004) by selling over 16M of shares at a price of $11.25. It was, however, perceived to be a discount price, because their SEC filings in November hoped for a higher target of $14-16/share. As a friend commented last week, "Well, $188M isn't chump change!"
Secondly, Reuters reported that the private French Biotech company, AB Science,
"is preparing for a 50 million euro ($70 million) initial public offering next month in a move that could make it France's first biotech stock exchange listing since mid-2008."
What's interesting about AB Science is that the company have yet to officially announce or confirm the date of the IPO, although they made clear their intent to pursue one in 1Q10 when we interviewed Alain Moussy, the CEO, in October.
The company has an interesting KIT inhibitor on the market in Europe, masitinib, for mastocytosis in dogs and is now developing the drug in pancreatic cancer for humans. In order to fund the phase III trials, more financing is needed so the IPO is clearly a sign that the company is going places.
This week heralds the annual BIO CEO meeting in New York, where there will doubt be a lot of interesting discussions and presentations going on. The schedule is packed with a quite a few oncology focused companies, so more news will be covered on this blog later this week as details emerge. Sadly, I will miss the event, as I'll be at the ePharma meeting in Philadelphia. More on that tomorrow!
This snippet from Reuters posted earlier this week while I was listening to the Roche earnings call in Basle, which was a nicely put together presentation:
"Roche Holding AG overhauled the sales efforts for its best-selling drug, the Avastin cancer treatment, after the company “lost steam” during the fourth quarter.
Sales of the medicine were hurt by a focus on selling it as a treatment for breast tumors, Pascal Soriot, the head of the pharmaceuticals division, said in an interview today. The company beefed up marketing by assigning the sales team responsible for the Herceptin breast cancer drug to also promote Avastin, while the group that sells the Xeloda therapy will promote it for use against colorectal cancer, he said.
“We focused on breast and then kind of lost steam on lung cancer a little bit,” Soriot said at Roche headquarters in Basel, Switzerland. “We’ll increase the promotional effort and I think we’re going to turn this around.”"
Sadly, though, this is not something that was unexpected, as many of us industry observers were secretly wondering how Genentech would fare once absorbed in the more conservative Roche system. One is very science based and the other is more corporate.
Just take a look at the two management teams and you get the big picture:
In the top picture, you see the Roche management team individually taken and in suits, but look like they have taken their ties off just for the photoshoot to make them a little less stiff and formal, perhaps.
In the bottom picture, the Genentech management team, taken as a team in fairly casual attire, with the CEO, Ian Clark, even wearing a fleece!
A tale of two very different cultures in one quick glance.
What impact does this have on the physicians? I asked around. Now, lung cancer doctors are fairly academic and science based, many also do translational research, for example. Underneath they are generally approachable, fun and always willing to answer questions or help people understand a complex topic. They're much more easy going than some of the other cancer specialties.
Which group do you think they would most likely mix with?
Therein lies the rub.
Corporate suits may look sharp, but do they engage and have fun with the scientists, or even understand their world? How much of a subtle impact might that have in the long run? While it is true that in the end, all marketing is ultimately about sales, the intangibles such as how you approach it and engage with customers along the way is often crucial to success.
Time to stop drinking the corporate Kool Aid and focus on the science, methinks.
As part of a four part series on personalized therapy for lung cancer, here is the second summary in the series based on some fascinating lectures at the AACR meeting on the molecular origins in lung cancer this week.
The second presentation I really enjoyed on biomarkers and personalized therapy looked at the ‘blind alley’ that
many are still using to distinguish patients. Histology, as Dr David Gandara aptly
described it, is a rather ‘crude form of molecular selection’ that is likely to
be a transient one. He provided a
telling example of two patients with a different case history:
65 yo
male who smokes, has a squamous histology, KRAS mutation, low ERCC1 and low
RRM1
39 yo
female who is a non-smoker with a adenocarcinoma, EGFR mutation and high ERCC1
and high RRM1
He then posed the question to the audience of whether it is still
appropriate to treat these two patients the same way?
What was abundantly clear at this meeting to me is that the
answer would be an emphatic ‘no’ based, not on their physical characteristics
and histology, but on the underlying biology. Whether that is a view held by the majority of community
oncologists, I’m not so sure though.
Excision repair cross-complementing gene (ERCC1) is an interesting biomarker that was first mooted nearly ten years ago and has received little attention, but is now coming back to the fore as clinical trials and modeling techniques catch up with basic biology. It encodes a nucleotide excision repair protein that repairs a range of lesions, including UV-induced thymine dimers and other photoproducts, and also lesions caused by a variety of chemical agents including the platinums.
Dr Gandara noted that low
levels are prognostic in early stage I/II NSCLC and predictive of a
poor response in metastatic disease, thus suggesting that platinum chemotherapy
would be optimal, e.g using a gemcitabine-cisplatin combination, whereas early
stage patients with high levels of ERCC1 would have a good prognosis and likely
do better without chemotherapy. ERCC1 has also been shown to play a role in DNA repair after cisplatin damage. Interestingly, high tumour tissue levels of ERCC1 mRNA in ovarian and gastric cancer patients have been associated with cisplatin resistance.
Similarly, RRM1 is useful for predicting response to
gemcitabine and TS for pemetrexed. Although pemetrexed is approved for use in treating non-squamous
patients, what about TS expression in lung cancer? Gandara noted the general trend towards high TS in SCLC and
squamous cell carcinoma and low TS in patients with adenocarcinoma. Knowing this kind of information about
the tumour biology (ERCC1, RRM1
and TS) can therefore be potentially useful in deciding which chemotherapy
regimen to use.
What this AACR meeting really brought to the fore to me is
the gradual move from rather crude methods to more sophisticated ways of
defining patient subsets as our knowledge and understanding of biology
improves.
Sometimes though, the
gap between published research and clinical trials also lags, mainly because of
either the cost of tumour biopsy and biomarker studies in large scale trials or
the development of new inhibitors designed to target the molecular abnormality
identified. The impression I came
away with is that the next five years may well produce some really big advances in
both basic science and clinical practices that will contribute to a more logical and scientific approach to the treatment of a hard to treat cancer.
Times are a-changin’ and that’s great news for patients with
lung cancer.
Dabholkar, M., Vionnet, J., Bostick-Bruton, F., Yu, J., & Reed, E. (1994). Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. Journal of Clinical Investigation, 94 (2), 703-708 DOI: 10.1172/JCI117388
Cobo, M., Isla, D., Massuti, B., Montes, A., Sanchez, J., Provencio, M., Vinolas, N., Paz-Ares, L., Lopez-Vivanco, G., Munoz, M., Felip, E., Alberola, V., Camps, C., Domine, M., Sanchez, J., Sanchez-Ronco, M., Danenberg, K., Taron, M., Gandara, D., & Rosell, R. (2007). Customizing Cisplatin Based on Quantitative Excision Repair Cross-Complementing 1 mRNA Expression: A Phase III Trial in Non-Small-Cell Lung Cancer Journal of Clinical Oncology, 25 (19), 2747-2754 DOI: 10.1200/JCO.2006.09.7915
I'm planning on posting some highlights and insights daily by the end of the evening or first thing the next morning at the very latest. Some tweets of key points may also appear from Tuesday morning PST - you can follow them on Twitter using the #AACR hashtag, if so inclined. AACR also has an official Twitter account (@AACR).
Some of the topics I'm particularly interested include microRNA profiling for resistance in small cell lung cancer (SCLC), a session on insulin-like growth factor receptor (IGF-1R) signalling, updates on an ALK inhibitor, gefitinib (Iressa) and other sessions.
Acute myeloid leukemia (AML) is a truly nasty disease and one I hope never to have the misfortune to be diagnosed with.
Last month, at the Chemotherapy Foundation in New York, Dr Norman Wolmark gave an entertaining lecture on what he called the "Decade of Discontent" in colorectal cancer, a bleak period where no new therapies or stunning ideas emerged and the researchers bogged themselves in answering minutiae rather than focusing on the bigger picture.
He could well have been describing AML.
Why?
Take a look at this slide that was shown at the AML Super Friday educational symposium (the reference is from Dohner et al., (2009), published in Blood and how complex the disease has become with a myriad of phenotypes being described:
But this approach begs a most important question:
Which of these mutations or phenotypes are actually relevant and what is driving the cancer's survival and ability to outwit treatment?
No one really knows and thus it illustrates the frustration inherent in making a nasty disease ever more complex. Just because a mutation exists or a pathway is overexpressed does not mean that it is critical to the survival of the leukemia cells! Sometimes the mutations occur as artifacts, a function of a generally increasing leukemic burden over time as the disease gets more established.
Undoubtedly, the 14% of AML patients who have no additional mutation beyond the t(9,11) translocation that defines the disease, probably do best and at least attain a complete response (CR). The issue of how to keep them there, thus preventing relapse from occurring is an entirely different matter. We need more smart young researchers like Dr Gail Roboz in New York who asked the Chemotherapy Foundation audience what can be done to keep more AML patients in remission?
In ALL, which is more common in children than adults, there are well accepted maintenance therapy strategies for maintaining remission. In AML, post transplant or chemotherapy, there are none. Why it is not clear, but certainly something that can be easily tested with the plethora of targeted agents we have available on the market or in the clinic.
At the American Society of Hematology meeting in New Orleans this week, we attended a number of education and oral sessions discussing AML and read many posters on the topic too. What was startling was how little real progress has been made over the last five years... there were numerous versions of induction and conditioning regimens associated with stem cell transplantation, a general agreement that using the current targeted agents in late stage relapsed or refractory disease is doomed to failure because the leukemic burden is too high...
Dr Wolmark's 'decade of discontent' comment rang loudly in my ears while walking around a huge cold hangar on Monday reading poster after poster with little positive news to inspire or encourage. Skipping to the CML, CLL or NHL poster sections brought cheer and hope by comparison.
Part of the problem with AML is that many of the patients are diagnosed in the elderly, thereby limiting options either because the regimens are highly toxic and less well tolerated, transplant is not an option (survival decreases in the over 55 yo) or they have co-morbidities and multiple mutations, reducing the effectiveness of therapy.
There is, therefore, a clear need for alternative approaches in this population as well as better therapies for the very young who at least have a chance of cure by preventing relapse.
At ASH, some abstracts did catch my eye. Genzyme's clofarabine (Clolar) is one such interesting drug, currently approved for acute lymphocytic leukemia (ALL) and being tested in elderly AML patients. FDA's ODAC recently declined to approve clofarabine in elderly AML patients in the relapsed/refractory setting because the trial was compared to placebo. The same thing happened with Vion's laromustine (Onrigin) in the elderly AML setting. We will probably have to wait until the comparative trial data is available for clofarabine in 2010 before any major decision can be made as to the drug's safety and efficacy in the elderly population. There were no new abstracts on laromustine at this ASH meeting.
Meanwhile, some other interesting companies with early phase I/II data in AML included Sunesis and Cyclacel, both of which have seen their stock price rise since ASH on publication of the data.
Sunesis are developing voreloxin, a chemotherapy given as an infusion and used either alone or in conbination with cytarabine (araC) in heavily pre-treated AML. In the combination study (#645), the researchers found that:
"Among evaluable first relapse (n=36) and primary refractory patients (n=28), preliminary median overall survival is 7.8 months and the remission rate is 31% (complete remission [CR] 27%, complete remission without full platelet recovery [CRp] 2% and complete remission with incomplete recovery [CRi] 2%).
Historical median overall survival data in primary refractory and first relapse patients on currently available chemotherapies range from Voreloxin in combination with either bolus or continuous infusion cytarabine was generally well-tolerated. Infection-related toxicities were the most common Grade 3 or higher non-hematologic adverse events. In addition, Grade 3 or higher oral mucositis was observed."
A poster (#1037) was also presented on voreloxin in elderly AML, and while the data looks interesting initially, I would have major concerns about the registerability of the data given that it is a single arm study of the sort that the FDA and ODAC has repeatedly baulked at:
"Median survival was 8.7 months in Schedule A; 5.8 months in Schedule B; and 7.3 months (preliminary) in Schedule C (72 mg/m2 on days one and four).
Median duration of remission was 10.7 months and one year survival was 38% for Schedule A. For the other schedules, median duration of remission has not been reached and one year survival is too early to evaluate.
Patients age 75 or older (N=49) with at least 1 additional risk factor at diagnosis, a population identified by the National Comprehensive Cancer Network (2010) AML Guidelines as having poor outcome to standard treatment,experienced a CR rate of 30% and a 30-day all-cause mortality of 5%.
Survival in these patients was too early to evaluate.
Based on trial results, Schedule C has been determined to be the recommended pivotal dose regimen. For Schedule C, response rates (CR and CRp) are 38%; 30- and 60-day all-cause mortality are 7% and 17% with improved tolerability over Schedule A."
Cyclacel is a NJ biotech developing an oral prodrug for AML, MDS and CTCL called sapacitabine, a nucleoside agent that targets DNA synthesis and cell cycle arrest. Several phase II studies were presented at ASH, including interesting data on long term follow up in elderly AML patients from an MD Anderson study (#1061) and another in MDS (#1758).
It should be noted that while the one-year follow up data looks promising in AML, the study design suffers from the same issue as tipifarnib, clofarabine, laromustine, and voreloxin in that there is no comparator arm from which to compare and determine if the investigational agent is actually significantly prolonging life in AML.
Overall, it was a disappointing meeting in AML and I sincerely hope that some mre enlightening data emerges in 2010 rather than face the dreaded precipice that Wolmark so pithily described.
Pharma Strategy Blog has reached an exciting double milestone today - 500 posts and 100,000 views! Although the blog was started in 2006, most of the posts have been written over the last 18 months on a wide variety of topics from AIDS/HIV to cancer to rare stromal tumours, as well as notes from numerous conferences and observations on diseases, the Pharma industry, mergers & acquisition, industry leaders and even political reform of health care. We hope you have all enjoyed the ride and will continue to do so in 2010. Do keep your suggestions for interesting topics to cover coming in, we're only as good as the readers who share in the experience.
Right now, I'm in New Orleans covering the American Society of hematology meeting, which is one of my favourite annual meetings, and one I've regularly attended for the last 14 years. Just before I headed south I interviewed Dr Mary Ann Burg about the recent survey undertaken by the Association of Social Work (ASOW). The organisation released an important report late last week, describing the financial and emotional impact of the cost of cancer care on patients, caregivers and how social workers can help facilitate and ease the process as part of a multi-factorial team.
What particularly struck me forcefully in the brief discussion with Dr Burg is summarised in this chart below:
The excellent AOSW report also focused on multiple myeloma as an example of what happens to cancer patients going through treatment and how the costs of prescription drugs can have an impact. For example:
This data reminded me very clearly how much more expensive Celgene's Revlimid is compared to Millennium's Velcade (around a third to twice the cost). Myeloma is a big focus at this ASH, as you will see in other posts this week around the new exciting data coming out in lymphomas, leukemias and myeloma.
The report was also poignant given that the WSJ reported this morning that Allos Therapeutics were launching pralatrexate (Folotyn) in PTCL, a rare form of NHL, at a cost of $30,000 per month. To me, that's unconscionable, especially as the drug has only be seen to shrink tumours and not impact overall survival. We'll see how they fare, but I think I would rather die with my dignity intact than face the sort of extreme stress and financial worries described in the excellent ASOW report than even the co-pay would require. It does beg the question of:
What price a life?
What were they thinking?
Part of being a sensible corporate citizen in the pharma industry is recognising that we all have a duty to be fair minded, responsible and caring; greed in it's extreme form at the expense of patients well being is just nauseous and reprehensible.
Here's a rare call for action.
Please read the AOSW information here and digest the full impact of their findings for yourself. This affects all of us, as industry professionals, friends, caregivers, maybe even as a patient. Share it with others, if you blog or Tweet, write something about the report yourself or share this post or the ASOW link.
More on the ASH meeting and more about the AOSW will continue in other posts later this week.
After the recent furore over the breast cancer guidelines, I've been ignoring the hype and hysteria in the news and quietly waiting for some thoughtful commentary from some breast cancer experts I respect.
This morning I got my wish with an email alert from the New England Journal of Medicine. In it, two well respected breast cancer physicians from rhe Dana Farber Cancer Insitute have summarised their views in an editorial. You can read the whole commentary for free here:
One point in particular struck me. The guidelines apply to those who are low risk, implying those women who are high risk (family history of breast or ovarian cancer, BRCA1 or BRCA2 positive etc), should still continue as before.
Their sensible and well thought out article is worth reading carefully and sharing with others.
A lot of people gave asked me what I'm going to do or would advise as one of those forty something women.
Well, I have a baseline and have been adjudged to be high risk so providing my insurance carrier is agreeable, I'll be continuing with annual mammograms at NY Weill Cornell imaging center. This last point is important. My own experience of mammograms in suburbia was less than satisfactory and I would absolutely advocate going to get any tests at a cancer center where they have the latest technology and the best teschnicians, radiographers and pathologists. It does make a difference, possibly even between an accurate result and a false positive or negative.
Once you reach 40, politely insist on a baseline at your annual physical and get tested for BRCA1 and 2, after all that distinct aunt wasn't aware in time and you don't want to make the same mistake. These mutations drive aggressive breast and ovarian cancers. The most important thing is to get a baseline done, that gives you a comparion from which any changes can be detected early.
Check out the article and let me know what you think in the comments below.
This week I've been reading a fascinating book about Michael Oher's journey to the NFL. The title?
The Blind Side.
And then I had a thought. That's exactly what the cancer cell aims to protect it's blind side from assault.
New developments in cancer (and peobably other therapy) treatments will come when scientists think strategically about attacking the vulnerabilities that either negate that protection or find new create ways to kill the menace.
Chemotherapy was used as blunt tool in the same way Lawrence Taylor was a one man sacking machine for the Giants. As offences evolved, smart defensive teams switched from a 4-3 to a 3-4 and had large, agile and athletic ends rush the passer. Strategy in football is constantly evolving on offence and defence.
What do we need now?
Maybe some creative and subtle gadget plays, such as nanotechnology approaches mentioned in the post on pancreatic cancer.
Or perhaps just thinking strategically out of the box as Gail Roboz did when she asked at the Chemotherapy Foundation, "why can't we keep more people in remission?"
There are many other interesting examples evolving and being tested in company pipelines right now, as the Novartis-Incyte deal shows.
I'll be interested in reporting what new at ASH next week: watch this space for more details!
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.
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