“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.
Urothelial carcinoma of the bladder is unique among epithelial carcinomas in its divergent pathways of tumorigenesis. Low-grade papillary tumours rarely become muscle-invasive and they frequently harbour gene mutations that constitutively activate the receptor tyrosine kinase-Ras pathway. By contrast, most high-grade invasive tumours progress to life-threatening metastases and have defects in the p53 and the retinoblastoma protein pathways. Correcting pathway-specific defects represents an attractive strategy for the molecular therapy of urothelial carcinomas.
CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder tumor-initiating cells compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro.
You can find out more here. It's called g-speak and it's a spatial operating environment; all it might take is some imagination and creativity to use in the medical space.
Imagine being at a Pharma exhibit booth and playing with a version that allows HCP's to learn and explore the complex pathways involved in cancer, or any part of the body for how diseases occur and how they can be addressed by therapy?
Imagine being overwhelmed with the possibilities of what you could do with such a tool? My mind boggles with all sorts of ideas. I'm sure you can see many too, for researchers, for physicians, for patients and caregivers…
Sometimes we forget that we're only limited by our imagination and not the technology.
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!
New results from a phase II clinical trial of the prostate cancer drug abiraterone suggest that it may help men with advanced disease who have tried standard treatments.
However, a Cancer Research UK clinician cautioned that there were still questions to be answered from ongoing studies about how best to use the drug.
Abiraterone was discovered in the Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research (ICR) and is taken once a day as four pills.
The latest trial, which was led by the ICR and the Royal Marsden NHS Foundation Trust, is the first to investigate the drug in men with such advanced prostate cancer.
A total of 47 men were recruited for the trial, all of whom had late-stage castration-resistant prostate cancer, which means that their disease was advanced and their tumours were no longer responsive to androgen deprivation therapy. In almost all cases, the men's cancer had spread to their bones.
All of the participants had already received hormone therapy and the chemotherapy drug docetaxel, but were no longer responding to those treatments.
By the end of the study period, researchers found that around three-quarters of men had experienced a drop in levels of prostate specific antigen (PSA), which is often raised in men with prostate cancer and can be used to measure disease activity.
In around half of the men, PSA levels fell by at least 50 per cent, while three-quarters of participants also had a drop in the number of tumour cells circulating in their blood.
Three years after the start of the trial, five of the patients were still taking abiraterone and benefitting from the treatment.
New phase II data on abiraterone was reported this week in the Journal of Clinical Oncology from the researchers at the Royal Marsden.
Standard chemotherapy with docetaxel (Taxotere) improves survival by 2 to 3 months, so if the 6 months seen with abiraterone is repeated in a phase III trial, Johnson and Johnson (J&J) and Cougar could well have an approvable drug on their hands. The other benefit is that the side effect profile is much milder than chemotherapy, which can cause severe myelosuppression in the majority of patients receiving it.
It should be noted that these are advanced patients who have received already several hormonal therapies. The data from this trial will likely provide impetus for larger scale phase III trials, which could be used to seek regulatory approval from the US and EU authorities.
It is, however, obvious that the investigators are unsure yet what role and where abiraterone will eventually be used in the treatment paradigm, but traditional research approaches require that trials investigate advanced disease and then more up the continuum as more data and experience with the treatment is gained.
Of course, there is no guarantee that phase III trials will mirror promising phase II results, especially in the cancer arena, but now, it's nice to report on positive data after a bad run of disappointing trials in oncology of late.
Reid, A., Attard, G., Danila, D., Oommen, N., Olmos, D., Fong, P., Molife, L., Hunt, J., Messiou, C., Parker, C., Dearnaley, D., Swennenhuis, J., Terstappen, L., Lee, G., Kheoh, T., Molina, A., Ryan, C., Small, E., Scher, H., & de Bono, J. (2010). Significant and Sustained Antitumor Activity in Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone Acetate Journal of Clinical Oncology DOI: 10.1200/JCO.2009.24.6819
In December 2009, 86% of the total US online population, or 178 million people, viewed video content, compared to 150 million people in December 2008. Americans also viewed a significantly higher number of videos in 2009 compared to the prior year, due to both increased content consumption and a growing number of video ads being delivered. The average online viewer consumed 187 videos in December 2009, up 95% from 96 videos in December 2008.
The number of videos viewed grew almost 150%, from 14.3 billion to 33.2 billion, while the duration of the average video viewed grew 28%, from 3.2 to 4.1 minutes.
Increasing use of video was something that came up at the ePharma conference the other week, which left me wondering:
"Despite the high volume of video use online, the views of Pharma videos are relatively low. What are patient needs in this space?"
Of course, for health information most people would probably prefer to read rather than watch it, but given the popularity of YouTube as shown in the ComScore Digital Year in Review, perhaps it's more a question of understanding more about what people, in this case, consumers and patients actually want.
At the the moment, the available Pharma videos tend to be rather corporate and bland. What if they were used as an education tool to help explain more about the science, the disease, how treatments work or practical, sensible advice on side effect management or how to use the drug if given as an injection?
Mind you, Pharma still has a ways to go in addressing more basic functions, as my buddy Xavier Petit pointed out very succinctly here.
That sure was a hot alert sitting in my inbox this morning.
In looking carefully at the AstraZeneca ($AZN) press release, it seems that the details are as follows:
Much of the focus in the news is on the RA indication, although AstraZeneca do not have a franchise in this area. All of their inflammation products on the market have been in the respiratory, not immunology, area as far as I can remember, making them an odd choice for a partner. Still, AZ have had a few flops recently (Iressa being a spectacular one in oncology) and with a weak pipeline, they are desperate for some near term success to drive revenues sooner rather than later. The recent announcement that 8,000 jobs will be cut is indicative of much cost cutting is going on.
Previously, we have discussed the Rigel RA data when the initial phase IIb data was disappointing and failed to meet at least one primary endpoint according to Rigel's press release last July. This raised alarm bells in many Pharma licensing departments and significantly raised the risk for fostamatinib in RA.
That said, the data for fostamatinib in chronic lymphocytic leukemia (CLL), are much more promising as discussed post ASCO last year. The agent is a SYK inhibitor and updated results presented by Dr Friedberg et al., at ASH in December confirmed that the data is still holding up.
All of the analyst news seems to be rehashes of the joint press release focusing on RA, which of course, is a much bigger, but higher risk, indication than CLL. In looking at the Rigel pipeline, fostamatinib was the last product seeking a partner:
My assumption is that AstraZeneca will also be taking up the options on all of the indications for R788, including the oncology ones and not just RA from Rigel.
It may well be that in the final analysis, the CLL data will turn out to be more solid than the RA data if the phase II trials are anything to go by, but time will tell. The good thing is that AZ have an oncology franchise, albeit not in hematologic malignancies.
Recently, I've noticed a few hits to this blog from Liquida, so curiousity got the better of me and this lead to research about what it was all about.
Turned out Liquida is a nifty search engine for looking up topics on blogs eg about science, cancer, just about anything you might be interested in:
Google search can be frustrating in that it often returns old posts from several years ago before more recent information unless you use the Options button to specify the date range or a more recent period.
Liquida presents the most recent information in a more user friendly, attractive and graphical fashion than merely pages and pages of links that you see on Google and have no idea what is relevant until you click through.
What I also liked about the site is that it offers the opportunity to insert a widget on your blog based on search terms that you might be interested in, such as Cancer or HIV or Diabetes, for example:
Another useful blog search tool that I find very helpful for finding disease information, especially blogs by patients about their disease or condition is Surchur. It aggregates social information around news, blogs, videos, pictures etc like this:
I used 'Glioblastoma' at random for both searches so that you can see the similarities and differences. Surchur also has nifty social features so you can vote things up or down, if you feel so inclined.
While everyone else is getting buzzed about Buzz, I'm fascinated with new ways to find insights and intelligence from patients about their treatments and how they manage side effects. Finding that on Google these days is like wading through treacle by comparison, even with the distracting sponsored ads turned off in my profile:
A patient guide from 2005? Oh really. Clicking on the item and scrolling to the bottom tells us that it was actually written in 1999. Ouch, so much has happened since then and this is why I'm using Google less and less these days – I want more recent, more relevant and more useful information. While some of the more modern tools aren't perfect, they at least attempt to organise the data in tabs and topics by clickable links to help you sort out the chaff from the wheat.
If you want to search Google for photos, blogs, or videos you have to do a search for each one, making the whole process time consuming and frustrating. Here's what you get from a blog search on Glioblastoma (all of these tests were done within minutes of each other):
As you can see, it's all a bit heavy compared to Liquida and Surchur. Try them out for yourselves on topics that interest you and compare them to Google. If I were a patient or caregiver, I would certainly give the new search tools a try.
What new tools so you recommend for medical information search and why?
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.
Last night and was chilling out and reading Dan Pink's new book about motivation in business, Drive(not an affiliate link), which arrived at my Post Office box yesterday. Excited, I didn't waste anytime digging the car out from the ice pile and dashing off to collect it!
Here's a quick synopsis from a TED talk that the author gave last summer:
Pink looked at research in motivation and realised that things were skewiff, in other words, most companies and businesses try to motivate people extrinsically using money, bonuses, perks etc.
However, scientific research shows that people are more intrinsically motivated than first thought and the carrot and stick approach may actually have a detrimental effect.
Interestingly, Pink found that people have:
"An innate need to direct our own lives, to learn and create new things, and to do better by ourselves and our world."
He went on to summarise this concept as:
Autonomy
Mastery
Purpose
The big question then becomes one of how do you create an environment in which this behaviour can flourish?
Well, you can see it in enlightened places like Google, where managers can have 20% of their time doing projects of their own volition, unrelated to their work. Some of these projects even make to the market, benefitting the company and the employees.
In an ideal Utopia, everyone would work in a results only work environment (ROWE) where people don't have schedules, show up when they like and get the work done when they want to, as long as deadlines are met.
In some ways, this is why I enjoy the life as a management consultant running my own firm so much, precisely because there is more freedom to get things done when I want to. For example, I prefer writing complex reports in the middle of the night in peace and quiet, free from distractions. It becomes almost a Zen-like experience where clarity of thought is much clearer and sharper. The output is much better that way and clients seem very happy. It's hard (but not impossible) to do that while working for a big corporation who expects employees to be in the next day by a certain time.
Of course, one is also free to read, learn and research things that interest you, excused the tyranny of days driven by interminable meetings, but that is another story!
If you haven't read the book, I would highly recommend it. It's very different from his previous book I read, A Whole New Mind, but equally enjoyable. If you have read it, what was your perspective?
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