“After Terence died, Flaherty drew me a picture of a bell curve, showing the range of survival times for kidney cancer sufferers. Terence was way off in the tail on the right-hand side, an indication he had indeed beaten the odds. An explosion of research had made it possible to extend lives for years — enough to keep our quest from having been total madness.
Terence used to tell a story, almost certainly apocryphal, about his Uncle Bob. Climbing aboard a landing craft before the invasion of Normandy, so the story went, Bob’s sergeant told the men that by the end of the day, nine out of 10 would be dead. Said Bob, on hearing that news: “Each one of us looked around and felt so sorry for those other nine poor sonsabitches.”
For me, it was about pushing the bell curve. Knowing that if there was something to be done, we couldn’t not do it. Believing beyond logic that we were going to escape the fate of those other poor sonsabitches.
It is very hard to put a price on that kind of hope.”
If you don’t do anything else today, please take a few minutes to read the link above about a caregiver’s experience with her husband’s kidney cancer. It describes the hopes, the fears, the process of what people really do go through with end of life cancer.
A powerful story.
One sadly, many people go through, but when is enough, enough? With the current debate raging around healthcare reform, this very human story gives us insight into what people actually go through, not just the treatments and side effect management, but also the billings, the paperwork, the quest for a cure. It makes one realise that any of us could have been there.
For all the pontification by the politicians on both sides of the House, I wish some of them would come to their senses and start thinking about what matters in healthcare reform. Their constituents are people, after all. If they don’t do what we think is fair and reasonable, we can always vote them out until they learn to get it right. There really should be an Amendment that says Congress cannot have a healthcare plan that is not available to everyone else. Only then will the deal get done properly.
Kudos: Thanks to my buddy, Bill Scully of the HCA Group, for sharing the article with me.
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A chance email yesterday from Matthew Herper of Forbes Health got me thinking. He was interested in whether a company, who have been successful in other therapeutic areas, could do well in cancer.
A question like that can quietly sit in the back of your mind for days percolating and brewing until you sit down and really think about it.
I've had some great opportunities to work in several different therapy areas including cardiovascular, dermatology, immunology, CNS, hematology and oncology. The last two have much in common, the others less so. But what makes them different, what factors are important to take into consideration and how do make it work?
Two of the big differences are data and science.
Cancer is much more technically complex than many diseases and the understanding of how the biochemistry and the drug interact can make or break a product. One of the first oncologists I ever met, a dour academic chap who did a lot of leukemia transplants and research in equal measure, memorably advised me in a most stern manner to "forget the fluff and puff, just show me the data!"
Cardiologists and dermatologists always seemed to ask 'how' questions… how much does this cost, how soon will you have slides for a lecture series, how many papers do you have published so far etc.
Oncologists are a different breed. They ask a lot of why and where questions… why should I use this drug, where is the evidence to show X or Y etc.
For me, it's about learning a completely different mindset and adjusting to a new customer focus. If your drug isn't better than what an oncologist has already, especially in efficacy, no amount of hype is going to give you a hook or an advantage. Risk-benefit trade-offs in a serious disease that may lead to deaths forces people to think about the treatments in another light.
Think about it, the most common questions an oncologist is going to hear from people who visit are:
Will I be cured?
Will it make me live a little longer?
Will the treatment make me feel better?
Intuitively, people with cancer focus on the most important things and for doctors hearing that many times during the course of a week, they will subconsciously be thinking that way too.
Going back to Matt's broad question, I was thinking about all these things yesterday while interviewing an oncologist about how he treats a certain cancer, which in rare cases is curative but in most situations 2) and 3) more clearly applied. My focus was a little sharper than usual because I found myself automatically asking why questions about a range of different regimens.
Now, some of the companies for the treatments he mentioned have indulged in typical marketing hype, with fancy programs, e-details and branded campaigns that could well have applied to an anti-hypertensive or skin cream. As the doctor walked through his treatment algorithm, I could almost imagine the critical survival charts on the wall in from of my desk. Finally, it became clear that he ranked them by the survival curves, with one exception that was reserved for a small, rare subset that had aggressive disease because the consequences of managing the concomittant myelosuppression were too high.
And there in is the rub.
Success in the oncology arena boils down to data and how well you stack up against the competition. Being first to market gives you a huge advantage too, since a hurdle is set and the ones afterwards are forced to demonstrate why they are better.
This is way many good marketers I've met avoid or dislike oncology: it's data driven, not marketing driven.
In oncology new products, the best thing you can do is focus on the data and find areas or niches where you can do well. It requires a more analytical approach to understand the science, work with the clinical and research teams and patiently build a blockbuster niche by niche. If a drug fails in an indication, either find another one quick or ditch it. Spend money wisely on more smaller phase I and II studies experimenting with different tumour types to match the biology of the disease with the drug's target. This is critical, but it also takes money and time with a high risk attached to it because more drugs fail than succeed.
Of course, once you get a drug to market, that's not the end. You have to practice 'kaizen' and continually invest more dollars in new indications. If you're too slow doing this, the second to market drug can be equivalent but have the advantage of a broader clinical program while you sat on your laurels for several years. Life cycle management means planning ahead for the second and third indications before you finish the first cancer type. If the first one fails, this also means you have a backup in advanced stages and that's a smarter strategy than everyone trying to get senior management's attention for resources and dollars if you put all your eggs in one basket.
Not every company has the scientific mindset and willingness to invest research dollars to succeed in cancer. Management by consensus doesn't work very well either, that just drags things down to the lowest (and often slowest) common denominator. You need passionate driven product champions who fight to the end and generate resources, focus and high priorities to get things moving by corralling the collective energy to get things moving at pace faster than the proverbial snail.
With regards to cancer pipelines, Roche/Genentech and Novartis probably have two of the most promising at the moment and are significantly ahead of the pack in my view. They invest heavily in science and research, as well as broad clinical programs that creates a continuous buzz. The mindset is clearly to accept a few negatives that are easily over shadowed by the many successes. This creates a groundswell and positive energy. Pfizer, Merck and BMS all have interesting pipelines, but also have to fight the internal entropy for execution as well.
Data matters. Execution matters.
Forget the hype in oncology and think about making a real difference to the lives of people with cancer and intelligent ideas around the concept of artisanal marketing, which my buddy Morgan Brown described in an intelligent and thought provoking post this week:
"Thoughtful, insightful, honest, embracing complexity and celebrating the craft of the product or products themselves."
"Merck's newly integrated pipeline follows a comprehensive prioritization process that closely examined all compounds in development at both companies prior to the merger. Candidates were prioritized based on a series of criteria, including potential for impact on human health, molecular characteristics, stage of development, probability of success and commercial potential.
The new combined pipeline is composed of small molecules, vaccines and biologics targeting a broad range of unmet medical needs including: atherosclerosis and thrombosis, cancer, diabetes, hepatitis C infection, insomnia, and schizophrenia.
Merck's pipeline is particularly strong in therapeutic areas in which both companies have long-established research programs, such as cardiovascular disease and infectious diseases; Merck has eight investigational medicines in each of these two categories."
Yesterday, Merck announced the results of their pipeline evaluation and prioritisation following the recent merger with Schering Plough. There are 19 projects in phase III development across all therapy areas. Although the two key areas for both companies were the same (cardiovascular and infectious diseases), there was little overlap, so the combined company now has 8 compounds in each area to manage.
What was interesting to me though, was what would happen in oncology where there was some overlap?
It now seems that Merck's IGF-1R inhibitor, dalotuzumab, which is in phase II development, has been selected as the lead cancer candidate. This is good news for those interested in the IGF-1R pathway after recent events that saw Roche handing back R1507 to Genmab and Pfizer's figitumumab hitting some roadblocks in newly diagnosed non-small cell lung cancer.
We know that adding an EGFR inhibitor reduces cross-talk between EGFR and IGF1R and including either an AKT or mTOR inhibitor may also reduce opportunities for resistance developing. Merck recently presented data at the ASCO GI meeting in pancreatic cancer with several drugs in combination, including metformin to reduce the hyperglycemia effect. The scientists and clinicians did a nice job thinking some of the issues through and managing the effects considering the side effect issues seen with figitumumab.
Of course, the co-development of the mTOR, ridoforolimus, continues in conjunction with Ariad and new data from the phase III trials in soft tissue sarcoma is eagerly anticipated by many at ASCO in June.
In my view, the most interesting cancer agents that Merck has are probably in phase I, time will tell what happens to those.
"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."
Source: Astellas US
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!
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.
With over a foot of snow overnight, Pharmaland is likely to be having another snow day in the New Jersey metro area.
That's a good thing because not only will people be safe and sound off the roads in the manic rush hour, but they will also be more productive.
Why?
Because meetings are cancelled and they'll get more done on important things or teleconferences without being driven by other people's agendas. And there will be fewer interruptions by colleagues practising management by walking around.
The bureaucracy in Pharma has always been bad, but lately I've noticed a lot more people complaining about it and things don't get done because there are so many processes and procedures to overcome.
During mergers, everyone turns inwards and started dealing with the consequences and implications of new colleagues, new teams, new processes or even debating this company's process over that one. Sometimes the end result is that not much gets done, or at least at a much slower pace, and people get frustrated.
Process.
One of my most hated words in the dictionary. It gets in the way of getting things done, of making magical things happen.
At one of my clients a new colleague joined one of the teams I'm working with. On a teleconference the other week, they asked the team, "what's the process for doing this?"
Someone, who had been in the company a longish time, piped up; "I don't know, we just do it around here!" Everyone laughed and the conversation moved on. A very true and apt statement that summed them up as a group. They make great things move and working with them is a delight.
Many people, though, hide behind rules and process, obfuscating those who are focused on getting things done. Sometimes experience teaches you that common sense is often the best approach:
"What's the right thing to do for our customers/people/patients/team?"
Give me a sensible, hard working practical team focused on people than individuals bogged down in process any day. It's all about making a difference and making things happen, not hiding behind rules about why you can't do something.
As the snow continues to waft down, the shackles of the office are removed and things are getting done in Pharmaland.
After yesterday's news regarding the negative data for bevacizumab (Avastin) in gastric cancer, I wasn't expecting to hear any more from Roche this week, however, the opposite happened and this morning positive data was sitting waiting for me in my inbox today!
What's new?
Well, results from phase III study demonstrated the combination of bevacizumab and chemotherapy followed by maintenance use of bevacizumab increased the time women with advanced ovarian cancer lived without their disease worsening as measured by progression-free survival (PFS) compared to chemotherapy alone. Advanced ovarian cancer generally has a poor prognosis, so new therapy options are much needed.
Roche's press release declared that:
"This is the first positive phase III study of an anti-angiogenic therapy in advanced ovarian cancer and continues to support Avastin and anti-angiogenesis as a fundamental pillar of cancer treatment today."
What does the data show?
The Gynecologic Oncology Group (GOG) completed a three-arm trial in women with newly diagnosed advanced ovarian cancer who already had surgery to remove as much of the tumour as possible were randomised to receive one of the following:
Placebo in combination with commonly-used chemotherapy (ie carboplatin (AUC 6 IV) and paclitaxel (175mg/m2) for 6 cycles), followed by placebo for a total treatment duration of up to 15 months.
Bevacizumab (5mg/kg for 5 cycles starting at cycle 2) in combination with carboplatin and paclitaxel (6 cycles), followed by placebo for a total treatment duration of up to 15 months.
Bevacizumab in combination with carboplatin and paclitaxel, followed by the continuation of bevacizumab alone as maintenance therapy, for a total treatment duration of up to 15 months.
Overall, the trial showed that women who continued maintenance use of bevacizumab alone, after receiving bevacizumab in combination with chemotherapy (Arm 3), lived longer without the disease worsening compared to those who received chemotherapy alone. Women who received bevacizumab in combination with chemotherapy, but did not continue maintenance therapy with bevacizumab (Arm 2), did not live longer without the disease worsening compared to chemotherapy alone.
The full results will be presented at ASCO in June.
Meanwhile this is an interesting development in ovarian cancer, given that J&J have a filing for trabectedin (Yondelis) with the FDA for the same disease, although ODAC expressed concerns about the risk-benefit profile given the side effects associated with the chemotherapy.
Time will tell what will happen later this year but at the moment it's looking more promising for Roche/Genentech than J&J.
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.
Things were so busy in the Icarus office yesterday I didn’t get a moment to post on the Roche/Genentech news that the latest topline phase III trial analysis for bevacizumab (Avastin) were disappointing. The company announced the findings in a press release:
“Avastin (bevacizumab) in combination with Xeloda (capecitabine) or fluorouracil and cisplatin chemotherapy in patients with inoperable, advanced or metastatic gastric cancer (stomach cancer). The study, known as AVAGAST, did not meet its primary endpoint of extending overall survival in patients treated with Avastin in combination with chemotherapy compared to the same chemotherapy plus placebo.”
The full data will be presented at ASCO in June.
Now, while initially disappointing, anyone who was at ASCO last year will remember the stunning data from the ToGA trial, presented by Eric van Cutsem. This study looked at the benefit of adding a different Roche drug, trastuzumab (Herceptin), to standard chemotherapy in patients with HER2 positive gastric cancer, and found a significant benefit of approximately 2.5 months compared to chemotherapy alone.
What is the significance of these two trials for gastric cancer?
Well, Avastin targets VEGF, Herceptin targets HER2, the first was negative, the second positive, which may tell us something useful about the biology of the disease and what mechanisms are driving the tumour growth.
Sometimes a negative result tells us more than we may realise at first. It helps define what really matters.
After yesterday's post about the NY Times article on Roche/Plexxikon's PLX4032, a few people wrote and asked about other therapies in development for the treatment of malignant melanoma.
Melanoma is the deadliest form of skin cancer and occurs in about 69,000 patients in the United States each year, resulting in approximately 9,000 deaths. Sadly, the number of melanoma cases worldwide is increasing faster than any other cancer.
One of the most promising agents in development is Pfizer's tremelimumab (CP-675,206), a humanised IgG2 monoclonal antibody targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), a natural brake on the immune system that has been implicated in melanoma. The basic idea is that tremelimumab inhibits CTLA4, thereby stimulating or enhancing the body's immune response to tumours and fight the cancer.
Tremulimumab has had a bit of a chequered history though. Pfizer discontinued a phase III study of the drug in patients with advanced melanoma after an interim review showed tremelimumab would not be superior to standard chemotherapy.
What's particularly interesting is that last month Pfizer announced another phase III trial of tremelimumab, declaring that analysis of the data from the discontinued study had identified the biomarker that will be used to select patients for the upcoming study completed in conjunction with Debiopharm, although details on what the biomarker actually was were not given.
Meanwhile, earlier this month, a new article appeared in Cancer Clinical Research, describing the data in a phase II study in people with relapsed melanoma, where the drug had already failed to work.
This trial, a single-arm phase II study, showed that 16 of the 241 evaluable patients had partial responses, ranging in duration from 8.9 to 29.8 months. Median time to response was 7.0 months. Eleven of the 16 patients (69%) had ongoing responses at their last assessment.
The clinical benefit rate was 21%, based on 16 partial responses and 35 people with stable disease.
One patient with a response, who had a family history of sudden death, died of an apparent cardiac event 321 days after enrolling in the study. The other 15 responders were alive when the researchers wrote the paper, with survival ranging from 20 to 34 months. Median overall survival for the entire cohort was 10.0 months.
The researchers noted that response rates with single-agent chemotherapy usually range from less than 8% to 15%, with limited durability. Immunotherapy with high-dose interleukin-2 produces similar response rates, with better durability but with more severe toxicities. The results with tremelimumab are therefore very encouraging and having a biomarker associated with it can only help screen out those patients who are more likely to respond to therapy.
Medarex and BMS are developing a similar anti-CTLA4 agent, ipilimumab (MDX-010), in melanoma and prostate cancer. This agent has received more attention in prostate cancer of late, but the phase II data in melanoma was presented at ASCO last year.
The updated survival results from follow-up extensions of three Phase II ipilimumab studies of patients with advanced metastatic melanoma (Stage III or IV) showed that the two-year survival rate ranged from 29.8 to 41.8 percent in patients who received ipilimumab.
Looking at the data in more detail, we can see that the results are based on follow-up of up to 37.5 months (median follow-up ranged from 10.1 to 16.3 months) of the patient population from studies 008, 022 and 007 treated with 10 mg/kg of ipilimumab during induction and maintenance therapy and showed:
Two-year survival rate of 32.8 percent in patients who had progressed while on or after receiving standard treatment (Study 008)
Two-year survival rate of 29.8 percent in patients who were previously treated, relapsed or failed to respond to experimental treatment or were unable to tolerate currently approved therapies (Study 022)
Two-year survival rate of 40.6 percent and 41.8 percent in patients receiving ipilimumab plus budesonide or ipilimumab plus placebo, respectively, which included treatment-naïve patients and patients previously treated with therapy other than ipilimumab (Study 007).
Novartis also have a RAF inhibitor similar to Roche's PLX4032, called RAF265, which is currently in phase I development. It differs in that it also inhibits VEGFR-2, which is associated with angiogenesis. Another TKI in development, TKI258 (formerly CHIR2558), is a fibroblast growth-factor receptor (FGFR) inhibitor, as well as targeting VEGF and PDGFR.
This raises an interesting idea – in some patients, inhibiting several pathways such as RAF, CTLA4 and FGFR or VEGF may be the ultimate answer to prolonging survival, although we don't know if that approach would work yet.
Coordinating studies across several companies, each with drugs not yet approved, is also fraught with difficulties. This is where patient advocacy groups such as the Melanoma Research Foundation and ACOR have most power in conjunction with the physicians to compel Pharma companies to:
a) consider combination trials earlier in collaborative efforts
b) speed up development of new and promising agents
Overall, the results from the anti-CTLA4 antibodies and RAF inhibitors look promising and it will be interesting to see what happens at ASCO this year as well as moving forward in the future.
Kirkwood, J., Lorigan, P., Hersey, P., Hauschild, A., Robert, C., McDermott, D., Marshall, M., Gomez-Navarro, J., Liang, J., & Bulanhagui, C. (2010). Phase II Trial of Tremelimumab (CP-675,206) in Patients with Advanced Refractory or Relapsed Melanoma Clinical Cancer Research, 16 (3), 1042-1048 DOI: 10.1158/1078-0432.CCR-09-2033
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