Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘BMS’

It came as no big surprise this morning to hear that Exelixis and BMS have announced they are terminating their agreement over XL184.  The compound is being tested in medullary thyroid cancer, glioblastoma multiforme (GBM) and non-small cell lung cancer (NSCLC).  This is a small molecule that inhibits several targets, namely MET, RET and VEGFR2.

According to Exelixis, the CEO stated in their press release:

"We certainly understand BMS' need to make pipeline and prioritization decisions."

It looks as if they couldn't agree on the priorities for the clinical development, which would be a little odd given the $240M invested in XL184 and XL281 in 2008, with the same indications planned.

It could also be a question of risk management for several reasons:

  1. Thyroid cancer is slow growing and thus development times will be relatively long, lung cancer is notoriously difficult to crack, as is GBM.
  2. BMS also have another VEGF inhibitor in late stage development called brivanib (BMS582664), which is in phase III and inhibits both VEGFR2 and FGFR.  This compound is being tested in a number of indications, including liver and colon cancers.

Recent BMS analyst meetings from have focused on brivanib as one of the promising new oncology agents in the pipeline, so my suspicion is that they probably decided they only needed one VEGF inhibitor and killed the Exelixis agent rather than their own homegrown one.  These things happen all the time. Sometimes you develop several molecules in the hope that one looks more promising in trials.

A few years ago, I remember reading about an incredibly brave and strong patient in one of the early brivanib trials, for advanced cancer.  In this case, the feisty young lady had a non-differentiated spindle cell sarcoma and blogged about the encouraging impact of her new treatment:

"My Scans came back with wonderful results. The Brivanib pills are working! My tumors are stable and haven't grown since my last scan! One tumor in my lymph node has actually died! There is no blood flow to the tumor! This is the best news I could get. My doctor is so happy with these results. 

I will be on the pills for 12 weeks. After that I will be given either a Placebo or continue on the pills. Because it is a trial it's a 50, 50 shot that I could get the Placebo. Booooo! I will know right away by how I am feeling. The reaction happens within 15 minutes after I take the pills. I am a walking zombie. If I do get the Placebo, I can then go back on the trial."

You can follow her incredible journey back to health here; it's an inspiration to us all.  

Thankfully, she's still blogging 2 years later, a testament to her resolve and ability to fight the disease. Long may she continue! Not everyone who gets cancer is elderly, often many people are diagnosed in their teens, twenties and thirties too.

I don't know about you, but I love happy stories and hope to be following her blog for a very long time.

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Yesterday brought two new approvals in a day from the FDA in completely different cancer types.

In the morning, sanofi-aventis' cabazitaxel (Jevtana) was approved in castrate-resistant prostate cancer after failure of docetaxel (Taxotere) several months ahead of schedule.  This approval comes hot on the heels of Dendreon's sipuleucel-T (Provenge) in asymtomatic metastatic prostate cancer last month.

What this means is that once androgen ablation therapies stop working, there are three new treatment options for men with prostate cancer, none of which compete with each other, with the possible exception of the chemotherapies, since docetaxel is often given in second-line in men who previously responded well and have had a treatment break.  It will be interesting to see if this approach continues or if oncologists will prefer cabazitaxel in those with a good performance status.

The real impact of cabazitaxel though, is on other agents in development. Currently, abiraterone (Cougar Biotech/J&J) and MDV3100 (Medivation/Astellas) were being tested in docetaxel refractory prostate cancer, but now there is a new standard of care, whereas previously there was none.  Clearly, common sense suggests that their role might be more impactful earlier in the disease, either after hormonal therapies fail, instead of or in combination with them, especially given that they are oral therapies, making them attractive to urologists. 

Classic drug development usually means starting in the relapsed or refractory metastatic setting. The next few years will be thus be interesting to watch, especially if the agents in clinical trials prove successful. For now, Dendreon have a couple of years breathing space until the market potentially starts to get more crowded.

The other Priority approval yesterday was for Novartis' nilotinib (Tasigna) in newly diagnosed chronic myeloid leukemia (CML) on the basis of higher and earlier response rates versus the current standard of care, imatinib (Gleeevc). Full approval follows later once the survival data is more mature, but the early 12 month data looks interesting with a significant advantage to nilotinib over imatinib. It's still early though, survival curves can do strange things over time and can cross over. 

Still, it's a promising start and a good result, especially since the bar was raised very high by imatinib. Prior to imatinib, ten year survival in CML was 10 to 20% at best with high dose interferon, but imatinib raised that dramatically to 90%. The second generation TKIs such as nilotinib and dasatinib (BMS) will thus potentially represent incremental survival improvements to 93 or 94%, to put them in context.

Of course, nilotinib's approval will possibly impact dasatinib (Sprycel) since they have just filed for the same indication, making Priority review more unlikely. The last time that happened to two drugs in the same cancer type was for Erbitux (ImClone) and Avastin (Genentech), who filed a few weeks apart, but in two different indications (newly diagnosed and 3rd line).  

If dasatinib does get a Priority review after nilotinib it will set a new precedent, but if it doesn't get Priority review, I wonder if an ODAC will occur given that's usually what happens with standard 12 month review?  

What's fascinating about the dasatinib data is that it also demonstrated earlier and deeper responses than imatinib, but the front-line data presented by Drs Kantarjian and Baccarani at ASCO and EHA respectively, did not appear to show any earlier survival benefit at 12 months for dasatinib vs imatinib, unlike nilotinib. I say 'appear' because the curves were very close together and no P value was given, so my assumption is that they weren't significantly different at this stage. That may change over time, but for now, the DASISION data presented by Dr Kantarjian showed a 12 month OS of 97.2% to dasatinib and 98.8% to imatinib, presumably not a significant difference. Deaths in the two arms were 10 and 6 respectively, again favouring imatinib, but not significantly. 

Obviously, comparing these curves at 5 years would be a much fairer comparison for overall survival, but for now, the 12 month data is all we have to go on and there are early differences between nilotinib and dasatinib.  

It was also interesting to watch the often hyped and inelegant reporting of the data by the media at the Congresses proclaiming superiority. We know that in solid tumours, shrinkage or tumour response does not always lead to an improved survival benefit for the patient. Similarly, in leukemia, we also measure response rates – in this case – complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR), as initial surrogate markers for initial approval, but survival is also critically important for full approval in the US. Interestingly, the early log 4 reduction (CMR) rates seemed to slightly favour nilotinib over imatinib (but not significantly), however none were presented at ASCO or EHA for dasatinib over nilotinib (unless I missed the slides).

Ultimately, ASH will herald the 2-year and 18-month data for nilotinib and dasatinib respectively, which will hopefully be an important milestone on the way to seeing how the mature five year surviv
al data will evolve.
< /p>


Disclosure:  I'm a former Novartis employee and marketing director for Gleevec, so naturally I'm slightly biased towards imatinib :).  Many thanks to @erohealth for proofreading suggestions.


It's been an interesting time here in San Francisco at the American Urology Association (AUA) meeting. Mostly, I've attended prostate cancer sessions to get both a breadth and depth perception of what's going on this cancer type.  

My focus is very much therapeutic development, so here are three key trends that I've noticed at the 2010 AUA meeting:

  1. PSA is not a brilliant biomarker, but it's all we have for now.
  2. Androgen ablation is not permanent.
  3. Immunotherapy is a hot new topic.

What alternatives are there to PSA?

An abstract today from the Colorado Cancer Center suggested that PCA3 may offer a urine based genetic assay for detection of prostate cancer in men with elevated levels of PSA. PSA can offer false positive results and up to 75% men with prostate cancer have a negative biopsy. This new approach sounds promising. PCA3 is overexpressed in more than 90 percent of prostate cancers and the gene overexpression is specific to prostate cancer.  It has been linked to more accurate prediction of positive biopsies compared to PSA, and it is easy to test in urine samples following a digital rectal exam of the prostate.

Presumably it may turn out to be more accurate than PSA and perhaps offer a better way to detect either the actual disease earlier or more aggressive disease earlier.  The test was developed by GenProbe and is not yet approved by the FDA, but a new test to watch out for.

Androgen ablation therapies are not particular effective

Often times, testosterone levels rise above the minimum castrate level after about a year.  Ultimately, more effective androgen receptor antagonists are needed, hence the significant interest in this meeting in abiraterone and MDV3100, two new antagonists in phase III development.  Long term use of androgen deprivation is also inevitably associated with side effects, which have not been well appreciated until recently.

The approval of Provenge gives hope that survival can be extended without drastic side effects

Pharma companies in the oncology space would do well to realise that sick people with cancer don't want to be reminded of such and most certainly do not want a 'relationship' with a brand.  This is not Nike or a FMCG brand offering coupons and offers.  What most people do want is less side effects and better efficacy without having to trade them off.  

Now that we have a proof of concept poster child in Provenge in a solid tumour, we can also see that it may ultimately offer a way to combine newer hormonal therapies with a vaccine to offer men a more effective tool against their disease, delaying the time not only to progression, but also to metastases and chemotherapy.

Other immunotherapies are also being evaluated in prostate cancer, including ipilimumab (BMS), an anti-CTLA4 inhibitor and ProstVac, a cancer vaccine.  More on ipilimumab in another blog post but having had a few queries as to what ProstVac is, here's my basic take on it.

ProstVac differs from Provenge in that it requires 7 infusions over a 6 month period as opposed to 3 within the first month.  My understanding is that it is a sequentially dosed combination of two different Poxviruses which each encode prostate specific antigen (PSA) plus three immune enhancing co-stimulatory molecules, B7.1, ICAM-1, and Lfa-3 (TRICOM). The first Poxvirus is Vaccinia-PSA-TRICOM, which is replication competent and is good for immune priming. The second Poxvirus is Fowlpox-PSA-TRICOM, a non-replicating virus, which is good for repetitive immune boosting.  In some ways, it seeks to achieve the same end as Provenge (T-cell stimulation) but via a slightly different approach.

What's next?

More on prostate cancer at the American Society of Clinical Oncology (ASCO) meeting next week!

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It's only 3 weeks to go to the Annual ASCO meeting in Chicago so I thought it would be a good time to kick off the annual preview of key data.  One of the things that sets the tone of the meeting is which abstracts are in the plenary session.  Sometimes I don't attend the session if it looks arcane, but this year looks really interesting and worthwhile attending.

The selected abstracts comprise the following:

#LBA1: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or Fallopian tube cancer (FTC): A Gynecologic Oncology Group study.

#2: Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC).

#3: Clinical activity of the oral ALK inhibitor, PF-02341066, in ALK-positive patients with non-small cell lung cancer (NSCLC).

#4: A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma.

Now, three of these trials promise some excitement.  The one I'm surprised about is the French Intergroup study looking at a taxane plus platinum in lung cancer.  In case anyone is wondering, the trial (link) states that:

"It thus seemed to us justified to compare a standard arm, the vinorelbine or the gemcitabine (with the choice of the center) in monotherapy with an experimental arm, association carboplatine + paclitaxel."

Carboplatin plus paclitaxel (with or without bevacizumab) is pretty much standard as first-line treatment for non-small cell lung cancer (NSCLC), so now we know that the doublet is likely more effective than single agent gemcitabine or navelbine in the elderly too, but for me all four are old drugs, likely available as generics and it's all an iteration of what we mostly know already.  I'm particularly interested in new and exciting agents that are coming through or new indications or more recent drugs as we see them expand their utility.

The results are no doubt important, but plenary important?  It could
have well led off an oral lung cancer session and received attention at
Best of ASCO perhaps, but for me, the plenary sessions should be
about groundbreaking new therapies or indications, which the other three
clearly are.

Still, the Korean study in ALK-positive people with NSCLC really gets my attention because we've only heard about a US study in the past, so seeing how this evolves Globally is vitally important.  Pfizer have done a nice job speeding this agent, PF-02341066 (crizotinib), through development having recognised the significance of the rearrangements and then invested significant resources to moving it forward.  They should be commended for that and I sincerely hope the results continue to be positive. 

What is also nice is that I've come across a few new ALK inhibitors at AACR and elsewhere that may work in patients where crivotinib stopped working, perhaps as a reult of new mutations.  This is an exciting area of research, even if it just affects a small subset of patients.  Cancer is a heterogeneous disease so researching and identifying different subtypes that can be then targeted with new therapeutics is critical.

After excitedly listening to the BMS R&D Day, I was expecting that ipilimumab might have a chance of a plenary with the melanoma data because the example they gave just took your breath away – this is what we all live for in cancer research – something that really makes a difference to the disease and makes you go, "oh wow!"  You can read more about that commentary hereRoche and Plexxikon also have a promising compound in development (PLX4032) that targets BRAF.  At Roche's R&D Day, they noted that they planned to present the phase II data later this year at a melanoma meeting.  That's how the timing rolls sometimes.

The bevacizumab (Avastin) data in ovarian cancer was previously announced by Roche earlier this year to be positive, so this is excellent news for women with ovarian cancer.  I really look forward to seeing the results in full.  What's particularly important about this trial is that it is the first positive phase III study of an anti-angiogenic therapy in advanced ovarian cancer.  I think Judah Folkman would be mightily pleased with the progress of angiogenesis inhibitors such as Avastin so far, if he could see them.  It's all too easy to forget the visionaries in research and focus on the results.

For some reason, ovarian cancer always seems to be the poor cousin to breast and lung cancers and regimens that work in either tend to dribble down to ovarian cancer years later, but all three share many similar regimens.

From tomorrow, I'll start an ASCO series taking a look at some of the bionic biotechs with interesting data and a review of some of the big cancers and the potentially interesting data that may be worth highlighting and checking out.

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This morning the newswires (HT Mike Huckman) are full of the BioSante (formerly Cell Genesys) news on their leukemia vaccine, GVAX, which is being tested to see whether it is a viable approach for eradication of minimal residual disease. Accordingly, BioSante announced:

"Positive results of a human clinical study that show that its GVAX Leukemia vaccine may be able to reduce or eliminate the last remaining cancer cells in some chronic myeloid leukemia (CML) patients taking the drug Gleevec (imatinib mesylate). All patients enrolled in the trial used Gleevec for at least one year and still had cancer cells present. The study was conducted by researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, led by Hyam Levitsky, M.D., professor of oncology, medicine and urology at the Cancer Center. The research was funded by the National Institutes of Health."

Currently standard of care for CML is daily treatment with an oral tyrosine kinase inhibitor (TKI), imatinib (Gleevec), with the option of two second generation TKI's nilotinib (Tasigna) and dasatinib (Sprycel) being available if the imatinib fails.  All three of these drugs are effective at inhibiting the enzyme associated with the gene BCR-ABL, which occurs in every CML patient and essentially shut off production of the excess white blood cells so that the cells stop growing and eventually die.

There are various degrees of response with TKIs and at the American Society of Hematology meeting in December, Tim Hughes from Adelaide presented the concept of a safe haven as you can see from the chart below:

Hughes_MMR
Source: Dr Tim Hughes, Adelaide, Australia

Obviously, the deeper the response, the more likely a patient would attain a major molecular response (MMR) and provide a safe haven from treatment relapse.

The important question then becomes one of how low should one go in order to 

  • Optimise treatment response and 
  • Provide enough protection without increasing side effects?

Going back to the quote at the top of the post about GVAX, we can see that the researchers goal was to eliminate minimal residual disease (MRD) and kill all detectable cancer cells below what is currently possible with TKI therapy.  

In the article published in Cancer Clinical Research (free PDF download courtesy of AACR), it seems that according to the researchers

"Thirteen patients had a progressive decline in disease burden, 8 of whom had increasing disease burden before vaccination. Twelve patients achieved their lowest tumor burden measurements to date following vaccine, including seven subjects who became PCR-undetectable."

Now while this is very good news to hear that it can be accomplished, the numbers are very small and we don't have any data whatsoever yet to prove that achieving the nirvana of MMR is actually necessary for the majority of CML patients. None, nada, zilch.  We also do not have any idea from the article how durable the vaccine results will be yet as there may be an attenuation of response over time.

We do know from the IRIS updates that newly diagnosed people with CML now have a much longer life expectancy of around 7+ years on average when treated with imatinib.  Stem cell transplants are curative in some patients, but that decision is fraught with a risk-benefit trade-off of 20% procedure related mortality and the risk of graft-versus-host disease and other long term complications afterwards.

In conclusion: 

It will be interesting to see what impact this vaccine will have in the long term in terms of improved survival for people living with CML and whether future research will demonstrate a clear need to eliminate minimal residual disease below what is currently possible.  These are promising results and I look forward to seeing more data over the next few years as the answers evolve.  The ultimate goal is always to find a cure but whether this approach will help achieve that remains to be seen.


ResearchBlogging.org
Smith, B., Kasamon, Y., Kowalski, J., Gocke, C., Murphy, K., Miller, C., Garrett-Mayer, E., Tsai, H., Qin, L., Chia, C., Biedrzycki, B., Harding, T., Tu, G., Jones, R., Hege, K., & Levitsky, H. (2010). K562/GM-CSF Immunotherapy Reduces Tumor Burden in Chronic Myeloid Leukemia Patients with Residual Disease on Imatinib Mesylate Clinical Cancer Research, 16 (1), 338-347 DOI: 10.1158/1078-0432.CCR-09-2046

While listening to last week's presentation by BMS on their pipeline, one slide in particular caught my attention:

Picture 10
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 acquiring Facet 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:

Picture 11
 

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.  

Such is life on the Pharma roller coaster.

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It's been a frantic week on the work front and today was no different, but I wanted to highlight a really interesting slide from the BMS pipeline presentation yesterday afternoon.

Here's one of the slides Elliot Sigal, President of R&D, showed from one of the ipilimumab trials.  More data may be available at ASCO if the submitted abstract is accepted, but for now, even though it's only an n of 1, a picture tells a thousand words:

Picture 29
Source: BMS

After all the recent good news about malignant melanoma, hopefully at least one of these promising agents will make it to market in the not too distant future, offering people suffering with the condition a glimmer of hope.  I sincerely hope the CTLA4 results turn out to be durable.

In the meantime, we can all wonder until June, when the annual ASCO meeting will held.

 

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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:

  1. Will I be cured?
  2. Will it make me live a little longer?
  3. 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."

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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.

ResearchBlogging.orgKirkwood, 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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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's rituximab (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!

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