Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

New imaging technique shows promise in detection of Alzheimer's Disease

By on June 25, 2010

"Dr. Skovronsky thought he had a way to make scans work. He and his team had developed a dye that could get into the brain and stick to plaque. They labeled the dye with a commonly used radioactive tracer and used a PET scanner to directly see plaque in a living person’s brain. But the technology and the dye itself were so new they had to be rigorously tested.

And that is what brought Dr. Skovronsky, a thin and eager-looking 37-year-old, to his e-mail that recent day. 

Five years ago, Dr. Skovronsky, who named his company Avid in part because that is what he is, had taken a big personal and professional gamble. He left academia and formed Avid Radiopharmaceuticals, based in Philadelphia, to develop his radioactive dye and designed a study with hospice patients to prove it worked. 

Hospice patients were going to die soon and so, he reasoned, why not ask them to have scans and then brain autopsies afterward to see if the scans showed just what a pathologist would see. Some patients would be demented, others not. 


Some predicted his study would be impossible, if not unethical. But the F.D.A. said it wanted proof that the plaque on PET scans was the same as plaque in a brain autopsy." 

Source: NY Times

If you haven't already read the article in the NY Times, click on the link above and check it out. It's well worth reading. How many of us have elderly parents who have Alzheimer's, who sadly died from the devastating condition or know friends going through the trials and tribulations as caregivers?

I love this story – a scientist gets germ of an idea, is convinced it will work, leaves his employment and sets up a company (Avid Radiopharmaceuticals) to research the possibilities. That's the very entrepreneurial spirit that made America great.

Basically, the concept is that using a special dye to highlight the plaques would show up on brain scans in Alzheimer's patients.  At moment, the only known way of showing proof of the disease is when a pathologist looks for the black specks of plaques in the brain during a post mortem.  Finding a way to be sure that the disease exists earlier has proven elusive so far.  In the NY Times article, they showed what Dr Skovronsky has found so far.  You can see the plaque buildup (red) in Alzheimers on the bottom compared to someone who did not have the disease:

image from graphics8.nytimes.com
Source: Dr Skovronsky in the NY Times 

If the results prove conclusive and the dye gets FDA approval, researchers will have the first reliable method of detecting the disease early and also a potential marker of determining whether any future therapies are having an impact in reducing the plaques.

The data is being presented next month at the Alzheimer's Association so there is bound to be a lot of excitement and anticipation surrounding the data.  This is the sort of thing we scientists get excited about, even if it's not in our field.  My first thoughts on reading the NY Times were, "A dye? Wow, I wish I had thought of that!"  I got goosebumps just reading it.  

Of course there is a long way to go, but let's hope for the future of new drugs in the pipeline that the dye will turn out to be a great marker and the tide turns on future development of better and earlier pharmaceutical intervention for a devastating disease.

Should use of CT scans be reduced?

By on June 24, 2010

Last night I was reading about the latest Iressa (gefinitib) data in lung cancer published in the NEJM, but unfortunately the DOI code isn't yet available for easy tagging and linking of the article in Research Blogging, so it will have to wait until it's out.

There was, however, a pair of interesting articles on computerised tomography (CT) scans (see references and links below).  While the use of such scans has clearly improved diagnosis, it has come at a cost – both in terms of expenditure and also with respect to increased risk of radiation exposure:

"We found that the risk of cancer from a single CT scan could be as high as 1 in 80 — unacceptably high, given the capacity to reduce these doses."

Source: Smith-Bindham, NEJM


"Changing the culture of medical practice to encourage more thoughtful use of imaging today will help to ensure that future patients will benefit from continued imaging innovation." 

Source: Hillman and Goldsmith, NEJM

Good points both, but little is likely to change unless the payers and insurers force them economically. Physicians are typically cautious and conservative by nature and would rather check to see if any cancer might be present than risk missing it or be hit with a law suit for negligence.  Given that radiation has not been shown conclusively to be cancer-causing, most would probably rather be safe than sorry.

ResearchBlogging.org

Smith-Bindman, R. (2010). Is Computed Tomography Safe? New England Journal of Medicine DOI: 10.1056/NEJMp1002530 

Hillman, B., & Goldsmith, J. (2010). The Uncritical Use of High-Tech Medical Imaging New England Journal of Medicine DOI: 10.1056/NEJMp1003173

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FDA Comments on Its Role in Rare Diseases & Orphan Drugs

By on June 23, 2010

In an effort to be more visible to the public, the FDA now publishes its own 'transparency blog".  This post deals with their role in regulating orphan drugs in service of the 7000+ rare diseases.

Link here.  

Fdagov_hp_logo

Posted by Bruce Lehr June 22nd 2010.

via thebigredbiotechblog.typepad.com

Saw this on Bruce Lehr's Big Red Biotech blog, which I'm a fan of.

Interesting video on the FDA blog via the link his post too.

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Pharma R&D is a rollercoaster – Mylotarg withdrawn and Ziopharm stumbles

By on June 22, 2010

Interesting news in Pharmaland today as we hear that Pfizer has decided to voluntarily withdraw gemtuzumab ozogamicin (Mylotarg) from the market and the FDA declined to grant Ziopharm an SPA for their phase III trial with palifosphamide (palifosfamide for those reading in American English) in soft tissue sarcoma.

The first is unexpected, the second interesting.

Mylotarg

image from www.physiciansofficeresource.com In 2000, Wyeth (now part of Pfizer) were granted accelerated (fast track) approval in AML for Mylotarg, an anti-CD33 monoclonal antibody, on the basis of response rates, with the intent that survival data would provide evidence for full approval. Unfortunately, like Iressa's situation in lung cancer, that did not happen so polite withdrawal is the only option in this situation. Perhaps the only surprise is that it took a decade for it to happen.

It's not a big loss for elderly AML patients, given the drug never showed any major efficacy benefit and the side effect profile of fevers, chills, nausea and vomiting severely impacted quality of life for many frail people. Many AML patients are over 60 and in much less robust health compared to younger, fitter patients who might be candidates for high dose chemotherapy and a transplant. This is where Mylotarg was supposed to offer hope, given the limited options. In this setting, the ideal drug would be a targeted therapy without too many debilitating adverse events. Early toxicities with Mylotarg, however, were not pleasant:

"… among all patients evaluable for early toxicity the
fatal induction toxicity rate was significantly higher in
subjects given the combination of standard induction chemotherapy
and Mylotarg than in those treated with chemotherapy alone."

Source: Pfizer

I always look at sales as a good indicator of whether physicians like a drug or not.  At around $35M annually, Mylotarg clearly wasn't a popular option. Sometimes we need to focus on what matters – response rates per se (around 10-13% complete responses) don't mean much in isolation, but extending lives does, hopefully without too much collateral damage. In this situation, Pfizer made a good call.

Palifosfamide

Ziopharm's management team have been very bullish and brimming with confidence lately, however, such sentiments can sometimes turn out to be irrational exuberance.  The phase II PICASSO trial with palifosfamide and doxorubicin versus doxorubicin alone has completed enrollment with initial promising interim results in metastatic or unresectable soft tissue sarcoma and the company were clearly hoping to negotiate an SPA with the FDA for the phase III trials, but it seems negotiations have broken down on that front, with concomitant fall in the share price.

The trial design is interesting for several reasons.  

Firstly, the current standard of care for treatment of soft tissue sarcoma is ifosfamide plus doxorubicin but there's no comparator arm with ifosfamide, an old chemotherapy now available generically.

According to the company:

"Palifosfamide (ZIO-201) is a proprietary stabilized metabolite of ifosfamide."

Meaning it's a second generation version of the generic, but is it any better than ifosfamide?  We won't know with the proposed design. Of course, the current reimbursement structure means that oncologists will make more revenue from a branded drug (6% of $1000 is more than 6% of $100), whereas in the old scheme, there was more usage of generics because the spread was greater than for newer, more expensive therapies.

Secondly, the big sticking point for the FDA was the proposed primary endpoint, ie PFS rather than overall survival (OS).  One does not always follow the other, but seriously, accepting OS as the goal may well have been an easy win-win for Ziopharm. It seems a little odd that they chose not to go there in the initial discussions with the FDA:

"In a recent communication, FDA has indicated that the Company could conduct the pivotal trial as designed without SPA and that approvability would be determined by the data, balanced with risks and benefits. FDA presently considers the endpoints as designated for the proposed pivotal trial as not supportive of SPA in this disease setting, although they would grant SPA with modified endpoints."

If changing the endpoint from PFS to OS is all that is needed for garnering an SPA, I think I would grab it and go. It's much easier to gain approval if you meet the criteria for a pre-negotiated SPA, as Roche/Genentech have shown with Tarceva several times, even with marginal, yet significant improvements, based on well powered studies. Going it alone without agreement with FDA is a recipe for disaster down the road, as many small biotechs have discovered to their dismay over the last 18 months.

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Exelixis and BMS part ways over XL184

By on June 21, 2010

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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Two new cancer drugs approved – cabazitaxel and nilotinib

By on June 18, 2010

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.


On chotchkes and scientific data in oncology

By on June 17, 2010

Getting back to the blogging groove after 3 weeks on the road at successive conferences (AUA, ASCO and EHA) is a bit of a shock, so the first post will be short and pithy.

AUA will be remembered for incredibly unsocial and early 6am education session starts.  No thanks, with three meetings in a row stamina trumps insanity by a long shot.  At ASCO, the Chicago venue is sprawling with long walks between sessions that appear to have no theme or cohesion around them and of course, the Press Room is way out in left field over the walkway no matter where you need to go.  The S406 Vista Room was particularly bad and became notorious for the #blisterwalk on Twitter.  Never again will I complain about switching between Halls A and F at Orlando, that's a piece of cake by comparison!

The second big difference I noticed between US and EU meetings was the presence or absence of chotchkes.  In the US they are now verboten of course, but the EU has no such constraints.

Now, I'm not sure a branded laptop sleeve or a Post-it pad ever made a difference to prescribing habits, but well done journal reprint carriers with a clear summary of the data do make a difference in oncology.  They help reinforce the efficacy, survival curves and key messages to your audience.

One thing I particularly remember most from EHA was a very well done piece that clearly differentiated the brand from the competitor, with data I hadn't noticed before.  Talking to some of the hematologists, they were equally interested in the pieces too as they included a peer reviewed journal reprint.  Some were taking copies back to share and discuss the data with their colleagues, which I found interesting.  What's going to have more impact – a branded item with no message or a clinical paper?

The Roche booth was particularly busy whenever I visited the exhibits.  The reason?  Great espresso coffee and the best quality nibbles, much appreciated early in the morning and late afternoon by drooping attendees.  I was less enthused by the aggressive ladies on the stand who wouldn't let me play with the interactive education quizzes for a USB key because the press passes didn't have a bar code on them.  I desperately needed a USB key to share a file with a physician.  We both walked away from that with a negative impression that overrode the nice refreshments.  A little flexibility goes a long way.

The other neat thing at the European Hematology Association meeting in Barcelona was a CD of many of the biology and clinical posters.  Great stuff, saves hours of work trying to piece together snippets taken on an iPhone!

Perhaps my favourite thing about European meetings, aside from the relaxed sociable hours with time to network with people, was the integration and inclusion of the patient advocate voice.  Critical, but largely ignored in American meetings.  More on this in another post.

This week I'll be putting up some synopses of data found interesting from the meetings, but the analyses may well be very different from what you saw in the news items.  Some of the reporting at ASCO in particular was sketchy puff pieces or hype at best, with very little real understanding of what the data actually means.

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Aggregating the EHA 2010 tweets

By on June 8, 2010

After the success of the American Society of Clinical Oncology (ASCO) Twitter aggregation, with over 250 readers over the course of the weekend, I thought it would be fun to repeat the experiment for the European Hematology Association (EHA) meeting in Barcelona this weekend.  The tweet volume is likely to be significantly less tough, with fewer people tweeting from the event.

Most of the topics I'm interested in will be on leukemias, lymphomas and myeloma, so if you are interested in these cancers, you can follow the feed below.  I've aggregated two hashtags, #EHA10 and #EHA2010. 

Additionally, Dr Anas Younes from MD Anderson Cancer Center will also be attending and following his tweet stream may also be instructive, especially if you are interested in his specialty, lymphomas.

Do feel free to join in remotely in the back channel and add links, comments or ask questions if you feel so inclined. The more the merrier!

I'm particularly looking forward to the Patient Advocacy symposium chaired by Jan Geissler, an awesome guy who just happens to have CML.  While the science and clinical data are important, it's also critical to hear and learn from the advocacy viewpoint.  

On the healthcare (#hcsmeu) front, I'm also hoping to meet fellow Twitter buddies, Miguel and Angel for an impromptu tweetup of #hcsmeuES.  If you're on Twitter and interested in healthcare, check them all out, all three are great gentlemen I would highly recommend!

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Aggregating the ASCO 2010 tweets

By on June 4, 2010

As with previous meetings, I'm aggregating the ASCO tweets using three key hashtags: 

#asco10 (the official twitter hashtag) 

#asco2010 (some people are using this) 

#ascopress (for press alerts)

The stream should be live as of 3pm CST and will run for the duration of the meeting until COB on Tuesday:


Ready, Steady, Go!

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#AUA2010: new perspectives and learnings in prostate cancer

By on June 2, 2010

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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