Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

Blocking POLQ gene could improve radiotherapy results

By on April 7, 2010

This was a very interesting article I came across in Cancer Research while looking for something else. Serendipity is a great thing sometimes.  A quote in the abstract caught my eye:

"We have conducted a small interfering RNA (siRNA) screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumor radiosensitivity."

Essentially, the researchers found that if they blocked the POLQ gene, which has a role in repairing damaged DNA, then radiotherapy was more effective.  What's more, POLQ knockdown has minimal effect on normal tissue, so blocking the gene did not have any effect on the sensitivity of normal tissue to radiation. This makes the gene an ideal target since it is more specific to, and abundant in, cancer cells.

The article stated that:

"Radiotherapy is a vital tool in the management of cancer patients. It is often given with curative intent either alone or with chemotherapy in patients with diseases as diverse as head and neck, cervix, bladder, and non–small cell lung cancer. The radiation dose that can safely be delivered to patients is limited by the dose tolerances of surrounding normal tissues. It is anticipated that the effectiveness of radiotherapy would be improved if tumor cells could be rendered more sensitive to ionizing radiation (IR) without altering the sensitivity of normal tissues."

It is therefore possible that POLQ inhibition might be used clinically to cause tumour-specific radiosensitisation.  In other words, if a new drug could be developed to block POLQ it might allow radiotherapy to be more effective without impacting normal surrounding tissues too much.


ResearchBlogging.org
Higgins, G., Prevo, R., Lee, Y., Helleday, T., Muschel, R., Taylor, S., Yoshimura, M., Hickson, I., Bernhard, E., & McKenna, W. (2010). A Small Interfering RNA Screen of Genes Involved in DNA Repair Identifies Tumor-Specific Radiosensitization by POLQ Knockdown Cancer Research, 70 (7), 2984-2993 DOI: 10.1158/0008-5472.CAN-09-4040

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Paralysis by analysis

By on April 6, 2010

Recently, I was talking to a couple of Pharma marketers and market researchers about their products in development, each in entirely different markets.

They had exactly the same issue though – making decisions about which tumour types to target out of a possible half dozen options. That sort of position often leads to total paralysis by a project team and an unwillingness to put their head on the block.

Too many what if's abound.

image from www.ysk.com The problem is drug development is often a leap of faith into the unknown, a total crapshoot.  You have to learn to play the percentages and perhaps consider several smaller phase II trials to minimise the phase III risks and see what data evolves.  Trying to pick only one tumour target at the end of phase I is a recipe for disaster and fraught with issues.

My answer is nearly always the same.  What data do you have so far?

What I've noticed is that the smart companies in oncology rigourously focus on solid proof of concept studies in phase I and even phase II before making the ultimate Go : No Go decision to pursue a phase III registration strategy.  This might mean embarking upon three phase II trials in different cancers before selecting a registration lead rather than just picking one and fretting about the other 5.  

Other times, it makes sense to try two indications in a head to head and hoping one emerges as a lead option, thus reducing your development costs.  This can be done when you have really solid preclinical data that really jumps out.

In the final analysis, making solid decisions based on actual scientific, clinical and preclinical data is a lot smarter than a total leap into the abyss just because a market looks bigger commercially.

No data, no dice.

Photo Credit: YSK

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Aeterna Zentaris and Keryx's Perifosine gets fast track designation for colorectal cancer

By on April 5, 2010

Last month at the ASCO GI Symposium, Keryx and Aeterna Zentaris reported statistically significant benefit in survival from updated results of a randomized, double-blind, placebo-controlled phase II study of KRX-0401 (perifosine) for the treatment of advanced metastatic colorectal cancer. 

The study was based on 35 evaluable, but heavily pre-treated patients, with relapsed or refractory metastatic colon cancer were randomized to receive capecitabine (Xeloda) from Roche at 825 mg/m2 BID on days 1 – 14 every 21 days plus either perifosine (P-CAP) or placebo at 50 mg daily (CAP).

The results showed that the P-CAP arm had 1 PR and 8 SD for an overall response rate of 64%, while the CAP arm had 0 PR and only 3 SD for a response rate of 27%.

In addition, looking at the overall survival, the data favoured the P-CAP arm a MOS of 15.3 weeks compared with 6.8 weeks for CAP alone.

Typical adverse events reported appeared to be relatively mild:

"The P-CAP combination was well-tolerated with Grade 3 and 4 adverse events of > 10% incidence for the P-CAP arm versus CAP arm as follows: anemia (15% vs. 0%), fatigue (0% vs. 11%), abdominal pain (5% vs. 11%), and hand-foot syndrome (30% vs. 0%)."

Perifosine is also being developed for the treatment of multiple myeloma, which is currently in phase III development.  The compound is an inhibitor of Akt and phosphoinositide 3-kinase (PI3K), as well as other pathways such as JNK and MAPK. These pathways are associated with programmed cell death (apoptosis), cell growth, cell differentiation and cell survival as shown in the diagram below:

Picture 1
Source: Aeterna Zentaris

Interestingly, this morning's news brought an announcement that the FDA have granted Fast Track Designation for the perifosine in advanced, refractory colorectal cancer.  Based on the phase II data, a randomised phase III trial is expected to begin this quarter based on a similar trial design.

Clearly, it will be a little while before the data is available, but definitely one to watch out for in the future given new therapy options are always needed in the refractory cancer setting.

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Day off for Easter Friday

By on April 2, 2010

My buddy Rob Z posted these beautiful Hot Cross Buns on Twitter this morning.   Made me homesick and a nice reminder of an ages old English Easter Friday breakfast tradition.  

This is a day to take off work and reflect.  The sun is also shining.  Have a great day, everyone!

 
image from gallery.me.com
Source: Robert Zarywacz 

The blog is closed until Tuesday, but I might post an Easter egg on Easter Monday 🙂

Thought for the Day

By on April 1, 2010

The 4-Hour Workweek, Tim FerrisImage by davemc500hats via Flickr

Recently, I've been re-reading Tim Ferriss's excellent book, The 4-Hour Workweek.  It's such a good book packed with tips and useful information that every time I read it, I learn something new and start implementing the ideas in practice.  They actually make a difference, too!

Sometimes, just getting things done in Pharma is half the battle, considering the seemingly ingrained inertia, procrastination and bureaucracy.

I was pondering a client's problem regarding various bottlenecks and wondered how they had the patience to keep chipping away at the coal face. Here's one snippet I came across yesterday in Ferriss's book that has made me think a lot about Pharma inertia:

"What you do is infinitely more important than how you do it." 


Paralysis by analysis is endemic in this industry and leads to torpor in decision making as well as the dreaded management by consensus because of an ingrained fear of failure. What happens is akin to herding cats, in other words very little effective action occurs.

There is though, an enormous difference between running a franchise or brand or business and busy-ness.

Sometimes Nike is right: Just Do It.

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Innovation, differentiation and me-toos

By on April 1, 2010

While everyone else is trying to spoof an April Fool post, here’s some real food for thought via an awesome cartoon from Tom Fishburne:

What are you doing to differentiate yourself from the competition by creating something new and innovative?  Or would you rather be one of the other little piggies?

This approach works as much for people and companies as it does for brands and drugs.

It’s also why we have a blog and not a static or glossy of fancy website: what you see is what you and get. You can also see what we do and how much experience we have in oncology from the daily musings and insights.

 

ArQule's ARQ 197 plus erlotinib has mixed early data in lung cancer

By on March 31, 2010

c-MET inhibitors are a class of drug I've been interested in and following for a little while.  All are in early development and most of the big oncology players have one lurking in their pipeline. The concept of blocking c-MET is appealing because of number of studies have shown that activated c-MET mutations may be associated with poorer prognosis and induce resistance, ie an escape route for cancer cells. 

Looking at the pathways we can see MET has a strategic position in the signalling as an upstream receptor, which makes it a good potential target, much in the way EGFR, VEGF have shown proof of concept to date:

image from www.n-of-one.com
Source: n-of-one

It was therefore interesting to see a press release this morning proclaiming:

"Biotechnology company ArQule Inc said its experimental lung cancer drug showed positive results in a mid-stage trial, sending its shares up 57 percent in pre-market trade.
The drug, ARQ 197, when used with another lung cancer drug, erlotinib, showed a 66 percent improvement in median progression-free survival (PFS) – the time without cancer growth or death – in patients with advanced, refractory non-small cell lung cancer, ArQule said."

66% improvement would normally get me very enthusiastic, but after the recent glut of promising phase II data leading to flops in phase III, I'm feeling a little more cautious and circumspect.  Especially when, on further examination it appears that:

"The median PFS was 16.1 weeks in the ARQ 197 plus erlotinib arm, compared with 9.7 weeks in the erlotinib plus placebo arm, the company said in a statement.
The company, however, said the difference in PFS between the two arms did not achieve statistical significance by applying a log-rank test."

In other words, there is no significant difference between the two groups!
Hmmm, why make a lot of noise about it then?  Perhaps that's a little harsh, but achieving significance is the sine quo non of clinical trials and that's a very black and white number.  Breathless hypey press releases do make me cringe though.

I suppose we can say that these are promising, but very early, data and more time will tell whether the approach will have any meaningful impact on survival and outcomes.  Perhaps some biomarker analysis will help determine which people with non-small cell lung cancer were most likely to respond to the combination, potentially improving the efficacy and significance.

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Genvec's TNFerade fails in phase III trials for pancreatic cancer

By on March 31, 2010

It's been a busy week on the road here at Icarus and today and tomorrow are no exception, so finding time to blog is a little more challenging.

Yesterday, I got back from a biomarker symposium in Princeton to find that my Twitter and almost everything else Pharma related were full of Genvec's announcement that their phase III trial for TNFerade was being discontinued in pancreatic cancer. 

It's not really a drug, more an experimental gene therapy, that according to Genvec:

"Acts as an adenovector, or DNA carrier, which contains the gene for tumour necrosis factor-alpha (TNFα), an immune system protein. It is directly injected into the tumour. After administration, TNFerade stimulates the production of TNFα in the tumour."

The abandonment of the trial isn't really big news though, as the drug previously failed in melanoma and other cancers, despite the magic words, "promising phase II data."  Let's face it, pancreatic cancer is also probably one of the toughest nuts to crack out there in the oncology world. Sadly, it was doomed to failure from the beginning; I would have been more surprised had it actually worked.

Genvec have a raft of other trials that are either currently enrolling people with various cancers or have recently finished enrollment; I wonder what the fate of the overall program will be given the repeated negative results?

At the beginning of this month many pharma and biotech pundits smiled at the 'beware the Ides of March' quips on Twitter, but by the end of March they seem much more accurate than one may realise!  

Looking back through the months posts, there were several spectacular phase III flops from Pfizer and Roche, Roche's ocrelizumab and AstraZeneca's cediranib bit the dust, the ODAC meeting on 22nd was brutal for Cell Therapeutics and ChemGenex with neither getting approved, Antisoma's ASA404 crashed on Monday, Merck KGaA are reviewing the EU cardiac data for Erbitux, which may also have implications for BMS and ImClone in the US.  Yikes, I could go on…

Let's hope that April and May bring more positive news to talk about.

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Bioclinica biomarker symposium in oncology and neurology #bioc

By on March 29, 2010

Tomorrow, I will be in Princeton, NJ for a one day meeting focused on addressing the Current and Innovative Imaging Biomarkers in Neurology and Oncology Drug Development, hosted by Bioclinica.  

If you have any questions about the event, please send a tweet to @maverickNY and I will do my best to answer them on Twitter. Comments on this widget will not be monitored until the end of the day as wifi and internet access is likely to be limited and I'll be tweeting from my iPhone.

If interested, you can follow the synopsis from the live tweets below by clicking on the Play triangle:  

The event will involve some interesting speakers including the following:

Cornelis van Kuijk, MD, PhD 

– Professor and Chair Department of Radiology, VU University Medical Center 

Frederik Barkhof, MD, PhD 

– Professor in Neuroradiology
Radiology and Image Analysis Centre, VU University Medical Center 

 Adriaan A. Lammertsma, MD, PhD 

– Professor of medical physics and positron emission tomography (PET)
Nuclear Medicine & PET Research, VU University Medical Center 

 Ali Guermazi, MD 

– Professor of Radiology
Director of Quantitative Imaging Center
Boston University School of Medicine
Section Chief, Musculoskeletal Imaging, Boston Medical Center

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Antisoma and Novartis lung cancer drug ASA404 flops in phase III

By on March 29, 2010

This morning I did a double take at an email alert that flashed through my email:

"ATTRACT-1 phase III trial of ASA404 halted following interim analysis"

Ugh, that's not good news considering the phase II data previously discussed in January looked very promising with a solid improvement (source data), ie median time to tumor progression was 5.5 months by investigator assessment and median survival was 14.9 months when used in combination with carboplatin-paclitaxel compared to the standard alone.

The Antisoma press release was very downbeat and clearly they were not expecting to receive any more funding from their partner, Novartis:

"The planned interim analysis of data from the ATTRACT-1 phase III trial of ASA404 in previously untreated non-small cell lung cancer (NSCLC) has shown that continuation of the trial would be futile, as there is little or no prospect of demonstrating a survival benefit with ASA404 in this setting. The ATTRACT-1 trial will therefore be halted."

Novartis (a client, but not on this particular agent) bought the global rights to ASA404 (vadimezan) from Antisoma, a British company, approximately three years ago. ASA404 was leading a new class of chemotherapy agents known as vascular targeting or disrupting agents, designed to inhibit angiogenesis and disrupt the flow of blood to tumours. The concept works in a different way to Roche and Genentech's bevacizumab (Avastin), which starves tumours from growing new blood vessels and proliferating the cancer mass.  ASA404 exerts direct and indirect effects on endothelial cells rather than the VEGF receptor, as this diagram shows:

Picture 48
Source: Novartis Oncology

Novartis and Antisoma were also developing ASA404 in breast cancer as well as non-small cell lung cancer, so we'll have to wait and see what happens to that program going forward.  For now, the negative news in lung cancer meant that investors cleared out their shares, sending the stock into a major freefall this morning.

It's been a tough year for cancer drugs in lung cancer in 2010 already, following several spectacular rounds of futile data from Pfizer's figitimumab, Novelos's NOV-002 and now ASA404, all of which had promising but early data in phase II, only to stumble in phase III.

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