Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘R&D’

Why do some cancer drugs work and others don't?

By on August 12, 2010

The news yesterday from Amgen that panitumumab (Vectibix) failed in Head and Neck cancer got me thinking.  Why did it fail where cetuximab (Erbitux) succeeded? They're both monoclonal antibodies to EGFR, so that makes it rather interesting.

Many of you will remember that bevacizumab (Avastin) and Erbitux were both approved within a month of each other for colorectal cancer, both monoclonals, to VEGF and EGFR respectively.  That was after a long string of failures for anti-angiogenesis compounds.  Subsequently, vatalanib (PTK787), a small molecule tyrosine kinase inhibitor (TKI) of VEGF from Novartis failed in the same indication and did not achieve statistical significance in survival.

It gets even more interesting when you consider prostate cancer as another example:

  1. Abbott's atrasentan got villified at it's ODAC meeting and never received approval.  In a few months, however, we will hear what happens in the phase III trial for another endothelin-A inhibitor, zibotentan (AstraZeneca).  The phase II data showed a difference in OS, but not PFS, so who knows what will happen with the phase III study?
  2. Avastin also failed to achieve a survival advantage in prostate cancer, but does that mean that other VEGF inhibitors, such as sanofi-aventis/Regeneron's aflibercept (VEGF-Trap), will fall the same fate?  We don't know yet, but as far as I know, that one's still alive and kicking.

I find it fascinating trying to work out why some drugs work and some don't even in the same class in the same indication.  It could be all sorts of reasons:

  • Dosing
  • Scheduling
  • Patient population
  • Study design
  • Drug combinations
  • Compound structure
  • Availability of suitable biomarkers
  • Indications

Or one of many many other things or combination of reasons.

And there there is the related issue of 'pure' inhibitors (single target such as VEGF or BCR-ABL) versus multi-kinases or monoclonals (more than one target such as VEGF, EGFR, PDGF or FGFR, for example).  Does it make a difference in efficacy and tolerability, will they affect outcomes differently?

Hopefully, we can learn from the failures to date for the future, allowing us to design better drugs and trials that have a more positive impact on outcomes.

Curiousity is killing this cat… R&D is such a crapshoot sometimes.

 

Somatic mutations and pathway alterations in cancer

By on August 5, 2010

"The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics."

So began today's journal article from a letter to Nature (link below) from scientists at Genentech.  They went on to state that they have looked at:

"The identification of 2,576 somatic mutations across 1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes.

Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets.

Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for Ga subunits in multiple cancer types."

The goal of this type of analysis is to look for patterns and alterations associated with disease and try to figure out which are potentially druggable targets for drug development.  The researchers went on to note:

"Our study represents a substantial expansion of the knowledge base of cancer somatic mutations. Of the 845 genes with proteinaltering mutations identified in this study, 361 (43%), including 13 significantly mutated genes like TLR4, SPOP and NRG3, have not previously been reported."

image from www.flickr.com That's great news. Of course, it should be noticed that theory is one thing, but until a pipeline compound enters into clinical trials and we see the results of extensive studies, we won't know whether the target is truly a relevant one in human cancers or not.

Not all mutations may occur in every person though, as we have seen in lung cancer where some people might have an EGFR mutation, some an ALK mutation and so on. The secret to this approach is to start documenting the likely targets and go looking to see how many exist, which ones might be a critical driver and which ones are merely passengers.

Clearly though, it does help to have an idea of what the needles in the haystack might look light before going hunting for them to increase the chances of success.

Photo Credit: Yellow Book

 

ResearchBlogging.orgKan, Z., Jaiswal, B., Stinson, J., Janakiraman, V., Bhatt, D., Stern, H., Yue, P., Haverty, P., Bourgon, R., Zheng, J., Moorhead, M., Chaudhuri, S., Tomsho, L., Peters, B., Pujara, K., Cordes, S., Davis, D., Carlton, V., Yuan, W., Li, L., Wang, W., Eigenbrot, C., Kaminker, J., Eberhard, D., Waring, P., Schuster, S., Modrusan, Z., Zhang, Z., Stokoe, D., de Sauvage, F., Faham, M., & Seshagiri, S. (2010). Diverse somatic mutation patterns and pathway alterations in human cancers Nature DOI: 10.1038/nature09208

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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