ResearchBlogging.orgA link from writedit pointed me to a review of drugs that were approved in the US with an eye to how they were identified. Swinney and Anthony (2011) identified 259 agents that were approved by the US FDA between 1999 and 2008. They then identified 75 which were “first in class”, i.e., not just me-too drugs or new formulations of existing drugs or whatnot. There were 20 imaging agents, not further discussed, and 164 “follower” drugs.

The review also focused mostly on small molecule drugs instead of “biologics” because of an assumption that the latter are all exclusively “target based” discoveries. The main interest was in determining if the remaining small molecule drugs were discovered the smart way or the dumb way. That’s my formulation of what the authors term “target based screening” (which may include “molecular mechanism of action”) discovery and “phenotypic screening” type of discovery. As they put it:

The strengths of the target-based approach include the ability to apply molecular and chemical knowledge to investigate specific molecular hypotheses, and the ability to apply both small-molecule screening strategies (which can often be achieved using high-throughput formats) and biologic-based approaches, such as identifying monoclonal antibodies. A disadvantage of the target-based approach is that the solution to the specific molecular hypotheses may not be relevant to the disease pathogenesis or provide a sufficient therapeutic index.

A strength of the phenotypic approach is that the assays do not require prior understanding of the molecular mechanism of action (MMOA), and activity in such assays might be translated into therapeutic impact in a given disease state more effectively than in target-based assays, which are often more artificial. A disadvantage of phenotypic screening approaches is the challenge of optimizing the molecular properties of candidate drugs without the design parameters provided by prior knowledge of the MMOA.

You will note that this is related to some comments I made previously about mouse models of depression.

The authors found that 28 of the first-in-class new molecular entities (NMEs) were discovered via phenotypic screening, 17 via target based approaches and 5 via making synthetic mimics of existing natural compounds. To give you a flavor of what phenotypic screening means:

For example, the oxazolidinone antibiotics (such as linezolid) were initially discovered as inhibitors of Gram-positive bacteria but were subsequently shown to be protein synthesis inhibitors that target an early step in the binding of N-formylmethionyl-tRNA to the ribosome

and for target based approaches:

A computer-assisted drug design strategy that was based on the crystal structure of the influenza viral neuraminidase led to the identification of zanamivir

The authors even ventured to distinguish discovery approaches by disease area:

Evaluation of the discovery strategy by disease area showed that a phenotypic approach was the most successful for central nervous system disorders and infectious diseases, whereas target-based approaches were most successful in cancer, infectious diseases and metabolic diseases

Unsurprising of course, given that our state of understanding of nervous system disorders is, to most viewers, considerably less complete in comparison with some other health conditions. You would expect that if there are multiple targets or targets are essentially unknown, all you are left with are the predictive phenotypic models.

Of the follower drugs 51% were identified by target based discovery and 18% by phenotypic screening. This is perhaps slightly surprising given that in the cases of the me-too drugs, you would think target-based would be more heavily dominant. Perhaps we can think of a drug which initially looked to have property X that dominated but then in the phenotypic screening, it looked more like a property Y type of drug.

The authors take on this is that it is slightly surprising how poorly target-based discovery performed within a context of what they describe as a period in which there was a lot of effort and faith placed behind the target-based approaches. I suspect this is going to be in the eye of the beholder but I certainly agree. I can’t really go into the details but there are areas where my professional career is…affected, let us say…by the smart/dumb axis of drug discovery. It should be obvious to my longer term readers that I align most closely with animal models of various things related to health and neurobiology and so therefore you may safely conclude that I have a bias for phenotypic screening. And even in the case of the target-based discovery:

at least three hypotheses that must be correct to result in a new drug. The first hypothesis, which also applies to other discovery approaches, is that activity in the preclinical screens that are used to select a drug candidate will translate effectively into clinically meaningful activity in patients. The other two hypotheses are that the target that is selected is important in human disease and that the MMOA of drug candidates at the target in question is one that is capable of achieving the desired biological response.

Right. You still need good phenotypic models and ultimately you are going to have to pass human clinical trials. The authors further worry that this higher burden, especially knowing the MMoA is going to lead to some misses.

in the case of phenotypic-based screening approaches, assuming that a screening assay that translates effectively to human disease is available or can be identified, a potential key advantage of this approach over target-based approaches is that there is no preconceived idea of the MMOA and target hypothesis.

Ultimately I think this review argues quite effectively for an “all hands on deck” approach to drug discovery but it can’t help but come off as a strong caution to the folks that think that “smarter” (aka, “rational drug design”) is the only solution. Yes, this points the finger at Francis Collins’ big thrust for a new translational IC at the NIH but also at the BigPharma companies that seem to be shedding their traditional models-based, phenotypic discover research units as fast as they can. No matter which side you come down on, this is a great read with lots to think about for those of us who are interested in the discovery of new medicines.
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Swinney, D., & Anthony, J. (2011). How were new medicines discovered? Nature Reviews Drug Discovery, 10 (7), 507-519 DOI: 10.1038/nrd3480

The Seattle PI’s Big Blog (Covering Seattle news, weather, arts and conversation, along with a grab bag of stuff that’s just plain interesting) has an article up covering an animal rights extremist group’s billboard campaign in their fair city. What is interesting about this is the rather fair handed set of options they have chosen.

  • Eye opening. Glad they’re spreading the message.
  • Unfair and sensationalistic.
  • Disturbing, but it’s a message we all need to hear.
  • Just plain incorrect.
  • Boring. I wish [AR extremist group] would go back to naked demonstrations.

Naturally I encourage you to visit the poll and cast your vote.
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My point about this being a refreshing change can be best understood by reading this post.

The Nature News Blog has a bit on the recent meeting of the Committee on the Use of Chimpanzees in Biomedical and Behavioral Research. The NIH commissioned the Institute of Medicine to:

Explore contemporary and anticipated biomedical research questions to determine if chimpanzees are or will be necessary for research discoveries and to determine the safety and efficacy of new prevention or treatment strategies. If biomedical research questions are identified:

Describe the unique biological/immunological characteristics of the chimpanzee that make it the necessary animal model for use in the types of research.
Provide recommendations for any new or revised scientific parameters to guide how and when to use these animals for research.

Explore contemporary and anticipated behavioral research questions to determine if chimpanzees are necessary for progress in understanding social, neurological and behavioral factors that influence the development, prevention, or treatment of disease.

I was struck by a comment reported by the Nature News blog from a participant who objected to the scope of the study.

Read the rest of this entry »

My email box overfloweth with references to an article in the Chronicle for Higher Education penned by Lawrence Hansen, M.D., a pathologist at the UCSD Medical School.
Dr. Hansen is an animal rights extremist who came to national attention with a fight to eliminate dog physiology lab classes from the UCSD medical education program. Since that era, he has penned a number of editorials and opinion bits that make it clear he has a more general interest in stopping the use of animals in research.
or…some animals, anyway.

Read the rest of this entry »

I admit I am not a highly regular reader of Ed Silverman’s Pharmalot blog, although I do keep up with his Twitts and read the occasional post. So I have little knowledge of where he’s coming from on this issue. But he had a post that basically parroted the animal rights extremist’s party line without a smidgen of critical thought.

The background is that pictures of severely wounded monkeys got out from a scientific supply company. The animal rights extremist organizations are all over this. Dog bites man story. They are, of course, certain that these pictures provide smoking gun evidence indicting all of animal research and nonhuman primate research in particular, demonstrating the general incompetence and uncaring nature of the industry.

This is their a priori belief. The extremist organizations that want to halt all use of animals in research by any means necessary do not have their opinion changed by facts either supporting or undermining their arguments. They feel free to lie, misrepresent or otherwise play fast and loose with any situation. This is what they do.

Ed Silverman should know this.

In his blog post, Silverman makes at least two glaring mistakes. The most troubling one is this one because it is deployed by the author in a way that makes it sound as if he agrees with the charge.

Primate Products ceo Don Bradford recently told NBC that the conditions depicted in the photos were not caused by medical testing, but due to injuries caused by other animals, and the monkeys have since healed. But the Animal Rights Foundation of Florida does not seem to believe him

the second item is a direct quote from an extremist group- still troubling because it contains an unexamined accusation:

These serious injuries may have resulted from self-mutilation, experimental procedures, or fights between animals who had been improperly housed.

As if the beliefs of anti-research extremist groups have any bearing on anything of evidentiary or probative value. They are against research. They are against researchers. They are against medical advances that are made possible only through the use of animals in research. Period. There is nothing that can be said or proven with facts that will make them “believe” anything anyone who is in support of well regulated humane use of animals in research has to say. Facts are irrelevant.

Which is why, Ed Silverman, it is essential for those who are presumably interested in the facts of a matter to account properly for the opinions offered by the person who comes from an unfalsifiable, unassailable fundamentalist belief structure that is impervious to fact. In this case properly means “deeply suspicious”.

Fortunately, the Speaking of Research organization has an excellent bit up on their blog which underlines something anyone might have come up with on only a moment’s thought. Anyone who has a National Geographic level understanding of the natural world and the behavior of species, that is.

There are two observations relevant to my points about Ed Silverman’s dismal coverage. First, that macaque monkeys are, at times, socially aggressive organisms in their natural social and environmental niche- this frequently results in major wounding and even death. Second, that this means that the only “proper” housing that can guarantee zero wounding is single housing. And we all know how the animal rights groups feel about the propriety of that choice.

In other words, the animal rights extremist reaction to this situation betrays their usual profound misunderstanding of the natural world. It also illustrates their theologically driven desire to make the world we actually live in conform to some Utopian ideal in which all species are somehow equivalently enlightened and interacting as truly sentient (in the real sense of the word) organisms.

Science fiction is a nice read, but it is just a fantasy.

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Additional reading is a mere PubMed click away.

Or you can visit the American Journal of Primatology and use the search box for macaque

It does not require much effort to turn half-baked opinion into even minimally-informed opinion…assuming one is unafraid to have one’s uninformed views modified by facts, that is.

Of course there is no particular reason to think that bike racing celebrity types should be any smarter than your average Hollywood actor or even one of those ruthless self-promoting celebrities who you can’t quite figure out why they are famous.

Levi Leipheimer is a US professional cyclist who has become, over the course of a long career, a top talent with a long list of accomplishments. Recently his accomplishments have been in association with Lance Armstrong who is an absolute pitbull when it comes to battling cancer. I’ve mentioned before that following his Twitter gives you a whole new appreciation for how much this guy works at the whole LiveStrong charity.

And it isn’t like Levi is just a passive participant. He puts the name of some kid with “pineoblastomas, a rare and aggressive brain cancer that afflicts less than 2% of all juvenile brain cancer patients” on his bike. Or remembers the name of a junior high school counselor who fell to colon cancer in another race.

He sponsors and promotes “Levi’s Gran Fondo“, a charity ride to raise money for various causes including “The Lance Armstrong Foundation received a $10,000 donation from the GranFondo for their ongoing funding of cancer research”.

Research.
So what in the hell is he doing
tweeting this?

Odesssa and I hanging w/ @richroll and @jaiseed at the 30th anniversary [famous ARA wackanut organization-DM] Gala. Great night http://yfrog.com/3upsxnj

I’ve said it before…we really need to get Lance Armstrong focused on including animal research as part of his message.

Dr. Isis has a post up responding to a Protocol Review question “Noncompliance in survival surgery technique” published in Lab Animal [2010; 39(8)] by Jerald Silverman, DVM. His column is supposed to be in the vein of practicum case studies that are a traditional part of the discussion of ethical issues. Given X scenario, how should person A act? What is the ethical course of action? Was there a violation? Should it be reported/evaluated/punished.

We see these sorts of examples all the time in the ethics training courses to which we subject our academic trainees, particularly graduate students and postdocs.

These exercises frequently annoy me and this IACUC / Animals-in-Research question is of the classic type. Read the rest of this entry »