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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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June 4, 2007

Phase Zero?

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Posted by Derek

We have a new phrase to toss around in in the industry: "Phase Zero". That's what they're calling a recent trial of an anticancer drug from Abbott (ABT-888), which was tested in humans before any safety dosing (Phase I) had been done.

So, how exactly can you do that? By giving extremely small amounts of the drug, that's how, and looking to see if you can detect a change in some marker for eventual efficacy. In this case, the marker was inhibition of the activity of PARP, poly(ADP-ribose) polymerase, which is involved in the cellular response to DNA damage. Inhibiting it should make cells much more likely to die once such damage had been detected, which one of many such signals that cancer cells tend to ignore under normal conditions. Abbott's drug seemed to do the trick, so work on it will continue.

The good part of this is that the drug got into humans more quickly than usual, and that its mechanism of action has now been verified (to a first degree of approximation, anyway - it hits the target). This should make a company a bit more confident about moving on to larger trials, and could potentially weed out losers early in the game.

But there are bad parts, too. For one thing, the patients in a phase zero trial have no hope of benefit from the drug: the dose is just too small. The small doses could give results that (for better or worse) aren't relevant to the later real-world ones, too. Another problem is that reliable biomarkers are thin on the ground despite great sums of money being spent to find and validate them. If you're going to let the future of your drug ride on one of these trials, you'd better be confident that you know what it's telling you. (And if you're not going to let the future of the drug ride on a phase zero trial, why are you running one, eh?)

What would be worth knowing is how many drugs fail because of lack of effect on their intended target, as opposed to those which hit the target but still have no effect. You'd also want to know: of that first group, what portion are going to be amenable to robust biomarker studies. Those two fractions would tell you how much of an impact this whole idea will have. Right now, I think the error bars are way too large to make a prediction. . .

Comments (10) + TrackBacks (0) | Category: Cancer | Clinical Trials


1. Chrispy on June 4, 2007 9:34 PM writes...

Perhaps Phase 0 would also apply to microdosing, where a subclinical dose of radiolabelled compound is given in order to assess its bioavailability and metabolism.

My understanding is that the kinetics remain first order down to low doses -- like 1/100 -- anyone know if this is true?

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2. Petros on June 5, 2007 1:57 AM writes...

The term Phse 0 is not new, although the context applied in this case is very different from that used previously.

Some years ago Pharmagene (noow Asterand) coined teh term to describe the studying of novel drugs on human tissue i.e. a preclinical study. While Roche's website used to use the phase 0 term to indicate those compounds which were in preclinical development (This category are now no longer listed).

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3. Kay on June 5, 2007 7:37 AM writes...

The fact that Abbott allowed NCI to fiddle with 888 indicates that the compound had no path to the clinic (we assume that Abbott is not so poor that it is forced to work with NCI). In this case, this is all upside for Abbott.

Because our current in vitro and animal-based approaches are so effective, there is no reason to take this level of risk.

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4. Keith Robison on June 5, 2007 8:14 AM writes...

Phase 0 has also been used to describe the validation of a pathway biomarker in a disease without any drug exposure.

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5. Morten on June 5, 2007 1:27 PM writes...

"The NCI is already conducting a second phase 0 trial, using an imaging technique rather than biomarkers, and is planning a third."
I would think that PET-imaging to look at BBB permeability would be the most useful application of phase 0 trials. I think IMAnet in Uppsala killed some drug already on the market because they showed that there was only BBB permeability in some humans (and apparently not enough).
Might be good for cancer as well if you expect the drug to target cancer cells.

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6. Groby Lington on June 5, 2007 2:25 PM writes...

This may not be so much to determine if the target is being hit but rather to provide an early dose validation of the biomarker for its subsequent use in Phase I and 2 studies where one can correlate dose level with toxicities and efficacy.

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7. Oren Grad on June 5, 2007 8:53 PM writes...

NCI's detailed explanation of what they mean by Phase 0 is here.

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8. Groby Lington on June 6, 2007 12:31 PM writes...

This excerpt from the useful NCI link (thanks Oren) seemed relevant here:

There are several different types of phase 0 trials, ranging from those that examine new drugs to those that test new imaging agents. Some examples include:

* Testing to see if a new drug that was developed in the lab can bind to, and inhibit, its target in humans
* Provide PD and PK data prior to definitive testing in more people
* Refine what type of biomarker is most effective using tumor tissue
* Determine which of two agents is the most promising
* Using a variety of novel imaging technologies, determine the extent of drug that is distributed in the body and whether it effectively acts upon its target

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9. Nilesh Jadhav on October 3, 2007 9:11 AM writes...

Phasse zero study not only examine safety and effectveness ,insted they gather data on the targetting, action and metabolism of adrug in the body.

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10. Dr. Swapnil bhowaet on November 9, 2009 11:56 AM writes...

Exploratory IND studies are clinical trials conducted early in phase I (hence, the term phase 0) that involve limited human exposure and have no therapeutic or diagnostic intent.2 The purpose of the phase 0 study is to assist in the go versus no-go decision-making process of a drug’s fate earlier in the development process, using
relevant human models instead of relying on sometimes inconsistent animal data, thus helping to confirm end points such as mechanism of action, pharmacology, bioavailability, pharmacodynamics, and metabolic
microdose assessments. These studies of novel agents expose a small number of patients (perhaps 10 or fewer) to a limited duration (eg, 7 days or less) and dose (in the range of one 100th of the dose required to yield a pharmacologic effect of the test substance with a maximum dose of _ 100 _g). They are conducted before the traditional phase I dose-escalation safety and tolerance studies. By not having the traditional phase I objectives of toxicity and dose finding, phase 0 studies can be conducted early in the development process and are actually considered more of a discovery, rather than development, tool. There must be several considerations before initiating a phase 0 trial, given that not all novel agents will be appropriate for pre–phase I analysis. To
evaluate target effect, a biomarker must be known and an assay to measure it must be developed and validated before study initiation.6 It is imperative that proper sample handling be acknowledged, and if a
surrogate is being used, that it gives meaningful results relative to the tissue/organ target of attack. The ethics of doing phase 0 trials must also be considered carefully. These trials have no therapeutic intent and often will require significant invasive procedures. They have a finite treatment duration and, theoretically, are not in the range of efficacious dosing. Fewer toxicology data are necessary, so there is some concern that this limited
toxicology will be insufficient and not well defined in every drug scenario to maximize patient safety. The patient must be made aware of the investigational nature of these studies, the lack of therapeutic intent, and the limited toxicology and safety testing.

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