Info

6-12 years in discovery

4-6 years in development

r Slow, expensive process (10 to 20 years, $500M) r Often trial and error r Time-consuming and inefficient r Slow, expensive process (10 to 20 years, $500M) r Often trial and error r Time-consuming and inefficient

Fig. 4.6. Traditional View of Drug Discovery( Reprinted with permission from Nature Publishing Group, London, England. From Graph in Myers S, Baker A. Nature Biotechnology 2001;19(8):727. Drug Discovery - an operating model for a new era.)

(i.e., it still needed to be optimized). For one, it was a racemic mixture of two stereochemical isomers, left (L) and right (R) handed versions of the same compound, but only the L isomer was an effective inhibitor of HMG-CoA reductase. Using specialized manufacturing techniques (running certain reactions at temperatures below -80°C), a procedure was developed during the transition to development for synthesizing only the L isomer in large scale, a process that took 3 weeks from raw materials to final product. Also during this time, studies were conducted in animals to demonstrate that lowering cholesterol level was beneficial (target validation) and that CI-981 had clinically desirable properties (lead validation). By 1989, the compound was ready for clinical testing and, in 1997, Lipitor® was approved by the FDA. From start to finish, Lipitor's discovery and development took about 15 years.

As is evident from the Lipitor® example, discovery and development are not as sequentially oriented as the earlier slides suggest. Instead, the process has evolved into a more integrated and overlapping approach that seeks to streamline the identification of new targets and therapeutics (Fig. 4.7) [5]. It is thus more common (and more beneficial) that target validation occurs in parallel with lead discovery and lead optimization, with one function helping to confirm (validate) the other. Similarly, the different disciplines (biology, chemistry, and pharmacology) typically operate in a more integrated fashion, facilitating the exchange of information and conducting earlier studies in animals, thereby shortening the discovery and development timelines (3-5 years vs. 6-12 years) and possibly saving research costs. The real financial savings occur because accelerated research has potentially consumed less patent life before approval and extended it after approval, yielding higher total sales revenue before generic substitution would occur.

Such an approach also allows for the early evaluation of new biomarkers, biochemical or biological surrogates that may be used as early indicators of efficacy or toxicity. The availability of such biomarkers is extremely important, as they can greatly accelerate clinical development by providing alternative and less time consuming and less costly end points for further development decisions. One such marker is prostate-specific antigen (PSA), a tumor-specific marker currently being explored in many clinical trials in patients with prostate cancer as a possible surrogate efficacy end point [10]. PSA levels are known to be elevated in patients with prostate cancer, but if it can be demonstrated that low or declining levels correlate with drug therapy and clinical benefit, the testing of new anticancer agents would be greatly facilitated. The biomarker must be validated for its disease association, and it must change under the influence of the produst to be approved. Furthermore, the regulatory bodies must also agree for the biomarker to be used in INDs and NDAs.

And why is it important to rapidly and efficiently screen and develop new drugs? Because the process itself takes a long time, it costs a lot of money, and most drug development efforts ultimately fail. These concepts are perhaps best illustrated by reviewing the efficiency with which new drugs get through clinical trials to approval (Fig. 4.8). For every small molecule that reaches the market, more than 5,000 compounds are synthesized, about 500 of these make it to preclinical studies, 10 make it to development, and 5 enter clinical trials. Similarly, although biologics give the appearance of being more efficient than small molecules (1 therapeutic approved

Target discovery

Target validation

Lead discovery

Transition to development

Development

Target validation

0.5-1 years

0.5-1 years

0.5 - 1 years r Guided process driven by disease biology Overlapping steps facilitate early decision making

Fig. 4.7. Integrated View of Drug Discovery (Adapted with permission from Nature Publishing Group, London, England. From Graph in

Myers S, Baker A. Nature Biotechnology 2001;19(8):727. Drug Discovery - an operating model for a new era.)

5,000 Synthesis -

5,000 Synthesis -

500 Preclinical 50

10 Development 10

5 Clinical 5

1 Approval 1

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