Repercussions of Toxicogenomics Project

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The outline of the project

Toxicogenomics is an emerging field in which elucidation of the mechanism of toxicity and prediction of toxicity are based on comprehensive gene expression data obtained from animals or cultured cells exposed to chemicals. Toxicogenomics has two strategies, i.e., 1) forward toxicology that elucidates the mechanism of toxicity based on gene expression changes resulting from toxicity, and 2) reverse toxicology that predicts toxicity based on the comparison of gene expression changes caused by known toxic chemicals. The Toxicogenomics Project is a cooperative research project joining both the nation and private companies to create a toxicology database that enables both forward and reverse toxicology. In the project, the liver and kidney are selected as the targets, since most clinical toxicity emerges in these organs. Test chemicals (medicines) are administered to rats or exposed to cultured cells to get gene expression data in the target

organs of the animals or cells, and the changes in the traditional toxicological markers are also collected from the animals. Our goal is to establish a forecasting system of toxicity in the early phase of drug development.

The objective of the project

In order to contribute to progress in medical treatments via the supply of innovative new drugs with high efficacy and safety, pharmaceutical companies actively conduct programs of research for drug development. However, it is practically impossible to avoid unexpected side effects. If the possible side effects that occur in clinical use are able to be predicted at the early stage of drug development, drug companies can assess the safety of new chemicals before the large scale non-clinical or clinical study, and subsequently save costs and supply safer medications for the patients. Along this line, the National Institute of Health Sciences and 17 pharmaceutical companies started a 5 year collaborative project in 2002, in an effort to contribute to the development of drugs with less adverse effects by elucidation of the interrelationship between toxicants and the expression of genes.

The practical aim is that about 150 chemicals are to be administered to rats or exposed to rat and human primary cultured hepatocytes, and the gene expression profiles in the liver and kidney of the animal or in the cultured cells are to be comprehensively analyzed by microarray. A database created by the accumulated gene information and a system forecasting the safety of candidate chemicals in the early stage of drug development is proposed.

Repercussions of Toxicogenomics Project

The success of our Toxicogenomics Project will contribute in these areas.

Contribution to human society

In the course of drug development, pharmaceutical companies estimate the toxic effects of drugs through many non-clinical studies, including genotoxicity, acute toxicity, long-term toxicity, reproductive toxicity and safety pharmacology, to ensure the safety of drugs before administered to humans. However, with the present technology, it is practically impossible to completely prevent unexpected side effects in the clinical field. Although it rarely happens, it has been observed that unexpected adverse effects first emerged even after the drugs were distributed in the open market because of their low incidence in the small-scale clinical trial.

At present, the results of non-clinical research are extrapolated to humans by the characterization of the toxicity observed in test animals. In the toxicogenomic approach, analysis of gene expression in animals or cells exposed to the chemicals leads to the elucidation of the mechanism of toxicity and the forecasting of potential toxicity. Applying this new strategy of toxicological science to drug development, peer understanding of the mechanisms of toxicity and prediction of toxic effects would be possible.

Once the forecasting system for toxicity is established by the Toxicogenomics Project, it will be possible that chemicals with high risk of side effects would be eliminated before entry into the clinical trial. It would reduce the risk of unexpected side effects and subsequently contribute to the assurance of safety for the patients. The time and cost of drug development are then reduced, and therefore, the total cost of medication is decreased.

The construction of a large scale database for forecasting the safety of drugs is quite difficult for an individual institute, academic department, or company due to the limitation of funds and time. The Toxicogenomics Project, as a joint program of the nation and private companies, enables the creation of a large scale database by sharing the expertise, talents, and cost among the members. This achievement will provide a common research basis that will propel research in the safety of drug development.

Contribution to toxicological science

Classical toxicology elucidates the mode of toxicity of a certain chemical by the measurement of the changes (body weight, clinical tests, functions of organs, histology) in a living body that is exposed to the chemical. This strategy is quite effective for the characterization of the apparent toxic effects, but it is not always useful to predict potential toxicity that has not yet emerged or to find out very subtle signs of toxicity. On the other hand, it is considered that changes in gene expression occur before the physical changes emerge. Therefore, it is expected that the toxicogenomics technique would allow the prediction of potential toxicity or to sensitively detect a small change that leads to toxicity.

For the elucidation of the mechanism of toxicity, molecular biological information is quite useful. Toxicogenomics enables a more precise risk assessment by the understanding of the mechanism of toxicity. This achievement would produce a rapid advance in toxicological science.

Contribution to drug development

If it is possible to predict the potential toxicity in the early stage of drug development, drug companies can avoid the huge financial losses due to withdrawal of drugs from the clinical trial or the market. This saves resources and stabilizes the management of the drug company. Moreover, efficient development of safer drugs is the social mission for the pharmaceutical companies.

Recently, the bottleneck of the selection for the most suitable lead compound is shifting from the screening for efficacy to that for toxicity. Effective estimation and prediction of toxicity based on the achievement of the Toxicogenomics Project will be useful in future drug development. Progress in understanding the mode of the medical effect as well as the toxicity of drugs at the level of gene expression by toxicogenomics will improve the extrapolation from animal tests to humans, and it will be possible to re-evaluate such drugs that had unique pharmacological activity but dropped out from development because of toxicity.

Copyright© 2007 Toxicogenomics Project in Japan

Best Regards

Mohammad Bashaar

From: Dr.Manoj Swaminathan <drmanoj@...>Subject: Introduction to the topicnetrum Date: Wednesday, July 16, 2008, 8:43 AM

Hi NetRUMians,

So, the topic "Repercussions of pharmaceutical company take over in developing economies" begins today..

Introduction:

Recently the Ranbaxy acquisition by the Japanese Daiichi Sankyo (A deal worth over Rs.10,000 Crores) has raised many doubts and concerns among the people from the healthcare industry. Whether this is good or bad for the Indian pharma industry is certainly a debatable issue.

It had been only few weeks since the news of Orchid Pharma's possible acquisition by Ranbaxy that we suddenly came across the Daiichi Sankyo's acquisition of Ranbaxy...

Although the current topic is related to all the developing economies of the world, we will concentrate on the Indian aspect of it. The repercussions due to the take-overs in India can, to a large extent be generalized to all the developing economies of the world.

Indian Pharma Industry

Globally the Indian pharmaceutical industry ranks FOURTH in terms of volume (with an 8 per cent share in global sales), 13th in terms of value (with a share of 1 per cent in global sales) and produces about 25 per cent of the world's generic drugs (in terms of value).

(Source: http://www.indiainb usiness.nic. in/industry- infrastructure/ industrial- sectors/drug- pharma.htm )

Mergers & Acquisitions (M & A):

Currently India is experiencing three types of M & A:

1. Indian company taken over by another Indian company

2. Foreign company being taken over by an Indian company and

3. Indian company being taken over by a Foreign company..

Besides these, there have been instances where certain products are being sold to another company, a particular division gets getting sold and minority stake sales..

Reasons behind the acquisition of generic companies:

"By 2012, more than three dozen drugs will lose patent protection – many of them blockbusters like Lipitor, the cholesterol lowering drug which is the biggest selling drug ever. Combined annual revenues of large drug companies from these drugs are a staggering $70 billion. This large number of patent expiries will open up unprecedented opportunities for generic drug companies, who profit by selling cheaper versions of patented drugs in unregulated markets and in regulated markets when the drugs go off-patent. Many of these generic companies have been preparing for this wave of patent expiries for a long time now".

(Source: http://www.domain- b.com/companies/ companies_ r/Ranbaxy/ 20080612_ ranbaxy.html )

Sincerely,-- Dr.Manoj Swaminathan MBBS, MPHPharmacovigilance PhysicianSciformix Technologies (P) LtdMLD Complex, MIDC, Andheri (E)Mumbai 400093India.Tel: +91-22-67304339