Although small molecule drugs remain the standard treatment for disease, new strategies based on the engineering of proteins, genes and cells as therapeutic agents are poised to revolutionize medicine in the coming decades. Areas may include gene therapeutics, tissue engineering, stem cell biology, cell-based therapeutics and gene correction technologies.
India has been a knowledge society - the zero came from India without which there would be no computer technology - but somewhere along the line it lost its position. There is now a clear hope that the current biological revolution, with its genuine depth and great diversity, will provide the country with new opportunity. There have been early successes that can provide the motivation with Bharat Biotech producing the fist biotherapeutic molecule from India and the first protein against staphylococcus infection. It has received a global patent for Lysostaphin, which works on staphylococcus infection. The market potential is $ 12 billion. The biotechnology industry is currently a colossal melting pot of many ascendant technologies, including molecular biology, pharmacogenomics, biotechnology, tools, genomics, proteomics, bioinformatics, nanotechnology, telemedicine, electronics, fibber optics and computerization. The gelling of the industry offers new approaches to the discovery, design and production of drugs, vaccines, medical devices and diagnostics.
For India, the issue is production facilities and it is important for India to develop a manufacturing base. A manufacturing base is neither patentable nor reproducible. What is also needed is an interdisciplinary approach, which is the beauty of the biotechnology field and without which there would be no Lysostaphin. Biotherapeutics is thus a complex matte, of funds among others. While companies such as Chiron can make huge investments. India is a land of the poor and there are no financial institutions giving money for R&D. One has to do one's best within these constraints. That is the challenge for India.
For global pharmaceutical and biotechnology industries, the primary value driver of the genomic era will be an explosion of targets. Today's 400 or so targets are estimated to increase to at least 4,000 during the next decade. The $300 billion pharmaceutical market could grow to $3 trillion by 2020. These targets will be used both as diagnostic and focal points for the development of new precision drugs.
There is also the risk factor to consider. The drug discovery value chain can be broken down into five stages: from target discovery (5000-10,000) to lead discovery (500-1000) to clinical trials, one has about five from the original 10,000, making it to phase III and, possibly, one goes to the manufacturing stage, to the market. The advantages lie in the advancements in genome research, which offer excellent databases. A comprehensive microbial resource contains 75 organisms, 74 completed and one incomplete genomes, 21 TIGR genomes, 54-externally sequenced genomes: 13 archaea and 62 bacteria.
Simplistically, the biotherapeutic business features generic biotherapeutics that is a pre-genome business and new biotherapeutics that is a post-genome. The question is how much is one lagging behind, even with pre-genomic biotherapeutics. Consider the case of Insulin that was approved in 1982 and companies are still struggling to come out with insulin. There are multiple approaches to biotherapeutics; natural products can be biotherapeutic. So can stem cells, improved and modified vaccines, proteins, genes and monoclonal antibodies. Not just protein alone. One has to look at the bigger picture. Natural products as biotherapeutics include plant sources such as taxol and trypsin inhibitors, animal sources such as immunoglobin produced by horses and cow urea and through the mining of microbial diversity. This has traditionally been used for small molecule but has not been exploited from the biological and therapeutic points of view. Most of it is used for antibiotics.
Therapeutic proteins and protein-based drugs mostly occur naturally in proteins and can be replaced or supplemented in the body for deficiencies or defects. They signal the body to initiate or cease a biological function. Among others signaling the body to initiate or cease biological function are insulin and TPA. Therapeutic proteins and protein-based products represent a promising class of drugs with sales in 2000 exceeding $20 billion.
Antibodies are an exploding field and are finding applications in therapeutics as drug delivery vehicles, diagnostics and imaging and in drug discovery research for both screening and validation for targets. While only 10 monoclonals have been approved so far, there are more than 100 antibodies in clinical trials and hundreds more in preclinical development. A conservative estimate points to about 1,100 biotherapeutics products currently in preclinical studies. Therapeutic antibodies should constitute nearly 20 per cent of all biotech drugs in development. One has to wait and watch as to when it will exactly happen.
A stem cell, which everyone is talking about these days, is the mother of all cells. It differentiates between the different environments that it is placed in and reproduces it. It is pluripotent or multipotent and can be used to correct certain things. Embryonic stem cells are the best-studied examples of pluripotent stem cells. Embryonic stem cells can be propagated indefinitely in an undifferentiated state. They also differentiate into all cell lineages. Stem cells form the basis of several strategies for gene therapy. Stem cell research promises yet another horizon in the world of molecular biology research owning to differentiation of cells due to differential expression pattern. This shows a new hope for healthcare.
Gene therapy is the ultimate end game of genomics whereby defective genes are simply identified and repaired. Gene therapy is a therapeutic technique in which the generic elements such as the cDNA for the gene of interest, antisense oligonucleotides or ribozyme are transferred into the tissue of a patient using viral and non viral gene delivery agents with a subsequent change in gene expression.
Vaccines as therapeutics, for Hepatitis B infected patients, for instance, would see a 200 times better attachment of the CpG motif and additions of other genes. This would be better than even Interferon in terms of therapy. For chemical modifications, therapeutics induces immunity. The production of therapeutic molecules takes the bacterial, yeast, tissue culture, chemical synthesis route and transgenic animals and plants are used now for biotherapeutics.
On the formulation side, the strategy for most western systems now is to beat the biogenerics segment. The complexities of biogenerics will change with the formulations strategies that now feature low dose, reduced dose, increased stability (increase half life), safety to humans (immunogenecity), protected IPR for a longer period, and technologies which include, pegylated, hydrogel, microsphere, nanotechnology and complexing with lipid. One way for the US market to beat the biogenerics market is to hold the patents rights by changing the formulations strategy.
There are regulatory constraints around biogenerics or therapeutics and thee is the non-regulated market in process development as in India, with too many ministries and too many approvals needed, making the minimum time for approval three years even for established products. Regulated markets have difficult IPR regimes for formulations and there are regulatory bodies such as the FDA in the United States. However, there are no rules like the ANDA for biotherapeutics as yet. The situation will get complicated unless the Congress passes a bill to change things. Unless the USA approves, other countries will not and it is going to be very difficult for a biogeneric company to fight in the market. This is a situation waiting to develop.
Biotherapeutics at Bharat Biotech is looking at three different approaches: bacillus, various strepto organisms and staphyloccus in the anti-infective segment. What makes spore-forming bacteria survive in adverse conditions? That is very important for the understanding of the impact of biological warfare. Some molecules have been isolated and protein may be a drug target here. Bharat Biotech has some success in this. Work is also being done in the anti-infective and the thrombolytic area with streptokinase, a new molecule, which was patented five years ago in the USA. The novel kinases had thrombolytic properties. Finally, there is the anti-infective segment with Lysostaphin and other lytic genes. Lysostaphin has been isolated in collaboration with CBT and Bharat Biotech is working with trying to pull out lytic genes from other genomic databases. There are no new genes but two have been cloned. The point is that all this needs visionaries. The good news is that India seems to have them now.
-- The author is Chairman and Managing Director, Bharat Biotech International Ltd, Hyderabad