The quote by famous French writer Victor Hugo - "An invasion of armies can be resisted, but not an idea, whose time has come"- would aptly describe the status of enzyme therapeutics today. Indeed, it is time to reintroduce to the world the potential of enzyme therapeutics!

Pharmaceutical sector by 2020
The likely pharmaceutical sector scenario globally will be a revolution of sorts for all concerned - the global pharmaceutical companies, the healthcare decision makers and the patients. Certain issues outlined below will have a major bearing on all stakeholders:
■ An aging population and a disease profile changing from terminal to chronic is to be seen
■ A shift in healthcare decision making from doctors to patients, i.e., self-care and primary care is evident. This translates into a shift from disease treatment to prevention. Ironically, majority of the current pharmaceutical spending is on disease treatment drugs
■ Medicines, particularly safe, efficacious and cost-effective, are being increasingly desired and sought. Findings of a new national survey (2007) done in USA reveal strong public interest in prescription drug safety issues, validating that drug safety is a real concern. Unfortunately, almost all drugs today have side-effects
■ Lack of R&D productivity in drug discovery programmes of all the major pharmaceutical companies has been reported

The solution undoubtedly is innovation - Innovation in delivery systems as well as introducing novel innovative drugs. A trend is being observed toward this. Pharmaceutical companies have started moving towards niche products rather than blockbusters to improve productivity. Approvals of new molecular entities (NMEs) for oncology are in the limelight followed by anti-infectives. Companies are moving away from developing innovative, risky, therapies for large competitive markets. Instead, they are favouring developing drugs for smaller populations. This could be the end of the blockbuster, in favour of the nichebuster! But more needs to be done in terms of making safe, efficacious, affordable and preventive drugs. Enzyme therapeutics could be an effective solution in this era of biologics in modern medicine. Therapeutic enzymes are part of this group, also known as biological response modifiers or BRMs.

BRMs
BRMs are substances of biological origin such as antibodies, cytokines and other immune system substances that can be produced in the laboratory for disease treatment. These molecules would boost, stimulate and restore the body's ability to fight disease by duplicating action of internal cellular mediators.
■ Monoclonal antibodies - may be used to enhance a patient's immune response or as a drug delivery system
■ Interferons - used to stimulate natural killer cells, T cells and macrophages, boosting the function of immune system
■ Interleukins such as IL-2 stimulate the growth and activity of many immune cells like lymphocytes
■ Colony stimulating factors or haematopoietic growth factors encourage bone marrow and stem cells to divide and develop into white blood cells, platelets and red blood cells
■ Vaccines - scientists are investigating ways that cancer vaccines can be used in combination with other BRMs
■ Gene Therapy - an experimental treatment that involves introducing genetic material into a person's cells to fight disease. Researchers are studying gene therapy methods that can improve a patient's immune response to cancer
■ Non-specific immunomodulating agents stimulate or indirectly augment the immune system. Often, these agents target key immune system cells and cause secondary responses such as increased production of cytokines and immunoglobulins

Therapeutic enzymes are also classified as important BRMs because they work together with the internal enzymes, interact and stimulate the immune system cells.

Enzymes as life force
Enzymes are, very simplistically and powerfully put, the 'life energy' of the body. There are about more than 3000 enzymes catalysing some 7000 reactions in the body. They are catalyst for every body function and an essential component of all major systems. Vitamins, minerals and hormones must have enzymes to work properly. Life cannot exist without enzymes, as they are responsible for functions of every organ. Every gene's programme is associated with the actions of enzymes.

Enzymes are involved in building, operating and maintaining life. If the body has such a magnificent system to run itself why talk about enzyme therapeutics. As you age, there is a reduction in production of enzymes. Tests have shown that 70 year old people have about 1/2 the enzymes of a 20 year old. Once illness or infection has invaded, the older body has to work overtime to produce enzymes needed to overcome the problem. Often it cannot produce enough enzymes and as a result chronic disease sets in. This is proved by the fact that many of the modern diseases have been proved to be due to enzyme shortages. Studies indicate that decreased enzyme levels are found in a number of chronic ailments, such as arthritis, diabetes, allergies, skin diseases, cancer, immune deficiencies and many more. This is also the case with genetic deficiencies.

Enzyme therapeutics - Past, present & future
Enzyme therapeutics has been used globally, though in a limited way. An important area of application of enzyme therapeutics has been enzyme replacement therapy. It is the most widely used application and the 10th largest selling class of biologics (total sales of USD 1.25 billion in 2005).

Enzyme therapeutics has been used for some specific diseases like Elspar (or L-asparaginase) in cancer. Here, the drug converts asparagine to aspartate so that cancer cells are starved of asparagine and die. Proteolytic enzymes such as Papain (brands such as Accuzyme, Ethezyme, Gladase, Kovia) and Trypsin (brands such as Xenaderm and Granulex) have been used in debridement of wounds. The US FDA approved oral drug with brand name Bromase containing bromelain is listed in the physician's desk reference in North America and is used as a prostaglandin modulator for inflammation.

There are also some enzyme therapeutics, which have been approved recently (2006) by US FDA as drugs. They include:
■ Myozyme, an alglucosidase alfa, for pompe disease
■ Elaprase, an idursulfase, for hunter syndrome.

On the horizon are investigational new drug (IND) filings with US FDA for enzyme therapeutics. Some of the examples are:
■ A polyenzyme mix for cystic fibrosis patients undergoing phase III studies under orphan drug and fast track status
■ A single enzyme molecule for hyperphenylalaninemia undergoing phase I trials
■ Drug Zentase for exocrine pancreatic insufficiency in phase III trials

All these examples highlight a case for enzyme therapeutics as mainstream drugs. In Europe and Japan, enzyme therapeutics has been extensively used for the last 40 years or so. An example is the drug Wobe-Mugos, a combination of systemic enzymes approved in 2000 by US FDA as orphan drug for adjunct therapy of multiple myeloma. It has been used successfully in Europe in conjunction with chemotherapy since 1977. Similarly, in South America and Japan, oral enzymes have been used extensively for cardiovascular health and as anti-inflammatory for over four decades.

In India, well accepted enzyme therapeutics includes:
■ Pancreatin - For pancreatic insufficiency, GI disorders and immobile life-styles
■ Trypsin, Chymotrypsin - Widely used as NSAID for post operative wounds, oedema and haematoma
■ Fungal diastase + Pepsin - Indicated for hyperacidity, peptic ulcer, oesophagitis and flatulent dyspepsis
■ Serratiopeptidase - anti-inflammatory, anti-oedemic, fibrinolytic for post surgery and infections

Enzymes - Drugs of choice
A well documented past, a looking up present can only lead to a bright future. This certainly seems to be the case with enzyme therapeutics. Their inherent attributes of being efficacious (specific in action), non-toxic (no LD50) and negligible side effects are well proven. A series of external circumstances are presenting themselves, including increased acceptance of biologics, change in mindset of global pharmaceutical companies, towards innovative drugs. And a huge body of evidence in favour of enzyme therapeutics from Europe, Japan etc., make enzyme therapeutics a front runner for 'drugs of choice.'

(The author is GM, strategy & development with Advanced Enzyme Technologies Ltd)