CONSTRAINTS IN MANUFACTURING DRUGS FOR RARE DISORDERS

Amyotrophic Lateral Sclerosis is a rare disorder of the central nervous system, causing degeneration of the muscles and slow death. As a cure had not been found for this disorder, one of the greatest physicists of the last century Hawking succumbed to the disease. However, one wonders how many other “mute, inglorious” Hawkings might have already passed into oblivion, either due to ALS or other diseases for which either no drugs had been discovered, or for curing which pharmaceutical companies had not been prepared to manufacture the drugs of choice due to financial constraints. These issues are also complicated by moral considerations which need the attention of society as a whole.

In the year 1981, a leading British pharmaceutical company suffered a huge financial loss of 26 crore rupees in a single day, when considerations of safety forced that firm to abandon a project involving the manufacture of an anti-asthma drug. In the coming years big companies are expected to face such a situation, thanks to higher stakes, greater risks and intensification of regulations. One worrying question that seems to trouble people owning giant pharmaceutical companies, as well as the medical community is whether any organisation can afford to pursue the search for drugs necessary for the treatment of extremely rare disorders.

The problem is illustrated by the controversy that arose over a disorder so rare that even the average medical practitioner has not heard of; in fact, its name Wilson’s disease did not even appear in many popular medical books. But for the age of computers it would probably have been within the knowledge of only specialists treating that disease.

It is an inherited ailment arising out of a simple error in the chemistry of the human body. This condition is caused by copper accumulating in the liver, the brain and other vital organs thwarting their normal functions and ultimately bringing about the death of the patient.

At one time, no treatment whatever was available for victims of this disease. Patients suffered increasing brain damage which gradually affected their speech and movement until death put an end to their disabling torments relieving them of their misery.

The picture changed dramatically with the discovery of substances that combine readily with metals, known as “chelating” agents: chemists used these agents in experiments but surprisingly they were also found useful in mopping up the excess metals that accumulated in patients suffering from Wilson’s disease and lead poisoning.

One Specific chelating agenting agent Penicillamine, was found to be highly effective in ridding tissues of toxic metals. It binds copper and lead tightly and is then excreted expelling the poisonous elements. Thus a derivative of one popular antibiotic penicillin wrought a miracle in benefiting people afflicted with the rare Wilson’s disease—a bonus the original manufacturers of penicillin perhaps could never have anticipated.

This is an example of serendipity. In this case the strategy for defeating a deadly disease had emerged from quite an unexpected field of research. The result was a drug of tremendous potency to prevent the ravages of Wilson’s disease.

John Walsh was the first scientist to describe in 1956 the use of penicillamine in Wilson’s disease He had discovered the compound in the urine of patients (including himself) who had taken penicillin and experimentally confirmed that it increased urinary copper excretion by chelation. They can also be used to reduce cystine excretion in cystinuria and to treat patients with severe, rheumatoid arthritis unresponsive to conventional therapy. Penicillamine is used as a form of immunosuppression drug to treat rheumatoid arthritis.

Unfortunately, a few patients developed side-effects so dangerous that pencillamine had to be withdrawn. This naturally brought about a rethinking of the entire issue. How could any pharmaceutical company be expected to commit enormous resources, and funds in projects involved in the search for a suitable drug with no side effects to treat a very negligible minority of patients. This is a problem involving eco­nomic as well as ethical considerations.

One scientist in the United States tackled the problem in an imaginative manner. He experimented with alternative chelating agents and came up with an equally effective drug ” TRIEN” which, unlike penicillamine, had no toxic side-effects. A sympathetic pharmaceutical company conducted a few tests with this new drug, but declined the scientists’ request to produce regular supplies. His attempts to make other companies take up the task also proved futile. Apparently, the pharmaceutical companies seemed to feel that the market for such a drug was too tiny to justify launching an all out, profit-oriented programme of production.

With no other alternative in sight, this scientist began synthesising, TRIEN by himself in a laboratory at a hospital in Cambridge, United Kingdom. However, as Britain’s sole supplier of this life-saving drug, he was justifiably worried about the drug’s future. What would happen to his patients when he retired or died. And he was plagued by questions such as if someone else can and was willing to continue supplying them would Britain’s regulatory authorities suddenly decide to insist on the drug being rigorously tested and approved before being administered.

The story of “TRIEN” underscores a broader problem.

For example, one leading pharmaceutical company is facing a rather tricky and embarrassing situation in producing a drug for mucocutaneous candidaisis a painful infection of mucosal, nail or skin surfaces. It is usually caused by the fungal pathogen Candida albicans. The symptoms of the disease are significant pain, weight loss and secondary complications, including carcinoma and aneurysms. Pharmaceutical companies are reluctant to manufacture. a drug for being used to treat only about 400 cases an year, of this terrible infection in the entire population of United States. This disease would probably be eradicated before licences and conditions could be satisfied by any drug manufacturer. Should such a drug be commercially manufactured or not? There are at least fifty other similar uncommon diseases. Naturally most pharmaceutical company owners feel that it would be too risky to embark on the process of satisfying statutory regulations, since drug companies have to survive on profit and are not charitable institutions. The manufacturing of medicines for rare disorders is a topic that surely needs urgent attention of the governments around the world. The only solution to this problem at this juncture seems to be giving incentives and in adopting a more flexible approach to licensing, provided someone is willing to manufacture a drug even in extremely small quantities.