In the first part, the need for alternate approaches to new drug discovery, development was emphasized and among the many options considered, attempts to revisit known drugs, drug candidates with the objective of developing new indications for them was discussed. The rationale for such an approach was also presented. In this concluding part, the current status and future prospects of this approach are elaborated.
Examples of new indications for existing drugs.
The portfolio of therapeutics available today has a large number of drugs currently used for therapeutic indications for which they were not discovered and registered with the regulatory agencies for marketing. The first therapeutic agent ever discovered (by Paul Ehrlich), Salvarsan for syphilis is hardly ever used today for that disease partly due to the decline in incidence and partly due to better and safer drugs (antibiotics) being available today. However, notwithstanding the negatives of this drug, it is now being used in the form of arsenic trioxide against promyelocyte leukemia, an indication discovered decades after the arsenic drug was first introduced. Nitric oxide based treatments used as early as the 19th Century for angina, is now being promoted for pulmonary hypertension. As early as 1949 a French surgeon, Henri Laborit observed while using Promethazine as an antihistamine, his patients showed unusual properties as a stress reliever and tranquilliser. The chloro derivative chlorpromazine later became a major drug and introduced the concept of tranquillisers, an important branch of psychopharmacology today. Further investigations showed the potential of phenothiazines to be antimicrobial agents active even against gram positive and negative resistant bacterial strains, even though this new indication has not been commercially exploited.
Tretinoin developed for acne and other skin disorders is also being used in the treatment of acute promyelocytic leukemia. Sildenafil citrate (Viagra) developed for treatment of hypertension by Pfizer had little efficacy against that condition, but showed unexpected penile erection and later became the first ever drug for the treatment of erectile dysfunction, now marketed in most of the countries of the world. Carbamazepine (Tegretol) originally marketed for trigeminal neuralgia is today the drug of choice for primary treatment of epilepsy. Acetyl salicylic acid discovered and used as an antipyretic is now used primarily for inhibition of platelet aggregation and is used as a prophylactic around the world for this indication. It's possible effect against colorectal cancer is being investigated. Metronidazole, the first of the nitroimidazole class used as an anti-amoebic drug is today primarily used against anaerobic infections routinely employed as a pre-surgical cover. Duloxetine belonging to the family of Fluoxetine (Prozac) developed as a follow up drug for the latter has shown excellent properties in conditions of stress urinary incontinence while another analogue of fluoxetine, Dapoxetine is under phase III trials for premature ejaculation. The serendipitous observation that Minoxidil when clinically tested as a cardiovascular drug showed hair growth in subjects on whom the drug was being tried, led to the development of the first ever drug for hair growth.
On the development front a number of new uses of marketed drugs are being explored. Non Steroidal Anti Inflammatory Drugs (NSAIDs), such as Ibuprofen and Peroxisome Proliferator Activator Receptors (PPAR) such as thiazolinediones are being tested for Alzheimers disease. In the area of cancer therapy, medications such as Fluphenazine and derivatives which affect the 5 HT and Dopamine receptors are being tried for multiple myeloma. Several new FDCs of existing molecules are being tried out for a variety of newer indications, even for those unrelated to their currently known uses.
The case of thalidomide
The fate of this drug since it was discovered in 1954, its withdrawal as a sequel to the most tragic ever consequences of any drug in the history of medicine deserves a special look. Thalidomide which was discarded (banned) for causing teratogenic effects on the foetus resulting in thousands of 'thalidomide babies' with malformed limbs was marketed as a sedative by the German Company Chemie Gruenthal in 1957 and banned in 1962. Thirty six years later the drug made a reappearance when it was cleared for use by the US FDA for a variety of conditions, many of them for diseases of a refractory and life threatening nature. It has now been shown to be an inhibitor of TNF alpha and other cytokines and has emerged as effective therapy against multiple myeloma, Hansen's disease (leprosy). cutaneous lupus, scleroderma and Crohn's disease. This is a clear example of the important role of scientific investigations for finding out the causes of adverse effects of a drug, in this case the teratogenicity associated with use of thalidomide as a sedative by pregnant women and for identifying its real potential use in other indications. The immuno-modulatory effects of the drug coupled with its anti-angiogenic properties were interesting leads in the deciphering new uses for a drug once considered the most dangerous of all drugs ever marketed. Investigations also revealed that there is a statistically significant increase in the degree of inhibition of TNF alpha with the S form of thalidomide compared to its chiral antipode, the R form. This observation endorses the importance of resolving racemate molecules to determine the pharmacological profiles of each isomer, since they could be totally different for the isomers constituting the original racemic form, both in terms of safety as well as efficacy. It is now more or less mandatory that drugs which are racemates should be resolved and their profiles established before they can be approved for marketing.
What are the approaches for discovery of new uses?
So far practically all such discoveries have emanated in a totally unplanned manner. The majority of them were based on observations during the clinical phase or even after the launch of the product, by patients and clinicians. The new use of an existing drug may be based on reported off-label use of drugs for indications for which they were not approved in the first place. Very often investigations into adverse effects of drugs observed during clinical trials or later use are the starting points for discovery of new indications based on their pharmacological and toxicological profiles. There have been very few systematic attempts at discovering new uses until recently since due to issues of patentability of new uses for a known substance pharma companies very seldom take up such efforts and invest in such efforts. The NIH Molecular Libraries initiative does not distinguish between known and unknown molecules or even scaffolds and relies on high throughput screening against phenotype based or molecular target-based screens with even as many as 100,000 molecules from diverse structural types being screened. An extension of this would be to blindly screen existing compounds against a large number of available targets. As many as 9000 molecules with known biological activity with most of them useful in therapy are available for such investigations. If some information is available from clinical use including during trials about the potential correlation between efficacy against known targets and the structural types, that would be useful for designing new entities. The advantage is that the availability of pharmacokinetic data already generated and available on the known drug would also be useful during the screening process.
Patentability of new uses
One of the crucial issues that confront the R&D based pharma industry with reference to efforts in the area of discovery of new indications for existing drugs (patented or generic) or known molecules with no established therapeutic uses is the difficulty in getting strong patent protection for such discoveries. Unless there is provision in the national patent laws to provide protection for new uses for known molecules, there is virtually no incentive for investments in this area. In other words, economic considerations due to failure of IP laws to assign sufficient value to patents involving new uses for old drugs are serious deterrents to investments. New uses of known drugs are patentable subject matter in some countries. But not all. The validity of Swiss type of claims referring to such cases have been challenged in many courts including in Europe. Indian Patent Act 1970 and the new TRIPS compliant variant of 2005 does not permit the patenting of new uses. The Act goes further under section 3(d), even prohibiting the patenting of any new form of the patented drug unless there is significant advantages established beyond doubt. It is contended under the Indian law that such trivial inventions are meant to evergreen the original patent and delay the introduction of generic versions.
Research efforts by Indian companies and institutions have not so far taken up research to discover new uses of existing drugs to gain advantage, speed up the discovery process and reduce costs substantially. It will be prudent to take some initiatives in this direction if India to gain global competitive advantages through R&D. The issue whether the Indian Patent Act should be amended to include patenting of new uses of known molecules also need to be considered in all seriousness.
(The author is a senior research scientist and industry expert based in Chennai)