Therapy Analysis - Drug Reprofiling
Failure to blockbuster
Perhaps the most well-known and successful example of drug reprofiling is that of the PDE-V inhibitor sildenafil citrate. The drug started its developmental life as an intended treatment for hypertension and angina; however, in UK Phase I studies it was found to have little efficacy in the treatment of these diseases. What was unexpectedly observed was that it induced penile erections in trial participants. In an astute reprofiling move, Pfizer decided to instead direct sildenafil toward the treatment of male erectile dysfunction, an indication in which, since its launch as Viagra in 1998, it has been the consistent market leader. It is now launched as Viagra in over 40 countries worldwide, and continues to hold its market position against many other PDE-V inhibitors now also available and developed specifically for this patient population.
Similarly, the infamous drug thalidomide, which was first launched in 1957 by Grunenthal as a sleeping aid and antiemetic for the treatment of morning sickness in pregnancy, is now seeing a new lease of life in different disease areas. When it was originally prescribed to pregnant women, the teratogenic effects, including phocomelia, cleft palates, blindness and deafness, were discovered too late, as they were only noticed once affected children were born. Consequently, the drug was completely withdrawn by 1962. It was not until 1964, when Israeli physician Jacob Sheskin gave a leprosy patient thalidomide as a last resort to help him sleep, that its potential in treating other conditions was uncovered. Not only did thalidomide help the subject sleep, but it almost totally suppressed the leprosy as well. As a result of this, thalidomide was reprofiled by Celgene, and was launched as Thalomid in 1998 for the treatment of erythema nodosum. It has also proved its worth in the treatment of various cancers, such as multiple myeloma, for which it was launched in 2003. Thalidomide is also currently in a Phase II/III trial in 210 colorectal cancer patients in combination with other chemotherapeutic drugs. Additional Phase III trials for renal cancer, myelodysplastic syndrome and rheumatoid arthritis are ongoing. Indeed, after its distinctly less than promising beginnings, thalidomide has become an important drug and may yet help a great many patients in a wide range of therapeutic areas in the future.
Aside from these more well-known examples, there are also current pipeline drugs that have benefited from the reprofiling process. NSL-043, for example, was under development by the Japanese company Sosei as a treatment for inflammatory disease. It progressed through all necessary toxicology screens and proved its oral bioavailability but ultimately failed to show sufficient efficacy on reaching Phase III trials, and development was subsequently terminated. It was then picked up by UK-based NeuroSolutions, which used its specialty screening platforms and expertise in neurological assays to establish the potential of this compound in neuropathic pain. NeuroSolutions promptly put NSL-043 through two Phase I trials with positive results and plans to establish proof of concept before out-licensing NSL-043 following Phase II completion.
Another potential reprofiling success story is that of
DDP-225, a dual 5HT-3 antagonist and noradrenaline
reuptake inhibitor. The compound was originally conceived
as MCI-225, and was developed by Mitsubishi
Pharma (now Mitsubishi Tanabe Pharma) for the treatment
of depression. Showing promise in early preclinical
testing, MCI-225 dose-dependently increased noradrenaline levels in the hypothalamus of non-stressed
rats, and showed antidepressant-like properties
in anxiety models. In subsequent clinical trials for
depression, it showed a good pharmacokinetic and
safety profile; however, once again, efficacy results
from late-stage trials were not good enough for Mitsubishi
to continue development. DDP-225 was given a second
chance though, when the specialty gastrointestinal
and genitourinary company Dynogen in-licensed the
compound for investigation. As Dynogen received complete
safety and pharmacokinetic profiles for DDP-225,
it was ready for use in patients straight away, saving
Dynogen the considerable time and expense involved in
conducting preclinical and Phase I testing. Thus far it
has proved efficacious in both irritable bowel syndrome
patients and for the treatment of nausea and vomiting.
Dynogen now plans to further expand the potential of
this product with a Phase II trial in patients with overactive
bladder.
