Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation email@example.com
SPECIAL REPORT #21
Repurposing/Repositioning of Drugs
For many years the biopharmaceutical industry has been very keen to repositioning existing active molecules for new therapeutic uses. More recently a series of small and large companies have adopted this new concept to yield marketable products in a relatively short time frame and at far lower cost than discovery and development of de novo drugs.
Drug repurposing, also known as drug repositioning, defines a process of identifying and validating a new therapeutic indication for an already existing drug or for an advanced clinical development candidate. The generic concept covers different approaches that can be independent or complementary to each other such as:
- Discovering a new clinical indication for a molecule distinct from the initial marketing approval.
- Reformulation of the original molecule different from the first approved indication.
- Combination of molecules to enable additive or synergistic effect for at least one of the respective indications.
In addition, drug repurposing can be applied to different types of molecules such as:
- Already marketed molecules for which exclusivity has expired or is close to expiry.
- Molecules which are no longer marketed.
- Molecules which have never reached market approval but where advanced clinical data are available.
In practice, there are several experimental approaches to uncover new potential applications outside the original therapeutic indication.
Serendipitous observations. In recent time the most notorious success story is the discovery of the erectile properties of sildenafil (marketed as Viagra). Sildenafil was originally developed as a treatment of coronary and heart disease but never reached the market for this indication. A series of confirmed unexpected clinical evidence let Pfizer, the sildenafil sponsor, successfully reposition the drug for the treatment of male erectile dysfunction.
High Throughput Screening or Target-Based Repurposing. This happen when through selected targeted screening, one discovers that a particular drug with a known mechanism also interacts with a new molecular/cellular target associated with a different disease. In recent years it was found that many drugs which were designed for a “selective” target were in fact interacting with several biological targets.
In Silico-Assisted Repurposing. With the advent of big data analysis and data mining, scientists have now the possibility to identify and select specific pharmacophores for a given biological target and then use homology and molecular modeling approaches to qualify the best candidates. Thorough analysis of “systems pharmacology” of in-house and publicly available literature databases with in vitro screening has allowed the identification of a series of already known molecules for new indications. A transdisciplinary study of such type has pinpointed digoxin and some analogs as potential drugs for the treatment of prostate cancer.
The use of combination of molecules to enable synergistic effects for an already known indication has already been reported in Special Report #7 where we have described the results of PXT3003 by Pharnext for the treatment of Charcot-Marie-Tooth type 1A (CMT1A) disease and of THN102 by Theranexus for the treatment of narcolepsy and Parkinson’s disease. PXT3003 is a combination of baclofen, a central nervous system myorelaxant, naltrexone, a drug for the management of opioid dependence and sorbitol, a laxative. THN102, combines modafinil a treatment for sleeping disorders with flecainide and antiarrhythmic drug repositioned to act on glial cells.
The reported story below is of particular interest to the author because of his past experience with one of the selected molecules. Earlier this year a group of scientists from the Centre International de Recherche en Infectiologie at the Université Claude Bernard in Lyon (France) have reported the identification of diltiazem as a potential influenza antiviral agent. The discovery was made through an in silico– assisted strategy based on transcriptional profiling, a technique which was successfully used to identify drug repositioning in the field of oncology and has now been transposed to the field of viral infectious disease. The team, led by Andrés Pizzorno, has developed a new therapeutic approach for the treatment of influenza that involves repurposing of drugs that targets the host rather than the virus itself with the rationale that the host is less likely to develop resistance to the treatment. Clinical gene expression signature data obtained from severe influenza-positive patients was used to screen potential drug candidates. During the infection the virus modifies cellular expression to create a host environment that will facilitate translation and replication of the virus. The goal was to find a drug that can reverse this process and create an environment within the host that is unfavorable for the virus. As many as fifteen already marketed drugs were identified. Amongst them diltiazem was selected as a strong candidate from in vitro and in vivo testing in mice and was shown to be protective with reduced peak viral titer
Diltiazem, a benzothiazepine, first synthesized in 1969, at Tanabe’s Organic Chemistry Laboratory, aimed to become a new CNS drug, was later identified as a strong vasodilator acting as an atypical calcium channel blocker. The drug was successfully developed and marketed in the late 70’s and early 80’s as a potent anti-anginal drug, an antiarrhythmic drug, as well as a mild antihypertensive agent by Tanabe in Japan, by Synthélabo in France, by Gödecke in Germany, by Esteve in Spain and by Marion in the United States.
Ongoing studies using a reconstituted human epithelial cell model are being performed to gain a better understanding of the precise mechanism of action of diltiazem on epithelial cell integrity. A French multicenter randomized clinical trial is currently investigating the effect of the combination of diltiazem and oseltamivir or Tamiflu (a neuramidase inhibitor) compared to oseltamivir alone for the treatment of severe influenza infections in intensive care units.
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