Drug Repurposing Approaches and Successes

What do Viagra, Rogaine, and Latisse have in common? They were all developed to treat hypertension but their side effects led to the drugs being repurposed to treat erectile dysfunction and hair loss as well as stimulate eyelash growth, respectively.

While serendipity has led to many of the drug repurposing, or repositioning, successes in the past, it is now a field unto itself with tens of organizations and companies searching for effective therapeutics without spending 10 to 15 years and billions of dollars starting from scratch.

Many of the groups working to repurpose drugs have compiled compound libraries that they use themselves and/or make available to others. Other groups have built advanced platforms to expedite their search or have a well-honed process that allows them to sort through potential candidates quickly and effectively.

Compound repositories

Among the organizations with open-access compound repositories is the Broad Institute with its Drug Repurposing Hub, which contains more than 6,000 compounds, including FDA and globally approved drugs, clinical trial drugs, and pre-clinical compounds. Broad researchers have documented the target, mechanisms of action, and indications for each of the 6,800 small molecules in the collection.

In collaboration with the Center for the Development of Therapeutics (CDoT) at the Broad Institute, the collection is being utilized by scientists in high-throughput screening campaigns to identify new uses for these highly optimized small molecules in a variety of disease models.

According to Karen Zusi-Tran from the Broad Institute, there are several dozen projects accessing the Repurposing Library for identifying possible novel therapeutics. “The most advanced is the Mucin-1 Kidney Disease project, which identified BRD4780 as a lead treatment after running a high content imaging screen. That candidate has undergone the preclinical validation process and is moving toward clinical trials. Several additional projects, including those targeting MIS for use in reproductive sciences and Sickle Cell Anemia, have identified lead candidates after running high-throughput screens and are in the process of preclinical validation with the hope of moving them into clinical trials.”

In addition, the rare disease community has recently expressed interest in using the library for screening. These requests usually come from patients who are suffering from a rare disease or parents of children diagnosed with the disease. CDoT works closely with these foundations to build the appropriate assay to search for a robust and durable phenotype on which to run a repurposing screen.

The CDoT scientists frequently use Cell Painting assays in their screening efforts. “When combined with feature extraction software, the technology yields ~1,000-dimensional feature signatures called image-based profiles and allows for an unbiased analysis of changes in cellular phenotypes. Additionally, the Cell Painting technology is being utilized in an extended panel of cell lines that include more non-diseased cell lines, which will be screened against the Repurposing library to understand how perturbation of the different pathways affects the phenotype of the cells,” Zusi-Tran explains.

Another group providing access to a compound library is the Medicines for Malaria Venture, whose COVID box contains 160 marketed drugs or compounds in development. Researchers at the Jundiaí Medical School in Brazil recently reported screening compounds from the COVID Box to find better ways to treat toxoplasmosis, which is caused by Toxoplasma gondii, a protozoan parasite. The team identified six compounds—ethaverine, almitrine, fluspirilene, thiethylperazine, PB38 and nebivolol—that they said were at least 30 times more deadly for T. gondi than for the host cells. Much more work is necessary before any of the six compounds can be repurposed for the treatment of toxoplasmosis, but the results so far are promising.

AI-powered discovery platform

Healx is a “techbio company” that uses AI to accelerate the development of rare disease therapeutics with repurposed compounds. Its AI platform, Healnet, identifies novel connections between drugs and diseases, which are then evaluated by in-house experts and tested in preclinical models.

In September, the company received Orphan Drug Designation from the U.S. FDA for its Neurofibromatosis Type 1 (NF1) treatment, discovered using the company’s tech-driven approach. While other treatments for NF1 are focused on MEK or kinase inhibitors, HLX-1502 utilizes a “first-in-class mechanism” to treat the rare genetic condition that causes tumors to grow along the nerves.

“Capital-efficient” drug development

Algernon Pharmaceuticals repurposes already approved drugs and says its business model is “highly capital efficient” as a result of the reduced risk of failure and shorter development time with repurposed drugs versus new chemical entities as well as longer active patent life.

The company is currently advancing two candidates. Ifenprodil, an N-methyl-D-aspartate (NMDA) receptor antagonist that was originally approved in Japan and Korea to treat vertigo; has been investigated as a treatment for COVID-19, small cell lung cancer, and pancreatic cancer; and is now in Phase 2 trials for chronic cough and idiopathic pulmonary fibrosis. Repirinast, which was originally developed by Mitsubishi Tanabe Pharma and marketed in Japan as Romet for asthma treatment, is anticipated to begin Phase 1 trials this year for chronic kidney disease.

Ongoing academic efforts

DFMO (α-difluoromethylornithine), approved by the FDA in 1990 to treat African Sleeping Sickness and later designated for neuroblastoma maintenance therapy after remission, is now being investigated for the management of type 1 diabetes. Indiana University researchers recently reported that DFMO treatment is safe and delays the onset of type 1 diabetes (T1D) by reducing β cell stress. A large, six-center clinical study to investigate the impact of DFMO treatment to preserve β cell function in type 1 diabetes is currently underway.

Trifluoperazine, an anti-anxiety drug used since the 1950s, could improve the efficacy of glioblastoma treatments, according to a new study from Flinders University researchers. The team was specifically looking at the impact of cerebrospinal fluid on cancer cells and found that CSF induces tumor cell plasticity and resistance to standard GBM treatments, including radiation and the chemotherapy drug temozolomide, but that trifluoperazine could re-sensitize glioblastoma cells to both therapies.

Repurposing drugs was not the panacea many hoped it would be against COVID back in 2020 but there have been notable successes with repurposed drugs and there will likely be many more as advanced technologies and novel approaches more effectively mine thousands of promising compounds that could have a more significant impact the second or third time around.