Repurposing approved drugs for new therapies

Virginia Kaklamani, MD, DSc, treats a patient in her clinic.
Virginia Kaklamani, MD, DSc, treats a patient in her clinic.

An old molecule with a new hope

By Michael Seringer

One way to short-circuit the “valley of death” is to repurpose an approved drug for a new indication. The Food and Drug Administration has approved more than 20,000 drugs, and these drugs have demonstrated safety and efficacy in human trials. This population of proven compounds also offers researchers rich data sets to discover new indications for these drugs.


Virginia Kaklamani, MD, DSc

Professor of Medicine; Leader, Breast Oncology Program at UT Health San Antonio’s Mays Cancer Center
Compound: Cyclosporin, repurposed new indication
Indication: Breast cancer
Stage: Pre-seed, protocol development, Phase 1 clinical trial
Timing: Approximately three years
Funding: NIH and Mays Cancer Center pilot grant
When an academic institution combines its research mission with best-in-class patient care, research is more focused on what really matters most — the patient.

When Associate Professor Kimi Kong, PhD, and Robert Hromas, MD, FACP, dean of the Long School of Medicine, discovered that cyclosporin, a widely used immunosuppressant, also killed a specif ic type of cancer cells, they needed a clinician who understood how to test the drug in humans. The collaboration between them and Virginia Kaklamani quickly led to preparing for a Phase 1 clinical trial that may bring hope to patients with inherited breast and ovarian cancer.

“A drug that we have used for years to give to transplant patients can actually help kill a certain type of cancer,” Kaklamani said. “Dr. Kong and Dr. Hromas had really good data that showed cyclosporin was effective against these specif ic breast cancer cells.”

Figuring out the dose

One of the main advantages of repurposing an approved drug is the speed in which Phase 1 human trials can be initiated. Unlike new drug development, existing drugs do not have to def ine the maximally tolerated dose during animal trials. Because an existing drug has a history of low toxicity in humans, repurposed compounds can start directly with Phase 2 human trials to test efficacy.

Testing a previously approved drug for a new indication greatly reduces the difficulty and risk in running clinical trials, because the toxicities are already known. While the risk is mitigated with repurposed drugs, the challenge remains in defining how best to use the known drug for the new patient population.

“The biggest challenge is figuring out the dose,” Kaklamani said. “Right now, we know the dose for transplant patients, but we are not using the drug for transplantation. Should we be using the same dose for our cancer patients? Is the mechanism of how this drug works dependent on the dose? This is really the biggest challenge that we have had to date.”

Recruiting for the clinical trial among breast cancer patients is also a challenge for Kaklamani and her team. The study population is women with one type of inherited breast cancer that has just been diagnosed, before any treatment, Kaklamani said. These patients not only have to deal with a range of complex emotions but also have to make a life-altering decision of whether to enroll in a clinical study.

Understanding a compound’s properties

The cyclosporin clinical trial for breast cancer has been designed to demonstrate efficacy quickly — a singular bright spot for patients navigating a complex health crisis. The cyclosporin class of compounds may also offer analogs that are lethal to this type of breast and ovarian cancers without compromising the immune system.

Research into these analogs may yield greater understanding of the anti-disease mechanisms of this entire class of drugs. These analog compounds may also lead to more comprehensive and targeted treatment for future trials.

“A weakened immune system is not good for cancer patients,” Kaklamani said. “Some of these analogs do the same thing in breast cancer as cyclosporin, but they are not inhibiting the ability of the immune system to fight diseases. All these compounds have unique properties that need to be taken into account.”

The repurposing of cyclosporin may help provide a road map to discover future drugs within the same class. However, unlike cyclosporin, any novel analogs would be required to successfully complete the Food and Drug Administration’s investigational new drug application before patients could be enrolled in human trials. A proven class of compounds helps researchers predict both the pharmacokinetics and pharmacodynamics of the drug given the history of how the compound performed during their past human trials. However,  traditional venture capital shies away from supporting development of repurposed drugs, given that the compound is in the public domain, and use patents are tough to enforce.

Rather, nonprofit funding sources such as disease-specific foundations are interested in these types of repurposed compounds because of the speed in which they can be tested in human trials.

“There is a trend now to repurpose drugs, and this is what we capitalized on,” Kaklamani said. “It’s faster drug discovery when you are just looking for a new indication of the drug. It’s definitely worthwhile to see if there is an older drug that has therapeutic effect.”

Nobody works in a silo

Academic institutions with a long history of research tend to work collaboratively. At UT Health San Antonio, collaboration is part of the institution’s DNA. There is a concentration of research investigators with experience in drug discovery who are willing to be a value-added resource located within the same institution. When an academic institution combines its research mission with best-in-class patient care, research is more focused on what really matters most — the patient.

The observations made in the laboratory should be perfectly aligned with the research being done in the clinic, Kaklamani noted. The patient should always be the focus of the work being done in the lab, she added.

This successful collaboration between the lab and the clinic not only helps keep the patient as the focus, but also leads to better science and an improved chance of getting a compound from bench to bedside.

“The lesson that I have learned throughout my career is that collaborations and partnerships are extremely important,” Kaklamani said. “It is not just, ‘Here’s my data, take a look at it.’ It’s how we design the next experiment and how we use what we learn in the lab to cure cancer. Curing cancer in mice is great, but it’s not the ultimate goal. Curing cancer in patients is.”


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In the 2022 issue of Future

Future is the official magazine of the Joe R. & Teresa Lozano Long School of Medicine at The University of Texas Health Science Center at San Antonio. Read and share inspiring stories highlighting our medical alumni, faculty and students who are revolutionizing education, research, patient care and critical services in the communities they serve.

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