Repurposing existing drugs by finding new targets, delivery methods, and formulations is a promising approach to speed the development of much-needed treatments
By Lindsay Brownell
(BOSTON) – Along with “SARS-CoV-2” and “cytokine storm,” the COVID-19 pandemic has added an alphabet soup of strange drug names to the public lexicon: hydroxychloroquine, tocilizumab, ivermectin, atovaquone. Though many of us were hearing those names (and struggling to spell them) for the first time, all of these drugs have been around for decades. It was our global “kitchen sink” attempt to identify something – anything – that showed efficacy against the novel coronavirus that brought them into our texts and email threads, along with the hope that some of these drugs could be repurposed to treat COVID-19.
The process of repurposing existing drugs for new uses has been practiced informally by physicians for years. Doctors can prescribe any FDA-approved drug to a patient for any condition, even “off-label” for an illness the drug is not technically approved to treat. In fact, it’s estimated that up to nearly 40% of prescriptions written today are for off-label use. The practice is especially common in cancer treatment, because a chemotherapy drug approved for one type of cancer may actually target many different types of tumors.
Despite their widespread use by doctors, repurposed drugs have historically played second fiddle to novel drugs in the pharmaceutical and biotech industries, in part because existing drugs are already commercialized and therefore it is difficult to obtain new patents on them. However, turning to drugs that have already been recognized as safe by the FDA is being increasingly recognized as an attractive strategy to get effective treatments to patients quickly.
”Most academics have traditionally focused on pursuing basic mechanistic research, hoping that someone else will develop a drug against a given biological target someday. But with the explosion of biotechnology in the last few decades, more scientists now want their work to have tangible, near-term impact, and repurposing existing drugs is one way to achieve that,” said Don Ingber, M.D., Ph.D., the Founding Director of the Wyss Institute. Ingber is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).
A head start in the race against COVID
When attempting to repurpose a drug for another use, there are three general approaches:
- Demonstrate that an existing drug for one disease is effective in treating a different disease
- Deliver an existing drug into the body in a new way that improves its safety and/or efficacy
- Chemically modify an existing drug to create a new entity that is safer, more effective, or expands treatment to more conditions
The first strategy has dominated the fight against COVID-19, in which the top priority has been speed. Like many labs around the world, in March 2020 Ingber’s lab quickly pivoted to focus its research on identifying existing drugs that showed activity against SARS-CoV-2. Unlike most labs, which tested those drugs on cells in a dish, Ingber’s team tested them in human Organ Chips: microfluidic devices that have been found to mimic the function of human organs more faithfully than human cells grown in conventional in vitro cultures or many animal models.
Their breakneck research led to the discovery that amodiaquine, an antimalarial drug first synthesized in 1948, reduced infection by about 60% in cells in a Human Lung Airway Chip. These results, which were validated by collaborators working with native SARS-CoV-2 in vitro and in an animal model, led to the drug’s inclusion in the ongoing ANTICOV clinical trial for COVID-19, which spans 19 sites in over 13 different countries in Africa, where amodiaquine is readily available.
“Amodiaquine was a great example of the success of putting a repurposed drug through its paces to identify its potential to address the global pandemic, but we’ve been repurposing drugs in many projects at the Wyss Institute for years. This was a central focus in our DARPA THoR and Biostasis projects, which have leveraged computational artificial intelligence approaches and technologies like CogniXense,” said Ingber. “Because they’ve already cleared the major hurdle of being approved by the FDA, they’re cheap, easy to get, and have the potential for enormous impact much more quickly than a new drug that’s being developed from scratch.”
Following in amodiaquine’s footsteps, another existing drug called azeliragon was found to reduce inflammation associated with viral infections in studies using a Human Lung Alveolus Chip, and was licensed to Cantex Pharmaceuticals in early 2022 for treating COVID-19. The company plans to start a Phase 2 trial of the drug in humans later this year.
It’s not the drug, it’s the delivery
Identifying a new use for an old drug that is already patented or generic doesn’t come with the same legal protections and financial benefits as creating a drug from scratch and filing a new patent for it. That reality means that repurposed drugs are often less appealing than novel drugs for pharmaceutical companies, even if the drugs themselves hold great therapeutic promise. But that doesn’t bother Wyss Core Faculty member Dave Mooney, Ph.D., whose lab at the Wyss Institute has been hard at work finding ways to improve the efficacy of existing drugs by changing their delivery mechanisms – the second approach to repurposing drugs.
“Many molecular compounds exist today that we know work beautifully against common conditions, like inflammation, cancer, and injuries. But they never made it to patients because they don’t persist long enough in the body after ingestion or injection, which are the two preferred drug delivery methods,” said Mooney, who is also the Robert P. Pinkas Family Professor of Bioengineering at SEAS. “They often require high doses or frequent injections to display any therapeutic effect, which can be too toxic for a patient to handle.”
Mooney’s team has found a solution to this problem in the form of flexible, tunable hydrogels made of alginate, a natural biopolymer found in the cell wall of brown algae. These hydrogels can be loaded with a drug, then injected into a patient’s body at the disease site. Once injected, they release their therapeutic cargo in a local and sustained manner, often reducing the required dose, toxic side effects, and frequency of treatments.
This approach has found numerous successful applications and has been licensed by several companies for commercialization. One of these companies, Alkem Laboratories Ltd., is a leading pharmaceutical manufacturer in India and plans to use the technology to deliver naturally occurring growth factors to patients who suffer from peripheral arterial disease (PAD). These growth factors, have been known to stimulate tissue and nerve regeneration for years, but so far have not been used clinically because of the difficulty of getting them to stay concentrated at the injury site.
Both molecules are generic drugs, meaning they are cheap to make and widely available. That combination is very attractive in a setting like India, where there are millions of people who suffer from chronic conditions but lack the finances to pay for expensive medications developed by pharmaceutical companies in wealthier countries. Alkem’s ability to produce an affordable option at a large scale has the potential to positively impact lives around the world.
While novel delivery methods for repurposed drugs do offer the opportunity for filing more robust patents, that’s not what drives Mooney to continue to find new clinical uses for his hydrogels. “Ultimately, success stories like Alkem are why we’re here at the Wyss, doing what we do – it’s not for the money, but to help as many people as possible,” said Mooney.
Body, heal thyself
Another approach to delivering therapies more effectively involves using the body itself to help drugs overcome the numerous biological barriers that often stand between them and their targets. Samir Mitragotri, Ph.D., a Wyss Core Faculty member who is also the Hiller Professor of Bioengineering and Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS, is attaching nanoparticles filled with drugs to red and white blood cells, harnessing both their ability to move freely throughout the body and their unique biological behaviors.
Red blood cells are found in high densities in the lung due to its many branching capillaries, making them the perfect vehicle for delivering a chemokine called CXCL10, a small protein that attracts immune cells, to cancerous lung tumors. Mitragotri’s team has also used red blood cells to deliver nanoparticles of the common chemotherapy drug doxorubicin (which often causes severe side effects) directly to the lungs, dramatically reducing toxicity in other parts of the body and increasing the percentage of the drug that reached tumors in mice.
While red blood cells largely remain in the blood vessels, white blood cells including macrophages can infiltrate most parts of the body, looking for foreign invaders and misbehaving cells to neutralize. By attaching nanoparticle “backpacks” filled with the generic compound interferon gamma (IFNγ) to macrophages, Mitragotri’s lab was able to keep them in their activated state when they encountered cancerous tumors in mice, which normally shut macrophages down as part of their self-defense. His group is currently investigating the commercial potential of these innovations.
New twists on old drugs
Finally, existing drugs can be repurposed by being chemically modified to tweak their physical and therapeutic properties. This third approach technically creates a new chemical entity that is considered to be a novel drug by the FDA and thus must go through the lengthy drug approval process. But there are benefits to using existing drugs as the starting point for drug discovery: not only can a new patent be filed for a chemically modified repurposed drug, but any compound that has already been recognized as safe and effective for another use by the FDA often makes its way through the drug development and approval process more quickly.
Charles Reilly, Ph.D., a Senior Staff Scientist in the Wyss Institute’s Bioinspired Therapeutics & Diagnostics Platform led by Ingber, creates computational models of biomolecules using molecular dynamics simulations to study their structures and physical properties, and has started using this method to design potential new drugs. In March 2020, he quickly realized that he wasn’t going to be able to identify a novel drug against SARS-CoV-2 and get it through the FDA quickly enough to treat the people who were falling ill at the time. But he also knew that viruses evolve, and there would be a longer-term need for drugs to address future variants. So, when the novel coronavirus’ genetic sequence was released, he started modeling the virus and studying regions that were likely to remain unchanged through generations of viral reproduction and mutation. He identified a promising region of the virus’ Spike protein and an existing drug that was able to bind to it across multiple variants, as well as other coronaviruses like SARS and MERS.
However, the candidate drug was originally approved to treat cancer, and affected the body in ways that weren’t needed to treat COVID-19. So Reilly enlisted the help of Wyss medicinal chemist Joel Moore, Ph.D. to chemically modify the drug so that it no longer exerted its original effects, but retained its activity against coronaviruses. This successful application of molecular modeling impressed the Open Philanthropy foundation, which is now funding the team to design new drugs for both SARS and influenza viruses using a similar strategy.
“Rather than just brute-forcing our way through testing hundreds of existing drugs, this approach of applying as much theory as possible to identify our top drug candidates and then experimentally evaluating those represents a really effective cross-pollination between drug repurposing and drug discovery,” said Reilly.
Mitragotri’s lab is also using existing drugs as jumping-off point for drug discovery, and has recently shown that using hyaluronic acid (a naturally occurring substance that lubricates our eyes and joints) as a “linker” molecule to attach generic drugs to each other dramatically improved resiquimod and bexarotene’s activity against melanoma tumors in mice, and doxorubicin and camptothecin’s killing of non-melanoma cancer cells in human skin tissue. Many other groups at the Wyss Institute are focused on developing new technologies to extract benefits from existing drugs to treat a wide range of conditions from lymphedema to autism.
“There are thousands of molecules that have already been shown to have a therapeutic effect on various systems in the human body, and we are just beginning to really explore what these drugs can do when they’re put in different contexts, delivery vehicles, and chemical states. Many of these drugs are far from being used to their full potential to treat disease, and we’re lucky that we have so many brilliant minds and resources at the Wyss Institute and our partner institutions to find and capture that value and bring it to patients,” said Mitragotri.