Drug repurposing: the industry’s all-rounder medicines

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rug repurposing has become an important element of the pharma industry. It’s an unsurprising development given that bringing a drug to the clinic now costs around $2bn and the failure rate for novel therapies is about 90%.

Repurposing occurs throughout all stages of drug development and approval; usually it is motivated by something particularly interesting or unexpected about the drug’s mechanism of action, which may indicate its usefulness in another indication.

The gold mine of therapeutic repurposing has been greeted especially warmly by life sciences investors. Not only does this approach save pharmaceutical companies money, it also speeds up the time it takes to bring a new treatment option to suffering patients. This is primarily because researchers are not required to repeat the earlier stages of development that simply demonstrate the safety of the drug.

This recycling approach has been seized upon particularly enthusiastically and effectively in the oncology space, where drugs originally developed for one specific cancer are trialled in other similar tumour types, creating all-rounder drugs. Cancer seems particularly ripe for drug repurposing since a single mechanism or biomarker is often associated with a range of different tumour types.

One example is Merck’s Keytruda (pembrolizumab). Originally approved for advanced melanoma in 2014, five years later the immunotherapy is now approved for a total of 14 cancer types ranging from lung and cervical cancers to two types of lymphoma.

Merck is continuing to investigate Keytruda for more cancers, including triple-negative breast cancer, and other patient groups within the already-approved oncology indications.

Keytruda was the first programmed cell death-1 (PD-1) inhibitor to be approved. Its mechanism of action in blocking the PD-1 receptor and its interaction with ligands helps to activate a T-cell mediated immune response against tumour cells. The clinical development of Merck’s immunotherapy has focused on patients who express PD-1’s ligand 1 (PD-L1) on their tumour cells.

Due to its similar PD-1-based mechanism of action, Bristol-Myers Squibb’s (BMS) Opdivo (nivolumab) is approved for ten cancers, and, similarly to Merck, BMS continues to trial the drug in further oncology indications.

Not only is repurposing drugs happening within various indications in one disease area, the industry is using same biomarker and mechanism-of-action approach to study whether drugs approved within one disease area can bring benefits to patients with an entirely different condition.

As oncology is the dominant disease area in the pharma industry, unsurprisingly, it is especially common for non-oncology drugs to be repurposed to treat cancers. One case study is antibiotic clarithromycin, which has been used to treat Lyme disease and infections associated with H. pylori since 1990.

Studies have shown that clarithromycin is effective in H. pylori-associated cancers, for example mucosa‐associated lymphoid tissue lymphoma, since eradicating the bacterial infection causes impressive tumour regression in many less severe patients. However, initiatives such as the ReDo project have also identified its efficacy in other cancers, including chronic myeloid leukaemia and multiple myeloma.

As the US National Institutes of Health has explained, there are various reasons behind clarithromycin’s anti-cancer properties; the primary mechanisms are a reduction in pro-inflammatory cytokines, autophagy inhibition, and anti-angiogenesis. Clarithromycin’s efficacy in cancer is often improved when it is combined with existing cancer drugs targeting other aspects of tumour activity; using drugs in combination is common across the oncology field.

Another example of a non-cancer drug being studied in oncology indications is aspirin (acetylsalicylic acid). However, this pain reliever’s clinical benefit goes beyond cancer; it has also been proven to be useful in both preventing heart attacks and increasing survival rate during the attack itself.

Acetylsalicylic acid has been used since ancient times to treat fever and pain, but it was only properly manufactured from the late 19^th century; it was marketed as Aspirin by German pharma company Bayer in 1899.

Low doses of aspirin have been found to reduce the risk of developing a range of cancers, including pancreatic and colorectal cancers.

The Anti-cancer Fund is currently funding an ongoing Phase III trial in colon cancer occurring in Belgium and the Netherlands. Focusing on improving overall and progression-free survival compared to placebo, the so-called ASPIRIN study’s estimated completion date is the end of 2026.

Studies have explicitly linked aspirin’s effectiveness in cancer with its wonder drug-worthy cardiovascular effects. Aspirin’s ability to prevent heart attacks is connected to its blocking of the enzyme cyclooxygenase, which produces hormones called prostanoids.

Since prostanoids play a role in encouraging platelets in the blood to stick together, inhibition of cyclooxygenase prevents the clumping of platelets and excessive blood clotting, the main cause of heart attacks. As a results of its proven success against heart attacks, aspirin has been included alongside three other cardiovascular drugs in a polypill proven to reduce heart and circulatory disease events by a third over five years; findings from the international study were published in the Lancet in August this year.

Since aspirin’s cardiovascular effects were first noticed in the mid-1900s, research has been underway to determine the benefits of daily use of aspirin can prevent heart attacks.

Current advice states that for those without cardiovascular disease, the side effects related to aspirin outweigh the benefits of preventing blood clots, meaning the drug should only be taken if prescribed by a healthcare professional.

Oncology indications are not only the recipients of drug repurposing; they are sometimes also the source. One case study is Novartis’s Arzerra (ofatumumab), a monoclonal antibody targeting the CD20 protein on the surface of B cell lymphocytes, originally developed to treat chronic lymphocytic leukaemia (CLL).

However, research shows CD20-positive B cells also play a role in destroying the myelin sheaths surrounding nerve cells, which are important in multiple sclerosis (MS). As a result, GSK and Genmab, Arzerra’s developers, began investigating the drug’s safety and efficacy in MS in 2013.

Novartis acquired Arzerra for $300m from GlaxoSmithKline (GSK) in 2015; however, the Swiss pharma giant paid an additional $200m for the remaining rights to Arzerra in relapsed remitting multiple sclerosis (MS) and other autoimmune diseases, as Arzerra had struggled to generate sufficient revenues in oncology due to strong competition in the CLL indication.

In August 2019, Novartis announced positive results from two Phase III trials of Arzerra in relapsing forms of MS. Compared to Sanofi’s Aubagio (teriflunomide), Arzerra showed a highly significant and clinically meaningful reduction in the number of confirmed relapses; Novartis’s drug also delayed time to confirmed disability progression, the secondary endpoint. Full data will be presented at an upcoming European MS conference.

Novartis plants to submit marketing approval applications for Arzerra with regulators for MS later this year.

Novartis chief medical officer and head of global drug development John Tsai wrote in a statement: “Ofatumumab, if approved, could be a highly attractive treatment option for a broad RMS patient population, including early MS.”

Patients with rare diseases often have few therapeutic options because the small treatment population often makes traditional approaches to drug development unviable commercially. With drug repurposing’s ability to drastically reduce the cost of pharma R&D, it could be particularly revolutionary for rare disease patients.

Although there are numerous examples of rare disease drug repurposing, one is immunosuppressant rapamycin. Originally extracted and synthesised from soil bacterium Streptomyces hygroscopicus on Chile’s Easter Island, rapamycin was initially developed as an anti-fungal drug. However, following the discovery of its immunosuppressive properties linked to its inhibition of the mTOR protein kinase, Pfizer’s branded version Rapamune was approved to prevent organ transplant rejection by the US Food and Drug Administration in 1999.

In 2015, rapamycin became the first drug approved for rare, genetic lung disease lymphangioleiomyomatosis (LAM).

LAM is caused by mutations in tuberous sclerosis complex (TSC) genes, TSC1 or TSC2; these activate rapaymycin’s target mTOR pathway, meaning the immunosupressant’s use in this indication can block the pathway, and reducing the resulting effects of the genetic mutation. Rapamycin successfully stabilised lung function and improved the quality of life of patients during the 2011 MILES trial.