By James Nurton, freelance writer
The COVID-19 pandemic has prompted worldwide interest in the repurposing of drugs such as remdesivir and dexamethasone. Repurposing can be crucial for delivering new treatments to patients, but also raises a number of IP-related questions.
In May 2020, the US Food and Drug Administration (USFDA) authorized emergency use of the anti-viral drug remdesivir for the treatment of COVID-19 after research suggested that patients who received it recovered four days faster than those receiving a placebo. The drug has not yet been approved, and further clinical trials are taking place to assess its effectiveness against COVID-19, including in combination with the anti-inflammatory drug baricitinib (sold under the brand name Olumiant). In June 2020, in a breakthrough in treating seriously-ill COVID patients on ventilators or oxygen, the low-cost anti-inflammatory steroid dexamethasone, which has been shown to significantly improve survival rates, became the “standard of care” in the UK.
With COVID-19 now affecting the entire world, and no vaccine or treatment approved, researchers are looking at the potential of many existing drugs, and particularly those that have been effective against similar viruses such as MERS and SARS.
Remdesivir was originally developed to treat Ebola, though it has not yet been approved for any condition. It is one of four treatments that are part of the WHO’s Solidarity trial for treatments, the others being chloroquine or hydroxychloroquine, lopinavir with ritonavir and lopinavir with ritonavir plus Interferon beta-1a. These treatments have previously shown results against diseases such as malaria, SARS, HIV and multiple sclerosis. The Solidarity trial will involve tests on thousands of patients in more than 100 countries.
The repurposing of known drugs is vital to developing new, safe and cost-effective treatments for a wide range of conditions.
Dexamethsone, on the other hand, is a low-cost, on-the-shelf, anti-inflammatory steroid, that has been around for some 60 years. Widely used in treating arthritis, asthma and various skin conditions, dexamethasone has been shown to reduce deaths by up to one-third among seriously-ill patients with COVID-19. The findings emerged from the RECOVERY (Randomised Evaluation of COVid-19 Therapy) clinical trial led by researchers from Oxford University in the UK.
“COVID-19 is a global disease – it is fantastic that the first treatment demonstrated to reduce mortality is one that is instantly available and affordable worldwide,” said Martin Landray, Professor of Medicine and Epidemiology at the Nuffield Department of Population Health at Oxford University, one of the trial’s lead researchers.
The importance of repurposing
The repurposing of known drugs is vital to developing new, safe and cost-effective treatments for a wide range of conditions. For example, Aspirin (acetylsalicylic acid) was developed by German company Bayer back in 1899 as a treatment for pain and fever, and has since been proved to be effective against heart attacks, strokes and blood clots. And today it is in phase 3 clinical trials for treating colon and other cancers.
But Aspirin is not the only example of a drug that has an afterlife. For example, thalidomide, originally developed for treating morning sickness, has since been used against leprosy and is now also approved for treating multiple myeloma. And several drugs have been found to be effective against different types of cancer: examples include Merck’s Keytruda (pembrolizumab), which was developed for advanced melanoma but is now approved for 14 cancer types, and Bristol-Myers Squibb’s Opdivo (nivolumab) which is approved for 10 cancers and is being tested for more. In December 2019, AstraZeneca and Merck announced that Lynparza (olaparib) had been approved for treating pancreatic cancer in the US in addition to ovarian and breast cancer.
Clinical opportunities and commercial benefits
Patents and the protection they confer help to justify the significant costs and risks associated with developing a new drug and bringing it to market. However, with the cost of developing a new drug estimated to be around USD 2.6 billion, drug repurposing is unsurprisingly becoming a priority for pharmaceutical companies as well as organizations such as the Anticancer Fund in Europe and the US-based Cures Within Reach, which has so far funded 80 repurposing projects. Improved use of data and the application of AI tools such as machine learning, also have the potential to facilitate repurposing, which until now has often depended on serendipity. And repurposing is particularly important for the world’s estimated 7,000 rare diseases, where low patient populations make original research financially unrewarding.
As well as clinical opportunities, there are commercial benefits in repurposing, as Allie Nawrat explained in an article for Pharmaceutical Technology published in November 2019: “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.”
Yet many observers agree that the potential of repurposing drugs has yet to be fully explored, due partly to the “technological and regulatory challenges that need to be addressed” (“Drug repurposing: progress, challenges and recommendations” in Nature Reviews Drug Discovery 18). According to one estimate, just 10 of the 1,541 new drug approvals in the United States from 1990 to 2007 were for new uses of generic drugs.
Another arrow in the quiver
Many of the legal and regulatory questions surrounding drug repurposing were addressed at the “Clinical Innovation: Fair and Effective Incentives for New Uses of Established Drugs” Conference organized by University College London and Georgetown University Law Center in Washington DC in 2018. The Conference included researchers, doctors, lawyers, regulators and judges. Transcripts of all the sessions are available online. Opening the Conference, Professor Robin Jacob of the UCL Institute of Brand & Innovation Law, said: “If you find a new use for a known medicine, you have in fact really found a new medicine. You have put another arrow into the quiver of the doctor… And, because it is cheaper to do it than to find a wholly new molecule, it ought to be possible somehow to encourage it.”
[W]ith the cost of developing a new drug estimated to be around USD2.6 billion, drug repurposing is unsurprisingly becoming a priority…
Given the expense of pharmaceutical R&D, innovators rely heavily on patents to provide a period in which they can recoup the huge investment made. In some jurisdictions, that period can also be extended to compensate for time lost in the drug approval process. But there are problems in obtaining and enforcing patents for new uses of existing drugs, related in part to concerns about so-called “evergreening” of patents. If the original innovation is old, it is hard to satisfy the novelty and inventiveness tests in patent law, while if the evidence of the new use is thin, the invention may not be sufficiently disclosed. Even if a patent is granted and valid, there are real questions about what constitutes infringement in the complex drug prescribing system.
From Swiss-style to EPC 2000
In Europe, applicants have been able to obtain patents for second medical uses, formerly by the legal fudge known as the Swiss-style claim, and since 2011, by the so-called EPC 2000 claim “product X for treating disease Y” – a purpose-limited product claim. However, cases over the validity and infringement of second medical use claims continue to come before the courts in Europe, with mixed outcomes. The consequence is that there is considerable uncertainty about the enforceability of second medical use claims, as former GSK patent counsel Julia Florence discussed in a webinar hosted by the Chartered Institute of Patent Attorneys (CIPA) in December 2019 (“Second Medical Use Claims – is there a cure for their ills?”).
Many of these cases have arisen in situations where a company owns a patent for a first use of a drug and a later patent for a second use. When the first patent expires, generic rivals can sell their versions of the drug, but only for the first use. Any use of the drug for the indication protected by the second patent would infringe it. Generic manufacturers seek to overcome this problem by using so-called skinny labels, specifying that the drug should not be prescribed for the uses that remain patented. Nevertheless, there is a significant risk of patent infringement.
The pregabalin battle
An example of the complications that can arise involved the drug pregabalin, developed by Pfizer and sold under the brand Lyrica as a treatment for epilepsy, generalized anxiety disorder and pain. It is one of the world’s biggest-selling drugs. Since the first patent lapsed in Europe in 2013, generic companies have sold versions of pregabalin with skinny labels carving out the pain indication (which was protected by a second medical-use patent). Nevertheless, evidence presented in court suggested that some 70 percent of prescriptions for pregabalin were for the patented use.
Over the past several years, Pfizer has brought cases throughout Europe with mixed results. In Denmark, it successfully sued the country’s pharmacies, which resulted in the Danish medicines agency changing its substitution rules to specify that if a prescription is issued for treating a patented indication, the pharmacy should dispense only the product with the patented indication. In the United Kingdom, the pregabalin litigation reached the Supreme Court, where a panel of five judges gave four different opinions in a judgment in November 2018. Three of the judges held that the disclosure in the specification did not support neuropathic pain, as the patentee had not provided data or a credible hypothesis showing efficacy, though the two dissenting judges preferred a lower standard of plausibility.
Other recent decisions involving Swiss-form and EPC 2000 claims include the EPO Board of Appeal rulings relating to zoledronic acid (Case T0239/16 ) and a multiple sclerosis treatment (Case T-2570/11 ) as well as the UK Supreme Court judgment in Actavis Group PTC EHF and others v ICOS Corporation and another  UKSC 15 of 27 March 2019 (concerning a patent for the use of the drug tadalafil in a dosage form for the treatment of sexual dysfunction). This judgment, upheld the Court of Appeal finding that clinical tests, involved familiar and routine procedures and the patent was therefore invalid for lacking an inventive step. “Hopefully this will not render all inventions that come out of clinical trials as obvious,” said Ms. Florence in the CIPA webinar.
If you find a new use for a known medicine, you have in fact really found a new medicine. You have put another arrow into the quiver of the doctor… And, because it is cheaper to do it than to find a wholly new molecule, it ought to be possible somehow to encourage it.
Professor Robin Jacob, Institute of Brand & Innovation Law, UCL, UK
How to incentivize repurposing
The extensive litigation over second medical use patents has provided some clarity but also revealed that patent law alone may not provide the necessary incentives for drug repurposing. As former US Court of Appeals for the Federal Circuit Judge Arthur J. Gajarsa said at the Georgetown Conference: “We need to have some new legislation at least to recognize that the new uses of drugs from old drugs that have been in existence for a while might need to have some incentive for the market to be provided so that the patent and the new use can be protected.” Some of the solutions suggested include:
- Prescribing: Change prescribing habits, either by separating the patented market by requiring prescribers to write the brand name for patented indications and the international non-proprietary name for non-patented indications, to require indications to be stated on prescriptions (as is the case in Denmark) or to prescribe drugs by category (as in Belgium). However, there are objections on the grounds of practicality and confidentiality.
- Pricing: A radical proposal made by Ben Roin of MIT Sloan School of Management is to price drugs by indication rather than by product. Another suggestion is to add a tax to each prescription to fund the development of new uses.
- Empowering physicians: many doctors prescribe drugs off label (that is, for indications the drugs are not yet approved for). Drugs companies are not generally authorized to promote off-label use, but rules could be loosened to facilitate repurposing. In addition, better use could be made of real-world evidence of efficacy in doctors’ day-to-day experience.
- Term of protection: IP consultant Bob Armitage, formerly of Eli Lilly, has proposed that patentees be able to choose a 14-year fixed period term of protection for newly approved drugs rather than a 20-year term from date of filing, with no extension, but other options could also be explored.
Life after patent expiry
“Drug rediscovery is invaluable because it can increase therapeutic options and reduce drug-development-associated costs. However, there is a need for a structured protocol for further development of old drugs to optimize licensing and avoid long-lasting procedures,” say the authors of a study of Thiosix (thiroguanine), which was published in Drug Discovery Today in January 2018. Thioguanine was developed as a treatment for leukemia in the 1950s and approved for treating irritable bowel disease in 2015. Its success shows that there can be a second act for innovative drugs, but also that much more work needs to be done to incentivize and encourage such repurposing.
RECOVERY (The Randomised Evaluation of COVID-19 Therapy) clinical trial, funded by the UK’s National Institute of Health Research (NIHR), was established in March 2020, in response to the COVID-19 public health crisis.
The largest randomized clinical trial of potential COVID-19 treatments for hospitalized patients in the UK, RECOVERY has enrolled over 11,500 patients so far from 175 NHS hospitals across the country.
The trial included a study of the potential of dexamethasone, an inexpensive steroid that is widely used to treat arthritis, asthma and various skin conditions. Led by Professor Peter Horby and Professor Martin Landray at Oxford University’s Nuffield Department, the study found that deaths among patients on a ventilator or receiving oxygen fell by one-third and one-fifth respectively, when they were treated with dexamethasone. The drug demonstrated no benefit among patients that did not require respiratory assistance or patients in the community.
The RECOVERY trial, which is constantly reviewing information on new drugs with the potential to improve COVID-19 health outcomes, is currently testing:
- Lopinavir-Ritonavir (commonly used to treat HIV)
- Low-dose Dexamethasone (now only recruiting children)
- Azithromycin (a commonly used antibiotic)
- Tocilizumab (an anti-inflammatory treatment given by injection)
- Convalescent plasma (collected from donors who have recovered from COVID-19 and contains antibodies against the SARS-CoV-2 virus).