At last, serious efforts to repurpose generic drugs to treat COVID-19

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More than a year into the pandemic, billions of dollars have been spent on developing vaccines and expensive novel treatments, but very little on repurposing existing drugs. Now at last calls from doctors have prompted action to find self-medicating affordable drugs that can alleviate the symptoms and severity of COVID-19, writes MedicalBrief.

There has long been disquiet among medical professionals about the overwhelming for-profit focus of drug innovation in the midst of the pandemic. But not surprise, given that most of the research and development, and likely all of the manufacturing, has been undertaken by pharmaceutical companies.

The disquiet has been over the fact that governments – especially the United States – have spent huge amounts of public money funding prevention and treatment drug development, however the outcomes have rarely been fully optimal for public health.

While repurposing drug efforts got off to a slow start, there is now growing demand for a COVID pill, writes MedPage Today in a highly informative article (see below) that outlines repurposing research and initiatives.

In Health Affairs in December 2020, researchers from the universities of Boston, Harvard, Stanford and MIT proposed “a programme dedicated to finding and deploying existing, off-patent medications against infectious diseases, starting with COVID-19.

“A strong federal role is needed because of the absence of financial incentives for the private sector to repurpose off-patent drugs, despite the public health advantages of such a strategy.”

On 19 April, the United States National Institutes of Health (NIH) announced that it would fund a large Phase 3 clinical trial to test several existing prescription and over-the-counter medications for people to self-administer to treat symptoms of COVID-19, among the majority of people who have mild to moderate symptoms.

 

Drug repurposing for COVID-19: What went wrong?

So far in the pandemic, support for research on drug repurposing – particularly for inexpensive generics – has not played a huge role in finding new treatments for COVID-19, but that appears to be changing, writes Dr Veronica Hackethat, Enterprise and Investigative writer for MedPage Today, on 22 April 2021.

Critics charge that drug repurposing is like looking for a needle in a haystack. It does not always work, and can raise false hopes and waste resources.

In a 7 March 2021 interview with 60 Minutes, for instance, NIH Director Dr Francis Collins said drug repurposing "is only going to work if you're kind of lucky, because you're basically picking things that were developed for a different disease".

Proponents say that the strategy can be faster and cheaper than de novo drug development. About 90% of de novo drugs fail at some point during development, and it can take 10 to 12 years and cost $2 to $3 billion for the winners to come to market.

In contrast, continues the Medpage Today article, the average repurposed drug can rely on past safety data to speed its development, and costs about $300 million to bring to market, according to a 2020 report by Roots Analysis.

Proponents are now finding their voices heard. As part of NIH's Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) trial programme, ACTIV-6 was launched to examine up to seven repurposed drugs for their efficacy in treating mild-to-moderate COVID-19 outpatients.

Feds overlooked repurposing

Early in the pandemic, the US failed to evaluate repurposed drugs for COVID-19 and "pursued an almost singular focus on vaccines that was very unusual and clearly driven by leadership", charges Dr Rena Conti, associate research director of the Institute for Health System Innovation and Policy at the Questrom School of Business at Boston University.

In the face of past infectious disease threats, the US has "always pursued an all-in approach by investing in preventives as well as therapies," Conti said.

Conti and colleagues at Harvard, Stanford, and MIT have argued (see below) that the sheer scale and number of people affected by the pandemic highlights the need for affordable, accessible treatments, writes MedPage Today.

But when the federal government did support development of certain therapeutics, that support was focused on new drugs or early-stage research, and rarely included relatively fast and cheap repurposed drugs. For example, among 17 total agents investigated in NIH's ACTIV trials, 47% are monoclonal or polyclonal antibodies.

Investments in COVID-19 therapeutics "clearly had something to do with favouring for-profit drugs that are largely novel for which there might be proof-of-concept to use in COVID-19. It was an investment in the future science and profit that might come from them," Conti said.

That investment came at a cost, MedPage Today continues. Regeneron's casirivimab/imdevimab and Eli Lilly's bamlanivimab/etesevimab monoclonal antibody cocktails have both received emergency use authorisation from the Food and Drug Administration (FDA).

But they must be administered in healthcare settings, which limits their accessibility. As of January, 75% of these monoclonal treatments allocated to states have gone unused.

While the price of these monoclonals is unknown, the US government paid $812.5 million for 650,000 doses of Lilly's bamlanivimab in December 2020, which works out to $1,250 per dose. The government is currently covering the cost of these doses, but payors may still need to pay for the infusions.

Additionally, Gilead has set the price of remdesivir (Veklury), the only fully FDA-approved drug for COVID-19, at $2,340 to $3,120 for a five-day course, depending on insurance.

In contrast, the generic steroid dexamethasone costs about $15 for a 10-day course.

Other repurposing efforts

While the US was preoccupied with hydroxychloroquine, the United Kingdom organised the RECOVERY study, a six-arm trial that validated the mortality benefit of dexamethasone in the treatment of hospitalised patients with COVID-19, and early on showed lack of benefit for hydroxychloroquine in hospitalised patients.

MedPage Today continues: RECOVERY has been "incredibly cost effective and highly productive", ringing up at about $20 million, a "drop in the bucket" compared to what the US spent on Zika, Ebola or H1N1, according to Conti.

The NIH also supported early-stage drug repurposing research via the National Center for Advancing Translational Sciences (NCATS). NCATS did high-throughput screening of thousands of approved compounds, and made their data sets publicly available.

The California Institute for Biomedical Research also screened thousands of approved compounds and shared their data sets with over 70 groups. The focus was on fit-for-purpose drugs, with the intention of making better COVID drugs at lower cost.

While some researchers are tweaking old drugs to make them better, reports MedPage Today, doctors have been prescribing drugs off-label to patients. Research is also needed to find out if any of these drugs offer viable options.

"Almost all the drug repurposing efforts early in the pandemic were high-throughput drug screens of antivirals to repurpose," said Dr David Fajgenbaum of the University of Pennsylvania, who launched the COVID19 Registry of Off-label & New Agents (CORONA) project in March 2020.

The goal of CORONA is to track every drug that has been used for COVID-19. It is now the world's largest database of COVID-19 treatments used in humans, with information on more than 500 drugs. The "vast majority" of these are generic, according to Fajgenbaum.

Recent 'sea change'

Despite these challenges, the tide may be turning. The last 60 days have brought a "sea change" in the federal government support for COVID-19 therapeutics, according to Dr Armand Balboni, CEO of Appili Therapeutics which is overseeing PRESCO, a phase III trial that is evaluating the oral antiviral favipiravir in the outpatient treatment of COVID-19.

In the 60 Minutes interview, MedPage writes, Collins said that at the beginning of the pandemic there were "an awful lot of scattershot efforts to try and find effective treatments… I wish we had had a stronger push for agents that you can take by mouth before you get in the hospital to prevent disease. It took a while after the hydroxychloroquine debacle to get that back on track.”

NIH has since announced a $155 million initial investment to fund ACTIV-6 to study repurposed drugs in mild-to-moderate COVID-19. The trial will use a more efficient, adaptive design and include three to six arms, with an early look at the data to assess for futility.

Knowledge of the natural history of COVID-19 has highlighted the need for drugs that can treat early illness, later-stage illness, and long COVID. Voices from disparate sectors – like Fajgenbaum, Balboni, and Conti – are asking the federal government to take a larger role in supporting drug repurposing to fill that toolbox, particularly for generics.

Dr Ameet Sarpatwari and colleagues at Harvard Medical School have proposed a national public pharmaceutical research and development institute focused "drugs of societal need". Its scope would stretch beyond COVID-19 to include other diseases and preparation for the next pandemic.

See link to the full MedPage Today article below.

 

NIH material

Large clinical trial to study repurposed drugs to treat COVID-19 symptoms

US National Institutes of Health

News release published on 18 April 2021

The National Institutes of Health will fund a large, randomised, placebo‑controlled Phase 3 clinical trial to test several existing prescription and over-the-counter medications for people to self-administer to treat symptoms of COVID-19.

Part of the Accelerating COVID-19 Therapeutic Intervention and Vaccines (ACTIV) public- partnership, the ACTIV-6 trial aims to provide evidence-based treatment options for the majority of adult patients with COVID-19 who have mild-to-moderate symptoms and are not sick enough to be hospitalised.

NIH will provide an initial investment of $155 million in funding for the trial.

“While we’re doing a good job with treating hospitalised patients with severe disease, we don’t currently have an approved medication that can be self-administered to ease symptoms of people suffering from mild disease at home, and reduce the chance of their needing hospitalisation,” said NIH Director Dr Francis S Collins.

“ACTIV-6 will evaluate whether certain drugs showing promise in small trials can pass the rigor of a larger trial.”

Several drugs currently are recommended for the treatment of hospitalised patients with moderate to severe COVID-19, including the antiviral drug remdesivir, the anti-inflammatory baricitinib, and corticosteroids.

Additionally, the FDA authorised emergency use of intravenous monoclonal antibodies in non-hospitalised patients with mild to moderate COVID-19 who are at high risk for severe disease. However, medications that can be self-administered at home to reduce COVID-19 symptoms are critically needed.

The ACTIV-6 protocol will explore a pool of up to seven drugs approved by FDA for other conditions – an approach called drug repurposing – and test their safety and effectiveness in treating mild to moderate COVID-19.

Because the drugs under consideration already have been tested in humans, repurposing could deliver COVID-19 treatment options sooner. Drugs will be administered orally or by inhaler and will be easy for participants to take at home. Participants will be assigned randomly to receive either a placebo or one of the treatments, which will be sent to them by mail.

Enrolment is expected to open in a few weeks to up to 13,500 participants who are at least 30 years old, have tested positive for SARS-CoV-2 infection and have experienced two or more mild-to-moderate symptoms of COVID-19 for no more than seven days.

Researchers plan to assess changes in patients’ symptoms over a 14-day period, as well as hospitalisations and deaths over a 28-day period. They also will assess long-term COVID-19-related symptoms at 90 days after treatment begins.

The list of drugs that will be added to the study arms is still being finalised. All the drugs will have established safety records and early indications from smaller or less controlled studies of effectiveness against COVID-19.

The trial will focus on enrolment of people within minority, rural and other communities that are significantly affected by COVID-19 but lack access to major academic medical centres, where large clinical trials usually take place.

With funding provided by the American Rescue Plan Act, NIH’s National Center for Advancing Translational Sciences (NCATS) will oversee the trial. The Duke Clinical Research Institute, a NCATS-funded Clinical and Translational Science Awards Program hub, will serve as the clinical coordinating centre, and the Vanderbilt Institute for Clinical and Translational Research CTSA Program hub at Vanderbilt University Medical Center, will serve as the trial’s data coordinating center.

To expedite enrolment in ACTIV-6, NCATS and its Duke-Vanderbilt Trial Innovation Center will partner with the Patient-Centered Outcomes Research Institute (PCORI), an independent non-profit research funding organisation.

PCORnet, the National Patient-Centered Clinical Research Network, which is funded by PCORI, will support the ACTIV-6 governance and operations. In addition, PCORnet sites will enrol participants from a broad range of communities.

“Getting approval for a new drug to come to market usually takes years,” said Dr Joni Rutter, NCATS acting director. “By leveraging drug repurposing and existing national clinical trial networks, ACTIV-6 aims to speed the delivery of definitive answers about available drugs that could help people manage COVID-19 symptoms at home.”

 

Drug Repurposing Service Providers Market, 2020-2030

Roots Analysis report

Published in July 2020

 

Summary introduction

Novel drug/therapy development is a complex and capital intensive process characterised by several challenges and setbacks. A prominent concern reported by innovators is attrition (close to 90%) of candidate drugs/therapies owing to various reasons, in addition to therapeutic efficacy and safety.

Moreover, it is estimated that a new drug takes anywhere between 10 to 12 years to progress from the bench to market. Given the increasing global population and rising incidence of various types of diseases, medical researchers and drug developers are faced with a growing need to expedite time-to-market for their respective therapeutic candidates, while optimising the R&D expenditure.

Of late, the repurposing of marketed/shelved/pipeline candidates for the treatment of diseases different from what they were originally developed for, has emerged as a viable business strategy.

The rising popularity of this approach may be attributed to benefits, such as reduced development timelines and relatively higher success rates (considering that the safety profiles of such candidates have already been established).

In fact, of 28 drugs (including both novel and repurposed) approved by the FDA in the first quarter of 2020, 12 were repurposed. Further, it is estimated that around 25% to 40% of annual pharmaceutical revenues are generated from the sales of repurposed drugs.

It is also worth highlighting that repurposing offers significant cost saving opportunities to innovators, while guaranteeing substantial returns on investment. In fact, the cost of developing and marketing a repurposed drug has been estimated to be $300 million, compared to the $2 to $3 billion investment required to bring a novel drug into the market.

In this context, it is worth mentioning that several drugs (150+) that are presently being used/evaluated to treat COVID-19 are repurposed; prominent examples include chloroquine/hydroxychloroquine (anti-malarial drug) and remdesivir (initially developed to treat hepatitis C).
A number of service providers, including contract research organisations, claim to provide the necessary support to drug developers in identifying or predicting prospective clinical trials for repurposing. Such companies offer a variety of services, encompassing both drug discovery operations and consultancy requirements.

In fact, many such players claim to have developed proprietary platforms based on advanced technologies, such as big data analysis, artificial intelligence and real-world evidence, in order to facilitate drug repurposing related decision-making.

This upcoming industry has witnessed significant partnership activity in the last 10 years, with service providers having established strategic collaborations with innovator companies, as well as information technology and data management experts.

In future, experts believe that outsourcing activity related to drug repurposing is anticipated to grow at a rate of 20% to 25%.

 

 

MedPage Today article – Drug Repurposing for COVID-19: What Went Wrong? (Open access)

Roots Analysis report – Drug Repurposing Service Providers Market, 2020-2030 (Restricted access)

Health Affairs article – Generic Drug Repurposing For Public Health And National Security: COVID-19 And Beyond (Open access)

 

SEE ALSO FROM THE MEDICALBRIEF ARCHIVES

 

Antidepressant drug repurposed for patients with coronavirus infection — JAMA

Gilead challenges WHO’s ‘conclusive evidence’ on repurposed drugs

Repurposed tocilizumab did not significantly improve severe COVID-19 pneumonia

COLCORONA trial: Is gout-drug colchicine set to be the next Ivermectin?

 

 


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