The U.S. Department of Health and Human Services announced Tuesday that it would invest $1.6 billion toward the commercial development of a COVID-19 investigational vaccine by the Maryland-based company Novavax.
HHS also announced that it would provide $450 million to Regeneron to manufacture and supply the company’s antiviral antibody treatment, REGN-COV2.
The clinical trials for both the vaccine and the treatment are still underway.
The funding projects were undertaken as a joint effort between HHS and the Department of Defense as part of Operation Warp Speed, the Trump administration’s initiative to deliver 300 million doses of COVID-19 vaccine by January 2021.
“Depending on success in clinical trials, today’s $1.6 billion investment supports our latest vaccine candidate, being developed by Novavax, all the way through clinical trials and manufacturing 100 million doses for the American people,” said HHS Secretary Alex Azar.
The $1.6 billion, according to Novavax, will be put toward clinical development and trials, the establishment of large-scale manufacturing, and the delivery of 100 million vaccine doses. As reported by the New York Times, Novavax has not yet brought a product to market.
The government will own any doses of the vaccine and treatment resulting from the projects, HHS said.
“If these doses are used in a COVID-19 vaccination campaign, the vaccine would be available to the American people at no cost,” said the agency in a press release. “As is customary with government-purchased vaccines, healthcare professionals could charge insurers for the cost of administering the vaccine.”
Regeneron said in a press statement that, should the U.S. Food and Drug Administration grant emergency use authorization or product approval for the treatment, “the government has committed to making doses from these lots available to the American people at no cost and would be responsible for their distribution.”
“This agreement with Regeneron is the first of a number of Operation Warp Speed awards to support potential therapeutics all the way through to manufacturing, allowing faster distribution if trials are successful,” said Azar.
HHS announced on May 15 that 14 vaccine candidates had been chosen under Operation Warp Speed with the intention of being narrowed down to about seven. The agency had already allocated hundreds of millions in funds to support the development of Johnson & Johnson, Moderna and AstraZeneca’s candidate vaccines.
The HHS announcement comes on the heels of the FDA’s decision to grant emergency use authorization to a point-of-care 15-minute COVID-19 antigen test produced by Becton Dickinson.
On Tuesday, however, the FDA also issued a warning about false positive rates from a different Becton Dickinson COVID-19 test, which had been granted an emergency use authorization in April.
There is a need for aggregation and analysis of the vast data that will be generated from the use of repurposed drugs such as Remdesivir, Favipiravir and Dexamethasone in the coming times to understand their true potential for COVID treatment
Repurposing broad-spectrum antiviral agents have been deemed ‘safe-in-man’ through testing on early phase clinical trials for COVID-19. In April 2020, an international collaborative research team conducted a large-scale drug repurposing survey to identify existing drugs that prevent the COVID-19 virus from replicating. The team consisted of scientists from the Sanford Burnham Prebys Medical Discovery Institute, Scripps Research Institute, University of California San Diego, University of California Los Angeles (all CA, USA), The University of Hong Kong (China), University of Vienna (Austria), Texas Biomedical Research Institute (TX, USA) and Icahn School of Medicine at Mount Sinai (NY, USA). The team discovered 300 drugs that could stop the virus from replicating. Utilising molecular tools such as PCR and immunofluorescence microscopy, the researchers were then able to determine 30 most effective candidates. A few are already under evaluation for use in COVID 19 around the world.
Back home, after extensive use of hydroxychloroquine, repurposed drugs Remdesivir, Favipiravir and Dexamethasone have been touted to show a lot of promise in early trials for the treatment of COVID-19. These drugs have been approved for treatment by the ICMR under emergency use authorisation conditions. There is an informed consent form which the prescribing doctor first explains to a patient before the patient starts the course. All patients will be observed and patient data will be analysed and submitted for review to the regulatory body in India. Now, each of these drugs responds differently and are utilised at different stages of the illness. For instance, as part of the FAITH trial, a combination of Umifenovir and Favipiravir has been used for ‘mild and moderate’ COVID-19 cases. Whereas, Remdesivir is for patients with more severe symptoms of the infection. Dexamethasone, a corticosteroid used in a wide range of conditions for its anti-inflammatory and immunosuppressant effects has been utilised to reduce the risk of death among severely ill patient. While all these drugs have shown some good outcomes in the initial trials some of these are termed as a wonder drug or miracle cure for COVID.
Express Healthcare in this article aims to understand the existing safety evidence on Indian patients from the clinician’s perspective.
So let’s begin with first understanding the advantages of repurposing drugs and then gain clarity on the original purpose of said repurposed drugs used for COVID treatment and why and how these drugs show promise for COVID treatment and what is the caveat emptor associated with these drugs.
The advantages of repurposed drugs
According to various scientific publications, repurposed drugs are an immediate response to the pandemic which has accelerated beyond the containment strategies. It is a strategy often used in the oncology space. A pharma technology review paper mention that borrowing drugs from other indications is a time saver because these drugs have proven themselves to be safe in pre-clinical and early clinical testing. They can be fast-tracked straight into the final stage of clinical development, Phase III and can be easily evaluated for their safety and efficacy as COVID-19 treatment. The expediency of this strategy has captured the imagination of pharma companies and university researchers committed to quickly resolving the COVID-19 pandemic. Some publications indicate the following benefits.
Creating access to patients sooner: Ensuring access to some treatment that can block or prevents a mechanism of action that a virus might use to replicate is very critical. This is where repurposed drugs come into the picture. Hospitals remain overwhelmed with patients who have contracted a virus for which no reliable treatments exist. Repurposed drugs could substantially accelerate the delivery of treatment and elevate the suffering of afflicted patients.
Relying on safety information from the existing drug: The primary reason that repurposed drugs have shorter development programmes is that sponsors can rely on existing drug safety data for a New Drug Application (NDA). Because the safety of the drug product has already been proven, typically fewer studies are required. Additionally, clinical trials to determine if a repurposed drug can halt disease progression can be relatively short-term and inexpensive since researchers generally know the safety profile and have a good idea of the proper dose and duration. Regulators can approve such drugs if several studies show consistent benefit when weighed against the observed side effects. Progress can be made with several candidates in consideration.
Reduced cost of drug development programmes: These shorter development timelines and streamlined studies lead to significant cost savings for sponsors. Moving rapidly to the clinic with so many unanswered questions about efficacy carries considerable risk, and the scale of manufacturing needed for COVID-19 therapies is enormous. Especially in an uncertain funding environment, having a cost-optimised strategy for a well-understood active ingredient could enable a programme to progress to approval or authorisation.
Repurposed drugs and one big human trial…
We are all aware that the safety evidence of these 3 drugs is not originally licensed for Covid-19. They are part of clinical trials and have been authorised for emergency use under clinician supervision. Therefore experts also provide a word of caution on the use of these drugs.
According to Dr Balasubramanian Mahadevan, Ex-Medical Director at PD Hinduja, Saifee, Bhatia, Shushrusha and Lilavati Hospitals in Mumbai, drug repurposing is an emerging strategy where existing medicines, having already been tested safe in humans, are redeployed to combat difficult-to-treat diseases.
While using such repurposed drugs individually may ultimately not yield a significant clinical benefit, carefully combined cocktails could be very effective, as was for HIV in the 1990s. In the absence of any vaccines to prevent COVID-19, there are many clinical trials (CT) taking place to find a treatment. These CTs are mainly focusing on either repurposing or repositioning the existing molecules. WHO has published a landscape of therapeutics which could be used for treating COVID-19, and some of them are undergoing CTs as well. Generally speaking, patents are not a concern when it comes to old molecules under CTs because these molecules are already out of patent protection. However, a few of these molecules are still under patent protection in many countries. Two in particular – Remdesivir and Favipiravir – are under patent protection in India. The generic availability of these medicines can facilitate compassionate use and CTs in India without depending on supply from the patent holders. Therefore, the Government of India should use the compulsory license or government use license to facilitate the generic production of these medicines.”
To understand the current clinical response of these drugs and its actual utilisation in the Indian market, we spoke to some clinical experts who have been prescribing these drugs to their patients and are constantly monitoring the efficacies of the same.
“All three drugs are beneficial when started at an early stage for the treatment. Once the patient is critical and on ventilatory support, their utility is limited. Having said that, Dexamethasone can be given to all patients, even the ones with mild changes on the chest CT scan. Favipiravir and Remdesivir are started to patients who require oxygen support and who we feel are likely to have a clinical deterioration,” says Dr Chinmay Godbole, Chief of Intensive Care, KJ Somaiya Hospital, Superspecialty Centre.
Dr Samrat Shah, Consultant Internist, Bhatia Hospital states that the main treatment in COVID-19 revolves around three main drugs-antivirals, anti-inflammatory and anticoagulation.
He further explains the antivirals first
FACTS of Favipiravir
Favipiravir, Remdesivir contains the viral replication and it’s not viricidal (doesn’t destroy the virus directly).
It doesn’t have any major role in saving you from mortality but it can reduce the days of your suffering from COVID-19.
Antivirals like Remdesivir and Favipiravir are falsely hyped as lifesaving drugs.
Advantages of Favipiravir are:
Favipiravir is effective in mild /moderate stages
It is easily administered orally
Disadvantages of Favipiravir include the following:
There is pill load because of a high dose of 18 tablets given on day one and followed by eight tablets per days for 7-14 days.
It causes Hepatotoxic which is damaging or destructive to liver cells.
Remdesivir is claimed to be effective in the severe and critical stage but its disadvantage lies in IV administration.
It is also hepatotoxic and damaging or destructive to liver cells.
Practically speaking viral replication ends in first 1-7 days, complications which occur in critical and severe COVID 19 post 7-8 days is due to an inflammatory response (SIRS). So this drug ideally should be used in the early stages when viral replication is happening to reduce the viral load in the body.
Similarly, Dr Shah updates us on anti-inflammatory Steroids- Dexamethasone/MPS saying, “Lifesaving as always, its key role is in severe and critical COVID 19 pneumonia and ARDS. This medicine should be used with extreme caution in early stages when viral replication is going on, early judicious use can boost the viral replication and lead to viremia.”
Similarly, Dr Kedar Toraskar, Chief of Critical Care, Wockhardt Hospitals, Mumbai Central, informs, “Favipiravir is an oral antiviral used forresistant influenza in 2014. It has been repurposed in the view of this pandemic. There were trials in Japan, China and there are ongoing trials in India. It is a relatively safe drug but the only problem is the dose is high. The patients have to take nine pills on day one and 4 pills, twice a day, on subsequent days for at least 6-14 days. The total course is 7-14 days, and that’s the problem. Also, if the patient has underline gout, he/she needs to be careful, and the patient will have to be monitored for their liver function before taking it. The cost of Favipiravir is around Rs 100, so the cost comes to be around Rs 7,000 Rs for a full course of seven days, and it can be unaffordable for a common man. Also, the pill burden is high. It is not a wonder drug; we are still waiting for the trial reports. It has to be used in initial stages (first seven to eight days). It is used for mild to moderate symptoms. It helps or doesn’t help is still not known.”
He further explains the clinical efficacy of Remdesivir. “This drug is intravenous right now. It is also a repurposed drug and an antiviral. Right now, it has been licensed for moderate to severe patients. It has to be administered early (between six to 12 days). If it is used late then efficacy is not good. Again, clinical trials are ongoing and it is not a proven benefit. Recovery time from this drug is less but whether mortality is low, is not known yet. But, Remdesivir seems to be promising. On the first day, 200 milligrams are given and the second day, subsequent 100 milligrams, and the cost of this drug is Rs 5,000. For administering it, liver and renal function tests have to be monitored. It can’t be given to those patients having renal failure. One will have to use antivirals in an early stage. They won’t work after 10-12 days. Dexamethasone is a steroid. It was found useful in the recovery trial done in the UK. It is for patients who have hypoxia (oxygenation problems). It is not to be used in the early phase as it can harm the patient than doing good. It has to be started after 10 days. It is used for patients with respiratory failure. If it is used too late then also it will not benefit. It is a steroid and can also cause secondary infections also. Use it with caution and in the patients, who have high sugar.”
Dr Deepesh G Aggarwal, Consultant and HoD Critical Care Medicine, Saifee Hospital speaking about how these repurposed drugs have given us a fighting chance in combating COVID 19 when used appropriately, states, “Steroids and Remdesivir have been quite effective. Our experience with favipiravir is relatively lesser as it has been recently introduced. Injection Tocilizumab has been a lifesaver in patients with Cytokine storm.”
Further sharing his observation Dr Toraskar expounds, “We will have to see the trial results. Dexamethasone and steroids are helpful for us.In some patient so. Remdesivir seems promising but we have to keep a close watch on it. It is like an option that wasn’t available before. The timing of the drugs and patient selection is important.Antivirals like favipiravir and Remdesivir have to be used early on in the viremia phase in the first 10 days of symptom onset. Remdesivir is to be used for moderate to severe cases between fifth to 12th day. Steroids will be harmful in the viremia phase if used early. They have only shown proven benefit in patients who have respiratory failure requiring supplemental oxygen and ventilation. Start using it when available on compassionate grounds after discussing the pros and cons with the patient and their relatives. Steroids in low dose seem to work as proven by the recent recovery trial results and that has been our experience in the last two months too.”
More data required and stringent rules against black marketing
Just as clinical experts point out that these drugs certainly bring hope to healthcare providers and patients alike, their application should be strictly monitored. Most doctors clearly indicate that the high dose of these drugs can be detrimental to patients. Moreover, there is a need for aggregation and analysis of the vast data that will be generated in the coming times. Only then can the true potential of these repurposed drugs be judged. Another issue that healthcare providers are currently facing is the shortage of drugs such as Remdesivir.
Dr Godbole raises his concerns on the shortage of drugs. “We should have some way to procure these drugs easily as currently procuring them is a challenge. More importantly, since these are observed to be life-saving drugs, it should be made available easily. Further, the awareness of the indications of these drugs is important. We do not want hoarding of these essential drugs by anyone,” he notifies.
Likewise, an industry source informed Express Healthcare that in many places, especially in Mumbai, Remdesivir is not available easily and is sold in black. The cost of which varies between Rs 50,000 to Rs 85,000 per vial. In order to tackle this menace, drug company Hetero, which has obtained a license to supply Remdesivir (COVIFOR 100 mg vial) has been directly contacting hospital pharmacies to ensure the drug is available at the right price. However, when Express Healthcare contacted the Pharma company, the company informed that the stocks for Remdesivir will be available only after July 10, 2020.
The Centers for Disease Control and Prevention has added new underlying conditions to its list of conditions that can lead to more serious COVID-19 cases.
Among the conditions added are diabetes and pregnancy.
The agency also has amended its guidelines on aging, now saying people are more vulnerable to serious cases as they get older instead of just people over the age of 65.
The Centers for Disease Control and Prevention (CDC) has updated its listTrusted Source of underlying conditions that may lead to more severe outcomes from a COVID-19 diagnosis.
The agency is warning that people with type 2 diabetes, kidney disease, whole organ transplants, and women who are pregnant could experience more severe outcomes if they contract COVID-19.
The updated guidelines also remove 65 as the age when more severe outcomes may occur. Instead, it is suggesting as people age, the chance of severe outcomes increases.
What does this mean to the public?
By removing a set age cut off, the updated guidelines give notice to people with underlying conditions of all ages that they are more likely to end up in an intensive care unit (ICU) if they contract the virus.
The guidelines do not suggest that people with these underlying conditions are more susceptible to developing COVID-19.
What should the public do?
Experts say the key is to stay in the know and practice safe habits such as masking, physical distancing, and, when needed, isolation.
Here’s a look at some of the underlying conditions added to the CDC list.
“Pregnancy is a situation with all kinds of hormonal changes in the mix,” said Dr. Alan Fishman, medical director for Obstetrix Medical Group in San Jose, California, and board certified in obstetrics and gynecology and maternal-fetal medicine. “Pregnancy is a stress on a healthy woman’s body.”
That’s why, he said, a pregnant woman who contracts COVID-19 may face more severe outcomes.
“It appears that pregnant women [who contract COVID-19] are 5.5 times more likely to be hospitalized than a non-pregnant woman,” Fishman told Healthline. “That’s pretty significant.”
“There is zero evidence that women who are pregnant are more likely to get COVID-19,” he added.
But the risks mean his office is carefully counseling those considering pregnancy.
“I counsel them to think about this information and how it sits with them,” he said. “They have to remember that it is not a good idea to skip a medical appointment or space them out more.”
While some pregnancy appointments can be done virtually, many must be done in person.
So what should a pregnant woman do?
“Common sense still holds,” Fishman said.
Wear a mask, wash your hands, keep a physical distance, and isolate when needed is still the key, along with not missing any medical appointments.
“Clearly these types of modifications are going to be with us for a long time,” he said.
There’s been some confusion around COVID-19 in the diabetes community.
First, there’s no evidence yet that people with diabetes are more likely to contract the novel coronavirus.
“The CDC has not come out and said that type 1 or type 2 diabetes makes you more susceptible [to COVID-19],” said Dr. Joshua Miller, the medical director of diabetes care for Stony Brook Medicine and an assistant professor of endocrinology and metabolism at the facility’s New York Campus, told Healthline.
However, there is research that concludes people with diabetes can develop more serious cases of COVID-19.
“What we are absolutely seeing are that people who carry a comorbidity struggle more when they contract this,” Miller told Healthline.
Figuring out what is going on with those with diabetes who contract COVID-19 is a challenge for healthcare providers.
“It’s challenging looking at the numbers and statistics because the way in which we [track diabetes] in the medical world is a challenge,” Miller said.
Even in medical reports, he said, type 1 can be mixed up with type 2.
Miller is working with the National Institutes of Health (NIH) to gather and assess data around COVID-19 patients with diabetes. But he points out that mixed information makes it harder to rely on the data.
Right now, the CDC has listed people with type 2 diabetes as being “at increased risk” of more severe outcomes if they contract COVID-19, and people with type 1 diabetes as “might be at an increased risk.”
Miller, who has had type 1 diabetes for 21 years, knows one thing for sure.
“When [a person with diabetes] is in the hospital for this, their insulin needs go way up,” he said.
Even those with type 2 diabetes who take medication may need injected insulin during treatment, he added.
His advice for those with any kind of diabetes?
“The big lesson we are learning here is simply this,” he said. “The healthier our patients are, the better they do with COVID-19. Focus in earnest more than ever on your health. Across the board, the best outcomes come from this.”
“While the area you live in has confirmed community spread, your risk is higher than not,” he added. “Stay at home if you can. And always, wear the mask, wash your hands, keep that distance. Be smart, be safe.”
The aging population
The CDC has moved away from a specific age cutoff for heightened concern to a more general statement on aging.
The CDC now says, “People in their 50s are at higher risk for severe illness than people in their 40s. Similarly, people in their 60s or 70s are, in general, at higher risk for severe illness than people in their 50s. The greatest risk for severe illness from COVID-19 is among those aged 85 or older.
That, say aging experts, is an important change.
“I have to give credit to the CDC for really clarifying that,” Dr. Ronald Caplan, author of “The Care of the Older Person” and “Long Life Strategy,” told Healthline. “Prior to this we were saying 65 and beyond, like the Cinderella phenomenon. At midnight (in this case 65 years of age) your coach just turns into a pumpkin? This is not the way medicine and real life works.”
Caplan says that when you consider that 60 percent of Americans have some kind of underlying health condition, that 40 percent of adults are obese, and that many aging Americans have heart health issues, it just makes sense that as a person ages, a COVID-19 battle gets more challenging.
What should older people do?
“The more you know, the safer you can make yourself and the less anxious you will be,” Caplan said. “We are all getting more familiar with this. We can see [the disease] attacks major organ systems, so knowing how to treat any [comorbidities] you have now will help you later.”
His best tips for older adults?
“Older people should not neglect seeing their healthcare providers, now more than ever,” Caplan said. “And get your vaccinations [for] flu and whatever else you need.”
The older population should also be careful about self-isolating when there is community spread, but they should do so with support.
“Suicide among older people is a non-talked about thing, but it is a thing,” Caplan said. “You lose a spouse, a friend or friends and all of a sudden you are alone, and then this virus comes along. It can be overwhelming.”
He suggests for those who must isolate making a small trusted bubble of friends or family who visit and check on you.
He also repeats the suggestions to wear masks, maintain distancing, and wash hands.
“All those common sense measures that the CDC is giving us all go back to when I was a kid, before vaccinations,” Caplan said. “This is what we did. And now, the answer is we need an effective vaccination. We’re going to have to wait for that, though, and do the right thing in the meantime.”
Expect additions, subtractions, and other changes to this list as the pandemic continues, experts say.
“It’s a fascinating virus,” Dr. Mary Dale Peterson, MSHCA, FACHE, FASA, president of the American Society of Anesthesiologists, told Healthline. “It has a propensity to attack organs, but we are still very much learning as we go along.”
Some of what medical professionals are seeing makes historic sense, she added, such as people with obesity having more difficulty recovering and pregnancy taxing the heart and lungs.
As one who sees the impact of comorbidity on COVID-19 recovery first hand, Peterson has suggestions.
“The way I look at it is this: We all have our own set of risk factors,” she said. “So look at what are in your spheres of control.”
“I can make sure I take care of my chronic disease. I can eat a good diet. I can get up and actually not be a couch potato as tempting as it is to be one right now,” she explained.
“Physical activity is actually a treatment we use in the hospital on COVID-19 patients,” she added. “Double down on your healthy habits. It will only help.”
As states lift restrictions and people begin to resume normal activities such as hosting cookouts or going to the nail salon, the Centers for Disease Control and Prevention has issued tips for reducing the risk of catching or spreading the coronavirus.
“I know that the people are eager to return to normal activity and ways of life,” Dr. Robert Redfield, director of the US Centers for Disease Control and Prevention, said on Friday, according to CNN. “However, it is important that we remember that this situation is unprecedented, and that the pandemic has not ended.”
In the guidance titled “Deciding to Go Out,” the CDC urges people to follow the basic rules of life in 2020: Wash your hands often, practice social distancing, wear face coverings, disinfect surfaces, and stay home if you’re sick.
The CDC also offers specific tips for different activities.
If you’re hosting a cookout or some other gathering, encourage guests to bring their own food and drinks. If food is being served, only one person should do it. Provide face masks and seating spaced for social distancing. Keep a list of guests in case contract tracing is necessary.
Before you visit a nail salon, make your appointment in advance. Wait in your car until it’s time for the appointment, if possible, or stay socially distant in the waiting area. Wear a mask and wash your hands — and make sure the employees are doing the same.
Call restaurants in advance to make sure the staff will be wearing masks and that socially distant seating is available. Sit outside if possible. Choose food and beverage options that are not self-serve. Ask about self-parking to avoid the use of valet parking.
Going to the library? Use advance checkout systems, if possible, and seek out digital materials over print. Curbside pickup of materials is best. Disinfect library materials in plastic containers, such as CDs or audio books, during returns and/or exchanges.
At the gym, don’t use shared items that can’t be easily disinfected, such as resistance bands and weightlifting belts. Wear a mask and perform vigorous exercises outside when possible. Don’t be surprised if showering is not allowed. No high fives.
If you’re traveling, ask the motel or hotel about their cleaning policies. Take the stairs instead of the elevator. Avoid places like fitness centers and game rooms where socially distancing is difficult.
The CDC provides a list of questions each person should ask before going out, such as: Is COVID-19 spreading in my community? What are the local orders in my community? Will my activity put me in close contact with others? Will I have to take mass transit?
The CDC emphasizes these guiding principles for gatherings:
The more people an individual interacts with and the longer the interaction lasts, the higher the potential risk of becoming infected.
The higher the level of community transmission in the area that the gathering is being held, the higher the risk of COVID-19 spreading.
The size of an event or gathering should be determined based on state, local, territorial or tribal safety laws and regulations.
“As communities and businesses are opening, you may be looking for ways to resume some daily activities as safely as possibly,” the CDC said on its website. “While there is no way to ensure zero risk of infection, it is important to understand potential risks and how to adopt different types of prevention measures to protect yourself and to help reduce the spread of COVID-19.”
Medicinal chemist Derek Lowe has worked in the US pharmaceutical industry for 30 years.
He provides frank and fearless commentary dissecting the latest research about coronavirus treatments in his long-running blog In the Pipeline, published on the website of the journal Science Translational Medicine.
“I have to say I type pretty quickly, but I’ve been typing faster than ever these past few weeks,” Dr Lowe says.
Not only is this the first global pandemic in the age of the internet, it’s also the first to occur at a time when scientists have powerful tools like genetic sequencing at their fingertips.
“There’s never been anything like this,” he says.
But in the scramble to find something, anything, that can staunch the mounting death rate from the disease the noise around coronavirus treatmentshas been “atrocious,” says Dr Lowe.
“One problem is there are people with their own political agendas who want to downplay the pandemic; or some of them want to boost it up and make it seem like the end of the world,” he says.
“Others want to act like they’ve got a cure for it, or just hope they’ve got a cure for it.”
“The hope part I understand, but the problem is that people who are not familiar with drug research … don’t realise how incredibly often this stuff fails.”
The sobering reality is that around 90 per cent of new drugs that initially look promising fail.
“No other industry fails like that, but it’s because it’s extremely hard and we don’t know enough about human biology to cure disease.”
There are currently no effective treatments for coronavirus, but there is a lot happening. Here are the latest developments and what they might mean.
Why we’re looking to old drugs to treat a new virus
You may have heard about a few drug treatments, such as hydroxychloroquine and remdesivir, but there are more than 200 are currently being tested in more than 1,100 trials around the world.
Many of the drugs under trial are already used to treat other conditions, including malaria, HIV, and rheumatoid arthritis, which means that doctors know how they work and how safe they are to use with people with those conditions.
And some of these drugs had shown early promise in the lab or in preliminary trials for SARS and MERS.
That means they can be fast-tracked into human trials, which is important when you’re trying to get on top of a pandemic.
This approach of repurposing drugs has often been used in the past for many viral diseases, including HIV, says Sharon Lewin, director of the Doherty Institute.
But while this coronavirus has parallels with HIV, there are also differences.
People with HIV get better once the virus has been controlled, but SARS-CoV-2 can trigger a unique response that throws your immune system out of whack, inhibiting your protective antiviral molecules and ramping up your inflammatory agents.
“Coronavirus is more complex than HIV because the immune system here is causing a lot of damage in people who are getting sick,” Professor Lewin says.
That means we need different types of drugs for different stages of the disease.
“It’s very unusual you just get a single silver bullet and say it’s done. Viruses interact with the immune system in a complex way,” she says.
Three approaches of drug treatment
It’s still too early to have more than a few results from large high-quality trials known as randomised controlled trials (RCTs) where some people are given the treatment and other aren’t.
There are basically three different approaches to drug treatment:
targeting the virus,
dampening the immune system,
treating later complications, such as blood clots.
“As the days go on we’re getting a better understanding of what needs to be targeted: the virus or the immune system, and when it needs to be targeted,” she says.
“You may use antiviral drugs early in the illness when there’s lots of virus around, but it is looking like you will use immune-dampening drugs in the latter part of the illness.”
Drugs that target the virus
Hydroxychloroquine has been used for years to treat malaria and lupus. It showed early some promise as an antiviral in the lab, but so far it has been found to be ineffective at treating severe disease.There are still no large RCTs, but smaller trials indicate the risk of side effects such as heart attacks outweigh the benefits of using it, and it was not approved for use outside of clinical trials.A large randomised trials of the drug as a potential treatment for severe disease by the World Health Organisation has been suspended due to safety concerns. The Doherty Institute has also suspended its trial.
Remdesivir is an experimental drug. It has not yet been demonstrated to be safe or effective for the treatment of COVID-19, but the latest studies suggest it may have some benefit reducing infection time.A small Chinese RCT that was ceased due to low numbers showed there was no benefit.The latest results of the trial of more than 1,000 people in the US indicate the drug could shorten the length of infection from 15 to 11 days.”The trick now is to work out how long to give it for,” Professor Lewin says referring to research that suggests either five or 10 days is the optimal length.The drug does not appear to reduce death rates from a severe infection. Outcomes from the most recent large RCT indicate it is clear that treatment with an antiviral drug alone is not likely to be sufficient.
Lopinavir/Rotanavir are repurposed anti-HIV drugs. They showed early promise in the lab against SARS and were the first to be trialled for SARS-Cov-2. So far studies haven’t shown benefit.
Antibodies produced in the lab can last for long periods of time and they can be used in combination to avoid the possibility of the virus getting resistant to a particular antibody.
This is an emerging area of research. There have been a few small studies but no randomised trials.
Boosts the immune system’s response to infection. It is a protein produced by infected cells to alert other cells to put up their defences.
It is widely used in HIV and Hep B and C.
There has been a small “promising” trial of this drug used in combination with ribavirin, says Professor Lewin.
Drugs that dampen the immune system
By the time someone is severely ill, the issue is not stopping the virus, it is stopping the immune system going into overdrive producing a cytokine storm.
These drugs either block cytokines that have been implicated in inflammation known as interleukin, especially IL6, or they block pathways inside the cell that cause inflammation.There have been small studies that indicate some anti-cytokine drugs have potential but no results yet from large trials.
Corticosteroids are another group of drugs that are used to treat a wide range of inflammatory conditions. They are not currently recommended for treatment, and may cause complications.”Steroids probably don’t work, they definitely did work in SARS,” Professor Lewin says.
Drugs to treat symptoms such as blood clots
There is ongoing research looking at when and for how long to give blood-thinning drugs such as heparin and clot busters used for heart attacks and strokes.
Where do we go to from here?
Over the next 12 to 24 months, scientists are hopeful they’ll identify a range of drugs that can target the virus based on what we’ve learnt through developing treatments for HIV and hepatitis C.
The first drug to treat HIV — AZT — was a repurposed cancer drug, but the virus wasn’t stopped in its tracks until it was hammered by a cocktail of drugs to stop the virus mutating.
You need to understand how a single drug works before you trial combinations of drugs, says Professor Lewin.
“There are now combination studies emerging and we’re almost certainly going to see more of those,” she says.
While repurposed drugs may help “a little” to start with, Dr Lowe predicts the best bet in the medium term will be monoclonal/polyclonal antibody therapies and vaccines.
“Making two or three absolutely new coronavirus drugs is a tall order so antibody therapies and vaccines have a much better chance of delivering something.”
Professor Lewin agrees there is a lot of buzz around these emerging therapies.
So far, hundreds of antibodies have been isolated and are showing promise in the test tube.
“There hasn’t been any evidence yet that monoclonal antibodies work in animal models or that they work in people,” she says.
“But there has been a huge amount of investment in this area in HIV to see if they can be made cheaply.”
And, even though antibody studies are still in the experimental stage, it may not take too long before they go into clinical trials.
“There is one company with a mono-antibody and they are thinking of putting it into clinical trials in the next few weeks to months so I think we will see antibodies reach the clinic quite quickly,” she says.
Some companies are also looking at stem cell therapies or therapies that modify and boost the immune system’s killer T cells.
But for now, Professor Lewin says these experimental techniques are too high-end.
“When you are looking at responding to a global pandemic you need interventions that are going to be relatively cheap and scalable.”
Is this the end for hydroxychloroquine?
Although the outlook is not rosy for hydroxychloroquine and many drug trials have been suspended, you haven’t heard the last of this drug.
There are still trials planned to see if it can be effective to prevent high risk people such as health workers from getting infected.
This approach, known as pre-exposure prophylaxis, has been successfully used in the prevention of HIV.
Professor Lewin is not overly optimistic saying that proving a case needs hundreds of thousands of people.
But Marc Pelligrini, who is heading up a randomised controlled trial with the Walter and Eliza Hall Institute, says the concept shouldn’t be dismissed.
“I think prevention studies are worlds apart from treatment studies,” Professor Pelligrini says.
“We are talking about healthy people who are screened, who don’t have illness.”
While he agrees the drug doesn’t appear to be effective for severe disease, he says there is precedence in for drugs failing to cure diseases such as HIV but showing great effectiveness in preventing infection.
“To not test a viable hypothesis rigorously is tantamount to surrendering to this virus and dismissing our scientific resolve.”