In March, professor Frank Grosveld told Erasmus Magazine about an antibody against Covid-19. Antibody ‘47d11’. The interview gave people hope for a solution against the pandemic, but an effective antibody is not (by any stretch) an actual medicine. Will the discovery of Frank Grosveld from the Erasmus MC and Berend Jan Bosch from Utrecht University really make a difference? To gauge that likelihood, experts reflect on the five hurdles that separate a good idea from a successful release. Spoiler alert: “It can still go wrong in so many ways.”
Medication based on antibodies is not the same as a vaccine
Grosveld: “A vaccine is usually made up of a protein derived from a virus. If you introduce a small amount of that into humans or animals, they produce antibodies against it. This creates so-called memory cells that memorise what they’ve already encountered. If the virus tries to invade, these memory cells are able to react quickly and fend off the virus. Antibodies act as medication, except the patient doesn’t create these themselves. If you administer this kind of drug, it will stay there for several weeks. That’s all it takes to recover, but it’s probably not enough to suppress the virus forever. That’s why it’s better if patients develop their own immunity.”
Bump 1: The preclinical phase
Where does the creation of a medication start? And how? “An average development trajectory for a drug takes twelve years and costs €2.3 billion,” says Peter Bertens, senior policy advisor at the Dutch Association for Innovative Medicines (VIG). The first phase in the development of a drug is the pre-clinical phase. “It starts in a lab,” says Bertens, who is noticeably accustomed to explaining this calmly and clearly. “That could be in large-scale screening programs whereby robots test existing substances for a disease to see if they react to it. Or through tests carried out by universities or private parties. Coincidentally for the EMC and the UU, there was already a candidate in the freezer.”
How come? The scientists responsible had previously done research on MERS and SARS coronaviruses as well as the relatively innocuous OC-43. “The aim of that research was to develop antibodies for all three viruses,” Grosveld explains. “From earlier research, we still had untested antibodies left over that did not react to all three mutations yet did react to SARS1. When the current SARS2 corona crisis broke out, we immediately tested whether the antibodies that had reacted to SARS1 also reacted to SARS2. That’s when we found the antibody that has now been publicised.” The antibody cross-reacted (the biology term for rejecting a non-native substance) with SARS-CoV-2. Consequently, provided it passes all the tests -it can be administered as a medicinal preventative measure. For example, it could be given to hospital staff at risk of coming into contact with the virus or ill people, so that they have antibodies against the virus and are able to fight it.
Nonetheless, an effective antibody is not by any stretch an actual medicine, Bertens notes. “For that you need three things: a great deal of time, money and luck. You may come across an effective antibody that you’ve tested using computer and animal disease models, but it must be in a form that can be administered, all side effects must be known, and it must be non-toxic and available worldwide.” That is how the race to find a treatment starts, and as Bertens notes: “After finding an active substance, ninety percent end up dropping out of the race.”
An unexpected world premiere
Saturday, 14 March. The morning after EM presents the 47d11 antibody to the world through the interview with Grosveld, several media outlets send out push notifications with this news. This makes some people even more enthusiastic: Grosveld hints in the interview that, if it all works out, the drug might be available sooner than a vaccine. This draws criticism, as not everyone is so optimistic. “Rather naïve,” Henk Jan Out thinks upon reading the interview. Out has been active in developing drugs for twenty years, was an endowed professor in Nijmegen and now works in Shanghai. Via Skype he explains his scepticism. “It was probably down to the enthusiasm of the moment.” Or did Grosveld want to lure pharmacists in? “I don’t think so. Pharmaceutical companies tend to keep tabs on academic literature themselves.”
The interview with Grosveld also came as a surprise to Eramus MC and his colleagues. That Saturday morning, press officers and co-researchers were phoned out of their beds by a whole host of media. Berend Jan Bosch, principal researcher and virologist at Utrecht University in whose freezer the antibodies were originally stored, looks back on that moment in early May. “I was flabbergasted. On Saturday morning I woke up to suddenly see our very own research on all sorts of news sites. That triggered quite a storm of phone calls and emails that I wasn’t prepared for. But ultimately it did a lot of good. You rarely get that much attention.
Bump 2: The pharmacist
Good news on 5 May: the scientific article by Grosveld and his colleague from Utrecht Berend Jan Bosch was published in the journal Nature Communications, as their peers officially approved it on May 4. “Fantastic!” Bosch exclaims. However, they are by no means there yet. On to the next hurdle. According to virologist Bosch (45, and described by The New Yorker as the ”Tintin of virology and uncannily boyish”) this involves dealing with pharmacists. “The antibody can help in the fight against the virus (…), but to do that, we first need to get a pharmacist on board to validate its safety and efficacy in humans and scale up production of the antibody,” Bosch tells EM.
Why are the researchers engaging a pharmacist? Professor Out knows exactly why. A university cannot develop its own medicine as it costs too much money and entails too much risk. “Scaling up medicine production is thereby crucial, but you can only produce small quantities within an academic setting. New factories often have to be built to make more. That’s an investment of hundreds of millions of euros. The medicine may not even be approved after all, or a rival might have a better medicine. That money is then wasted.” But even that hurdle appears to have been overcome as of late May. Grosveld scores another scoop in the media. On 30 May, he announces in the Dutch EO radio program Dit is de Dag that there is a deal with the major American pharmaceutical company Abbvie. More good news. The presenter is enthusiastic, Grosveld remains calm. In a press release issued by Abbvie on 5 June, they state that they will support the researchers in their preclinical activities while preparing for subsequent preclinical and clinical research. In return, the pharmacist is given an exclusive license for the global commercialisation of it. The Chief Scientific Officer at Abbvie Tom Hudson revels in the press release: “The antibody is extremely promising.”
Bump 3: Animal testing
In the radio broadcast, Grosveld also talks about the successful trials with hamsters by his colleague Bart Haagmans (Erasmus MC). Grosveld believes that these represent a good model when it comes to the progression of corona in humans, because both species suffer problems in their airways when infected by Covid-19. The hamsters were first given an antibody. “The animals received a dose of the virus. Those that were treated with the antibody didn’t get sick, and those that had an irrelevant antibody or were not treated, did.” A breakthrough, says Grosveld, as the antibody appears to protect living organisms. Grosveld sends another e-mail on 15 July announcing a new round of animal experiments. “Soon the tests will be done on monkeys.” Bertens from the VIG considers this type of animal testing vital to see whether the antibody will bind not just during tests on cells and computer models but also in real animals. “Before being tested on humans, there’s usually studies in two animal species. It is important that these animals go through the same disease process as humans. Among other things, the animals are examined to see if the antibody works and is non-toxic, what dosage works and how the antibody is metabolised.” Meanwhile, Grosveld has started to develop alternative antibodies in case the current antibody is ineffective.
‘It’s actually very satisfying to do research on a virus that’s ravaging the world’
Bump 4: Clinical phase: 'First in man'
This is when we reach uncharted territory where the 47d11 antibody is concerned. On average, it takes six to seven years before the clinical phase of research begins. Grosveld mentions in the same 15 July email that this process could be considerably faster this time around. “AbbVie still thinks that antibody 47d11 will be the ‘first in man’ by November. If these tests [with monkeys] yield favourable results, November might work, but things might just as well go awry, then alternatives will have to be sought.” Pharmacologist Out adds: “Even then, the risk of failure is high. In this phase you traditionally make a distinction between phases 1, 2 and 3. In the first phase, safety is paramount.” Bertens: “Then you test twenty to one hundred people. What happens if you give them the drug? Plenty of drugs will fail because the body cannot tolerate the substance or because the drug breaks down too quickly.”
But supposing all goes well, then the second phase starts. “In this phase, researchers test the drug on one hundred to five hundred ill patients to determine whether the drug has the intended effect and establish which dosage is suitable and which method of administration works best,” continues Bertens. “Everything is tested to prove that the potential drug can work on a patient.” Then the medication may not turn out to be any good, as it might not be strong enough to combat the disease in humans.”
If the results are all still positive, then it is time for the final test phase, although there are still unanswered questions. For one thing, genetic variances between people around the world are relatively large, whereas tests are often carried out on a homogeneous group. Does it work on everyone? On all age groups? On both sexes? On people with other conditions who are taking multiple medications? And what about the rarer side effects? Out: “Testing is carried out with the obligatory statistical rigour on thousands of patients in the final phase to substantiate claims of efficacy and safety.”
Bump 5: Approval
Has it come through all the tests with flying colours? Then you might think that you have made the grade. Not yet. One final phase is next: external analysis and investigation by the European Medicines Agency (EMA), based in Amsterdam, and the American Food and Drug Administration (FDA).
In this phase, the authorities receive all research data and review it. They also check whether the factory meets all the standards required to manufacture medication. “On average, this takes about a year,” Bertens says. “But the EMA and the FDA have developed special programmes to evaluate corona medication as quickly as possible. The maximum number of days required for certain procedures has been reduced by half or more.
We are still not there yet. Even if the EMA and the FDA give the green light to everything, the drug still needs to find its way into treatment guidelines so that doctors actually prescribe it. Negotiations start concurrently with the government, hospitals and insurers so as to be included in health insurance packages. Only then will a patient have access to the medicine.
All stakeholders are working hard to accelerate this lengthy process for corona medications and vaccines. “For example, by building factories, even though it’s not yet clear whether or not a drug will work, or by giving priority to licensing,” Bertens adds. “However, standards will not be compromised, even for a drug that has the potential to save the world,” Out asserts.
So, when will 47d11 be ready as a medicine? And how long will a vaccine take? As a society, there is nothing else we can do but hope for the best. And for virologists and other scientists: Keep up the hard work. Bosch: “We are working 24/7 on research to combat the coronavirus. It’s pretty exhausting, but it’s not too bad. It’s actually very satisfying to do research on a virus that’s ravaging the world.”
Who knows, in a few years’ time, it may turn out that a solution to this global virus is found in the laboratories of Utrecht University and Erasmus MC. And all thanks to the efforts of Grosveld and Bosch.