The New Coronavirus Magic Drug that has Made the Limelight in the Past Two Days : What is the Antibody Therapy of Regeneron?

Regeneron is one of the most creative pharmaceutical companies in the world and the originator of neutralizing antibody cocktail therapy. There has been a precedent for the success of Ebola antibodies. This is also an important reason why its cocktail therapy is highly expected.

Trump's illness brought the 'neutralizing antibody drug' from Regeneron to the spotlight.

On October 3, White House doctor Sean Conley announced a list of drugs for Trump’s treatment, including vitamin D, Famotidine, Melatonin, Aspirin, Remdesivir and Regeneration Cocktail Therapy REGN-COV2.

The first thing that sparked public debate was of course the 'drugs' such as 'disinfectant and hydroxychloroquine' that Trump had previously touted vigorously, and none of them were on the list.

Then there are two really therapeutic drugs: Remdesivir and REGN-COV2. These two drugs were selected by the top medical team in the United States from many candidates. What is the magic?

In contrast, Regeneron’s cocktail therapy REGN-COV2 is not well known to the public. This time, the President broke the circle for the first time and entered the public eye.

People in the industry know that Regeneron is one of the most creative pharmaceutical companies in the world and the originator of neutralizing antibody cocktail therapy. There is a precedent for the success of Ebola antibodies. This is also an important reason why its cocktail therapy is highly expected.

The so-called cocktail therapy refers to a combination therapy composed of multiple drugs. REGN-COV2 therapy consists of a combination of two monoclonal antibodies (REGN10933 and REGN10987). Researchers first initially screened more than 200 candidate antibodies from genetically modified mouse models and the blood of recovered patients with new coronary pneumonia, and then further selected these two most suitable monoclonal antibodies to form a "cocktail" therapy.

The reason why two antibodies are needed is because in order to prevent the virus from mutating, the treatment method is greatly compromised. The two antibodies target different key positions of the virus and are combined for treatment, which greatly improves the cure effect.

How effective is cocktail therapy?

Just a few days before Trump’s diagnosis, Regeneron had just announced the latest phased effects of REGN-COV2 therapy. The key points are as follows:

1. 275 COVID-19 patients were randomly divided into three groups and received high-dose antibodies (8 grams), low-dose antibodies (2.4 grams) or placebo.

2. Reduced the viral load and shortened the time it takes for non-hospital patients with new crown to relieve their symptoms.

3. The median time for symptom relief in seronegative patients receiving placebo was 13 days, patients receiving high-dose therapy for 8 days, and patients receiving low-dose therapy for 6 days. Both doses of antibody cocktail therapy were well tolerated. (This time Trump received 8 grams of high-dose treatment)

4. The effect is particularly significant in patients who "have no effective immune response before treatment".

5. Most of the 275 subjects announced this time are younger than Trump, and the symptoms are not serious, excluding hospitalized patients.

6. This part of the trial is only part of a large ongoing project. The project also includes research on the efficacy of cocktail antibody therapy on hospitalized patients and the prevention of infection in people who have been exposed to new crown patients. No more results have been announced.

As Eric Topol, director of the Scripps Research Institute in the United States, said in an interview with the media, although these data are currently not enough for the FDA to issue an emergency use authorization, everything is moving in the right direction.

Antibody therapy: it can cure and prevent

To understand antibody therapy, we must first know what neutralizing antibodies are.

When pathogenic microorganisms such as viruses and bacteria invade the human body, they will stimulate the body's immune system and produce a variety of antibodies.

However, only part of the antibodies can quickly recognize pathogenic microorganisms, bind to antigens on their surface, and prevent the pathogenic microorganisms from binding to receptors on the surface of target cells to invade cells, thereby protecting the human body from infection. This process is called neutralization, and the antibodies that work are called neutralizing antibodies.

Similar to chemical acid-base neutralization, neutralization means that the virus comes, and immune cells secrete the neutralizing protein into the blood, bind with the virus particles, prevent the virus from infecting the cells, destroy the virus particles, and "neutralize" the virus. Drop.

Neutralizing antibody therapy is a method of passive immunotherapy directly using neutralizing antibodies, which is equivalent to artificially supplementing "bullets" to support the immune system.

Neutralizing antibody is a kind of macromolecular drug. Compared with small molecule drugs (such as Remdesivir), it has better specificity and less side effects. In recent years, there have been successful precedents for developing neutralizing antibody drugs to deal with infectious diseases.

Neutralizing antibodies have a dual effect of treatment and prevention. Compared with vaccines or antiviral drugs, antibody drugs are unique because they can both treat and prevent new coronavirus infections.

Antibodies are highly stable in the blood, and injection of neutralizing antibodies can provide passive immunity and achieve the effect of preventing new coronavirus infections. Before the advent of preventive vaccines, neutralizing antibodies may be an effective way to provide immunity to certain high-risk groups (such as the elderly and front-line medical workers).

However, neutralizing antibodies also have a big disadvantage: neutralizing antibodies can only guarantee short-term prevention, and it needs to be injected every 1 month or every 2 months. If you want to achieve universal immunization, you must wait until the vaccine is developed.

More to look forward to than a vaccine

At present, the focus of the market is mainly on the progress of vaccines. However, due to the long development time of vaccines, they cannot be popularized in the short term. Neutralizing antibody drugs may become the most anticipated "magic drug" in the short term.

The development of vaccines is a long and expensive process with a high failure rate. The development of traditional vaccines generally follows linear steps and generally takes 5-10 years; during a pandemic, multiple steps may be carried out in parallel because of the rapid development of vaccines, but overall it also takes 1-5 years.

Take the Ebola vaccine as an example. In 2014, the Ebola epidemic broke out in West Africa on a large scale. The Russian GamEvac combination vaccine was the first to be approved through Phase I/II clinical research results, which took 2 years. Merck’s VSV-EBOV vaccine was approved by the European Union EMA and the US FDA in November and December 2019, respectively. At this time, five years have passed since the 2014 Ebola outbreak.

The director of the CDC of the US Centers for Disease Control and Prevention of the new crown vaccine said that the new crown vaccine will be given priority to medical workers and on-site emergency personnel after it is launched at the end of this year or January next year, and it is expected to be distributed to the general public in the spring and summer of 2021.

In contrast, the development cycle of neutralizing antibody drugs is much shorter. Like other drug development, clinical trials of monoclonal neutralizing antibodies for the new coronavirus are also divided into three phases. If all goes well, the development is expected to be successful in 8-12 months, maybe even faster. Specifically:

Phase I clinical trials: preliminary clinical pharmacology and human safety evaluation trials. The number of cases included is generally 10-50, and the fastest is not less than 20 days.

Phase II clinical trial: preliminary evaluation stage of therapeutic effects. The purpose is to preliminarily evaluate the therapeutic effect and safety of the drug on patients with target indications (may be grouped according to the severity of the disease, age, race, etc.), and also to provide a basis for the design of phase III clinical trials and the determination of the dosage regimen. The shortest time required is 1 month, and the number of cases included is generally 100-500.

Phase III clinical trial: the stage of confirmation of the therapeutic effect. Layout for multiple indications, mainly divided into treatment trials and prevention trials.

-Treatment trial: According to the patient's condition, it is divided into mild treatment and severe treatment. The subjects enrolled in the mild treatment clinical trial are mild to moderate patients who are not hospitalized; the subjects enrolled in the severe treatment clinical trial are Severely ill hospitalized patients. After a course of treatment (about 4 weeks), the blind can be uncovered.

-Prevention test: The purpose is to verify the effectiveness and safety of neutralizing antibodies in preventing the infection of new coronary pneumonia in high-risk infections, divided into pre-exposure prevention and post-exposure prevention. Pre-exposure prophylaxis can generally obtain preliminary test results within 8 weeks, and post-exposure prophylaxis can obtain preliminary results within 1 month. The completion of the study requires follow-up for 6-8 months.

Race against time

At present, Regeneron's REGN-COV2 is the neutralizing antibody drug with the fastest progress and has entered Phase III clinical trials, followed by Eli Lilly's LY-CO555.

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The faster the research and development is successful, the broader the market for neutralizing antibody drugs. Neutralizing antibody drugs that are on the market before the end of the epidemic are the most valuable. Therefore, the development of neutralizing antibodies is a race against time. Not only must it be ahead of the virus, but it must also be in the forefront of limited but fierce R&D competition.

According to Industrial Securities' estimates, with the rapid advancement of vaccine research and development, the time window for neutralizing antibodies to be used for prevention is from the market to the end of 2020; and after the vaccine is marketed, as herd immunity is gradually formed, the epidemic may be controlled, and neutralization is expected The time window for the antibody to be used for treatment is from the market to the end of 2021 (assuming that the epidemic continues until the end of 2021 or longer).

Industrial Securities predicts that if the new crown epidemic continues until the end of 2020, the commercialization market space of Neutralizing Antibody will be approximately US$1.83-38.4 billion. The actual market space mainly depends on the pricing of Neutralizing Antibody and the speed of each company's volume; assuming the new crown epidemic Until the end of 2021, the market space of neutralizing antibodies can reach US$6.87-144 billion.

Note: The neutralizing antibody analysis part of this article is mainly integrated from the Industrial Securities Research Report "Neutralizing Antibody: Both Treatment and Prevention, "Special Drugs" for New Coronary Pneumonia"

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