Image source @ Visual China
Text | Amino Finance
From neutralizing antibodies, to injecting remdesivir, to today's new crown oral drugs, concept stocks have taken turns to continuously stimulate market nerves.
Just as everyone was focusing more on oral medicine, the once-declining player, interferon, became active again.
At the beginning of the COVID-19 outbreak, interferon was included in the potential treatment regimen for COVID-19, but there was no clinical success until March 20.
On February 21, Synairgen announced that after the results of the phase III trial of interferon SNG001 to treat COVID-19 failed, the company's stock price plunged by 84.11%.
The SNG001 fold, once considered a game changer, not only suffered a heavy blow to Synairgen, but also cast a shadow of defeat on the entire interferon family.
However, the fascinating thing about drug development lies in its unpredictability, and the turning point of interferon is inadvertently coming.
On March 17, Eiger announced the clinical success of long-acting interferon in Lambda's treatment of COVID-19 PHASE III, which can reduce the risk of COVID-19 death by up to 60%, and the company's stock price rose sharply, rising by more than 60% in 4 trading days.
In this regard, many people lamented that the treatment of new crown, although interferon is late.
Interferon is an old "old" drug, which was almost forgotten by the world before, and this new crown epidemic has given this old drug a chance to shine again.
This also reminds us that old drugs that have passed the patent period, careful watering, old drugs may also sprout new shoots.
01 New players of COVID-19 therapeutic drugs
Since March 9, Eiger's stock price has been rising continuously. Smart investors seem to have smelled the triumph of the peginterferon Lambda (lambda).
Indeed it is. On March 17, Eiger announced the results of lambda's clinical success in the treatment of COVID-19 Phase III.
In a study called TOGETHER, Lambda significantly reduced the risk of PROGRESSION of COVID-19.
Specifically, among PATIENTS TREATED WITHIN 7 days of the first onset of symptoms, the risk of COVID-19-related hospitalization or emergency visitation in the Lambda group was reduced by 50% compared with the placebo group (primary endpoint).
Notably, when symptoms appear within 3 days of treatment with Lambda, a higher clinical benefit was observed, with a 60% reduction in hospitalization or mortality. That said, the sooner Lambda is used to treat COVID-19, the better it will be and will be effective for more than half of COVID-19 patients.
From the data alone, this drug is better than Merck's oral drug molnupiravir, which only reduces the risk of hospitalization or death by 30% (non-head-to-head comparison).
Although compared to Pfizer's oral drug Paxlovid, Lambda is dwarfed. After all, Paxlovid, taken within three days of symptoms, reduces the likelihood of hospitalization or death by 89%.
Lambda doesn't seem to have much of an advantage over neutralizing antibodies either. The combination therapy of the neutralizing antibody amphavir monoclonal antibody/romizumab of Temexbopharmaceuticals can reduce hospitalization and mortality by 80% in phase III clinical trials for patients with new coronary pneumonia.
However, the mechanism of action of interferon is completely different from that of neutralizing antibodies and Paxlovid, and it is theoretically possible to combine interferon with both to play a more powerful role.
This starts with the mechanisms of the parties. Interferon mainly induces human cells to synthesize antiviral proteins and inhibit the synthesis of viruses by binding to receptors on the surface of human cells. In simple terms, interferon does not directly fight the virus, but by improving the body's combat effectiveness against the new crown virus.
Whether it is neutralizing antibodies or Paxlovid, it is directly facing the new crown virus that has invaded the human body, interfering or chasing accordingly, and playing a therapeutic effect.
Since the target is human cells, in theory, interferon is not afraid of the mutation of the new crown virus, whether it is Delta or Omi kerong is the same way of playing. This also makes it possible for interferon to become the golden partner of other treatment options.
02 Behind the same drug is not the same life
Lambda's success may surprise many people.
In fact, given the potential broad-spectrum antiviral effects of interferons, interferon therapy was written into the protocol at the beginning of the COVID-19 pandemic. In the "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (Trial Third Edition)", it is written that "α can be tried - interferon".
PS: There are three types of interferon families found so far, namely type I interferons (IFN-α, IFN-β, IFN-ω), type II IFN (IFN-γ) and type III IFN (IFN-λ).
However, at present, there is no clinical success of α-interferon. Take China as an example, Ternary Gene said in the third quarter report of 2021 that the phase III clinical trial of human interferon alfa1b for the prevention and treatment of new crown pneumonia began phase III clinical trials, and it is also an international multi-center. But so far there has been no progress.
The players of the β family, who are also type I interferons, have suffered successive blows.
In December 2020, the results of a large-scale trial by the WHO showed negative conclusions, with 243 deaths in 2050 patients treated with interferon-beta1a and 216 deaths in the control group in 2050 (ratio ratio 1.16). This study showed that interferon did not help patients with COVID-19.
And that's not all. On 21 February 2022, Synairgen announced the phase III clinical failure of the inhaled β interferon SNG001 to treat COVID-19, with the company's stock price plunging by 84.11% and a market capitalization of around £0.5 billion.
Successive failures have called into question interferon's ability to fight the coronavirus. But fortunately, the interferon family is big, and IFN-lambda player Lambda withstood the pressure.
Why are they all family, but the therapeutic effect on the new crown is very different?
On the one hand, the locations that the two can protect are different, and the protection time provided is also different.
A study in Biomed Rep showed that IFN-λ provides protection in both the upper and lower respiratory tracts, and signaling leads to more sustained expression of ISGs (interferon-stimulating genes) to provide long-lasting protection; type I interferons only provide protection in the upper respiratory tract and are more transient.
In fact, as early as 2018, a clinical trial of influenza virus found that type I interferon may not penetrate the upper airway mucosa, and its antiviral effect is poor both intranasal and systemic.
On the other hand, the side effects are different.
Type I interferon will promote pro-inflammatory cytokine secretion and immune cell infiltration and exacerbate the disease, that is, a cytokine storm, and finally the new crown virus may not crush us, but it is crushed by its own strong immune response.
A study published in Cell Host Microbe found that interferon type I was used improperly and became a "two-sided killer." In a study of mice, it was found that interferon therapy was used in early stages of COVID-19 before replication peaked to protect mice from COVID-19 attacks, but in late COVID-19, interferon therapy hindered virus clearance and exacerbated the immune response.
By binding to IFN receptors on epithelial cells and neutrophils, IFN-λ not only does not cause validation, but also prevents the development of "cytokine storms" while inhibiting viral replication, so that patients do not progress to severe disease.
Although it seems to have similar effects, some subtle differences also determine the different fates of different members of the interferon family.
03 Old medicine also has spring
In fact, interferon is an ancient variety that was born in the 1980s. Previously, interferon occupied an important position in the field of hepatitis.
However, after decades of development, some products with more prominent efficacy and better safety have been born on the market, and the interferon market has gradually shrunk. The scale of interferon income of several major foreign giants has been declining in recent years.
Interferon, an old drug, is also gradually fading out of people's vision. A sudden new crown epidemic has changed the fate of this old drug, making this old medicine tree sprout new shoots and show new vitality.
In fact, the new use of old drugs in foreign countries has become something new.
James Black, winner of the 1988 Nobel Prize in Physiology and Medicine, once said "The best way to discover a new drug is to start with an old one", which means that the best way to develop new drugs is to start with old drugs.
As we all know, new drug research and development has to go through a decade, a billion dollars, and a 10% success rate. The new use of old drugs is much simpler.
First of all, the old drug has been used in the clinic for many years, and its safety has been fully confirmed; second, the old drug has undergone preclinical testing and safety assessment, which will shorten the drug development cycle; finally, because the old drug has been pre-clinically validated, there will be less investment in research and development.
In this battle against the new crown epidemic, the new use of old drugs has played a big role.
Take Paxlovid, which is a combination of a 3CL protease inhibitor and a ritonavir. One of the adjuvants, ritonavir, is an old drug that was first developed as an inhibitor of HIV virus proteases. In Paxlovid, ritonavir plays a role in slowing the metabolism or breakdown of 3CL protease inhibitors.
In addition to covid-19 drugs, there are also many other old drugs that have been reborn with new uses, such as thalidomide, rifaximin, metformin and so on.
One of the most well-known is probably the story of Sildenafil, which is commonly known as "Viagra".
Sildenafil was developed by Pfizer in the 1980s as a treatment for angina pectoris, but unfortunately sildenafil did not meet expectations in clinical trials, and clinical studies failed in 1991.
But when it came time to recycle the subjects' medications, many subjects were reluctant to return the remaining medications, and Pfizer was surprised to find that sildenafil could treat erectile dysfunction in men. In March 1998, sildenafil was approved for marketing and became a "blockbuster" drug for Pfizer.
In 2021, another scholar published a paper saying that the discovery of sildenafil may help prevent or treat Alzheimer's disease. After 20 years, the old drug of sildenafil may regain new uses.
Back to The country, it is still difficult to find an innovative drug from "0", so you may wish to try to focus on the old drug. The cost performance of the redevelopment of old drugs may be higher than that of innovative drugs, carefully cultivated, and old drugs may also have a spring.