JAK inhibitors on the same track have repeatedly encountered safety issues. Pfizer, AbbVie, Eli Lilly...Who can break the game first?

The recent period is undoubtedly exciting for AD patients all over the world.

Seeing this one can't help but ask questions, is there any progress in the treatment of Alzheimer's disease? But the protagonist of this article is not Alzheimer's disease, but another disease that is not inferior to a terrible degree-Atopic Dermatitis

Faced with such a large patient base, it is naturally a vast sky for the AD treatment market.

And just last week, Dupixent made another move

Although Dupixent is the best in the AD market, this does not mean that other track players are willing to give up this blue ocean market.

After successfully completing the head-to-head study, JAK inhibitors have undoubtedly launched a strong impact on Dupixent.

The answers to these questions seem to be somewhat clues at the moment, but it is difficult to make a conclusion.

Dupixent is still in a period of rapid growth

How will Sanofi/Regenerant defend their position?

The pathogenesis of AD usually involves a variety of factors, but it has not yet been clarified

Previous AD treatments usually adopted skin moisturizing emollients, topical steroids or calmodulin inhibitors and cyclosporin-based anti-inflammatory drugs, and antihistamines to relieve itching.

At that time, with the continuous advancement of immunotherapy and antibody drugs, a monoclonal antibody drug Dupixent was born and became the first biological agent approved for the treatment of atopic dermatitis.

The clinical data of Dupixent, which has brought the treatment of atopic dermatitis into a new era, naturally need not be repeated.

The picture shows the Dupixent clinical trial data, from reference [2]

Relying on historical clinical data, Dupixent was quickly approved by the FDA in March 2017 for the treatment of moderate to severe AD patients.

Later, the development of Dupixent naturally went smoothly.

In addition, like other blockbuster drug development strategies, Sanofi/Regeneron has also completed the development of Dupixent's other diseases, such as patients with moderate to severe asthma and chronic sinusitis, but these indications are all adjuvant treatments.

In addition, Dupixent currently has a number of clinical trials in progress.

Dupixent clinical development situation, from Sanofi official website

Although Dupixent still seems to be in the limelight, there are hidden dangers behind it.

Security issues are still the biggest shackles

JAK inhibitors will be full of resistance in the future

As mentioned above, the head-to-head clinical study of Pfizer’s Abrocitinib has shown its superiority.
In terms of data, JAK inhibitors have posed a great threat to Dupixent.
However, whether it is an analysis institution or industry insiders, most people have a positive attitude towards Abrocitinib.
And other JAK inhibitors have adopted a more conservative attitude
.
There is only one reason for the conservative attitude of these experts, and that is the safety issue that has not yet been resolved by JAK inhibitors
.

The picture shows the mechanism of JAK inhibitor, from reference [3]

Although Michael Corbo, head of Pfizer's Inflammation and Immunology Department, is optimistic that Abrocitinib may help patients with moderate/severe atopic dermatitis significantly reduce itching and achieve near-complete skin clearance, obviously not many people buy it
.

As the first-generation player of JAK inhibitors, Pfizer successfully developed the first approved JAK inhibitor tofacitinib.
However, due to the numerous adverse reactions, its safety issues have been criticized.
Finally, tofacitinib was released in January this year.
The failure of the post-marketing safety study ORAL Surveillance to reach the primary endpoint has reignited a new round of public and FDA questions about the safety of JAK inhibitors
.

This result quickly triggered the butterfly effect.
The FDA has successively announced the postponement of the review of Eli Lilly/Incyte’s Baricitinib, AbbVie’s Rinvoq, and Pfizer’s Abrocitinib.
Although these drugs have good effectiveness data in AD clinical studies, the results are However, none of them were spared the postponement of review
.
In other words, the FDA has issued a strict signal and does not solve the safety issue.
No matter how good the clinical effectiveness data, JAK inhibitors still cannot pass the review
.

However, what is surprising is that, unlike the tough attitude adopted by the FDA, the European Commission has recently directly approved Rinvoq for the treatment of adult patients with atopic dermatitis.
Rinvoq has also become the first JAK inhibitor approved for the treatment of AD.
It is not difficult to see from previous Rinvoq's AD clinical studies that Rinvoq has already disclosed the safety concerns of serious infections in the three previous clinical studies conducted in AD, and it was approved for the treatment of rheumatoid arthritis.
He was marked with black box warnings for serious infections, malignant tumors and thrombosis
.
These factors have not affected its approval in Europe, and it is somewhat puzzling
.

In any case, JAK inhibitors can now enter the European market and have achieved little results to a certain extent.
However, the current threat to Dupixent is still slightly lacking before the FDA approval of the treatment of AD
.
However, JAK inhibitors are not without opportunities.
As mentioned above, Dupixent is expensive and is administered by injection.
There are still limitations in compliance.
Both Rinvoq and Abrocitinib are administered orally.
Successfully passing the FDA review, I believe that Pfizer and AbbVie will launch a fierce impact on Dupixent from the commercialization strategy
.

In addition, JAK topical cream has fewer safety issues due to external use.
Delgocitnib cream was also approved by Japan PMDA last year for the treatment of mild to moderate AD in adults.
At present, Incyte is also represented.
Many companies are making arrangements for this.
How to break the safety issue will become a problem that pharmaceutical companies will try their best to solve.
In the third quarter, these JAK inhibitors will also usher in the trial period again, and they will pass the review and once again.
Whether it is postponed or sentenced to death directly, please wait and see
.

summary

In fact, in addition to Dupixent and JAK inhibitors, there are also many pharmaceutical companies that are gearing up to enter the AD treatment market.
Last month, Eli Lilly announced that its Lebrikizumab, which targets IL-13, has reached the primary endpoint in phase III clinical trials.
The data is also relatively good.
In addition, its administration method is once every two weeks or once every four weeks, which is better than Dupixent from this point of view
.
In addition, the strength of European upstart LEO Pharma cannot be underestimated.
From the company’s pipeline, it can be seen that LEO Pharma focuses on the development of different types of AD treatment drugs.
This year it also ushered in the first IL-13 approved by the European Commission.
Anti-Tralokinumab, some analysts believe that the drug's prospects will be more optimistic than Pfizer's Abrocitinib
.
At present, the BLA of Tralokinumab is in the formal review stage.
If approved, the drug will become the first biological agent to challenge Dupixent
.

LEO Pharma's R&D pipeline

Atopic dermatitis has a very significant clinical manifestation, that is, intense and continuous itching.
Countless patients can't sleep because of itching, and the torture of various accompanying symptoms seriously affects their normal life
.
For major pharmaceutical companies, what they need to do is not only to successfully develop drugs to treat atopic dermatitis to stop the itching of patients, but also to satisfy the itchiness in the face of the tens of billions of dollars in the market
.
Although the pathogenesis of atopic dermatitis is not yet clear, it can be seen from PubMed that the amount of literature on atopic dermatitis is also increasing year by year.
I believe that in the future, whether it is a controversy of a hundred schools of thought, or drugs that redefine treatment standards will emerge again.
In the end, hundreds of millions of patients will be benefited
.

references:

1.
Overview of Atopic Dermatitis, Carmela Avena-Woods, BS Pharm, PharmD, BCGP;

2.
Dupilumab: A review of its use in the treatment of atopic dermatitis;

3.
JAK-inhibitors-prevent-JAK-activation-The-signaling-cascade-that-originates-upon-binding;

4.
Pfizer says its JAK drug topped Dupixent in a head-to-head eczema test — but you'll have to wait on the data;

5.
Regeneron and Sanofi Monopoly on Atopic Dermatitis Market May Soon End