Who can change the pattern of atopic dermatitis treatment?

On September 23, 2021, the FDA approved the first JAK topical cream for the treatment of atopic dermatitis (AD)
.
Since Dupilumab led the development of IL-4/13 inhibitors in AD, JAK inhibitors have fully joined the competition in the mild-to-moderate and moderate-to-severe AD treatment market, which fully proves that the Th2 pathway is an important pathogenic factor in AD.
In addition, many targets are still being explored
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The immune-related pathogenesis of AD has three main stages
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When the epidermal barrier is destroyed due to dryness and other reasons, the first stage begins when the skin's innate immunity is activated; then the second stage, the adaptive immune response, is rapidly activated.
The core of this stage is Th2 activation and accompanied by IgE factors.
Sensitivity to allergens increased and release increased, and then Th1, Th17, and Th22 also responded to increased and released corresponding cytokines, the disease became more complicated; after the immune response continued to expand, it entered the third AD with atopic disease In the chronic development period of non-atopic diseases, combined atopic diseases include food allergies, asthma and rhinitis, and combined non-atopic diseases include cardiovascular diseases such as atherosclerosis that may be caused by inflammation
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01 Dupilumab develops adaptive immune response Many new drug developments are focused on the second stage of adaptive immune response
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Dupilumab (anti-IL-4 and IL-13 antibody), which has been obtained including adolescents and adults with AD of 6 years and older, is also the best proof that IL?4 and IL?13 are important cytokines that mediate the pathogenesis of AD.
It is currently under development.
Children with AD from 6 months to 6 years old
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This success also opened up the question of whether targeting only IL-4 or IL-13 can better improve the efficacy of AD
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Although from the mechanism of action, IL-4 is considered to be in a more central position because it can drive Th2 cell differentiation, IL-13 has a higher concentration in AD skin.
Expression can lead to destruction of the skin barrier, increased risk of skin infections, further inflammation, itching, and, in the chronic stage, remodeling and thickening of the skin
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Conrad’s CBP-201 is an IL-4Rα antagonist.
The results of a phase Ib study of 31 patients showed that after 4 weeks of treatment, up to 50% of patients who received CBP-201 had IGA 0/1.
, And 13% in the placebo group
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The average reduction in EASI from baseline was 74%, compared with 33% in the placebo group
.
Although the mode of action is theoretically similar to dupilumab, it seems to work faster
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Tralokinumab, the first antibody specifically targeting IL-13, has been approved by the European Union in July.
It is a fully humanized antibody against IL-13 that blocks IL-13 and IL-13Rα1 and IL-13Rα2.
In combination, in the phase III key monotherapy studies (ECZTRA 1 and ECZTRA 2), tralokinumab (300 mg subcutaneously injected every 2 weeks) showed a better effect than placebo at week 16, reaching IGA0/1 The ratios are 16% vs.
7% (ECZTRA1) and 22% vs.
11% (ECZTRA2), and the ratios reaching EASI-75 are 25% vs.
13% (ECZTRA1) and 33% vs.
11% (ECZTRA2)
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Adverse ocular events (including conjunctivitis, keratoconjunctivitis, and keratitis) were previously of particular concern in the dupilumab study, with an incidence rate of 11% in the key study.
In the ECZTRA1 and ECZTRA2 study of tralokinumab, 16 weeks of ocular The incidence of adverse events was 7.
6%, compared with 3% in the placebo group.
These ocular adverse events may be mainly related to IL-13 blocking activity, but longer-term safety data are needed to illustrate
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Two key phase III trials of Lebrikizumab, another IL-13 targeting antibody, ADvocate1 and ADvocate2, also reported reaching the 16-week EASI-75 primary endpoint.
The difference between Lebrikizumab is that it prevents the IL-13Rα1/IL-4Rα heterodimer complex.
The formation and signal transduction of IL-13, but does not affect the binding of IL-13 to IL-13Rα2 receptor.
Whether this feature affects safety and efficacy data needs to wait for specific data to be released
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After the influx of these antibodies targeting IL-4 or IL-13 into AD development, whether the efficacy or response time is better than dupilumab, and has a role in dupilumab partial response and non-response patients, it will take time to verify
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02 Widespread application of JAK inhibitors The application of JAK inhibitors in AD is also aimed at cytokines related to the adaptive immune response stage.
At present, both oral and creams of JAK inhibitors can show efficacy in moderate to severe and mild to moderate AD populations, respectively
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Among oral JAK inhibitors, it can be seen from the results of phase III clinical trials that have been obtained so far that JAK1 specific inhibitors abrocitinib and upadacitinib have completed head-to-head clinical trials with dupilumab.
In terms of current efficacy, dupilumab is strong A strong competitor may become a better choice, and among JAK inhibitors, these two JAK1 specific inhibitors also show better efficacy than the JAK1/2 inhibitor baricitinib.
It is discussed that moderate to severe AD is due to The area of ​​skin lesions is wide, and the scope of inflammation is wider than RA mainly affects the joints.
Therefore, the efficacy of baricitinib for AD may be limited by insufficient doses, but increased doses will also bring safety problems
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Rucotinib cream was approved by the FDA for the treatment of mild to moderate AD on September 21.
The key phase III trial results showed that 0.
75% BID and 1.
5% BID IGA-TS can reach 39%-53.
5 after 8 weeks of treatment.
%, while only about 7.
6%-15.
1% in the placebo group
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This curative effect is significantly better than crisaborole, another PDE4 inhibitor for mild to moderate AD.
The development of PDE4 inhibitors in AD is currently only a cream, and the systemic PDE4 inhibitor apramilast has been approved for treatment Moderate to severe psoriasis, but its development in AD has not progressed
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At the same time, JAK inhibitors are also troubled by toxicity.
In September of this year, the FDA requested that some JAK inhibitors for the treatment of chronic inflammation be revised: tofacitinib, baritinib, and upadacitinib’s black box warnings to indicate that these drugs will increase cancer, The risk of blood clots, serious cardiac events, and death
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Baritinib and upadacitinib have not been studied in similar large-scale safety clinical trials, so the risks have not been fully assessed
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Because they have the same mechanism of action as tofacitib, the FDA believes that these drugs may have similar risks
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The other two JAK inhibitors Rucotinib tablets and fedratinib on the market have been approved for myelofibrosis and are not suitable for the treatment of arthritis and other inflammations, so they are not included in the increased risk warning requirements
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Rucotinib cream is the first JAK external preparation approved by the FDA.
The FDA currently states that the use method is "short-term, non-continuous use".
Is there a time limit for the medication? Will it be warned with a black box? In fact, there are similar descriptions in topical calcineurin inhibitors, but not in crisaborole, a PDE4 inhibitor
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03 Exploration in and beyond Th2 The increase in immunoglobulin E (IgE) in the Th2 pathway is one of the key factors in the diagnosis of AD.
In most AD patients, the total IgE level or at least one allergen-specific level can be seen Omalizumab is a humanized monoclonal antibody that selectively binds to IgE, inhibits the binding of IgE to high-affinity receptors on the surface of effector cells, prevents effector cell activation, degranulation, release of inflammatory factors, and Recruit inflammatory cells
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In a trial called ADAPT, it was found that when omalizumab was used in AD children with high serum total IgE, SCORAD decreased by 33% from baseline at 24 weeks, and the final efficacy needs to be verified in a randomized controlled trial
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The epithelial cell-derived thymic stromal lymphopoietin (TSLP) and IL-33 in the skin innate immune response stage will directly or indirectly stimulate the innate type 2 lymphocytes (ILC2), thereby activating Th2 type cells.
Given that they are activating the skin The key role in the innate immune phase reaction, so it has also been explored in AD, but the current exploration effect for these two targets in AD is not good
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On May 10, 2021, Amgen announced that it had submitted the first TSLP antibody Tezepelumab to the FDA for the treatment of severe asthma
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The results of a trial called Navigator confirmed that Tezepelumab can significantly reduce the annual asthma attack rate (AAER) regardless of the patient's baseline eosinophil level
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Asthma and atopic dermatitis are equivalent to atopic diseases, and many patients are also combined.
About 50% of severe asthma cases have eosinophilia, so IL-4/IL-13 are related to them.
Both dupilumab and mepolizumab for IL-5 have been approved for asthma indications with elevated eosinophils, but there has been no medicine available for non-eosinophilic asthma
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However, its development has not been smooth sailing.
The Phase II trial of indications for atopic dermatitis failed.
64.
7% of patients reached the EASI50 endpoint, compared with 48.
2% in the placebo group
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Etokimab (ANB020) is a humanized anti-human IL-33 monoclonal antibody
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In a phase 2b randomized double-blind placebo-controlled ATLAS clinical study of 300 patients with moderate to severe atopic dermatitis, each administration group of etokimab failed to reach the primary endpoint of the trial, which shows that at week 16, compared with In the placebo group, the eczema area and severity index (EASI) did not improve statistically
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In early trials, it was found that it can inhibit neutrophil migration, and neutrophils are rarely seen in inflammatory infiltration in the later stages of AD disease.
Regeneron’s REGN3500 succeeds in asthma and fails in AD.
This is IL-33.
The future of restraint in atopic dermatitis brings more uncertainties
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The development of Treg targets in the field of autoimmunity is also attracting attention.
In AD and other diseases, Treg cells cannot properly exert their inhibitory activity, which leads to immune polarization.
The strategy for AD treatment is to enhance the immune system Treg cell limbs.
The strategy will restore tolerance and suppress chronic inflammation
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Merck spent US$1.
85 billion to buy the IL-2 fusion protein drug PT101 from Pandion Therapeutics.
PEGylated recombinant human IL-2 (LY3471851) is a drug conjugated to IL-2 and a polymer, a traditional IL-2 antibody The half-life of the drug is only 1-2 hours, and NKTR358 only needs to be injected 1-2 times a month, so the half-life is significantly prolonged, and it is currently in the phase Ib trial
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