(Health Korea News / Lee Chung-man) H4 receptor antagonists, which are expected to effectively treat atopic dermatitis, are emerging as innovative new drugs, but their development is facing many difficulties.
Atopic dermatitis, which is accompanied by itching and inflammation of the skin, is a representative allergic disease. It is believed that inflammation occurs deep in the skin due to complex causes such as genetics, environment, skin barrier abnormalities, pharmacological factors, psychological factors, and immunity.
Since the cause of atopic dermatitis has not yet been clearly identified, it is difficult to expect a complete cure. The current standard treatment is to use drugs that can reduce symptoms.
A representative drug is ‘Dupixent’ (ingredient name: dupilumab) from Sanofi in France. This drug selectively binds to cytokines IL-13 and IL-4, which promote the activity of immune cells, thereby inhibiting the inflammatory response.
Previously, treatment for atopic dermatitis relied on symptomatic treatment. ‘Dupixent’ has risen to the ranks of blockbuster drugs by providing excellent therapeutic effects based on a mechanism that fundamentally inhibits the cause of skin inflammation. In 2023, sales alone reached 11.59 billion dollars (about 16.5 trillion won). This is the 5th place in global pharmaceutical sales.
However, Dupixent is not a panacea for atopic dermatitis. Dupixent’s target cytokines, IL-13 and IL-4, are the main causes of atopic dermatitis, but not all atopic dermatitis is caused by IL-13 and IL-4. Accordingly, some patients do not respond to Dupixent.
‘Dupixent’ is an injection type, and it also carries with it the fear of needles and the inconvenience of injections. Since the efficacy decreases when exposed to room temperature for a long time, it must be refrigerated, and there is a risk of secondary infection, and there is also the disadvantage of generating medical waste.
For this reason, the pharmaceutical industry has focused on developing an oral drug that can overcome the limitations of Dupixent, and the H4 receptor antagonist has emerged as an alternative.
The H4 receptor is a subtype of histamine compound. Histamine is involved in a variety of physiological functions, including allergic responses, regulation of gastric acid secretion, regulation of immune responses, central nervous system function, vascular responses, and appetite regulation.
There are four known histamine receptor subtypes: H1 receptor, H2 receptor, H3 receptor, and H4 receptor. Of these, H1 to H3 receptors were discovered early, and H1 and H2 receptors are already being used to treat various diseases.
On the other hand, because the H4 receptor was discovered rather late, its physiological role and function are less understood than those of other types of histamine receptors, and attempts at drug development have only recently been made.
The H4 receptor is mainly expressed on immune cells and is related to inflammatory responses. This is why it has emerged as a promising target in diseases related to inflammatory response regulation, such as atopic dermatitis. In particular, since it is being developed as an oral drug, it is expected to increase patient convenience.
With these expectations in mind, the pharmaceutical industry is working hard to develop H4 receptor antagonists, but is facing difficulties.
JW Pharmaceutical of Korea is a representative example. The company’s H4 receptor antagonist ‘JW1601’ (ingredient name: izuforant) is a drug with a dual inhibition mechanism that selectively acts on histamine H4 to block the activity and movement of immune cells that cause atopic dermatitis and inhibit histamine signaling that causes itching.
JW Pharmaceutical transferred technology for ‘JW1601’ to Denmark’s Leo Pharma during the preclinical stage of ‘JW1601’ in August 2018. The contract size was 402 million dollars (approximately 550 billion won).
JW Pharmaceutical was in charge of the domestic phase 1 clinical trial of ‘JW1601’ until June 2020, and Leo Pharma continued the global phase 2 clinical trial of ‘JW1601’. The phase 2 trial was to evaluate the efficacy and safety of ‘JW1601’ and placebo in adult patients with moderate to severe atopic dermatitis.
However, in October 2023, Leo Pharma suddenly returned the development technology of ‘JW1601’ to JW Pharmaceutical, saying that the interim results of the phase 2 trial ‘JW1601’ did not meet the primary endpoint of the trial.
Global big pharmas are also having difficulty developing H4 receptor antagonists. Novartis of Switzerland and Janssen of the United States also attempted to develop H4 receptor antagonists, but stopped development due to lack of therapeutic efficacy or occurrence of side effects.
The companies did not disclose the reason for discontinuing drug development, but some analysts say it may have revealed the limitations of the H4 receptor.
An industry insider said, “Drugs that only act on specific pathways, such as the H4 receptor, can upset the balance of the entire immune system and cause secondary autoimmune diseases,” and “The reason cytokines are widely used as targets in immunosuppressive therapy is because cytokines are directly involved in immune responses, so they have relatively high specificity and safety.”
Meanwhile, unlike Novartis and Janssen, JW Pharmaceutical showed a desire to continue developing ‘JW1601’. At the time, a JW Pharmaceutical official said, “‘JW1601’ met safety requirements in all related clinical results,” and “We plan to review future development directions based on the intermediary research data of ‘JW1601’.”
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