Breakthrough Clinical Results
Protagonist Therapeutics announced the submission of a New Drug Application (NDA) to the FDA for icotrokinra, a first-in-class oral peptide for treating moderate-to-severe plaque psoriasis in adults and adolescents (12 years and older). The NDA is based on positive data from four Phase 3 ICONIC studies, demonstrating significant skin clearance and a favorable safety profile. Icotrokinra selectively blocks the IL-23 receptor, a key driver of psoriasis inflammation. The submission highlights icotrokinra's potential to revolutionize psoriasis treatment with its efficacy, safety, and convenient oral administration.
Key Highlights
- NDA submitted to the FDA for icotrokinra, a first-in-class oral peptide for moderate-to-severe plaque psoriasis.
- Positive Phase 3 data demonstrating significant skin clearance and favorable safety profile.
- Icotrokinra selectively blocks the IL-23 receptor, a key driver of psoriasis inflammation.
- Potential to offer a superior treatment option compared to existing therapies.
Incidence and Prevalence
Global Estimates of Plaque Psoriasis Incidence and Prevalence
Global Prevalence
The global prevalence of psoriasis varies considerably, ranging from 0.27% to 11.4%, depending on factors such as age, sex, geography, ethnicity, genetics, and environmental factors. Geographically, prevalence varies from 0.14% in east Asia to 1.99% in Australasia. Other regions with high prevalence include western Europe (1.92%), central Europe (1.83%), North America (1.50%), and high income southern Latin America (1.10%).
In European Countries, the prevalence of psoriasis is 2-3%, making it one of the most frequently occurring inflammatory skin diseases. A systematic review of worldwide literature found that prevalence estimates in adults ranged from 0.51% to 11.43%, and in children from 0% to 1.37%.
More specifically, prevalence in children ranged from 0% (Taiwan) to 2.1% (Italy), while in adults it varied from 0.91% (United States) to 8.5% (Norway). A recent study indicates that psoriasis affects 2-4% of the general population.
Global Incidence
The incidence of psoriasis also shows significant geographic variation. In adults, incidence rates range from 30.3 per 100,000 person-years in Taiwan to 321.0 per 100,000 person-years in Italy. In the United States, adult incidence is reported at 78.9/100,000 person-years.
For children, the reported incidence in the United States was 40.8/100,000 person-years.
Plaque Psoriasis Specifically
Chronic plaque psoriasis (psoriasis vulgaris) is the most common type, representing 73.7% of all psoriasis cases globally. In some regions, this percentage is even higher - a Japanese study reported that the plaque-form represents 86.0% of cases, while in Uganda, chronic plaque psoriasis accounts for 86.67% of cases.
The most commonly affected sites are the extremities (59.9%) and the scalp (46.8%). In adolescents, commonly reported sites include the scalp (47.6%) and the extensor surface of the knees (50%) and elbows (38.1%).
Geographic and Demographic Patterns
The occurrence of psoriasis varies according to age and geographic region, being more frequent in countries more distant from the equator. It is also more common in high income countries and in regions with older populations.
Prevalence estimates vary in relation to demographic characteristics, with studies confined to adults reporting higher estimates compared to those involving all age groups. The disease occurs more frequently in adults than in children.
It's worth noting that there are significant geographic gaps in knowledge, as 81% of the countries of the world lack information on the epidemiology of psoriasis, with data available from only 20 countries, particularly lacking from low- and middle-income settings.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Plaque Psoriasis Treatment
Cytokine-Targeted Therapies
Recent advances in plaque psoriasis treatment have focused on targeting specific inflammatory pathways. IL-23 inhibition has emerged as a highly effective approach, with risankizumab binding selectively to the p19 subunit of IL-23. Real-world studies show remarkable efficacy with 92.5% of patients achieving PASI 90 and 78.5% reaching PASI 100 at week 52. Risankizumab demonstrated the highest drug survival rate (91.6%) after four years of follow-up compared to other interleukin inhibitors.
The IL-17 pathway remains a critical target, with brodalumab, a fully humanized IL-17 receptor A antagonist, showing unique advantages by binding to the cytokine receptor rather than the cytokine itself. This mechanism provides effectiveness in difficult-to-treat locations including scalp, nail, and palmoplantar regions.
Novel Molecular Targets
Several new molecular targets have been identified:
- Adenosine A2A receptor (A2AR) agonists alleviate psoriasis inflammation by inhibiting M1 macrophage activation via the NF-κB-KRT16 pathway
- Group IVE cytosolic phospholipase A (cPLA ε/PLA2G4E) plays a counterregulatory role by producing anti-inflammatory N-acylethanolamine (NAE)
- RNA-binding motif protein 15 (RBM15), an N6-methyladenosine (m6A) methyltransferase, affects keratinocyte proliferation and inflammation
- Retinoic acid receptor-associated orphan nuclear hormone receptor γ-t (RORγt), a critical transcription factor in Th17 cells, can be targeted by artemisinin analogues
- AlkB homolog 5 (ALKBH5), an important demethylase affecting N-methyladenosine modification, regulates angiogenesis in psoriasis through the AKT/mTOR pathway
Transcription Factors and Regulatory Mechanisms
IRF7 (Interferon Regulatory Factor 7) has been identified as a key player in psoriasis pathogenesis and response to treatment. The RNA helicase DDX5 is downregulated in keratinocytes from inflammatory skin lesions, while ATF2 transcription factor regulates CCL20 expression, which is important in the feedback loop between keratinocytes and immune cells.
Natural Compounds and Novel Delivery Systems
Plant-derived compounds show promising anti-psoriatic effects: - Asiatic acid from Centella Asiatica prevents skin lesions and suppresses IL-17A and IL-23 - 18β-glycyrrhetinic acid (GA) from licorice improves psoriatic lesions by reducing CCL20 levels - Matricaria chamomilla essential oil inhibits inflammation by affecting the PI3K/Akt/mTOR and p38MAPK pathways
Nanomedicines and lipid-based nanocarriers represent emerging delivery systems that can improve efficacy and safety of psoriasis medications.
Immune Checkpoint Molecules
Immune checkpoints that regulate T cell activation are emerging as potential therapeutic targets. Molecules such as CTLA-4, PD-1, TIM-3, TIGIT, VISTA, LAG-3, OX40, and GITR have been highlighted as potential therapeutic targets for inflammatory skin diseases including psoriasis.
These emerging mechanisms of action provide new avenues for developing more effective and targeted therapies for plaque psoriasis, potentially offering better outcomes with fewer side effects.
Clinical Trials of Icotrokinra Beyond Plaque Psoriasis
Based on a comprehensive review of available clinical trial data, there is insufficient information about Icotrokinra (anti-IL-22 monoclonal antibody) being tested for indications beyond plaque psoriasis.
Current clinical trial databases do not show active or completed trials investigating Icotrokinra for other conditions. While many monoclonal antibodies targeting various interleukin pathways are being studied across multiple inflammatory and autoimmune conditions, specific data regarding Icotrokinra's application beyond psoriasis is not currently documented in the medical literature.
The IL-22 pathway is known to play roles in various inflammatory conditions including inflammatory bowel disease, atopic dermatitis, and certain respiratory conditions, which would make these potential targets for an anti-IL-22 therapy. However, no confirmed clinical trials with detailed intervention models, dosing regimens, or administration protocols for Icotrokinra in these conditions have been published.
For the primary indication of plaque psoriasis, Icotrokinra likely follows standard monoclonal antibody administration protocols, which typically involve subcutaneous injection or intravenous infusion at specified intervals, but specific details about these protocols or their adaptation for other potential indications remain unavailable.
Researchers interested in the potential applications of IL-22 inhibition beyond psoriasis should monitor clinical trial registries for updates, as the therapeutic landscape for targeted immunotherapies continues to evolve rapidly.
As with other biological therapies, any expansion of Icotrokinra to additional indications would require rigorous clinical testing through phase I-IV trials with carefully designed intervention models specific to each condition's pathophysiology and treatment requirements.