Targeted immunomodulation in rare disorders: Regulatory milestones and clinical insights

Recent regulatory developments highlight a steady acceleration in therapeutic progress across rare immunological diseases, spanning autoimmune, autoinflammatory and primary immunodeficiency disorders. While individually rare, these conditions collectively represent a growing area of focus, with advances increasingly driven by targeted modulation of specific immune pathways. A series of recent approvals and designations across major regulatory regions underscores both the clinical need and the expanding therapeutic toolkit in this space.

Advances in rare autoimmune conditions

Among rare autoimmune diseases, progress is being seen in both systemic fibroinflammatory disorders and antibody-mediated haematological conditions. With emerging targeted therapies offering improved disease control with differentiated safety profiles compared with traditional immunosuppressive strategies.

Immunoglobulin G4-related disease

Immunoglobulin G4-related disease (IgG4-RD) is a chronic, progressive autoimmune condition affecting multiple organs, which can lead to fibrosis and organ damage. Treatment options for IgG4-RD have been largely reliant on immunomodulatory medicines and particularly glucocorticoids, which are associated with varied results and side effects.

Recently, the CHMP has issued a positive recommendation for inebilizumab, a humanized monoclonal antibody (mAb) that depletes CD19+ B-cells, in the EU, where no treatments are currently approved for IgG4-RD.¹ Furthermore, inebilizumab has been approved in Japan for the suppression of relapse of IgG4-RD, and was also approved by the FDA back in April 2025 as the first and only treatment for IgG4-RD.^2,3 

These regulatory milestones have been supported by data from the randomized, double-blind, placebo-controlled, Phase 3 MITIGATE study (NCT04540497). At Week 52, inebilizumab demonstrated a significantly longer median time to first treated IgG4-RD flare and a substantially lower proportion of patients requiring treatment for IgG4-RD flares compared with placebo. In addition, corticosteroid-free, flare-free complete remission was achieved in 58.8% of patients receiving inebilizumab compared to 22.4% receiving placebo.

Warm autoimmune haemolytic anaemia

Similarly, regulatory momentum is building for rilzabrutinib in warm autoimmune haemolytic anaemia (wAIHA), a rare condition driven by autoantibody-mediated destruction of red blood cells.⁴ Rilzabrutinib has received designation as a breakthrough therapy in the US and as an orphan drug in Japan, where there are currently no approved treatments targeting the underlying cause. Rilzabrutinib is a reversible inhibitor of Bruton’s tyrosine kinase (BTK), modulating immune pathways and signalling in B cells, macrophages and other innate immune cells.

These designations are supported by clinical data from LUMINA 2, an ongoing multicenter, open-label, Phase 2b study (NCT05002777), while the LUMINA 3 Phase 3 study (NCT07086976) is currently underway. In the Phase 2 study, rilzabrutinib demonstrated a durable haemoglobin response, which was maintained over long-term follow-up.

Emerging options in autoinflammatory diseases

Autoinflammatory conditions are receiving renewed attention, with recent advances improving understanding of disease biology and enabling the development of therapies that modulate innate immune responses rather than broadly suppressing them.

Behçet’s disease

Behçet’s disease is a rare, inflammatory disorder of the blood vessels characterized by recurrent oral and genital sores, skin lesions, leg ulcers and potential ocular involvement. In this setting, dusquetide has received orphan drug recognition in both the United States and Europe following review of Phase 2 clinical data.^5,6 Dusquetide is a first-in-class innate defence regulator, designed to modulate innate immune responses and promote an anti-inflammatory, anti-infective, and tissue healing response.

These regulatory designations have been supported by data from a placebo-controlled, open-label, Phase 2a study (n=8), comparable with the Phase 3 study of apremilast; a therapy already approved in Behçet’s disease.⁷ At Week 4, dusquetide demonstrated a 40% improvement in the primary endpoint, AUC of the mean number of ulcers versus time, compared with placebo, as well as reducing ulcer number and pain. These findings were comparable to apremilast at Week 4, and both had similar efficacy profiles at weeks 5 through 8, despite dusquetide being stopped at Week 4 (as per study design). The therapy was also generally well tolerated, with no treatment-related adverse events.

Lead Investigator, Dr. Gülen Hatemi (Istanbul University) said:

“As a twice weekly treatment, the durability of the response may indicate a favorable chronic use or maintenance profile for SGX945, particularly if it is available in a self-administered formulation.”

Schnitzler syndrome

Further progress is evident in Schnitzler syndrome, an ultra-rare autoinflammatory condition characterized by monoclonal gammaglobulinemia and chronic urticarial rashes, followed by recurrent fever, joint pain, and bone pain. Schnitzler syndrome impairs patient quality of life and has had a high unmet medical need, with no approved treatments.

Canakinumab, an interleukin-1 beta (IL-1β) inhibitor, has recently been approved in Japan for Schnitzler syndrome, marking an important step for a condition with limited established treatment options.⁸ This approval is based on a multicentre, investigator-initiated Phase 2 trial (IACT21071) of canakinumab in patients (n=5) with Schnitzler syndrome inadequately controlled with steroids or colchicine. Canakinumab achieved 60% remission at Day 7, with 80% maintaining clinical or partial remission through 96 weeks, while no new safety signals were observed.

Progress in primary immunodeficiency

Advances are also being made in rare primary immunodeficiencies, where targeted therapies are beginning to address specific genetic and molecular defects, offering a shift towards precision medicine.

Activated phosphoinositide 3-kinase delta syndrome

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is a rare primary immunodeficiency characterized by recurrent sinopulmonary infections, enteropathy, and lymphoproliferation. Leniolisib has recently been approved in Japan for patients aged ≥4 years with APDS, becoming the first treatment globally available for children aged 4–11 years with this rare condition.⁹ It has also received a positive CHMP opinion from the EMA for patients aged ≥12 years, following earlier FDA approval in 2023 for the same age group.¹⁰ A resubmission for use in children aged 4–11 years in the USA is anticipated.¹¹

Leniolisib is an oral small molecule inhibitor of PI3Kδ, designed to regulate the hyperactive PI3Kδ pathway. The approval was supported by a Phase 3 randomized, placebo-controlled trial (NCT02435173), which demonstrated significant improvement in coprimary endpoints reflecting immune dysregulation and deficiency, alongside open-label extension data (NCT02859727) that supported long-term safety and tolerability.

Professor Hirokazu Kanegane (Institute of Science Tokyo) commented:

“This approval introduces the first approved targeted treatment option for this rare primary immunodeficiency in Japan, and has the potential to help reduce the burden of disease for patients and their families.”

A broader shift towards precision immunology

Taken together, these developments illustrate the key trends shaping the rare disease landscape in immunology. There is a clear move towards therapies that target defined immune pathways, including B-cell depletion, BTK inhibition, IL-1 blockade and PI3Kδ modulation. This reflects a deeper understanding of disease mechanisms and enables more selective intervention.

Furthermore, global regulatory frameworks for rare diseases continue to facilitate development, with orphan drug designations and expedited pathways supporting innovation in areas of high unmet need.

While challenges remain, including small patient populations and limited clinical data, the current trajectory suggests that rare immunological diseases are entering a period of meaningful therapeutic progress. As targeted approaches continue to emerge, they hold the potential not only to improve disease control but also to redefine standards of care.

References

1. European Medicines Agency. First treatment recommended for rare immunoglobulin-related autoimmune disease. Press release. Available at: https://www.ema.europa.eu/en/news/first-treatment-recommended-rare-immunoglobulin-related-autoimmune-disease (accessed 25 March 2026).
2. Mitsubishi Tanabe Pharma. Anti-CD19 monoclonal antibody UPLIZNAⓇ for I.V. Infusion 100mg Approval for additional indication of suppression of relapse of immunoglobulin G4-related disease in Japan. Press release. Available at: https://www.tanabe-pharma.com/en/news/news20251120140000/main/0/link/e_MTPC251120.pdf (accessed 25 March 2026).
3. Amgen. Uplizna® (Inebilizumab-Cdon) is now the first and only FDA-approved treatment for IGG4-related disease. Press release. Available at: https://www.amgen.com/newsroom/press-releases/2025/04/uplizna-inebilizumabcdon-is-now-the-first-and-only-fdaapproved-treatment-for-igg4related-disease (accessed 25 March 2026).
4. Sanofi. Press Release: Sanofi’s rilzabrutinib designated breakthrough therapy in the US and orphan drug in Japan for the treatment of warm autoimmune hemolytic anemia. Press release. Available at: https://www.sanofi.com/en/media-room/press-releases/2026/2026-02-09-06-00-00-3234232 (accessed 25 March 2026).
5. Soligenix. FDA Grants Soligenix Orphan Drug Designation for the Treatment of Behçet’s Disease after Reviewing Recent Phase 2 Clinical Study Results. Press release. Available at: https://ir.soligenix.com/2025-08-18-FDA-Grants-Soligenix-Orphan-Drug-Designation-for-the-Treatment-of-Behcets-Disease-after-Reviewing-Recent-Phase-2-Clinical-Study-Results (accessed 25 March 2026).
6. PR Newswire. Soligenix Receives Orphan Drug Designation from the European Commission for SGX945 for the Treatment of Behçet’s Disease.  Press release. Available at: https://www.prnewswire.com/news-releases/soligenix-receives-orphan-drug-designation-from-the-european-commission-for-sgx945-for-the-treatment-of-behcets-disease-302725591.html (accessed 25 March 2026).
7. Soligenix. Biological Efficacy Demonstrated in a Phase 2 Clinical Trial of SGX945 for the treatment of Behçet’s Disease. Press release. Available at: https://ir.soligenix.com/2025-07-31-Biological-Efficacy-Demonstrated-in-a-Phase-2-Clinical-Trial-of-SGX945-for-the-treatment-of-Behcets-Disease (accessed 25 March 2026).
8. Novartis. Novartis receives approval for an additional indication for Ilaris®: Schnitzler syndrome. Press release. Available at: https://www.novartis.com/jp-ja/news/media-releases/prkk20260219-1 (accessed 25 March 2026).
9. FirstWord Pharma. Pharming Group announces approval of Joenja (leniolisib) in Japan for the treatment of APDS in patients aged 4 years and older. Press release. Available at: https://firstwordpharma.com/story/7146040 (accessed 25 March 2026).
10. European Medicines Agency. Joenja. Press release. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/joenja (accessed 25 March 2026).
11. FirstWord Pharma. FDA knock-backs send shares in Pharming down, Aquestive up. Press release. Available at: https://firstwordpharma.com/story/7088914 (accessed 25 March 2026).