- Indian Rheumatology association
Devarasetti Phani Kumar MD (Internal medicine), DM (Rheumatology)
Associate Professor, Department of Clinical Immunology and Rheumatology
Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
Treatment of lupus is moving from non-specific or global immunosuppression to targeted therapies. In this review, recently approved drugs, and emerging therapies showing promise in early trials were reviewed
Anifrolumab
The TULIP trials and their long-term extension showed that anifrolumab is efficacious in moderate to severe non-renal lupus with no major safety concerns at 3 years. A phase III trial (IRIS) in active class III or IV LN (with or without class V) is ongoing.
Voclosporin
AURORA trial showed the efficacy of voclosporin in active proliferative lupus nephritis.AURORA 2 showed that treatment was well tolerated and improved proteinuria persisted across three years of treatment.
Drugs targeting various arms of the immune system such as Dendritic cells, B cells, T cells, costimulators, intracellular signals, and cytokines are being developed in SLE. Table 1 summarizes drugs that have achieved end-points in Phase I/II and then moved to Phase II/III/IV.v
Sequential and Combination Biological therapies
Post Rituximab (RTX) flares are associated with rising levels of BAFF which expands autoreactive B cells supporting the rationale of combining BAFF inhibitors with RTX.
In non-renal lupus, Belimumab (BLM) following rituximab significantly reduced anti-dsDNA and the risk of severe flare in a phase II trial for refractory SLE (BEAT-LUPUS). A combination of RTX/BLM was tried in the phase III SynBiose-1 study which showed important lab and clinical response.SynBioSe-2 study is currently recruiting to study the long-term efficacy and safety of RTX+BLM in active non-renal lupus. Other novel combinations tried include rituximab with telitacicept and telitacicept with low-dose IL-2 (phase II/III trials).
In renal lupus, the addition of BLM to RTX in refractory LN (CALIBRATE) failed to show clinical efficacy. A phase III trial of belimumab in combination with mycophenolate, and tacrolimus is underway.
Cellular therapies:
New experimental cellular therapies include transplantation of tolerogenic dendritic cells, engineered MSCs, MSC-extracellular vesicles, in vitro-expanded Treg cells, engineered NK cells with CARs, and B-reg cells.
Amongst emerging drugs, obinutuzumab shows promise in renal lupus, and litifilimab, telitacicept, and deucravacitinib have encouraging results in non-renal lupus. There are upcoming combinations with B-cell-depleting agents. CAR-T cell therapy is an exciting option for severe refractory lupus. However, long-term data on disease progression and safety are needed for all novel therapies.
Molecular target | Name of drug | Evidence so far (PICO) | Ongoing trials (Non-renal lupus) | Ongoing trials (Lupus nephritis) |
|---|---|---|---|---|
Dendritic cells | ||||
BDCA2 | Litfilimab | Phase I and II P – Cutaneous lupus, arthritis I – litifilimab s/c C – placebo O – Greater reduction in CLASI and joint count in the intervention group | Phase III – active SLE (refractory skin, joint) – TOPAZ-1 & 2, AMETHYST | |
B Cells | ||||
CD 20 | Obinutuzumab | Phase II – NOBILITY trial P – active lupus nephritis on MMF and steroids I – obinutuzumab IV C – placebo O – CRR at w52 greater with obinutuzumab | Phase III – active SLE – ALLEGORY | Pediatric LN – POSTERITY Induction of LN – OBILUP |
CD 38 | Daratumumab | Promising in case series (Refractory LN) | Phase II – moderate to severe SLE | Phase II |
BAFF receptor | Ianalumab | Phase II P – cutaneous lupus, arthritis, SLEDAI >4 I – Ianalumab s/c C – placebo O – Met composite endpoint of SRI4 response at w28 | Phase III – active SLE, (SIRIUS- SLE) | Phase III (SIRIUS-LN) |
BAFF & APRIL | Telitacicept | Phase II and III trials successful in China P – active SLE with SLEDAI >8 I – Telitacicept C – placebo O – Met composite endpoint of SRI4 response at w28 | Phase III – Active SLE -/ in combination with IL-2 | Phase II – LN |
BAFF | Belimumab | Approved for SLE and LN | Phase IV – early lupus < 2 years (BE-EARLY) | Phase III – BLM+MDT in LN |
Ikaros and Aiolos | Iberdromide | Phase II P – SLEDAI >4 I – iberdromide + SOC C – placebo O – higher % patients with SRI4 response at w28 | – | – |
B-T cell interaction | ||||
CD 40 ligand | Dapirolizumab Pegol | Phase II P – moderate to severe active SLE (SLEDAI-2K score ≥6 & ≥1 BILAG A or ≥2 BILAG B) I – Dapirolizumab and SOC C – Placebo O – numerical Improvement but the primary endpoint (BICLA at w24) not met | Phase III – Severe SLE (PHOENYCS GO) | |
mTOR | Sirolimus | Phase I/II P – active SLE I – Sirolimus for 12 months C – none O – reduction in BILAG/ SLEDAI over 12 months | Phase II – SLE | Phase II/III |
Cytokine targets | ||||
TYK2 | Deucravacitinib | Phase II P – moderate to severe active SLE (SLEDAI-2K score ≥6 & ≥1 BILAG A or ≥2 BILAG B) I – Deucravacitinib for 32 weeks C – placebo O – higher response rate for SRI-4, BICLA, LLDAS, CLASI-50 | Phase II – cutaneous lupus Phase III – SLE – POETYK | |
Type 1 IFN R | Anifrolumab | TULIP I and II – Approved for SLE | Phase III – SLE in Asian population Phase III – SLE – subcutaneous formulation: TULIP-SC | Phase III – LN IRIS |
IL2 | Low dose IL-2 | Phase II P – active SLE including nephritis I – IL-2 + SOC C – placebo O – Did not meet composite endpoint of SRI4 response at w28, but higher rates of CRR in patients with LN | Phase III – active SLE | |
