In the last 2 years, two landmark papers have been published that show that the introduction of new treatment modalities (i.e., belimumab [the Belimumab International Study in Lupus Nephritis study] and voclosporin [the AURORA study]) on top of standard of care immunosuppression in lupus nephritis results in significantly higher remission rates (1,2). The expansion of the therapeutic armamentarium is a welcome addition for the treatment of patients with lupus nephritis, of whom merely 27%–35% achieve long-term remission (3,4) and 10% develop kidney failure in 5 years, increasing to 20% in 15 years (5,6). At first sight, it may come as no big surprise that intensifying immunosuppression in lupus nephritis would also result in higher remission rates, but both drugs may also have specific advantages over the use of broad-acting immunosuppressive drugs, such as cyclophosphamide, mycophenolate, and/or steroids, that constitute the backbone of the current standard of care. Belimumab is a recombinant IgG mAb that inhibits the B cell activation factor and therefore specifically targets the humoral autoimmune responses in the pathophysiology of lupus nephritis. It has been reported to have a favorable safety profile. Voclosporin is a calcineurin inhibitor that has a consistent pharmacokinetic profile and seems to have a more favorable effect on lipids and glucose metabolism than other CNIs (7).
Accessibility to these new treatments will be a critical factor for future clinical implementation of these study results, and the pricing of these new drugs will most likely be an important determinant of their accessibility. In this issue of CJASN, Mandrik et al. (8) model the health economic effect of the introduction of these two new drugs for the treatment of lupus nephritis. They build their model on the basis of a US population of lupus nephritis with associated ethnic distribution and on the basis of current known pricing for belimumab and voclosporin; thus, the cost-effectiveness analysis might not be applicable in other health care systems or populations. Patients were assumed to be treated with the novel compounds for 3 years when responding, whereas treatment was assumed to be stopped after 1.5 years if no response could be detected or if side effects occurred. Then, long-term prognostics on survival and kidney failure were included in relation to known risk factors, such as response to treatment, sex, and ethnicity. Unfortunately, health-related quality-of-life (QoL) values had to be extrapolated from other lupus nephritis studies and cohorts into the model because the actual QoL data of these studies, although collected, have not been reported (yet). A positive correction to QoL values was imputed for patients on low-dose steroids or no steroids and when a patient was classified as a (partial) responder to treatment.
The model of Mandrik et al. (8) demonstrates that the costs per gained quality-adjusted life year (QALY) for belimumab treatment in patients with lupus nephritis were $95,269 and $70,077 if the subcutaneous formulation will be used. The cost per gained QALY for voclosporin treatment was $150,344. It needs to be re-emphasized that the study design does not allow for a direct head-to-head comparison between the costs per QALY between belimumab and voclosporin. However, as stated before, the study was modeled on a 1.5-year treatment regime, whereas current practice is to treat lupus nephritis usually for between 3 and 5 years (9), which would bring not only voclosporin but also belimumab above the agreed threshold for willingness to pay in rare diseases of $100,000 per annum.
A strong aspect of the study by Mandrik et al. (8) is that they were able to present incremental cost-effectiveness ratio outcomes for alternative scenarios: for example, belimumab and voclosporin are being used for longer or shorter periods, or in the case of voclosporin, a hypothetical permanent drop in kidney function is a side effect of calcineurin inhibition. Additionally, the authors also evaluated in a sensitivity analysis how the costs per QALY could be improved.
The study of Mandril et al. (8) exposes a fundamental problem in drug development, where potential costs that can be saved in health care expenditure by a new drug are nullified by the price of this drug. In the case of voclosporin, this result is perhaps more distressing given the established efficacy of tacrolimus in the treatment of lupus nephritis (10), strongly suggesting that calcineurin inhibition in itself is most likely the underpinning mechanism of the clinical effect in the voclosporin studies. In recent years, we have learned to take value-based health care as the basis of our care system, whereas recent initiatives, such as ICHOMS, have given us a good understanding of what patients value (11). We propose that value-based pricing, which also takes into account how new drugs perform with respect to side effects and long-term safety, should serve as a basis to negotiate reasonable pricing with drug companies. This would not only increase access to new treatments for our patients but also be conditional for the sustainability of our health care system and drug development in general.
Y.K.O. Teng reports consultancy agreements with Aurinia Pharmaceuticals, GSK, KezarBio, Novartis, Otsuka Pharmaceuticals, and Vifor Pharma; research funding from Aurinia Pharmaceuticals and GlaxoSmithKline; and serving on the editorial board of Rheumatology. The work of Y.K.O. Teng is supported by Dutch Kidney Foundation grant 17OKG04 and by the Arthritis Research and Collaboration Hub (ARCH) Foundation. ARCH is funded by the Dutch Arthritis Foundation. The Leiden University Medical Center received consulting fees from Aurinia Pharmaceuticals, GSK, KezarBio, Novartis, Otsuka Pharmaceuticals, and Vifor Pharma for consultancies delivered by Y.K.O. Teng. The remaining author has nothing to disclose.
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s).
T.J. Rabelink and Y.K.O. Teng conceptualized the study, wrote the original draft, and reviewed and edited the manuscript.
1. Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, Amoura Z, Yu X, Mok CC, Santiago MB, Saxena A, Green Y, Ji B, Kleoudis C, Burriss SW, Barnett C, Roth DA: Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med 383: 1117–1128, 2020
2. Rovin BH, Teng YKO, Ginzler EM, Arriens C, Caster DJ, Romero-Diaz J, Gibson K, Kaplan J, Lisk L, Navarra S, Parikh SV, Randhawa S, Solomons N, Huizinga RB: Efficacy and safety of voclosporin
versus placebo for lupus nephritis (AURORA 1): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 397: 2070–2080, 2021
3. Bertsias G, Ioannidis JP, Boletis J, Bombardieri S, Cervera R, Dostal C, Font J, Gilboe IM, Houssiau F, Huizinga T, Isenberg D, Kallenberg CG, Khamashta M, Piette JC, Schneider M, Smolen J, Sturfelt G, Tincani A, van Vollenhoven R, Gordon C, Boumpas DT; Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics: EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 67: 195–205, 2008
4. Zen M, Iaccarino L, Gatto M, Bettio S, Nalotto L, Ghirardello A, Punzi L, Doria A: Prolonged remission in Caucasian patients with SLE: Prevalence and outcomes. Ann Rheum Dis 74: 2117–2122, 2015
5. Tektonidou MG, Lewandowski LB, Hu J, Dasgupta A, Ward MM: Survival in adults and children with systemic lupus erythematosus: A systematic review and Bayesian meta-analysis of studies from 1950 to 2016. Ann Rheum Dis 76: 2009–2016, 2017
6. Mahajan A, Amelio J, Gairy K, Kaur G, Levy RA, Roth D, Bass D: Systemic lupus erythematosus, lupus nephritis and end-stage renal disease: A pragmatic review mapping disease severity and progression. Lupus 29: 1011–1020, 2020
7. Busque S, Cantarovich M, Mulgaonkar S, Gaston R, Gaber AO, Mayo PR, Ling S, Huizinga RB, Meier-Kriesche HU; PROMISE Investigators: The PROMISE study: A phase 2b multicenter study of voclosporin
(ISA247) versus tacrolimus in de novo kidney transplantation. Am J Transplant 11: 2675–2684, 2011
8. Mandrik O, Fotheringham J, Ren S, Tice JA, Chapman RH, Stevenson MD, Pearson SD, Herron-Smith S, Agboola F, Thokala P: The cost-effectiveness of belimumab and voclosporin
for patients with lupus nephritis in the United States. Clin J Am Soc Nephrol 17: 385–394, 2022
9. Fanouriakis A, Kostopoulou M, Cheema K, Anders HJ, Aringer M, Bajema I, Boletis J, Frangou E, Houssiau FA, Hollis J, Karras A, Marchiori F, Marks SD, Moroni G, Mosca M, Parodis I, Praga M, Schneider M, Smolen JS, Tesar V, Trachana M, van Vollenhoven RF, Voskuyl AE, Teng YKO, van Leew B, Bertsias G, Jayne D, Boumpas DT: 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis 79: 713–723, 2020
10. Mok CC, Ho LY, Ying SKY, Leung MC, To CH, Ng WL: Long-term outcome of a randomised controlled trial comparing tacrolimus with mycophenolate mofetil as induction therapy for active lupus nephritis. Ann Rheum Dis 79: 1070–1076, 2020
11. Verberne WR, Das-Gupta Z, Allegretti AS, Bart HAJ, van Biesen W, García-García G, Gibbons E, Parra E, Hemmelder MH, Jager KJ, Ketteler M, Roberts C, Al Rohani M, Salt MJ, Stopper A, Terkivatan T, Tuttle KR, Yang CW, Wheeler DC, Bos WJW: Development of an international standard set of value-based outcome measures for patients with chronic kidney disease: A report of the International Consortium for Health Outcomes Measurement (ICHOM) CKD Working Group. Am J Kidney Dis 73: 372–384, 2019