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The prices of two new drugs that have been approved by the US Food and Drug Administration (FDA) for the treatment of lupus nephritis are in “reasonable alignment” with the drugs’ estimated benefits for patients with the disease, the Institute for Clinical and Economic Review (ICER) has determined.

“Both belimumab [Benlysta] and voclosporin [Lupkynis] are important new treatment options,” Steven Pearson, MD, president of the ICER, observes in a summary of the report’s findings.

“Despite remaining uncertainty about both treatments’ longer-term outcomes, their estimated net prices appear to be aligned with their anticipated clinical benefits…. [F]or patients and clinicians to have responsibly priced options specifically indicated for lupus nephritis is a win for patients and the entire health system, abilify and urinary retention ” Pearson adds.

The estimated annual price of belimumab is approximately $43,000 per patient; the estimated annual price for voclosporin is approximately $92,000 per patient.

The incremental cost-effectiveness ratio for belimumab is approximately $90,0000 per quality-adjusted life year (QALY); the corresponding value for voclosporin is higher, at approximately $149,000 per QALY, the ICER authors note.

The report was published by the ICER this month.

Large Unmet Need for Treatment of Lupus Nephritis

In their report, the ICER reviewed belimumab, a parenteral B-lymphocyte inhibitor, as well as voclosporin, an oral calcineurin inhibitor, as initial treatment of patients with lupus nephritis. Lupus nephritis is a serious complication of systemic lupus erythematosus (SLE).

Belimumab was first approved for the treatment of lupus in adults in the United States in March 2011. In April 2019, it was approved for use for the same indication for children aged 5 years and older. The FDA expanded the indication in December 2020 to include adults with active lupus nephritis who are receiving standard therapy.

Voclosporin was approved for the treatment of lupus nephritis in January 2021.

In the pivotal trials for the two agents, each drug was added to standard induction therapy for lupus nephritis, which consisted of high-dose corticosteroids combined with either mycophenolate mofetil (MMF) or cyclophosphamide.

Compared with standard therapy alone, belimumab increased the complete renal response (CRR) and the primary efficacy renal response at 2 years. With voclosporin, complete response (CR) was nearly doubled, and there was marked increased in partial response at 1 year compared with standard therapy alone.

Table. Complete Response at 1 and 2 Years

 One yearTwo years
Belimumab CRR32.5%30%
Placebo CRR25.5%19.7%
Voclosporin CR42.3%
Placebo CR23.3%

 

Neither drug appeared to increase the adverse event rate or the rate of discontinuations compared with standard therapy, although the FDA did add a black box warning regarding the possible risk for serious infections and malignancies with voclosporin use.

“There is a very large unmet need for the treatment of lupus nephritis,” Chris Phillips, MD, Paducah Rheumatology, Paducah, Kentucky, told Medscape Medical News.

“A very large percentage of patients who do not achieve complete remission on traditional treatments have side effects or contraindications to these treatments, so we’ve needed new ones for sure,” he stressed.

The ICER authors make it clear that there is considerable uncertainty as to how short-term assessment of each of the two drugs’ performance might translate into meaningful long-term outcomes for patients, especially given that SLE is a lifelong illness.

On the other hand, “there are a lot of attributes for both of these new drugs that suggest there is potential for kidney benefit over time,” Brad Rovin, MD, professor of medicine and pathology, the Ohio State University Wexner Medical Center, Columbus, Ohio, told Medscape Medical News.

For example, data from the BLISS-LN study, reported by Rovin during a meeting last year, suggest that belimumab reduces the flare rate and appears to stabilize kidney function over time, compared to standard therapy alone.

“BLISS-LN was 2 years long, so it gave us an opportunity to look at kidney function over a longer period of time than most of our prior trials in lupus nephritis,” he explained.

“The stabilization of kidney function is important, because it suggests that belimumab has a kidney protective effect, while a decrease in lupus nephritis flares is also important, because each time the disease flares, you can accumulate chronic tissue damage, which can eventually cause end-stage renal disease [ESRD],” he explained.

Rovin also pointed out that the BLISS-LN trial results indicate that patients who achieve a urine protein level <700 mg/d after the first year of treatment do very well on long-term follow-up — another hint that belimumab may have long-term benefits for kidney function.

Voclosporin is a calcineurin inhibitor, which are protective of podocytes. “When you start to lose too many podocytes, the kidney can again progress onto ESRD, so this is again an extra benefit of the calcineurin inhibitors in the context of kidney disease that affects the glomeruli,” he noted.

“So both of these drugs have these interesting attributes that go beyond, or at least are maybe tied to, their immunosuppressive actions, but they do offer some kidney protective effects,” he reaffirmed.

Black Patients Underrepresented in Trials

The ICER authors voice concern over the fact that individuals most at risk for SLE — mostly Black patients, but also patients of other racial groups ― were underrepresented in clinical trials that evaluated both agents.

“We cannot stress enough that the results are highly uncertain due to the small numbers of Black patients in the available clinical trials and the lack of data on differences among subgroups in long-term outcomes,” they state.

This is not an academic issue, Phillips pointed out. Responses to both MMF and cyclophosphamide differ among persons of different races, “so it’s not unreasonable to consider that there could be racial differences in treatment responses to both drugs, and these definitely need to be investigated,” he stressed.

This is not an academic issue, Phillips pointed out, because there are racial disparities in how patients respond to both MMF and cyclophosphamide — “so it’s not unreasonable to consider that there could be racial differences in treatment responses to both drugs, and these definitely need to be investigated,” he stressed.

The ICER authors appear to agree. They urge the manufacturers of the two new agents to expand their research to include adequate representation of lupus nephritis patients from Black and other non-White communities.

However, it is somewhat reassuring that the pivotal voclosporin trial enrolled about 30% of Hispanic patients and that about 17% of participants in the BLISS-LN trial were also Hispanic, Rovin pointed out.

This is important, because Hispanic patients can have very aggressive disease, as can Black patients, he noted. There is some evidence to suggest both drugs are effective in aggressive disease.

The ICER also pointed out that the length of time that both drugs can be used prior to tapering of treatment, after which patients receive standard maintenance therapy alone, has yet to be established.

This is important, Rovin and Phillips agree, because calcineurin inhibitors are known to be nephrotoxic, and both drugs are immunosuppressive. At least with respect to voclosporin, there is some cause of concern regarding prolonged use of the drug for patients with kidney disease.

“We don’t want patients to be on an immunosuppressive drug forever if they don’t need to be,” Rovin emphasized.

“But we are seeing really long-term remission in the setting of other inflammatory diseases, like vasculitis with rituximab. So there is hope that we can achieve the same thing in lupus. If we use drugs that target T cells in the immune system, like voclosporin, or B cells, like belimumab, maybe we can ‘reset’ the immune system and get rid of potentially autoreactive cells that could allow long-lasting disease remission, which is an unanswered question but an intriguing possibility,” he concluded.

Rovin has served as a consultant for GlaxoSmithKline. Phillips has disclosed no relevant financial relaitonships.

ICER. Lupus Nephritis. Published online April 2021. Full text

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