Biopharmaceutical Report I
Aurinia Pharmaceutical’s (NASDAQ:AUPH) voclosporin has potential long-term nephrotoxicity concerns that could preclude widespread first-line use in lupus nephritis (LN) until extended safety data becomes available, most experts said. The mode of action, though, means there is first-line treatment potential for patients with elevated proteinuria risk, which typically occurs in more severe LN, some said.
However, a Phase III investigator countered this view, noting the mechanism of action (MOA) means there will be no significant nephrotoxicity concerns. Voclosporin will most likely serve as a second-line treatment for patients unsuccessful on current standards of care (SOCs), this investigator added.
After demonstrating statistically significant improvement in the primary endpoint of complete renal response over placebo in the 52-week Phase III AURORA trial (NCT03021499), voclosporin has a high likelihood of becoming the first FDA-approved LN treatment, experts agreed. The drug’s regulatory chances are bolstered by the study’s heavy taper of corticosteroids, which carry a multitude of side effects in high doses. In addition, the study found no apparent added toxicity over SOC.
Nevertheless, nephrologists are typically more concerned with sustained renal remission and nephrotoxicity concerns over at least several years, rather than the primary endpoint, most experts said. As a result, nephrologists could be hesitant to prescribe voclosporin, a calcineurin inhibitor (CNI), first-line to patients with an elevated risk of nephrotoxicity until more extended safety data and additional pharmacokinetic analyses of kidney biopsies of treated patients become available, they added.
The CNI class has been prone to nephrotoxicity concerns in the kidney transplant indication. As a result, most experts said they are unclear whether voclosporin, which offers a more stable metabolic profile than the first generation of CNIs, poses similar concerns.
The FDA granted voclosporin a PDUFA date of 22 January 2021, according to a 21 July company press release. According to a one analyst report, voclosporin in LN has expected peak sales of USD 2.13bn in 2034. Aurinia did not respond to a request for comment. Aurinia has a market cap of USD 1.96bn.
Lack of extended safety data hampers placement
Though there are no FDA-approved treatments for LN, mycophenolate mofetil (MMF) or cyclophosphamide are widely considered to be the two SOC first-line treatment options for LN alongside corticosteroid use. In AURORA, patients on voclosporin and MMF together had greater complete renal response and no apparent added toxicity over monotherapy MMF, which experts said will most likely mean FDA approval.
Though the rate of renal remission and safety profile demonstrated in AURORA are encouraging from a regulatory and clinical perspective, nephrologists are typically most concerned with sustained renal remission and nephrotoxicity concerns over at least two to three years, agreed a LN researcher and AURORA investigator Dr Brad Rovin, nephrologist, Wexner Medical Center, University of Ohio. As a CNI, voclosporin could cause nephrotoxicity or kidney fibrosis, which is more likely to occur at least two years after diagnosis, they said. Similar concerns are present in first-generation CNIs and in their use for kidney transplant patients.
As a result, the lack of extended safety data will likely preclude many nephrologists from considering voclosporin as a first-line therapy until this data becomes available, agreed Rovin, the LN researcher and Dr Joan Merrill, professor of medicine, University of Oklahoma Health Sciences Center, Oklahoma City. As a result, both Rovin and the LN researcher said it was unlikely any LN patients with pre-existing impaired kidney function or more susceptible to profibrotic risk would be prescribed voclosporin, particularly as a first-line therapy.
However, voclosporin’s more stable metabolic profile compared to the previous class of CNIs likely means nephrotoxicity will not be a significant concern, AURORA principal investigator Dr Mary Anne Dooley said. As a result, voclosporin could be an effective later-line treatment option for patients who are not successful on cyclophosphamide or monotherapy MMF initially, said Dooley, rheumatology specialist, Raleigh Neurology Associates, North Carolina.
When compared to cyclosporine, a CNI sometimes used as a later-line LN treatment, voclosporin binds more tightly to the site of activity, uses smaller doses, and does not require constant dose adjustments. These all will likely significantly reduce nephrotoxicity concerns, Dooley added.
Still, the LN researcher said initial signs of nephrotoxicity are often delayed and subclinical, meaning they may not appear during the study’s one-year time period. Additionally, because the voclosporin dosage is fixed and does not require consistent metabolic data monitoring to adjust doses, initial clinical signs of nephrotoxicity could be harder to detect, he added.
Rovin agreed with the LN researcher, adding that his lab and several others were histologically examining tissues from kidney biopsies done in some AURORA patients before and after the study in both treatment groups. Additionally, a three-year extension safety study (NCT03597464) is underway for AURORA patients, though neither these results nor data from the biopsy examinations are likely to be available prior to voclosporin’s PDUFA date, he said.
MOA beneficial for high-risk proteinuria patients
As a CNI, voclosporin counteracts LN by targeting T cells, which in turn helps stabilize podocytes and reduces proteinuria and inflammation, Rovin and the LN researcher said. As a result, LN patients with high levels of proteinuria could gain a more pronounced benefit from using voclosporin, making them candidates for-first line use of voclosporin and MMF, they said.
Still, most nephrologists would only prescribe this treatment to patients with high levels of proteinuria who are not at a high risk of nephrotoxicity and do not have significant pre-existing kidney damage, they said. Though the heterogeneity of the LN population makes it difficult to predict the number of patients who could benefit from first-line voclosporin use, the LN researcher predicted 10–40% of the patient population.
Positive results in AURORA are a strong indicator of voclosporin’s ability to counteract proteinuria, as urine protein/creatinine ratio (UPCR) was used in part to define complete renal response, Rovin and the LN researcher said. In AURORA, the study’s primary endpoint of complete renal remission was defined as UPCR of ≤0.5 mg/mg, estimated glomerular filtration rate (eGFR) ≥60 mL/min, or no decrease from baseline in eGFR of > 20% (Arriens, et al. Annals of the Rheumatic Diseases 2020; 79: pp. 172-173).
Strong efficacy, safety in trial support approval likelihood
Because AURORA demonstrated efficacy on top of MMF without any apparent added toxicity, FDA approval is likely, said Rovin. In the 367-patient AURORA study, 40.8% of patients receiving 23.7mg of voclosporin twice a day with 2g of MMF daily had a complete renal response, compared to 22.5% of patients taking only MMF (p<0.001), according to the aforementioned paper.
While both immunosuppressors are known to cause side effects, including infection, the lack of increased toxicity in combining voclosporin with the most commonly accepted SOC will be important for regulators, agreed Dr George Tsokos, immunology faculty member, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Severe adverse events (SAEs) were largely consistent in both groups, occurring in 20.8% of patients in the treatment arm, including one death, and 21.3% of patients in the placebo arm, including five deaths. The most commonly occurring SAE was infection, which occurred in 10.1% of voclosporin patients and 11.2% of placebo patients, and no significant changes in eGFR, blood pressure, lipids, or glucose in the voclosporin arm, according to the paper.
Still, most nephrologists would only prescribe this treatment to patients with high levels of proteinuria who are not at a high risk of nephrotoxicity
Because of the steroid taper, voclosporin demonstrated efficacy against a low placebo response, increasing confidence in the voclosporin’s ability to immediately help patients during the study’s one-year timeframe from a regulatory standpoint, said Merrill.
Further, in line with a growing movement in nephrology to lower steroid use in light of their many side effects, which include increased blood pressure and bone damage, the steroid taper adds to voclosporin’s attractiveness from a clinical standpoint, agreed Merrill and AURORA investigator Dr Cristina Arriens, clinical assistant member, Arthritis & Clinical Immunology Research Program, University of Oklahoma Health Sciences Center. Additionally, despite being only one small molecular change from cyclosporine, voclosporin does not cause hypertension and does not require constant metabolic data monitoring and dose adjusting, Merrill and Rovin said.
In the 265-patient Phase II AURA-LV (NCT02141672) study, patients taking the lower-dose of voclosporin, which was used in the AURORA trial, had complete renal response in 32.6% of patients compared to 19.3% of patients in the placebo group after 24 weeks. Like AURORA, patients in all AURA-LV trial arms underwent background MMF therapy and an aggressive steroid taper (Rovin, et al. Kidney International 2019; 95(1): pp. 219-231). Experts said the strong efficacy in the Phase II trial further bolsters voclosporin’s regulatory chances.
William Newton is a healthcare reporter for GlobalData focusing on central nervous system diseases and ophthalmology. Previously, he worked at the healthcare information firm Close Concerns, where he covered breaking news in diabetes therapeutics and technology for the company’s industry-facing publication, and at the digital health startup Fitscript, where he assisted in researching digital health and lifestyle intervention approaches to treating diabetes. He graduated Williams College with a BA in Economics and Spanish and worked as a News Editor, Executive Editor, and Managing Editor of the Williams Record.