Recommendations Published online in Annals of the Rheumatic Diseases Propose That Physicians Consider Earlier Intervention with Therapies Including LUPKYNIS® (voclosporin) as a New LN Treatment Paradigm
Aurinia Pharmaceuticals Inc. (NASDAQ: AUPH) (Aurinia or the Company) – Aurinia welcomes the 2023 updated recommendations from The European Alliance of Associations for Rheumatology (EULAR) for the management of systemic lupus erythematosus (SLE) based on emerging new evidence, including a new treatment paradigm for lupus nephritis (LN).
The new recommendations suggest that in addition to traditional anchor drugs, therapies including LUPKYNIS® (voclosporin) should be considered for any active class of lupus nephritis. Combination therapy can be used first-line (i.e., in treatment-naïve patients). If combination therapy is not used first-line, then add-on treatment with therapies, including voclosporin, should be considered if adequate response is not achieved within three to six months or in patients who experience disease flare. In most cases, patients should continue the therapy they were initially treated with for at least three years following treatment response, including voclosporin, as the guidelines cited the stable estimated glomerular filtration rate (eGFR, an important measurement of kidney function) observed with voclosporin over 3 years.
Importantly, the recommendations suggest that 5 mg/day should serve as the highest acceptable maintenance dose of steroids in SLE or LN (previous recommendations suggested achieving <=7.5 mg/day by three to six months of LN treatment). This recommendation was based on the significantly lower glucocorticoid doses used in recent randomized clinical trials, including the AURORA clinical studies of voclosporin.
The recommendations highlight the profound repercussions of delaying diagnosis, thus recommending vigilant monitoring for new organ damage, especially lupus nephritis, at every visit (at least yearly).
“Aurinia appreciates EULAR’s thoughtful consideration for improving the management of lupus nephritis with recommendations that reflect therapeutic advancements in this underserved patient population. The updated recommendations reflect the growing recognition of the clinical value that a therapy like voclosporin provides to people living with lupus nephritis. These recommendations provide clear guidance for the importance of initial therapy with voclosporin plus standard of care to preserve kidney health in patients with active LN without reliance on chronic high-dose glucocorticoids,” said Dr. Greg Keenan, Chief Medical Officer of Aurinia.
For the 2023 updated recommendations, a task force of global SLE experts, including 35 rheumatologists and five nephrologists, were assembled to conduct a systematic literature review. The task force agreed on five overarching principles and condensed recommendations to a total of 13. The task force placed significant emphasis on a shift in LN treatment strategies, advocating for the earlier and more frequent use of immunosuppressants with the aim of reducing patient reliance on steroids.
According to the recommendations, the pace of new developments in SLE has accelerated over the last five years and the field of LN has also witnessed advancements for the option of earlier use of combination therapies, with the goal of reducing the reliance on steroids. These advancements have encouraged the consideration of a paradigm shift in the treatment of LN, moving from the traditional induction-maintenance regimen to the early use of combination therapies. These observations created the impetus for an update of the recommendations, to provide guidance on an evolving landscape and capitalize on the experience gained thus far.
The recommendations were based on the understanding that LN is a severe disease by nature and is associated with worse rates of mortality and morbidity. LN causes nephron loss over time that can lead to chronic kidney disease and end-stage renal disease. Given the consistently low rates of complete response at one to two years of treatment observed in the control arms of LN clinical trials (i.e., 20-30%), the option for additional therapy upfront should be considered. Since recently approved therapies are indicated for all adult patients with active LN, it was deemed reasonable that they be considered as a first-line option.
The recommendations noted that the final decision for the treatment of active LN should depend on the individual patient characteristics, such as histological class, baseline eGFR, proteinuria, presence of extrarenal manifestations, comorbidities, risk for toxicity, access to drugs and cost issues, and patient preferences.
About the AURORA Clinical Program
In AURORA 1 (NCT03021499), a 12-month, phase 3, double-blind, randomized-controlled pivotal study, the efficacy and safety of voclosporin was compared with a control group in achieving complete renal response (CRR) in patients with LN. AURORA 1 demonstrated the clinical superiority of voclosporin with mycophenolate mofetil (MMF) and low-dose glucocorticoids compared to MMF and low-dose glucocorticoids alone. Significantly more patients in the voclosporin group achieved a CRR at 52 weeks of treatment and did so significantly faster than those in the control group. The safety profile in AURORA 1 was comparable between treatment groups, in line with previous studies; no new safety concerns were observed. Results from the completed Phase 3 randomized, double-blind, placebo-controlled, multicenter AURORA 1 study were published in The Lancet.
AURORA 2 (NCT03597464) is a Phase 3, double-blind, extension study to assess the long-term safety and tolerability of voclosporin, in addition to MMF and low-dose glucocorticoids, for the treatment of patients with active LN. Patients who completed 12 months of treatment in the Phase 3 AURORA 1 study were eligible to enroll in the AURORA 2 extension study with the same randomized treatment of voclosporin or placebo, in combination with MMF (target dose of 2 g/day) and low-dose glucocorticoids (target dose of ≤2.5 mg/day), for an additional 24 months.
A total of 216 LN patients continued into the extension study, with 116 patients in the voclosporin group and 100 patients in the control group; 90 and 78 patients, respectively, received 36 months of total treatment at the completion of the study. Study drug dose changes decreased over time.
Voclosporin was well tolerated with no new or worsening safety signals in the extension study. Clinical efficacy over three years of treatment was maintained, as observed by maintenance of urine protein creatinine ratio (UPCR) reductions, sustained CRR and preserved kidney function, suggesting a positive benefit-risk profile for voclosporin in LN patients. These results were achieved with most patients in both groups (>75%) maintaining glucocorticoid tapering throughout the study and receiving doses of ≤2.5 mg/day at the end of the extension study.
AURORA 2 results were published in Arthritis & Rheumatology, the official peer-reviewed journal of the American College of Rheumatology.
About Lupus Nephritis
Lupus Nephritis is a serious manifestation of systemic lupus erythematosus (SLE), a chronic and complex autoimmune disease. About 200,000-300,000 people live with SLE in the U.S., and about one-third of these people are diagnosed with lupus nephritis at the time of their SLE diagnosis. About 50 percent of all people with SLE may develop lupus nephritis. If poorly controlled, lupus nephritis can lead to permanent and irreversible tissue damage within the kidney. Black and Asian people with SLE are four times more likely to develop lupus nephritis and Hispanic people are approximately twice as likely to develop the disease, compared to White people with SLE. Black and Hispanic people with SLE also tend to develop lupus nephritis earlier and have worse outcomes, compared to White people with SLE.
About LUPKYNIS®
LUPKYNIS® is the first U.S. Food and Drug Administration and European Commission-approved oral medicine for the treatment of adult patients with active LN. LUPKYNIS is a novel, structurally modified calcineurin inhibitor (CNI) with a dual mechanism of action, acting as an immunosuppressant through inhibition of T-cell activation and cytokine production and promoting podocyte stability in the kidney. The recommended starting dose of LUPKYNIS is three capsules twice daily with no requirement for serum drug monitoring. Dose modifications can be made based on Aurinia’s proprietary personalized eGFR-based dosing protocol. Boxed Warning, warnings, and precautions for LUPKYNIS are consistent with those of other CNI-immunosuppressive treatments.
About Aurinia
Aurinia Pharmaceuticals is a fully integrated biopharmaceutical company focused on delivering therapies to treat targeted patient populations with high unmet medical needs that are impacted by autoimmune, kidney and rare diseases. In January 2021, the Company introduced LUPKYNIS® (voclosporin), the first FDA-approved oral therapy dedicated to the treatment of adult patients with active lupus nephritis. The Company’s head office is in Edmonton, Alberta, its U.S. commercial office is in Rockville, Maryland. The Company focuses its development efforts globally.
INDICATION AND IMPORTANT SAFETY INFORMATION
INDICATIONS
LUPKYNIS® is indicated in combination with a background immunosuppressive therapy regimen for the treatment of adult patients with active LN. Limitations of Use: Safety and efficacy of LUPKYNIS have not been established in combination with cyclophosphamide. Use of LUPKYNIS is not recommended in this situation.
IMPORTANT SAFETY INFORMATION
BOXED WARNINGS: MALIGNANCIES AND SERIOUS INFECTIONS
Increased risk for developing malignancies and serious infections with LUPKYNIS or other immunosuppressants that may lead to hospitalization or death.
CONTRAINDICATIONS
LUPKYNIS is contraindicated in patients taking strong CYP3A4 inhibitors because of the increased risk of acute and/or chronic nephrotoxicity, and in patients who have had a serious/severe hypersensitivity reaction to LUPKYNIS or its excipients.
WARNINGS AND PRECAUTIONS
Lymphoma and Other Malignancies: Immunosuppressants, including LUPKYNIS, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to increasing doses and duration of immunosuppression rather than to the use of any specific agent.
Serious Infections: Immunosuppressants, including LUPKYNIS, increase the risk of developing bacterial, viral, fungal, and protozoal infections (including opportunistic infections), which may lead to serious, including fatal, outcomes.
Nephrotoxicity: LUPKYNIS, like other CNIs, may cause acute and/or chronic nephrotoxicity. The risk is increased when CNIs are concomitantly administered with drugs associated with nephrotoxicity.
Hypertension: Hypertension is a common adverse reaction of LUPKYNIS therapy and may require antihypertensive therapy.
Neurotoxicity: LUPKYNIS, like other CNIs, may cause a spectrum of neurotoxicities: severe include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremor, paresthesia, headache, and changes in mental status and/or motor and sensory functions.
Hyperkalemia: Hyperkalemia, which may be serious and require treatment, has been reported with CNIs, including LUPKYNIS. Concomitant use of agents associated with hyperkalemia may increase the risk for hyperkalemia.
QTc Prolongation: LUPKYNIS prolongs the QTc interval in a dose-dependent manner when dosed higher than the recommended lupus nephritis therapeutic dose. The use of LUPKYNIS in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongation.
Immunizations: Avoid the use of live attenuated vaccines during treatment with LUPKYNIS. Inactivated vaccines noted to be safe for administration may not be sufficiently immunogenic during treatment with LUPKYNIS.
Pure Red Cell Aplasia: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with another CNI immunosuppressant. If PRCA is diagnosed, consider discontinuation of LUPKYNIS.
Drug-Drug Interactions: Avoid co-administration of LUPKYNIS and strong CYP3A4 inhibitors or with strong or moderate CYP3A4 inducers. Reduce LUPKYNIS dosage when co-administered with moderate CYP3A4 inhibitors. Reduce dosage of certain P-gp substrates with narrow therapeutic windows when co-administered.
ADVERSE REACTIONS
The most common adverse reactions (>3%) were glomerular filtration rate decreased, hypertension, diarrhea, headache, anemia, cough, urinary tract infection, abdominal pain upper, dyspepsia, alopecia, renal impairment, abdominal pain, mouth ulceration, fatigue, tremor, acute kidney injury, and decreased appetite.
SPECIFIC POPULATIONS
Pregnancy/Lactation: May cause fetal harm. Advise not to breastfeed.
Renal Impairment: Not recommended in patients with baseline eGFR ≤45 mL/min/1.73 m2 unless benefit exceeds risk. Severe renal impairment: Reduce LUPKYNIS dose.
Mild and Moderate Hepatic Impairment: Reduce LUPKYNIS dose. Severe hepatic impairment: Avoid LUPKYNIS use.
Please see Prescribing Information, including Boxed Warning, and Medication Guide for LUPKYNIS.
References
Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Annals of the Rheumatic Diseases. Published Online First: 12 October 2023. doi: 10.1136/ard-2023-224762.
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Aurinia welcomes the 2023 updated recommendations from EULAR for the management of systemic lupus erythematosus based on emerging new evidence, including a new treatment paradigm for lupus nephritis.
Contacts
Media Inquiries:
Andrea Christopher,
Corporate Communications Director, Aurinia
achristopher@auriniapharma.com
Investor Inquiries:
ir@auriniapharma.com
