Aurinia Pharmaceuticals’ voclosporin (Orelvo) is a novel calcineurin inhibitor, structurally related to cyclosporine but designed to offer increased potency, a more predictable PK/PD relationship—thus allowing flat dosing—and improved safety. Until now, no other emerging therapy was able to achieve what voclosporin accomplished in its development program—the drug met the primary induction and the secondary maintenance endpoints assessing complete renal remission in a global clinical trial in patients with active lupus nephritis. Lupus nephritis is a serious chronic disease of the immune system, currently treated primarily with older nonspecific and toxic off-label immunosuppressants and oral corticosteroids. No agent is approved for lupus nephritis in the United States or Europe, and the level of unmet need in this area is high.1,2

 

 

The global Phase IIb trial of voclosporin in lupus nephritis (AURA-LV; clinicaltrials.gov, NCT02141672) was designed to test the performance of two doses of voclosporin (23.7 mg and 39.5 mg) administered as an add-on treatment to the current lupus nephritis standard of care, an off-label immunosuppressant mycophenolate mofetil (used in combination with oral corticosteroids). In this trial, Aurinia successfully addressed possible reasons for some previous lupus nephritis drug failures by incorporating steroid sparing in the trial design—thus making sure that use of high doses of corticosteroids would not mask the effect of voclosporin—and by sufficiently powering the trial statistically to detect the difference in efficacy between voclosporin and the control group. As a result, the primary endpoint of the trial—the percentage of patients who achieve complete renal remission at 24 weeks—was successfully met; 32.6% of patients in the low-dose voclosporin arm attained complete renal remission, compared with 27.3% in the high-dose arm and 19.3% in the control arm.3 Even more impressively, voclosporin also met a secondary maintenance end point measuring the percentage number of patients who achieved complete renal remission at 48 weeks—with 49% of patients in the low-dose voclosporin arm, compared with 40% of patients in the high-dose arm and 24% of patients in the control group achieving this outcome.4 Importantly, the company also recently presented data on durability of remission with voclosporin, showing that 100% of patients in the low-dose arm who achieved complete remission at 24 weeks remained in complete remission at 48 weeks.5 Moreover, voclosporin helped patients to achieve quicker complete and partial remission when compared with patients treated with the standard of care alone.6

Although voclosporin demonstrated an impressive efficacy profile in its Phase IIb trial, the trial also raised concerns about its safety. Thirteen deaths were reported during the induction stage of the trial (at 24 weeks), with 11 deaths recorded in the low-dose voclosporin group alone. Although potentially alarming, all deaths were considered by the investigators to be unrelated to drug exposure, and rather, were attributed to the severity of the disease in these patients and the fact that many of these patients were recruited from developing countries and thus were at a higher risk of not receiving proper medical help in the case of a serious adverse event. Another piece of evidence that the deaths observed in the Phase IIb lupus nephritis trial may be unrelated to the study drug is the lack of safety signals from the agent’s earlier trials in other indications (e.g., plaque psoriasis and renal transplant rejection), in which more than 2000 patients were exposed to the drug and no unexpected serious adverse events were observed. It is also reassuring that the FDA—having reviewed the safety data available for voclosporin—is comfortable with a single Phase III trial of the agent in patients with lupus nephritis. The overall rate of serious adverse events was numerically higher in both voclosporin groups compared with the control group (28% in the low-dose arm, 25% in the high-dose arm and 19% in the control) in the AURA-LV trial.6 Because of the safety concerns raised during the Phase IIb trial, it will be very important for voclosporin to demonstrate a clean safety profile in the ongoing Phase III trial in order to allay physicians’ concerns regarding the drug’s safety profile.

There is still a long road ahead for voclosporin. The Phase III trial (AURORA; clinicaltrials.gov NCT03021499; N = 324) is ongoing with an estimated primary completion date in December 2019. In addition to confirming its auspicious Phase IIb efficacy in a larger Phase III trial, demonstrating an excellent safety profile will be a must-do for voclosporin, especially if the drug is to be used as a first-line induction agent (together with mycophenolate mofetil and oral corticosteroids) and/or if it is to be used for long-term maintenance of remission. Indeed, long-term remission is one of the major goals of lupus nephritis treatment; thus, more data on the durability of renal remission—preferably beyond 48 weeks—would be desirable. Also worth noting, patients with lupus have a notoriously low quality of life when compared with many other chronic conditions; thus, demonstrating improvement in quality of life outcomes could also be a boon for the drug. Because lupus is a multiorgan disease, rarely restricted to the kidneys alone, showing efficacy in nonrenal domain scores would also be appealing.

If successful in its Phase III program and approved by the regulatory agencies, the next challenge for the company will be to secure favorable reimbursement terms with payers in order to optimize voclosporin’s market potential. With many countries moving toward value-based healthcare, robust efficacy in inducing complete renal remission, coupled with evidence of voclosporin’s efficacy in corticosteroid dose reduction, improvement in quality of life, and decrease in the number of renal (and possibly nonrenal) flares—if evaluated—could all provide a much-needed market access tailwind and make the drug more competitive against other emerging agents and, ultimately, optimize its uptake. Its oral formulation will also be a clear advantage for voclosporin against other emerging agents in the late-stage pipeline. However, careful pricing considerations will be essential for a successful launch, as the drug will enter a market dominated by older, genericized agents, including two off-label agents from the same drug class. Availability of the cheaper calcineurin inhibitor tacrolimus will likely limit the pricing potential of voclosporin, especially in Japan, where tacrolimus is approved for the treatment of lupus nephritis and, as a result, is well entrenched in the treatment algorithm. In the United States and Europe, if the price is high for voclosporin, payers may restrict the drug to the second line of treatment (i.e., to patients who are refractory to mycophenolate mofetil/oral corticosteroids or IV cyclophosphamide/oral corticosteroids regimens), instead of opening its use to patients who are just starting induction treatment.

Because voclosporin is still several years away from possible approval, the competitive landscape at the time of its launch is uncertain. Although voclosporin’s Phase IIb data look strong, if another agent in the late-stage pipeline is successful in its Phase III trial,7 it could have several potential advantages over voclosporin. GSK’s Benlysta, for example, is a drug that is already approved for moderate to severe nonrenal lupus and is currently in a Phase III trial in patients with lupus nephritis. If launched for lupus nephritis, it would enjoy several years of physician familiarity, will offer a proven track record in suppressing disease activity in nonrenal lupus, will likely offer an outstanding safety record and—based on the design of its Phase III trial—will have renal efficacy data collected for a longer period of time (two years) compared with voclosporin (48 weeks). Competition from the current off-label agents is also likely in some markets. For example, the launch of rituximab biosimilar could provide physicians with a more-affordable option of a drug they are highly familiar with—despite its off-label status—that has a proven quick onset of action, has shown efficacy in the most difficult refractory patients, is conveniently administered (typically four IV infusions per year), and for which compliance can be closely monitored. An off-label older calcineurin inhibitor, tacrolimus, will also compete with voclosporin, particularly strongly in Japan—where it is approved for lupus nephritis—and among nephrologists in the United States and Europe, as these specialists are very familiar with tacrolimus in the context of renal transplant patients and have some experience prescribing the drug off-label for lupus nephritis.

Lupus is a difficult disease to target and although we don’t know who will win this game and capture the largest sales share of the lupus nephritis market, we do know that voclosporin is well poised to fight. All eyes are now on voclosporin.

Notes:

  1. Please see DRG’s white paper on lupus nephritis: https://decisionresourcesgroup.com/downloads/lupus-nephritis-pipeline-shakespearean-tragedy/
  2. Please see DRG’s Lupus Nephritis | Unmet Need | US/EU content: https://decisionresourcesgroup.com/report/313745-biopharma-systemic-lupus-erythematosus-unmet-need/
  3. Aurinia Pharmaceuticals, press release, August 15, 2016.
  4. Aurinia Pharmaceuticals, press release, March 1, 2017.
  5. Tumlin JA, et al. Steroid Sparing Efficacy of Voclosporin in Active Lupus Nephritis: Stable Kidney

Function and Blood Pressure without Electrolyte Complications at 48 Weeks. European Renal Association-European Dialysis and Transplant Association Congress, June 2017. Abstract.

  1. Dobronravov V, et al. 48 Week Complete Remission of Active Lupus Nephritis with Voclosporin. European League Against Rheumatism Congress, June 2017. Abstract.
  2. Please see DRG’s Systemic Lupus Erythematosus | Disease Landscape & Forecast | G7 content: https://decisionresourcesgroup.com/report/151966-biopharma-systemic-lupus-erythematosus-landscape/

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