A Randomized, Controlled, Double-blind Continuation Study Comparing the Long*term Safety and Efficacy of Orelvo (voclosporin) (23.7 mg Twice Daily) with Placebo in Subjects with Lupus Nephritis

The trial AUR-VCS-2016-02 proposed indication is active lupus nephritis (LN).
LN is the most common serious manifestation of systemic lupus erythematosus
(SLE). LN is divided into different classes according to the level of treatment
required, using a classification system for renal biopsy pathology originally
developed by the World Health Organization (WHO).
LN manifests as diverse patterns of immune complex-mediated renal disease
affecting glomerular, tubulointerstitial, and vascular compartments. It can
lead to permanent and irreversible tissue damage within the kidney, resulting
in end-stage renal disease (ESRD), and thus making LN a serious and potentially
life-threatening condition.
The current treatment paradigm for LN includes two goals, based on the severity
of disease. The first goal of treatment in subjects with active LN is intended
to bring the disease under control as quickly as possible to limit the
potential for extensive renal scarring or loss of life.
The second goal of treatment, after the patient successfully responds to
treatment, is to maintain remission by preventing renal flares and any
resulting deterioration in renal function. In this second phase of treatment,
lower doses of both corticosteroids and immunosuppressant are used.
However, the treatment of SLE remains unsatisfactory. No therapy has been
specifically approved for the treatment of LN in either the USA or Europe. In
many patients, the disease is inadequately controlled, resulting in the
progression to end-stage organ failure.
Current therapies, such as corticosteroids (CS) and other immunosuppressive
drugs, which must be administered at high doses, can also lead to serious side
effects.
In this trial, Investigational medicinal product Orelvo (voclosporin) is a
Calcineurin inhibitor (CNI). CNIs are a class of immunosuppressants which
reversibly inhibit immunocompetent lymphocytes, particularly T-lymphocytes in
the G0 and G1 phase of the cell cycle, and also reversibly inhibit the
production and release of lymphokines. CNIs mediates its suppressive effects by
binding to an ubiquitous intracellular protein cyclophilin. This complex, in
turn, inhibits the calcium- and calmodulin-dependent serine/threonine
phosphatase activity of the enzyme calcineurin. Calcineurin inhibition then
prevents the activation of various transcription factors necessary for the
induction of cytokine genes during T-cell activation, such as interleukin-2,
interleukin-4, tumor necrosis factor-*, granulocyte macrophage colony
stimulating factor, and interferon-*.
Orelvo (voclosporin) is a next-generation CNI developed for the treatment of
autoimmune diseases and for use in the prevention of organ graft rejection.
Voclosporin is structurally similar to cyclosporine A (CsA) except for a
modification of a functional group on the amino acid 1 residue of the molecule.
This alteration has changed the binding of voclosporin to calcineurin leading
to a 3- to 5-fold increase in potency when compared to CsA. This modification
has also shifted metabolism away from amino acid 1, the major site of
metabolism for CsA, thus altering the metabolic profile. This in turn has led
to faster elimination of metabolites resulting in lower measured metabolite
exposure as compared to CsA. The combination of increased potency and decreased
measured metabolite exposure, for voclosporin as compared to CsA, has led to
better pharmacokinetic (PK)/ pharmacodynamic predictability.
In the proposed AURORA 2 clinical study, subjects from the AURORA 1 study will
have the option to be consented and enter this protocol. Subjects will
continue to receive treatment as assigned by randomization in AURORA 1 (either
Orelvo or matching placebo) plus background therapy of MMF and/or oral
corticosteroids starting at the same dose as at the end of the AURORA 1 study.
After 12 months treatment in the AURORA 2 Continuation Study (ie., 24 months of
treatment in total), subjects with controlled urine protein creatinine ratio
(UPCR) taking the 23.7 BID dose, will be permitted to reduce the dose of Orelvo
to 15.8 mg BID, if considered appropriate and at the discretion of the
Investigator.

Primary Objective
* To assess the long-term safety and tolerability of Orelvo compared with
placebo for up to an additional 24 months following completion of treatment in
the AURORA 1 study in subjects with LN.
Secondary Objectives
* To assess the long-term efficacy of Orelvo compared with placebo for up to an
additional 24 months following completion of treatment in the AURORA 1 study in
subjects with LN.

Prospective, placebo-controlled, double-blind, parallel-group, 24-month
continuation study to the AURORA 1 study (AUR VCS 2016 01).

N/A

Because Orelvo is investigational, there is a risk of your lupus nephritis
getting worse or not changing if the drug does not work for you. Signs of lupus
activity will be closely monitored and patients will be managed according to
medical practice if this occurs.
Use of immunosuppressants in general can increase risk of developing a serious
infection which may lead to death, or may reduce body's ability to fight
serious infections. Use of immunosuppressants in general can increase your risk
of certain cancers.
Side effects reported by subjects and considered by the Study Doctor to be
related to Orelvo treatment are described below.
Common side effects, those reported by >10% of subjects receiving Orelvo
include high blood pressure and changes in kidney function. Less common side
effects (>5% of subjects) include upper respiratory infections and headache.
Other side effects reported by between 1 and 5% of subjects include sore
joints, nausea, abdominal pain/discomfort, weakness,
abnormal hair growth, and pain in your limbs extremities.
It is not known if you will experience any of these side effects. Since Orelvo
is investigational, there may be other risks that are currently unknown or
unforeseen. Any drug has the potential risk of an allergic reaction which, if
serious and not treated promptly, can become life-threatening.
The side effects and discomforts reported for MMF include, but are not limited
to mild to moderate stomach pain, nausea, vomiting, diarrhea, fever, anemia,
headache, infection (including tuberculosis, opportunistic infections and
Progressive Multifocal Leukoencephalopathy * a neurological disorder caused by
a virus that can lead to brain damage), fluid retention,
swelling, weakness, shakiness, pain, high blood pressure and a low amount of
white blood cells. The most frequent side effects of corticosteroids are
increased appetite, weight gain, high blood pressure, indigestion and
nervousness or restlessness. There may also be side effects and discomforts
from the treatments that are not yet known. In addition, when treated with
intravenous (IV) methylprednisolone, you might experience some discomfort that
includes bruising or infection at the IV site.
Some people have discomfort or pain when blood is collected. The insertion of
needles into the arm can cause pain, swelling, bruising and occasionally
fainting reactions; in rare occasions nerve damage can occur. Fainting
reactions are usually harmless, of short duration, and typically produce
feelings of weakness accompanied by sweating, slowing of the heart rate and an
abnormal decrease in blood pressure. There is also a risk of infection and
small blood clots in blood vessels.