A two-part randomized, double-blind, placebo-controlled multicenter dose ranging and confirmatory study to assess the safety and efficacy of VAY736 in autoimmune hepatitis patients with incomplete response to or intolerance of standard therapy (AMBER)

Autoimmune hepatitis (AIH) is a chronic autoimmune disease of unknown etiology
characterized by hypergammaglobulinemia, aminotransferase elevations,
histological changes and specific autoantibodies. AIH is a rare (approximately
20 prevalent cases per 100,000, Lohse 2015) but potentially devastating disease
burdened by significant morbidity and potentially lethal outcomes (untreated
mortality at 5 years is 75%.
The treatment goal in AIH is suppression of liver inflammation, thereby
preventing progression to cirrhosis and liver failure. Serum transaminases are
utilized as surrogate markers for severity of inflammation.
Guidelines for treatment include use of corticosteroids, combination of
corticosteroids with azathioprine or azathioprine alone, and use of
mycophenolate mofetil (MMF) as a second line therapy. Non-adherence to
treatment because of intolerance is a wellrecognized issue.
Not all patients respond completely to conventional treatment with
predniso(lo)ne and azathioprine, and others may develop treatment-related side
effects, requiring drug withdrawal. Therefore, new and better tolerated
targeted treatments are needed to better control disease activity in these AIH
patients.

Part 1 - To determine effects of different ianalumab doses on ALT normalization
at Week 24 in patients with AIH who are incomplete responders or intolerant to
standard therapy.

Part 2 - To confirm the efficacy (biochemical and histological remission) and
safety of the dose determined from Part 1 in this population.

Part 1 is a randomized, placebo-controlled, double-blind, multicenter, parallel
group study in approximately 80 adult patients with Type 1 autoimmune hepatitis.
Patients will be randomized into four study arms, treated as follows:
Arm 1: VAY736 5 mg s.c. every four weeks (q4w);
Arm 2: VAY736 50 mg s.c. q4w;
Arm 3: VAY736 300 mg s.c. q4w;
Arm 4: Placebo s.c. q4w
while continuing to receive corticosteroids and/or azathioprine.

At the end of 24 weeks of treatment, the primary analysis and dose-response
modeling will be performed to determine the dose to be evaluated in Part 2.
Patients in the placebo arm, who remain on treatment to Week 28, will be
reassigned to VAY736 150 mg s.c. q4w treatment at the Week 28 visit. Patients
from the VAY736 arms will continue on the assigned dose of active drug every 4
weeks, with the last dose being administered at Week 48.

Part 2 is a randomized, placebo-controlled, double-blind multicenter, parallel
group study in approximately 280 AIH patients to confirm the efficacy and
safety of VAY736 at the selected dose from Part 1, as outlined in Figure 3-2.
The Part 2 population differs from Part 1 in the inclusion of (i) any type of
AIH patient, and (ii) AIH pati ents from 16 to 75 years of age. Part 2 Patients
will be randomized in a 5:2 ratio to VAY736 (at the dose determined from dose -
response modeling in Part 1) or placebo.
Part 2 will start only after an appropriate dose of VAY736 is identified from
Part 1 of the study and incorporating any changes to the study design
necessitated by the results of Part 1 and agreed to by Regulatory Authorities.
For Part 2 a different group of patients will be enrolled (i.e. no patients
from Part 1 will participate in Part 2).

VAY736 or placebo

- Minimum of 22 (part 2) and 23 (part 1) site visits with duration of 1 to 4
hours. Duration of study is minimum 76 weeks, depending on recovery of B-cells.
- Day 1 visit lasts around 8 hours so the physician can monitor patient after
first injection of study medication. This is also the case at Week 28 visit in
Part 1 of study.
- Full physical exam: Prescreening (in case treated with MMF/MPA), Screening,
Baseline, Week 24 and 52
- Short physical exam: All other visits.
- Liver biopsy in part 1: Screening and week 24
- Liver biopsy in part 2: Screening and week 52
- Subcutaneous injections: starting at baseline every 4 weeks two injections.
Before first study medication injection intraveneous prednisolone will be
administered.
- Blood samples: each visit.
- Completion of PRO: 4 times
- Heart rate, blood pressure and weight: almost each visits.
- Urine dipstick: almost each visits.
- Fibroscan: 3 times.
- ECG: 4 times.
- Optional: 1 extra blood sample for pharmacogenetics

Risks of VAY736 injections:
- First-dose mild-to-moderate injection reactions were observed in the phase
1/2a studies in a substantial subset of patients.
- An increase in mild-to-moderate upper respiratory tract infections compared
to placebo has been associated with use of VAY736.
- Neutropenia as result of depletion of B-cells. This has not yet been observed
with VAY736.
- Although no allergic reactions following i.v. or s.c. administration were
observed so far, the potential to develop an allergic reaction in a predisposed
subject cannot entirely be ruled out.
- Liver biopsy is associated with some discomfort like mild to moderate pain
occurring in the upper abdomen or the right shoulder.