Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: A proof‐of‐concept study

Abstract

; for the PURIFI Study Group * The interleukin (IL)-12 signaling cascade has been associated with primary biliary cholangitis (PBC). This multicenter, open-label, proof-of-concept study evaluated the anti-IL12/23 monoclonal antibody, ustekinumab (90 mg subcutaneous at weeks 0 and 4, then every 8 weeks through week 20), in adults with PBC and an inadequate response to ursodeoxycholic acid therapy (i.e., alkaline phosphatase [ALP] >1.673 upper limit of normal [ULN] after 6 months). ALP response was defined as a >40% decrease from baseline and ALP remission as ALP normalization (if baseline ALP 1.673-2.83 ULN) or <1.673 ULN (if baseline ALP >2.83 ULN). Changes in Enhanced Liver Fibrosis (ELF) scores and serum bile acids were also assessed. At baseline, patients had median disease duration of 3.2 years, median ELF score of 9.8, and highly elevated total bile acid concentration (median, 43.3 lmol/L); 13 of 20 (65%) patients had baseline ALP >33 ULN. Although steady-state serum ustekinumab concentrations were reached by week 12, no patient achieved ALP response or remission. Median percent ALP reduction from baseline to week 28 was 12.1%. ELF score decreased slightly from baseline to week 28 (median reduction: 0.173), and total serum bile acid concentrations decreased from baseline to week 28 (median reduction: 8.8 lmol/L). No serious infections or discontinuations resulting from adverse events were reported through week 28. One patient had a serious upper gastrointestinal hemorrhage considered unrelated to test agent by the investigator. Conclusion: Open-label ustekinumab therapy, though associated with a modest decrease in ALP after 28 weeks of therapy, did not otherwise appreciably change ALP and overt proof-of-concept was not established as per prespecified primary endpoint of proposed efficacy. No new ustekinumab safety signals were observed. (HEPATOLOGY 2016;64:189-199)

Genetics and epigenetics in the pathogenesis of primary biliary cholangitis

“…Although antibodies or drugs targeting the IL-12 pathway would seem to be effective, clinical trials using ustekinumab, a human monoclonal antibody directed against IL-12 and IL-23, failed to produce clinical effects in phase II trials [62]. One reason explaining this disconnection between GWAS and clinical testing results may be that clinicians typically encounter patients who have already become complicated with cholestasis; in fact, the immunological destruction of cholangiocytes occurs in the very early stages of PBC.…”

Geoepidemiology and changing mortality in primary biliary cholangitis

“…An enormous effort has been made to define the genetics and immuobiology of human autoimmue liver diseases in both human and mouse models [59][60][61][62][63][64][65][66][67][68][69][70][71][72]. Yet there remains an enormous gap between these investigative efforts and clinical translation.…”

Why Doesn’t Primary Biliary Cholangitis Respond to Immunosuppressive Medications?

“…Clinical efficacy was either very limited or absent in pilot trials with rituximab [46] and with ustekinumab [47], respectively. Rituximab is an anti-CD20 monoclonal antibody that produces selective B cell depletion and potentially could ameliorate autoimmune disease by decreasing autoantibody production and antigen presentation by B cells.…”

“…Of note, significant reduction in ALP was observed that persisted for up to 36 weeks after treatment [46]. In contrast, no overall ALP response or remission was observed at week 12 in those 20 PBC patients who were treated with ustekinumab, which is a human monoclonal antibody that specifically binds to the shared p40 protein subunit of human IL-12 and IL-23 [47]. Interestingly, in those PBC patients who showed a decline in ALP levels during ustekinumab treatment, a modulation of biochemical pathways was observed, including Th17 lymphocytes [47].…”

“…In contrast, no overall ALP response or remission was observed at week 12 in those 20 PBC patients who were treated with ustekinumab, which is a human monoclonal antibody that specifically binds to the shared p40 protein subunit of human IL-12 and IL-23 [47]. Interestingly, in those PBC patients who showed a decline in ALP levels during ustekinumab treatment, a modulation of biochemical pathways was observed, including Th17 lymphocytes [47]. A potential benefit of anti-IL-12 treatment had been suggested by increased serum IL-23 levels in patients with PBC [48] and, in particular, by significant genetic associations of PBC for IL-12A and IL-12 receptor beta subunit from GWAS data [8, 16].…”