1 Making Oraquick quicker Real world data on pan-genotypic regimens - - PDF document

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1 Making Oraquick quicker Real world data on pan-genotypic regimens - - PDF document

Disclosures Dr. Feld International Liver Congress Research : Abbott, Abbvie, Gilead, Janssen, Merck Consulting : Abbvie, Gilead, Merck 2019: Update from Vienna Dr Shah Jordan J. Feld MD MPH Consulting Fees: Abbvie, Gilead, Merck,


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International Liver Congress 2019: Update from Vienna

Jordan J. Feld MD MPH

Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health University of Toronto

Disclosures

  • Dr. Feld
  • Research: Abbott, Abbvie, Gilead, Janssen, Merck
  • Consulting: Abbvie, Gilead, Merck

Dr Shah

  • Consulting Fees: Abbvie, Gilead, Merck, Intercept, Lupin

Learning Objectives

  • 1. Appreciate recent advances in HBV and HCV presented at the

International Liver Congress 2019

  • 2. Put into context the recent Phase 3 trial results for a new therapy

for NASH

Outline

  • HCV

– Screening & linkage to care – Treatment efficacy – Treatment monitoring – HCC post-SVR

  • HBV

– Current therapies

  • Cancer risk
  • Transmission risk
  • NASH

– Obeticholic acid for NASH – REGENERATE Trial

HCV Care Cascade: Diagnosis Gaps by Physician Type

46 % 49 % 57 % 54 %

Gap: Ab+ patients seen by physician group who did not have confirmatory HCV RNA testing by that physician group HCV Detection by Specialty (%) HCV Confirmation by Specialty (%) Generalist* HCV specialist† OB/GYN Other Missing specialty *Includes primary care, family practice, internal medicine.

†Includes

hepatologist, gastroenterologist, and ID specialist.

46% of Ab+ patients received no HCV RNA test

  • Rege. EASL 2019. Abstr PS-066.

HCV Diagnosis by Specialty (%) HCV Treatment by Specialty (%) Generalist* HCV specialist† OB/GYN Other Missing specialty *Includes primary care, family practice, internal medicine.

†Includes

hepatologist, gastroenterologist, and ID specialist.

90% of diagnosed patients received no HCV therapy

  • Rege. EASL 2019. Abstr PS-066.

Gap: patients with ≥ 2 HCV RNA tests by physician group but did not receive treatment from that physician group 95% 83% 91% 87% 91%

HCV Care Cascade: Treatment Gaps by Physician Type

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SLIDE 2

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Making Oraquick quicker

5 10 15 20

Viremic Non-Viremic

Time (minutes)

Mean p < 0.001

OraQuick HCV Ab Viremic Non- Viremic Predictive Values Positive at 5 min 102 16 PPV: 86.7% 95% CI (0.79- 0.92) Negative at 5 min 15 NPV: 100.0% 98% CI (0.73- 1.00) Sensitivity: 100.0% 98% CI (0.96-1.00) Specificity: 48.3% 95% CI (0.32-0.65)

If negative at 5 minutes, can tell people they are not viremic Once positive, stays positive – no reason to wait to 20’

Smookler, Vanderhoff EASL 2019

Real world data on pan-genotypic regimens

Mangia ILC 2019 GS-03, Cornberg M ILC 2019 GS-07 Not surprising but very reassuring data – this should apply to most of our patients

SMART-C: Monitoring During GLE/PIB in Treatment-Naive Patients With GT1-6 HCV Infection

  • Multicenter, randomized, open-label

phase IIIb study

  • Simplified monitoring: Medication dispensed

at BL; no on-treatment clinic visits

  • Standard monitoring: Medication dispensed

at BL and Wk 4; clinic visits with physician, study nurse, and pathology at Wks 4 and 8

  • Primary endpoint: SVR12 in ITT population

(6% noninferiority margin)

  • Secondary endpoints: SVR12 in mITT and PP

populations, adherence by Wk 20 pill count, treatment discontinuation and completion, safety

GLE/PIB With Simplified Monitoring (n = 253) GLE/PIB With Standard Monitoring (n = 127) Treatment-naive patients with GT1-6 HCV infection, HCV RNA > 10,000 IU/mL, and no cirrhosis* (N = 380) AEs and adherence assessed by study nurse via phone contact at Wks 4 and 8 in all patients. GLE/PIB dosed orally at 300/120 mg QD. *Exclusion criteria: anticipated poor adherence, IDU within past 6 mos, positive urine drug screen. Wk 8 Dore, LB – PS 178 EASL 2019

SMART-C: Efficacy and Safety

20

  • VF: 2 (1.6%) standard vs 6 (2.4%) simplified
  • Adherence > 95%: 98% standard vs 96% simplified

121/ 127 233/ 253 121/ 123 121/ 123 233/ 241 233/ 239 n/N =

SVR12 (%) Treatment-Emergent AEs, n (%) Standard (n = 127) Simplified (n = 253) AEs

  • Grade 1/2
  • Grade 3
  • Grade 4

70 (55) 69 (54) 1 (0.8) 133 (53) 131 (52) 2 (0.8) Common AEs (> 5%)

  • Fatigue
  • Headache
  • Nausea

30 (14) 26 (12) 25 (12) 52 (15) 43 (13) 17 (5) Serious AEs 3 (1.2) Unscheduled visits

  • On treatment
  • Total

3 (2) 8 (6) 11 (4) 20 (8)

*Excludes death (n = 1), LTFU (n = 14), or missing HCV RNA (n = 1).

†Excludes discontinuation (n = 2) in addition to mITT exclusions.

ITT mITT* PP† 40 60 80 100

95 92 98 97 98 97

Standard Simplified

Difference: -3.2% (95% CI: -8.2 to 1.8)

  • Overall performed very well but did not quite reach noninferiority
  • Highlights need for good patient selection for this approach

Dore, LB – PS 178 EASL 2019

Factors associated with HCC risk Risk of HCC after SVR

Lau EASL 2019

Factors associated with HCC after SVR in patients with F3/F4

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SLIDE 3

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Change with treatment does not help

Lau EASL 2019

Effective for finding low risk patients

Lau EASL 2019

If validated, could forego surveillance in low risk group

Therapy for HBV – is 1 nuc better than another?

  • Usually we think of Nucs (tenofovir or entecavir) as almost interchangeable
  • Slight differences in resistance profile (less with tenofovir) and renal toxicity (less with entecavir)
  • Recent study from Korea found a higher of liver cancer in those treated with entecavir vs tenofovir

Study from Hong Kong – consecutive treated HBV 2008-2018 28,041 ETV with 1,386 HCC vs 1,309 with TDF with 8 HCCs

Lower risk of cancer with tenofovir treatment

T CK Yip, G Wong EASL 2019

Does U=U for HBV?

Serum from patients with HBV on nuc therapy with HBV DNA detectable but <LLOQ used to infect humanized mice

  • 9 of 31 established viremia
  • Unclear if they had taken <LLOD
  • But highlights transmission of HBV
  • Importance of vaccination
  • Importance of disclosure

Burdette ILC 2019 PS 150

REGENERATE: Study Design

Slide credit: clinicaloptions.com

  • Primary endpoint at interim analysis by paired biopsy: either fibrosis improvement by

≥ 1 stage without NASH worsening or NASH resolution without fibrosis worsening

End of Study (Event Driven)

  • Younossi. EASL 2019. Abstr GS-06.
  • International, randomized, double-blind phase III study of FXR agonist obeticholic acid

Patients with biopsy-confirmed NASH, fibrosis stage 2/3, NAFLD activity score ≥ 4 (target N ~ 2400) OCA 10 mg QD (n = 312) Placebo QD (n = 311) OCA 25 mg QD (n = 308) Mo 18 Interim Analysis (Histology)

  • Primary endpoint at interim analysis by paired biopsy: either fibrosis improvement by

≥ 1 stage without NASH worsening or NASH resolution without fibrosis worsening

Stratified by T2DM, treatment with thiazolidinediones or vitamin E End of Study (Event Driven) Slide credit: clinicaloptions.com

  • Younossi. EASL 2019. Abstr GS-06.
  • Younossi. EASL 2019. Abstr GS-06.

REGENERATE Primary Endpoint: Fibrosis Improvement

  • Study met fibrosis primary endpoint at 18 mos (ITT)

Fibrosis Improvement by ≥ 1 Stage With No NASH Worsening 20 40 60 80 100 P = .04 P = .0002 11.9 17.6 23.1 Patients (%) Placebo OCA 10 mg QD OCA 25 mg QD

n =

  • In PP analysis, OCA 25 mg QD

also associated with fibrosis improvement across subgroups defined by fibrosis stage, NAS, T2DM status

311 312 308

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SLIDE 4

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Slide credit: clinicaloptions.com

  • Younossi. EASL 2019. Abstr GS-06.
  • Younossi. EASL 2019. Abstr GS-06.

REGENERATE Primary Endpoint: NASH Resolution

  • Study did not meet NASH resolution primary endpoint at 18 mos (ITT)

NASH Resolution With No Fibrosis Worsening P = .18 P = .13 11.2 11.7 8.0 20 40 60 80 100 Patients (%) Placebo OCA 10 mg QD OCA 25 mg QD

n = 311 312 308 *According to overall assessment by pathologists.

  • In post hoc analysis, OCA 25 mg QD

associated with steatohepatitis resolution* (placebo, 12.2%; OCA 10 mg, 16.3%; OCA 25 mg 23.1%; P < .001 for OCA 25 mg vs placebo)

  • OCA 25 mg QD also associated with

improvement of NAS score, grade of ballooning, and inflammation

  • Younossi. EASL 2019. Abstr GS-06.
  • Younossi. EASL 2019. Abstr GS-06.
  • OCA also associated with improvement in fibrosis staging, NAS parameters, ALT, AST, GGT

REGENERATE Secondary Endpoints: Changes in Fibrosis

Fibrosis Regression/Progression by ≥ 1 Stage (per Protocol With Postbaseline Biopsy) OCA 25 mg (n = 213) OCA 10 mg (n = 223) Placebo (n = 220) 20 40 10 30 20 10 30 Patients (%) 13.1 16.6 20.9 38.0 28.3 23.2 Improved Fibrosis Worsened Fibrosis

REGENERATE: Safety

  • Pruritus incidence peaked within first 3 mos

before declining

  • In OCA 25 mg arm, 9% discontinued due to

pruritus, mostly protocol driven ‒ Rates comparable between arms

  • Cardiovascular AE rates ≤ 2% in all arms
  • LDL increased and HDL decreased early with

OCA; recovered with clinical management

  • Hepatic TEAE rates similar across arms

‒ Hepatic serious AEs in < 1%, numerically more cases in OCA 25 mg arm ‒ Low rates of cholelithiasis, cholecystitis AEs

TEAEs Occurring in ≥ 10% of Patients in Any Arm, n (%) OCA 10 mg (n = 653) OCA 25 mg (n = 658) Placebo (n = 657) Pruritus 183 (28) 336 (51) 123 (19) LDL increased 109 (17) 115 (17) 47 (7) Nausea 72 (11) 83 (13) 77 (12) Fatigue 78 (12) 71 (11) 88 (13) Constipation 65 (10) 70 (11) 36 (5) Abdominal pain 65 (10) 67 (10) 62 (9) Diarrhea 44 (7) 49 (7) 79 (12)

  • Younossi. EASL 2019. Abstr GS-06.

Summary – EASL 2019

  • HCV

– Still need to improve diagnosis and linkage – especially in primary care – Rapid read of Oraquick may enhance screening – if negative at 5’, no HCV RNA – Pangenotypic treatments – SOF/VEL and GLE/PIB – highly effective! – Monitoring can simplified for most people…but not all – know your patients – HCC surveillance still important post-SVR for cirrhosis…even if things look like they improved, scores may help risk stratify based on baseline factors

  • HBV

– Lower risk of cancer with tenofovir than entecavir…not sure of implications – Transmission can still occur in people on nuc therapy – New therapies coming (next year!)

  • NASH

– Landmark as 1st positive trial for NASH therapy… – Obeticholic acid likely to be approved – Improvement in fibrosis without worsening of NASH…modest effect – Some toxicity concerns – itch and ?LDL and price! – Unclear how much this will get used…but important to know about – lots more coming