Cost per SVR: Is it Worth it?

Douglas T. Dieterich, M.D

Professor of Medicine

Division of Liver Diseases,

Icahn School of Medicine at Mount Sinai

Disclosure

• Dr Dieterich has served as a consultant or scientific advisor for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc,Idenix Pharmaceuticals, Inc, Merck & Co, Inc, and Janssen Therapeutics. He has received grants or research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Merck & Co, Inc, and Janssen Therapeutics (Updated 02/17/14)

Increasing Health Care Costs Associated With Progressive Liver Disease in the Aging HCV-Infected Population

Razavi H, et al. Hepatology. 2013. Epub ahead of print.

Prevalence

(95% CI)Health Care Cost

(95% CI)

While the prevalence of HCV infection is declining from its peak, the incidence of advanced liver disease and associated health care costs continue to rise

Modeling does not take into account any impact of birth cohort screening

A system dynamic modeling framework was used to quantify the HCV-infected population, the disease progression, and the associated cost from 1950-2030.CI=confidence interval.

Pre

vale

nce (

Millio

n)

Healt

h C

are

Co

st

(Billio

n)

Liver-Related Hospital Admissions

Liver-Related HCV Hospital Charges

AASLD 2013

Overview

• Costs per sustained virological response (SVR)

pegylated interferon/ribavirin (IFN/RBV)

• Cost per SVR Telaprevir/IFN/RBV

• Simeprevir/Sofosbuvir (PEG/RBV)

Costs per SVR

Decompensation/serious adverse events (5%)

Mortality (0.6%)

• Sofosbuvir/Ledipasvir early data

Interferon and ribavirin had low SVR rates

and side effects that limited their use

RibavirinPegylated-interferon

Dual Therapy

SVR ~20-50%

Cost per SVR of peg-IFN/RBV

for genotype 1 HCV was $70,364

Jonk et al. AJPB 2013,Cure et al. J Med Econ 2013

Camma et al. J. Hepatol 2013, Liu et al. Ann Intern Med 2012

In 2011, two new drugs were approved to

use with interferon and ribavirin

RibavirinPegylated-interferon

Dual Therapy

SVR ~20-50%

Boceprevir

Telaprevir

OR

Triple Therapy

SVR ~70% in

Registration Trials

2011

Based on SVR rates in registration trials

telaprevir IFN/ RBV was expected to be

cost-effective vs. IFN/RBV

However

• Drugs typically perform better in registration trials than

in real life clinical practice

• Registration trials often enroll patients who are highly

motivated and relatively healthy

• We expected lower SVR rates and more side effects in real

world clinical practice

• We wanted actual data to inform the debate

(to improve modeling by improving assumptions)

Observational Cohort Study

Specific Aims

Primary:

Estimate the cost per SVR of teleprevir-based triple-

therapy for chronic genotype 1 HCV in a real world setting

from the payer’s perspective

Secondary:

- Identify major cost drivers

- Analyze costs of treating drug toxicity and adverse

events

- Determine the cost per SVR on an intention-to-treat

basis

- Provide data for future cost-effectiveness analyses

Bichoupan et al. Hepatology, 2014

Methods of Recruitment and Data Collection

• Obtain lists of patients from Mount Sinai providers

• Search the Mount Sinai Data Warehouse using an

“electronic phenotype* ”

- Filter on ICD-9 code and prescriptions for TVR

- Verify results by medical record chart review

• Collect medical record data on 147 consecutive patients who

initiated TVR-based triple therapy at Mount Sinai, May to

December 2011

• Patients received at least one dose of TVR, were 18 years of

age or older, and received adverse event

management as determined by the individual provider

Additional Methods

• Calculate costs using data from Medicare, Agency for

Healthcare Research and Quality (AHRQ, 2010), and Red Book

Wholesale Acquisition Costs (WAC), adjusting for inflation

• Estimate fibrosis using the FIB-4 score (≥3.25 indicated

advanced fibrosis/cirrhosis)

• Analyze data on an intention-to-treat (ITT) basis using SPSS

and Excel, with a secondary analysis on a per-protocol basis

Costs of teleprevir (TVR), peg-IFN and

ribavirin (RBV) from Red Book WAC 2012

Per wk 12 wks RGT 48 wks

TVR $4,606 $55,273 $55,273 $55,273

peg-IFN $633 $7,596 $15,209 $30,418

RBV $102 $1,231 $2,463 $4,926

Total $5,342 $62,993 $72,945 $90,617

TVR

peg-IFN

RBV

peg-IFN

RBV peg-IFN

RBV

Wk 48Wk 24Wk 12Wk 0

24 wk follow-up

24 wk follow-up

Response

Guided Therapy

Costs of Drugs and Blood Products

from Red Book WAC 2010

Products Cost

Epoetin-α $525 per 40,000 IU

G-CSF $132 per 150 μg

Blood $210 per unit

Telaprevir accounted for 61% of total costs

0

2

4

6

8

10

12

14

0 8 16 24 32 40 48

$, in

milli

on

s

Time, weeks

Fees

AE's

RBV

PEG

TVR

0

2

4

6

8

10

12

14

0 8 16 24 32 40 48

$, in

milli

on

s

Time, weeks

Fees

AE's

RBV

PEG

TVR

Fees to providers were less than 1% of costs

OutcomeMedian cost

per patient

SVR

rate

Cost per

SVRa

Total $83,509 44% $188,859

a Cost per SVR = [Median cost per patient × (1/SVR rate)]b Cannot be calculated

Median Cost of SVR: $188,859

Two new direct acting antiviral agents

(DAAs) were approved in late 2013

SimeprevirSofosbuvir

The new regimens had high SVR rates in

registration trials

RibavirinPegylated-

interferon

Sofosbuvir

Lawitz, N Engl J Med, 2013

SVR rate

after 12 weeks

~89%

IFN-based treatment

Sofosbuvir Simeprevir

Lawitz, EASL, 2014

AASLD, HCV guidelines, 2014

SVR >90%

Clinical guidelines recommend

off-label IFN-free regimens

Ribavirin

Sofosbuvir was priced at $1,000 per pill

• TVR-based therapy cost $190,000 per SVR

• They did a back calculation based on an expected

SVR rate of 90%

$1,000 x 12 x 7 = $84,000

+ $8826 for IFN and RBV

= $93,000/.9 = $103,333

A BARGAIN, except TVR-based

therapy was supposed to cost

less than IFN/RBV = $70,000

How was the price calculated?

Performance and Cost-

effectiveness of Simeprevir- and

Sofosbuvir-based

HCV Treatment in Real World

Clinical PracticeKian Bichoupan, David Del Bello, Rachana Yalamanchili, Neal

Patel, Sweta Chekuri, Alyson Harty, Sanders Chang, Michel Ng,,

David B. Motamed, Keith M. Sigel, Donald Gardenier, Alicia

Stivala, David Sachs, Michael Linderman, Viktoriya Khaitova,

Meena B. Bansal, Priya Grewal, Ritu Agarwal, Charissa Y.

Chang, Jen Leong, Gene Y. Im, Lawrence U. Liu, Joseph A.

Odin, Nancy Bach, Scott L. Friedman, Thomas D. Schiano,

Ponni Perumalswami, Douglas T. Dieterich, Andrea D. Branch

Methods

• Data were collected on the complete cohort of

patients with chronic HCV infection who started

treatment at MSMC after simeprevir (SMV) and

sofosbuvir (SOF) received FDA approval (n=514).

• All patients initiated therapy between December

2013 and June 2014.

• Patients with HIV infection or liver transplantation

were excluded.

• Data on 223 patients treated with telaprevir(TVR) or boceprevir (BOC) were included for comparison.

Pharmaceutical Costs

Drug (duration) Total Weekly Daily

Sofosbuvir (12 weeks) $84,000 $7,000 $1,000

Sofosbuvir (24 weeks) $168,000 $7,000 $1,000

Ribavirin (12 weeks) $1,307 $109 $16

Ribavirin (24 weeks) $2,614 $109 $16

Pegylated-interferon (12 weeks) $8,068 $672 .

Simeprevir (12 weeks) $66,360 $5,530 $790

The SMV/SOF cohort is older and has more

advanced disease than the TVR/BOC cohort

Compared to a TVR- or BOC-based triple therapy cohort treated at

MSMC between 2011 and 2012, the SOF-containing cohort was

significantly older and had more advanced liver disease.

p<0.01

p <0.01

SVR4 and SVR12 Responses by Drug

83%

69%

87%93% 92%

72%

56%

73%81% 86%

0%10%20%30%40%50%60%70%80%90%

100%

% u

nd

ete

ctab

le

SVR4 SVR12

Cost per SVR12 was $175,000

Regimen (duration) N (column%) Total cost SVR12 rate % Cost per SVR12 (SD)

Total 224 $28,300,000 162/224 (72%) $175,000 ($51,500)

SOF/RBV (12/24 weeks)

Genotype 1 (24 weeks)

Genotype 2 (12/16 weeks)

Genotype 3 (24 weeks)

Genotype 4 (24 weeks)

72 (32%)

22 (30%)

41 (57%)

7 (10%)

2 (3%)

$8,350,000

$3,280,000

$3,800,000

$849,000

$413,000

40/72 (56%)

4/22 (18%)

34/41 (83%)

1/7 (14%)

1/2 (50%)

$209,000 ($86,000)

$821,000 ($260,000)

$112,000 ($29,000)

$849,000 ($468,000)

$413,000 ($96,000)

SOF/PEG/RBV (12 weeks)

Genotype 1 (12 weeks)

Genotype 4 (12 weeks)

55 (25%)

44 (80%)

11 (20%)

$5,180,000

$4,120,000

$1,060,000

40/55 (73%)

31/44 (70%)

9/11 (82%)

$129,000 ($16,000)

$133,000 ($18,000)

$117,000 ($2,000)

SOF/SMV (12 weeks) 27 (12%)* $4,140,000 22/27 (81%) $188,000 ($4,450)

SOF/SMV/RBV (12 weeks) 70 (31%) $10,700,000 60/70 (86%) $178,000 ($14,000)

*One patient who received SOF/SMV was infected with genotype 4 HCV.

30% of total costs were in patients who

failed to achieve SVR12

0,00

5,00

10,00

15,00

20,00

25,00

SVR No SVR

Co

st, i

n m

illio

ns

Total Ae's

Fees

Labs

Drug Costs

$20.65

$7.67

Conclusions

• Patients treated with SMV- and/or SOF- containing

regimens were older and had more advanced liver

disease than those in the TVR/BOC cohort.

• The overall SVR12 rate was 72%, and ranged from

56-86%

• In comparison to our previous studies, the overall

SVR rate increased significantly while cost

remained steady.

Clinical- and Economic-performance of

Ledipasvir and Sofosbuvir for HCV

Genotype 1 in New York City: $100,000 per

SVR12

Kian Bichoupan, Daniel J. Waintraub, Neal M. Patel, Sweta Chekuri,

Joshua Hartman, Alyson Harty, David B. Motamed, Alicia Stivala,

Viktoriya Khaitova, Angela Woody, Meena B. Bansal, Priya Grewal, Ritu

Agarwal, Charissa Y. Chang, Jennifer Leong, Gene Y. Im, Lawrence

Liu, Joseph A. Odin, Nancy Bach, Scott L. Friedman, Thomas D.

Schiano, Ponni V. Perumalswami, Albert Min, Lan S. Wang, Jahnavi

Naik, Douglas Dieterich, Andrea D. Branch

Study Objectives

Primary:

Determine the real world SVR12 rate of LDV

and SOF (LDV/SOF) for patients chronically

infected with HCV

Secondary:

- Characterize the cohort of patients initiating

LDV/SOF

- Determine real world SVR4 rate

Methods: Recruitment and Data

Collection• Obtain lists of patients from Mount Sinai providers

• Search the Liver Disease data mart:

- Using HCV ICD-9 codes and orders for LDV/SOF

- Verify cohort by medical record review

• Collect medical record data on HCV patients who initiated LDV/SOF

regimens at Mount Sinai Medical Center between October 2014 and

January 2015 (GCO#: 10-00032).

• Patients received at least one dose of an HCV medication, were at

least 18 years of age, and received adverse event management at

the discretion of the provider

• HIV/HCV co-infected patients and patients who received liver

transplants in the past were excluded

Methods: Statistical Analysis

• Descriptive statistics of the cohort initiating treatment were calculating

using R software

• To calculate SVR rates, only patients with available data 4 or 12

weeks after the end-of-treatment were included in the calculation.

• FIB-4 scores were calculated and used to determine the presence of

advanced fibrosis or cirrhosis (FIB-4 score ≥ 3.25).

• Patient death before the end-of-treatment was considered a virologic

failure.

Methods: Cost Analysis

• Cost of pharmaceuticals were obtained from the RED

Book Wholesale Acquisition Cost

• Cost-per-SVR calculated with the following formula:

Total cost of pharmaceuticals for all patients

Number of patients who achieved SVR

• Cost-per-SVR with LDV/SOF was compared to the

cost-per-SVR with simeprevir and SOF

Total

n 243

Hypertension 107 (44%)

Diabetes 56 (23%)

Depression 43 (18%)

Advanced fibrosis or cirrhosis 94 (39%)

Comorbidities of Patients Who

Initiated LDV/SOF ± RBV

Normal range Total

Hemoglobin, g/dL 13.9 – 16.3 14.0 (12.9 – 14.9)

Log HCV viral load - 6.27 (5.87 – 6.67)

ALT, U/L 1-50 57 (38 – 97)

AST, U/L 1-53 54 (39 – 88)

Albumin, g/dL 3.5 – 4.9 4.1 (3.8 – 15.7)

Platelet count, x103/µL 150 - 450 169 (121 – 227)

Creatinine, mg/dL 0.70 – 1.40 0.90 (0.79 – 1.07)

Alpha-fetoprotein, ng/mL 0.0 – 9.0 6.8 (3.8 – 15.7)

eGFR, mL/min/1.73 m2 ≥60 84 (70 – 95)

Laboratory values

90% SVR12 rate in standard clinical

practice

SVR4 SVR120

20

40

60

80

100

SV

R r

ate

, %

96%

(133/138) 90%

(43/48) 4 relapsed after EOT

1 died on treatment

Cost-per-SVR

• Average cost of pharmaceuticals was $90,234

• Average cost-per-SVR was $100,727

• Treatment with LDV/SOF was $68,337 per-SVR

lower than SMV/SOF ($169,064)

Conclusion

• We observed high SVR rates with SOF/LDV in

standard clinical practice:

96% SVR4

90% SVR12 (still collecting data)

• 4 patients relapsed after completing treatment

• 1 patient died before completing treatment.

• The average cost-per-SVR was $100,727

• Additional data are needed to identify factors

associated with SVR

A COST-EFFECTIVENESS ANALYSIS OF LDV/SOF+RBV FOR 12 WEEKS VS. LDV/SOF 24 WEEK VS. SOF+SMV 24

WEEKS IN CHC GT1 TE CIRRHOTIC PATIENTS

Ahmed, A1; Dieterich, DT2; Park, H3; Saab, S4; Gordon, SC5; Younossi, ZM6

1) Stanford University, Stanford, CA, United States2) Mount Sinai Hospital, New York City, NY, United States3) University of Florida, Gainesville, FL, United States4) University of California, Los Angeles, Los Angeles, CA, United States5) Henry Ford Hospital, Detroit, MI, United States6) Inova Fairfax Hospital, Falls Church, VA, United States

May 16-19, 2015

WASHINGTON, DC

Digestive Disease Week 2015

BACKGROUND AND AIMS

• Ledipasvir / sofosbuvir (LDV/SOF) is the first all-oral, PR-free regimen with high efficacy in HCV patients, including difficult-to-treat TE, cirrhotic patients1

• LDV/SOF+RBV 12W has demonstrated similar efficacy to LDV/SOF 24W in clinical trials2

• Sofosbuvir in combination with simeprevir (SOF+SMV), has been shown to have similar efficacy to LDV/SOF as measured in a phase 2b clinical trial3

BACKGROUND

LDV/SOF = ledipasvir / sofosbuvir; RBV = ribavirin; TE = treatment-experienced; CC = compensated cirrhosis;1. Afdhal et al., 2014; 2. Bourliere et al., 2014; 3. Lawitz et al., 2014

OVERALL STUDY AIM

To evaluate the lifetime health and economic outcomes from a decision-analytic model for LDV/SOF+RBV versus SOF+SMV in GT1 treatment-experienced patients with compensated cirrhosis

EFFICACY AND UTILITY INPUTS

• SVR rates, adverse events, and treatment duration values were obtained from relevant clinical trials

• Data not reported for granular fibrotic stages was inferred via a relative risk approach and validated by a national panel of hepatologists

• Utility scores for each health state were sourced from clinical studies or published literature

• Utility decrements were assigned to each specific treatment regimen, based on clinical trial data and published literature

• Patients who achieved SVR were assumed to experience an increase in utility value

SVR RATE

REGIMEN STUDY NAME SVR: F4 1a SVR: F4 1b

LDV/SOF+RBV 12W1,2 ION-2 / SIRIUS 96% 97%

LDV/SOF 24W1,2 ION-2 100% 100%

SOF + SMV 24W3 COSMOS-2 100% 100%

1. Bourliere et al., 2014; 2. Afdhal et al., 2014; 3. Lawitz et al., 2014; 4. McLernon et al., 2008; 5. Wright and Tompkins, 2006; 6. Hsu et al., 2012; 7. Younossi et al., 2015; 8. Assumption

COST INPUTS

• Costs include drug acquisition costs, monitoring costs, adverse event costs, and health state costs

• The cost of each regimen incorporates WAC1 adjusted by treatment duration along with adverse event costs (drug and management costs)

• In each health state, the baseline cost of disease has been obtained from publications that evaluated the direct medical costs of HCV

• Patients who achieve SVR are assumed to only require long-term costs related to treatment of DCC and HCC

MOLECULE REGIMEN COST

TOTAL COSTS

LDV/SOF+RBV 12W $95,007

SOF+SMV 24W $297,144

LDV/SOF 24W $187,390

HEALTH STATE ANNUAL COST

F42,3 $5,834

F4 SVR Year 14 $704

F4 SVR Years 2-34 $322

F4 SVR Year 4 Onwards4 $403

DCC2,3 $40,120

HCC5 $70,224

LT2,3 $179,746

PLT2,3 $44,228

F = METAVIR fibrosis stage; DCC = decompensated cirrhosis; HCC = hepatocellular carcinoma; LT = liver transplant; PLT = post-liver transplant; EM = extra mortality; SOF = sofosbuvir; SMV = simeprevir; RBV = ribavirin; LDV/SOF = ledipasvir / sofosbuvir1. Redbook, 2014; 2. Gordon, 2012; 3. McAdam-Marx, 2011; 4. Assumption validated by a national panel of hepatologists; 5. Catana 2014

NOTE: All costs are in 2014 USD

HEALTH OUTCOMES: ADVANCED LIVER DISEASE EVENTS

357

711

54

922

357

711

54

922

546

821

82

1.161

0

200

400

600

800

1.000

1.200

1.400

DCC HCC LT EM

NU

MB

ER O

F EV

ENTS

P

ER 1

0,0

00

PA

TIEN

TS

• LDV/SOF 24W and SOF+SMV 24W, based on Phase 2b data, show equal efficacy in terms of lifetime health outcomes, with equal numbers of patients experiencing DCC, HCC, LT and EM

• Utilizing LDV/SOF+RBV 12W results in a slight increase of all ALD events vs. the 24W treatments due to the slight reduction in efficacy for the 12W regimen

53%

15%

52%

26% 2.044 2.044

2.610

0

500

1.000

1.500

2.000

2.500

3.000

TOTA

L A

LD E

VEN

TS

PER

10

,00

0 P

ATI

ENTS

28%

SOF+SMV 24W LDV/SOF 24W LDV/SOF+RBV 12W

LDV/SOF = ledipasvir / sofosbuvir; RBV = ribavirin; SOF = sofosbuvir; SMV = simeprevir; ALD = advanced liver diseaseDCC = decompensated cirrhosis; HCC = hepatocellular carcinoma; LT = liver transplant; EM = extra (liver-related) mortality

COST PER SVR RESULTS

$300.003

$190.762

$102.328

$0

$50.000

$100.000

$150.000

$200.000

$250.000

$300.000

$350.000

SOF+SMV 24W LDV/SOF 24W LDV/SOF+RBV 12W

CO

ST P

ER S

VR

(U

SD)

• LDV/SOF+RBV 12W is projected to have the lowest cost per SVR compared to SOF+SMV 24W and LDV/SOF 24W due to its slightly lower efficacy and substantially lower cost

• 46% decrease in cost per SVR vs LDV/SOF 24W

• 66% reduction in cost per SVR vs SOF+SMV 24W

-36%

-46%

-66%

LDV/SOF = ledipasvir / sofosbuvir; RBV = ribavirin; SOF = sofosbuvir; SMV = simeprevir

AASLD and the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society-USA (IAS-USA), yesterday released the latest section of www.hcvguidelines.org.

The new section, “When and in Whom to Initiate HCV Therapy,” offers clinicians information on:

How to prioritize patients who will derive the most benefit, or will have the greatest impact on limiting further HCV transmission.When to treat patients with complications such as advanced fibrosis, compensated cirrhosis, liver transplant, or severe extra-hepatic complications.Additional conditions that warrant prioritization of treatment.Visit www.hcvguidelines.org to view the new section and to keep up with the changing landscape of HCV treatment.

This is where managed care has stopped reading !

www.prevent.org/National-Commission-on-Prevention-Priorities/Rankings-of-Preventive-Services-for-the-US-Population.aspx.Rein DB, et al. Ann Intern Med. 2012;156:263-270.

Co

st P

er

QA

LY S

ave

d (

Do

llars

)Cost-Effectiveness of HCV Testing and Rx vs

Other Routine Preventive Services

*Birth cohort testing, 1945-1965.2-drug treatment=PegIFN+RBV; 3-drug treatment=PegIFN+RBV+PI.QALY=quality-adjusted life-year.

Conclusions

• New oral DAA Rx with high SVR’s has reduced cost per SVR dramatically

• The actual costs are much lower than those used in these models due to discounting and rebates and are likely to fall further

• The question is not “Is it worth it to treat?” but

• Can we afford to NOT treat all patients?