Behandlung der Hepatitis C - Neue

Entwicklungen

7. Europäische Konferenz zur

Gesundheitsförderung in Haft, 13 und 14 März

2014, Bonn

Jürgen RockstrohMedizinische Klinik I

Universitätsklinikum Bonn

Gesamt-Mortalität bei US HCV-positiven und -negativen Veteranen

195,585 HCV+ Patienten202,739 HCV- Veteranen

All cause mortality43.9 per 1000 person-years

HCV Positiv

All cause mortality24 per 1000

person-years

Erqou S, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 453.

HCV Negativ

Prädiktoren für Mortalität bei US HCV-infizierten Veteranen

Predictor Hazard ratio (95 % CI)

Decompensated Liver Disease 3.05 (2.97‐3.14)

Anemia 2.03 (1.98‐2.08)

Cancer 1.72 (1.67‐1.77)

Chronic Kidney Disease 1.42 (1.38‐1.46)

COPD 1.40 (1.35‐1.44)

HCV Treatment 0.43 (0.41‐0.46)

Erqou S, et al. 48th EASL; Amsterdam, Netherlands; April 24‐28, 2013. Abst. 453.

IFN, interferon; RBV, ribavirin; SVR, sustained virologic response

1. Adapted from Manns MP, et al. Gut 2006;55:1350–59. 2. Tran TT. Am J Manag Care 2012;18(14 Suppl):S340–9. 3. Kowdley KV, et al. EASL 2013. Abstr 3. Available at: www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Amsterdam%202013/Viral%20Hepatitis/Capsules/3.aspx. Accessed 25Jul13

Heilungserfolge bei Hepatitis C

6%

13–19%

38–43%

54–63%

67–79%*

31–35%

45–47%

*In patients with HCV genotype 1; ** In treatment-naïve patients

83–96%**???

IFN 24 wk(daily)

IFN 48 wk3 times/wk

IFN/RBV24 wk

IFNα/RBV48 wk

IFNα/wbRBV48 wk

pIFNα/RBV48 wk

1992 2001–20121,2 20133

2 DAAs + RBV12 wk

?pIFNα/RBV + 1st gen DAA

48 wk

NS3 inhibitor2

•Inhibits activity of NS3 protease•Prevents processing of HCV proteins required for replication

NS5B inhibitor(s)2

•Inhibits NS5B RNA replicase•Prevents replication of viral genome

NS5A inhibitor2

•Inhibits activity of NS5A, a multifunctional protein•Prevents viral replication

HCV lifecycle and potential therapeutic targets

HCV virion

New HCV virion

PEG-IFN lambda3

• Type III pegylated interferon

• Expression of receptor is more limited than Alfa, should lead to improved tolerability and safety

1. Manns MP, et al. Nat Rev Drug Discov 2007;6:991–1000. 2. Rice C. Top Antivir Med 2011;19(3):117–20. 3. Donnelly R, et al. Trends Immunol 2011;32(9):443–50. 4. Gallay P, Lin K. Drug Des Devel Ther 2013;7:105-15.

Endocytosis

SR-B1

CD81

Cytoplasm

Liver cell

ER

Maturation

Nucleus

Uncoating

RNA replication

Virionassembly

Golgi

Adapted from reference 1

ER Lumen Adapted from reference 2

Cytoplasm

NS4A NS4B

Cyclophilin Ainhibitor4

•Inhibition of cyclophilin A reduces HCV replication

1. Soriano V, et al. J Antimicrob Chemother 2011;66:1673–86. 2. Belda O, et al. Virus Res 2012;170:1–14. 3. Pol S, et al. ICAAC 2011, oral HI-376. 5. Gane EJ, et al. N Engl J Med 2013;368:34–44. 6. Wedemeyer H, et al. Hepatology 2013; doi: 10.1002/hep.26274 [Epub ahead of print]. 7. Gallay P, Lin K. Drug Des Devel Ther 2013;7:105-15. 8. Donnelly R, et al. Trends Immunol. 2011 September ; 32(9): 443–450. 9. http://clinicaltrials.gov/ct2/show/NCT01464827. 10. http://ir.achillion.com/releasedetail.cfm?releaseid=698938. 11. http://clinicaltrials.gov/ct2/show/NCT01030432. 12. Poordad F, et al. AASLD 2012. Abstract 83. 13. Delang L, et al. Viruses 2010;2:826–66. 14. Dieterich D et al. CROI 2013. Abstr 40LB. Available at: http://www.natap.org/2013/CROI/croi_02.htm. Accessed 13 Aug 2013. 15. www.gilead.com/research/pipeline 16. http://clinicaltrials.gov/ct2/show/NCT01353911. 17. Rehman S, et al. Genet Vaccines Ther 2011;9:11. 18. Gish RG & Meanwell NA. Clin Liver Dis 2011;15:627–39. 19. http://clinicaltrials.gov/ct2/show/NCT01448200. 20. Gane E, et al. EASL 2013. Abstr5. 21.http://www.vrtx.com/research-development/pipeline22.www.pipelinereport.org/browse/hcv-treatment/bi-207127. 23. www.pipelinereport.org/browse/hcv-treatment/abt-072. 24. http://clinicaltrials.gov/show/NCT01193361. 25. http://clinicaltrials.gov/show/NCT0158113826. http://clinicaltrials.gov/show/NCT01309932. 27. Coelmont et al. PLoS One 2010;5:e13678.

NS3/4AProteasehemmer

NS5AInhibitoren

NS5BPolymerasehemmer Cyclophilin A IFN-lambda

Characteristics• Low-to-medium

barrier to resistance1

• QD, BID or TID dosing1

• Some may require ritonavir boosting1

• General picomolar activity against multiple GTs in vitro2

• Low-to-medium barrier to resistance2

• QD dosing3

Nucleos(t)ide analogue (NUC)• Broad GT

coverage1

• High barrier to resistance1

• QD or BID dosing5,6

Non-nucleoside analogue (NNI)• Most are

GT/subtype specific1

• Low barrier to resistance1

• QD or BID dosing1

• Broad GT coverage in vitro7

• High barrier to resistance7

• BID/QD dosing7

• More limited receptor expression maylead to fewer adverse events8

• No evidence of haematological toxicity8

DrugsABT-450/r9

Sovaprevir10

Asunaprevir11

Simeprevir12

Faldaprevir14

Danoprevir13

GS-945115

MK-517216

ACH-806/GS-913217

Daclatasvir18

Ledipasvir18

ABT-2679

PI-68819

AZ-68918

MK-8742BMS-82439318

PPI-46118

Sofosbuvir20

Mericitabine6

VX-13521

Deleobuvir22

ABT-3339

ABT-07223

BMS-79132524

Tegobuvir13

Setrobuvir13

VX-22225

Filibuvir13

Alisporivir27,

SCY-63517BMS-91414326

HCV Substanzklassen und Einzelsubstanzen

Warum brauchen wir dennoch zusätzliche DAAs?

• (Noch) höhere SVR

• Weniger Nebenwirkungen

• Kürzere Therapiedauer

• Geringere Pillenlast

• Weniger Medikamenteninteraktionen

• Geringere Therapiekosten

• Bessere Resistenzprofile

• Therapieoptionen für Non-Responders und andere difficult-to-treat populations (Zirrhose, oLTX)

Simeprevir + P/R in GT1 therapienaiven Patienten & Relapsern

100

80

60

40

20

0

SVR

12 (%

)

80

50

210/264

65/130

81

209/257

50

67/134

QUEST-1[1] QUEST-2[2]

100

80

60

40

20

0SV

R12

(%)

79

37

206/260

49/133

PROMISE[3]

Treatment-Naive Patients Prior Relapsers

1. Jacobson I, et al. EASL 2013. Abstract 1425. 2. Manns M, et al. EASL 2013. Abstract 1413. 3. Lawitz E, et al. DDW 2013. Abstract 869b.

P/RSMV + P/R

Simeprevir: Effektivitätsverlust bei Q80K Resistenz

100

80

60

40

20

0

SVR

12 (%

)85

58

228/267

49/84

84

138/165

GT1b GT1a no Q80K

GT1a +Q80K

Q80K present in 34% of GT1a patientsNo benefit of simeprevir if Q80K positive

53

70/133

43 52

36/83

23/44

SMV + P/RP/R

n/N =

Jacobson I, et al. AASLD 2013. Abstract 1122.

12 weeks 36 weeks

Simeprevir + P/R bei HCV GT1: Indikationen

Simeprevir 150 mg/day with food, administered with P/R

– Fixed duration (no RGT)

Treatment-naive patients and relapsers (including cirrhotic patients)

Previous partial or null responders (including cirrhotic patients)

Stopping rules

12 weeks 12 weeks

Treatment Wk HCV RNA (IU/mL) Action4 ≥ 25 Discontinue simeprevir, pegIFN, and RBV

12 ≥ 25 Discontinue pegIFN and RBV (SMV stops at 12 wks)

24 ≥ 25 Discontinue pegIFN and RBV

Simeprevir + P/R P/R

Simeprevir + P/R P/R

Simeprevir [package insert] November 2013

Faldaprevir + P/R in GT1therapienaiven Patienten

Patients treated with FDV: 84% achieved ETS, stopped treatment at Wk 24Treatment failure more common with subtype 1a; no impact of Q80K on SVRSafety profile of FDV 120 mg regimen similar to placebo

SVR

12 (%

)

50

73 72

100

80

60

40

20

0FDV 120 mg + P/R

(n = 523)FDV 240 mg + P/R

(n = 526)Placebo + P/R

(n = 264)

131/264382/521 378/524

Jensen D, et al. AASLD 2013. Abstract 1088.

P < .0001

n/N =

Higher virologic failure rates with subtype 1a; no impact of Q80K

Higher rates of bilirubin with 240 mg dose than with 120 mg dose in naive trials

SVR

12 (%

)

14

70

100

80

60

40

20

0Relapsers Partial

RespondersNull

Responders

7/49 69/99

Jacobson I, et al. AASLD 2013. Abstract 1100.

n/N =

70

71/102

3

58

1/29 33/57

47

26/55

33

45/145

33

46/141

PlaceboFDV 240 mg QD 12 wksFDV 240 mg QD 24 wks

N/A

Faldaprevir + P/R in GT1vorbehandelten Patienten

Simeprevir und Faldaprevir:Pro und Contra

Pro

– Einmal täglich

– Deutlich weniger NW

– >85% verkürzte Therapiedauer (6 Monate)

Contra

– Q80K großes Problem bei Simeprevir: Resistenztestung vor Therapiebeginn

– Weiterhin Medikamenteninteraktionen (SMV > FDV)

– Nur mit P/R

Sofosbuvir (SOF) Phase 3 Studien

POSITRON PegIFN-Unable

PBO, n=71

SOF + RBV, n=207 SVR12

FUSION Treatment-ExperiencedSOF + RBV, n=103 PBO SVR12

SOF + RBV, n=98 SVR12

NEUTRINO Treatment-Naïve

GT 1/2/3

All Oral Therapy

GT 1/4/5/6

FISSION Treatment-Naïve

SOF + RBV, n=256 SVR12

SOF + PegIFN + RBV, n=327 SVR12 SVR24

No response-guided therapy

VALENCE Treatment-Naïve and Treatment-Experienced

SVR12GT2: SOF + RBV, n=73

SOF 400 mg/d; PegIFN 180 µg/wk; RBV 1000-1200 mg/d for SOF+RBV arms and 800 mg/d for PegIFN+RBV arm

0 12 16 24 36Week �

PegIFN + RBV, n=243 SVR12�

SOF + RBV, n=68 SVR12

SVR12GT3: SOF + RBV, n=250 �PHOTON-1 Treatment-Naïve

SOF + RBV, n=114 SVR12�

Sofosbuvir + P/R in therapienaiven GT 1/4/5/6 Patienten (NEUTRINO)

Open-label, single-arm study of sofosbuvir 400 mg QD + P/R for 12 weeks in treatment-naive patients with GT1/4/5/6 HCV

– 17% cirrhosis; 89% GT1; 9% GT4; < 1% GT5; 2% GT6

Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

Overall

SVR

12 (%

)

89 96 100100

80

60

40

20

0GT1 GT4 GT5,6

261/292 27/28 7/7n/N =

90

295/327

9280

100

80

60

40

20

0No

CirrhosisCirrhosis

252/273 43/54

VALENCESOF + RBV

12 wk

LONESTAR-2SOF + PegIFN + RBV

12 wk

FISSIONSOF + RBV

12 wk

VALENCESOF + RBV

12 wk

SVR

12 (%

)SVR12 Raten der SOF Studien in HCV GT 2 Patienten

Treatment-Naïve Treatment-Experienced

Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085.Jacobson IM, et al. N Engl J Med. 2013 May 16;368(20):1867-77.

FUSIONSOF + RBV

12 wk

POSITRONSOF + RBV

12 wk

97% 100%

29/30 2/20%

20%

40%

60%

80%

100%98%

58/59

91%

10/11

60%

96%

25/26 6/10

91% 88%

30/33 7/8

92%

85/92

94%

16/17

100%

9/9

93%

13/14

Noncirrhotic Cirrhotic

Treatment-Naïve Treatment-Experienced

Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085.Jacobson IM, et al. N Engl J Med. 2013 May 16;368(20):1867-77. Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4.

Noncirrhotic Cirrhotic

61%

87%

60%

SVR

12(%

)

89/145 86/92

FUSION SOF RBV 16 wk

VALENCESOF + RBV 24 wk

LONESTAR-2SOF + PegIFN + RBV

12 wk

87/10014/23

83%

10/12

92%94%

12/13 25/40

63%

27/45

83%

10/12

68%

21%

61%

34%

0%

20%

40%

60%

80%

100%

FISSIONSOF + RBV 12 wk

VALENCESOF + RBV 24 wk

13/38

POSITRONSOF + RBV 12 wk

57/84 3/14

SVR12 Raten der SOF Studien in HCV GT 3 Patienten

PHOTONPHOTON--1: Study Design1: Study Design

• Broad inclusion criteria• Cirrhosis permitted with no platelet cutoff• Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females)

• Wide range of ART regimens allowed • Undetectable HIV RNA for >8 weeks on stable ART regimen

• Baseline CD4 count• ART treated: CD4 T-cell count >200 cells/mm3 and HIV RNA <50 c/mL• ART untreated: CD4 T-cell count >500 cells/mm3

Wk 0 Wk 12 Wk 24 Wk 36

SOF + RBV, n=114 SOF + RBV, n=114 GT 1 TNGT 1 TN

SOF + RBV, n=41SOF + RBV, n=41GT 2/3 TEGT 2/3 TE

SOF + RBV, n=68 SOF + RBV, n=68 GT 2/3 TNGT 2/3 TN

Wk 48

SVR 12SVR 24

Naggie S, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 26.

PHOTONPHOTON--1 Study:1 Study:Virologic Response Virologic Response -- Genotype 1, 2, and 3Genotype 1, 2, and 3

Patie

nts

with

HC

V R

NA

<LL

OQ

(Per

cent

age)

Naggie S, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 26.

Treatment Naïve12 Weeks SOF + RBV

Treatment Experienced24 Weeks SOF + RBV

Treatment Naïve12 Weeks SOF + RBV

Treatment Experienced24 Weeks SOF + RBV

25/26

22/23

23/26

23/26

24/24

23/23

22/24

22/24

41/41

39/40

28/42

28/42

41/41

39/40

28/42

28/42

86/114

110/114

103/103

87/114

Genotype 2Genotype 1 Genotype 3

PHOTONPHOTON--1 Study: Virologic Outcome1 Study: Virologic Outcome

Outcome, n (%)

Treatment Naïve

Treatment Experienced

GT 1 n=114

GT 2n=26

GT 3n=42

GT 2n=24

GT 3n=17

SVR12 87 (76) 23 (88) 28 (67) 22 (92) 16 (94)

HCV virologic failure 26 (23) 1 (4) 12 (29) 1 (4) 1 (6)

Relapse 25 (22) 0 12 (29) 1 (4) 1 (6)

Completed study drug 19 0 11 0 1

Did not complete study drug 6 0 1 1 0

HCV viral breakthrough 1 (<1) 1 (4) 0 0 0

Other 1 (<1) 2 (8) 2 (5) 1 (4) 0

Naggie S, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 26.

Sofosbuvir bei HCV und HCV/HIV-Patienten: Indikationen

GILEAD Sovaldi 400mg Filmtabletten Fachinformation Januar 2014

Sofosbuvir bei HCV und HCV/HIV-Patienten: Nebenwirkungen

GILEAD Sovaldi 400mg Filmtabletten Fachinformation Januar 2014

1. Soriano V, et al. J Antimicrob Chemother 2011;66:1673–86. 2. Belda O, et al. Virus Res 2012;170:1–14. 3. Pol S, et al. ICAAC 2011, oral HI-376. 5. Gane EJ, et al. N Engl J Med 2013;368:34–44. 6. Wedemeyer H, et al. Hepatology 2013; doi: 10.1002/hep.26274 [Epub ahead of print]. 7. Gallay P, Lin K. Drug Des Devel Ther 2013;7:105-15. 8. Donnelly R, et al. Trends Immunol. 2011 September ; 32(9): 443–450. 9. http://clinicaltrials.gov/ct2/show/NCT01464827. 10. http://ir.achillion.com/releasedetail.cfm?releaseid=698938. 11. http://clinicaltrials.gov/ct2/show/NCT01030432. 12. Poordad F, et al. AASLD 2012. Abstract 83. 13. Delang L, et al. Viruses 2010;2:826–66. 14. Dieterich D et al. CROI 2013. Abstr 40LB. Available at: http://www.natap.org/2013/CROI/croi_02.htm. Accessed 13 Aug 2013. 15. www.gilead.com/research/pipeline 16. http://clinicaltrials.gov/ct2/show/NCT01353911. 17. Rehman S, et al. Genet Vaccines Ther 2011;9:11. 18. Gish RG & Meanwell NA. Clin Liver Dis 2011;15:627–39. 19. http://clinicaltrials.gov/ct2/show/NCT01448200. 20. Gane E, et al. EASL 2013. Abstr5. 21.http://www.vrtx.com/research-development/pipeline22.www.pipelinereport.org/browse/hcv-treatment/bi-207127. 23. www.pipelinereport.org/browse/hcv-treatment/abt-072. 24. http://clinicaltrials.gov/show/NCT01193361. 25. http://clinicaltrials.gov/show/NCT0158113826. http://clinicaltrials.gov/show/NCT01309932. 27. Coelmont et al. PLoS One 2010;5:e13678.

NS3/4AProteasehemmer

NS5AInhibitoren

NS5BPolymerasehemmer Cyclophilin A IFN-lambda

Characteristics• Low-to-medium

barrier to resistance1

• QD, BID or TID dosing1

• Some may require ritonavir boosting1

• General picomolar activity against multiple GTs in vitro2

• Low-to-medium barrier to resistance2

• QD dosing3

Nucleos(t)ide analogue (NUC)• Broad GT

coverage1

• High barrier to resistance1

• QD or BID dosing5,6

Non-nucleoside analogue (NNI)• Most are

GT/subtype specific1

• Low barrier to resistance1

• QD or BID dosing1

• Broad GT coverage in vitro7

• High barrier to resistance7

• BID/QD dosing7

• More limited receptor expression maylead to fewer adverse events8

• No evidence of haematological toxicity8

DrugsABT-450/r9

Sovaprevir10

Asunaprevir11

Simeprevir12

Faldaprevir14

Danoprevir13

GS-945115

MK-517216

ACH-806/GS-913217

Daclatasvir18

Ledipasvir18

ABT-2679

PI-68819

AZ-68918

MK-8742BMS-82439318

PPI-46118

Sofosbuvir20

Mericitabine6

VX-13521

Deleobuvir22

ABT-3339

ABT-07223

BMS-79132524

Tegobuvir13

Setrobuvir13

VX-22225

Filibuvir13

Alisporivir27,

SCY-63517BMS-91414326

HCV Substanzklassen und Einzelsubstanzen

Nuc Backbone + NS5A

Sulkowski M, et al. AASLD 2012. Abstract LB-2.

SOF (Nuc) + daclatasvir (NS5A) ± RBV x 24 wks

Caveats: Kleine Fallzahl, keine Phase III Studie geplant

100

80

60

40

20

0

SVR

4 or

12

(%)100

14/14

100

15/15

DCV + SOF

24 wks

SOF (Nuc) + daclatasvir (NS5A) ± RBV x 12 wks

40/41

98

39/41

95

12 wks

DCV + SOF+ RBV

DCV + SOF

DCV + SOF+ RBV

1x1: Nuc + NS5A

Treatment-naive patients (noncirrhotic)

SVR

4 or

12

(%)

95

19/20

100

21/21

SOF/LDV SOF/LDV + RBV

8 wks

95

18/19

SOF/LDV

18/19

95

21/21

100

SOF/LDV+ RBV

SOF/LDV

12 wks

PI failures (50% cirrhotic)

12 wksNo breakthrough; 2 relapses, both without RBV1 case of resistance – retreated with SOF/LDV + RBV x 24 weeks → SVR

Lawitz E, et al. AASLD 2013. Abstract 215.

LONESTAR: SOF (Nuc) + ledipasvir (NS5A) FDC ± RBV

100

80

60

40

20

0

Study Design•Sofosbuvir (nucleotide NS5B inhibitor) 400 mg/ledipasvir (NS5A inhibitor) 90 mg once daily•GS-9669 (non-nucleoside NS5B inhibitor) 500 mg once daily•GS-9451 (a protease/NS3/4 inhibitor) 80 mg once daily

•

Treatment Response (ITT)

SVR 12

SVR 12

SYNERGY (NIH Trial): Sofosbuvir + SYNERGY (NIH Trial): Sofosbuvir + Ledipasvir Ledipasvir ±± GSGS--9669 or GS9669 or GS--9451 in HCV GT19451 in HCV GT1

Kohli A, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 27LB.

Wk 0 Wk 6 Wk 12

Sofosbuvir + Ledipasvir (n=20)Sofosbuvir + Ledipasvir (n=20)

Sofosbuvir + Ledipasvir + GS-9451 (n=20)Sofosbuvir + Ledipasvir + GS-9451 (n=20)

Sofosbuvir + Ledipasvir + GS-9669 (n=20)Sofosbuvir + Ledipasvir + GS-9669 (n=20)

Treatment NaïveAll Stages Fibrosis

Treatment NaïveCirrhosis Excluded

Treatment NaïveCirrhosis Excluded

SVR 12

Perc

enta

ge o

f Pat

ient

s w

ithH

CV

RN

A <

LLO

Q (I

TT)

48 weeks

Study Design•ABT-450/r/ABT-267: 150 mg/100 mg/25 mg QD•ABT-333: 250 mg BID•RBV: 1,000 mg if body weight was <75 kg, 1,200 mg if body weight ≥75 kg, or matching placebo

SVR12 ≥99% Achieved after 12 Weeks with 3-DAA ± RBV

PEARLPEARL--III Study: ABTIII Study: ABT--450/r/ABT450/r/ABT--267 + 267 + ABTABT--333 333 ±± RBV in treatmentRBV in treatment--naive GT1bnaive GT1b

Ferenci P, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 29LB.

SVR

12,

Perc

enta

ge o

f Pat

ient

s

Assess for SVR12

ABT-450/r/ABT-267 + ABT-333 + RBVABT-450/r/ABT-267 + ABT-333 + RBVABT-450/r/ABT-267 + ABT-333 + Placebo for RBV

ABT-450/r/ABT-267 + ABT-333 + Placebo for RBV

N = 210

N = 209

Day 1 Wk 12 Wk 24 Wk 60

48–wk follow upStudy drug dosing

Superiority Threshold (84%)Noninferiority Threshold (73%)

3-DAA regimen was noninferior to 3-DAA + RBV regimen (95% Cl for difference in SVR12 rates, -2.1% to 1.1%)

ITT populationDashed horizontal line depicts noninferiority thresholdSolid horizontal line depicts superiority threshold

207/210 207/209