TMC125 Safety and Tolerability: 24-week Results of the Pooled DUET-1 and -2 Trials

TMC125 Safety and Tolerability: 24-week Results of the Pooled DUET-1

and -2 Trials

R Haubrich, M Schechter, S Walmsley, M Peeters, M Janssens, G De Smedt

on behalf of the DUET-1 and DUET-2 study groups

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Haubrich R, et al. Oral presentation presented at IDSA 2007. Abst 1210.

Inclusion criteria plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for

≥8 weeks ≥1 NNRTI mutations,‡ current or documented historical ≥3 primary PI mutations sites: Thailand, Australia, Europe and the Americas

DUET: Study Design

24-week primary analysis

Randomized

*All patients received a background regimen of DRV/r plus NRTIs and optional enfuvirtide

TMC125 + BR*

Placebo + BR*

‡From extended list of NNRTI mutations; BR = background regimen; DRV/r = darunavir with low-dose ritonavir; RAM = resistance-associated mutation

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Baseline Characteristics and Treatment Duration

Parameter, % or median (range)

TMC125 group (n=599)

Placebo group(n=604)

Treatment duration at time of analysis (weeks) 30 (1–60) 29 (3–55)

Patient demographics

Male (%) 90 89Caucasian (%) 70 70Age 45 (18–77) 45 (18–72)

Disease characteristics

Viral load (log10 copies/mL) 4.8 (2.7–6.8) 4.8 (2.2–6.5)

Viral load >100,000 copies/mL 38 36

CD4 cells (cells/mm3) 99 (1.0–789) 109 (0.0–912)

CD4 cells <50 cells/mm3 36 35

CDC category C (%) 58 59

Hepatitis B/C coinfection 13 12

Patient history Psychiatric symptoms (any type) 46 42

NNRTI-associated rash 8 14

Prior ARV use 10 ARVs (%) 80 83

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Overview of Adverse Events

Parameter, %TMC125 group

(n=599)Placebo group

(n=604)

Any AE (any cause) 92 93Grade 3 AE 22 25Grade 4 AE 7 9Serious AE (SAE) 13 19Death (any cause) 1 2Discontinuation due to AE 6 4

Most common AEs (>10% in either group, regardless of severity and causality)*Rash (any type) 17 9Diarrhea 15 20Nausea 14 11Headache 9 12

AEs leading to death were not reported in more than one patient except for pneumonia and sepsis (n=2 each) in the placebo group

None of the deaths in the TMC125 group were considered related to TMC125

*excluding injection site reactions; §p=0.0001 vs placebo; AE = adverse event

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Grade 3 and 4 Adverse Events

AE regardless of causality, n (%)TMC125 group


(n=604)

Any grade 3/4 AE 25 27

Most common grade 3/4 clinical AEs (>0.5% in pooled TMC125 group)*

Rash (any type) 1.3 0

Peripheral neuropathy 1.0 0

Pancreatitis 0.7 0

Pneumocystis jiroveci pneumonia 0.7 0.7

Renal failure 0.7 0.3

*excluding injection site reactions and grade 3/4 laboratory abnormalities reported as AEs

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Rash

In the TMC125 group: Early onset: median 12 days Limited duration: median 11 days Low severity: most mild to moderate; 1.3% grade 3, none grade 4

mostly maculopapular; no mucosal involvement Infrequently led to discontinuation: 2.2% of patients (0% with placebo)

most resolved with continued treatment

Clinical associations with rash No association with baseline CD4 cell count No increased risk with prior NNRTI-related rash

Investigator assessment of cause of rash, %


Placebo group(n=604) Significance

Any cause 17 9.4 p<0.001

Possibly related to study medication 12 4.8

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Incidence of Rash by Gender

Patients experiencing rash (any type), %

TMC125 group

Male (n=539) Female (n=60)

Overall incidence 16 28Grade 3 1.1 3.3

Leading to permanent discontinuation 1.9 5.0

Higher incidence in women: 28% vs 16% in men No clear difference in severity or discontinuations between genders

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Incidence and Prevalence of Rash (Any Type) by Treatment Group

Incidence Prevalence

Placebo group (n=604)TMC125 group (n=599)

Inci

den

ce

(%)

10

8

6

4

2

0

Pre

vale

nce

(%

)

0 4 8 12 16 20 24

Week0 4 8 12 16 20 24

Week

10

8

6

4

2

0

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Nervous System*

Similar incidence to placebo: 15% in TMC125 group versus 18% in placebo group (p=0.09)

Low severity: mostly grade 1 and 2

Did not lead to discontinuation: none in TMC125 group and 1.0% of placebo group

Patients experiencing nervous system-related AEs, %


Placebo group (n=604)

Grade 3 0.3 1.6

Grade 4 0 0

Most common (reported in ≥1.0% of patients in the TMC125 group)

Headache 9 12

Dizziness 3 4

Somnolence 2 2

*Includes only nervous system events associated with the use of approved NNRTIs

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Psychiatric Disorders

Patients experiencing psychiatric-related AEs, %

TMC125 group

(n=599)

Placebo group

(n=604)

Grade 3 0.2 1.3Grade 4 0 0.2

Most common (reported in ≥1.0% of patients in the TMC125 group)Insomnia 6 7Depression 3 5Anxiety 3 3Sleep disorder 1 1

Similar incidence to placebo: 13% in TMC125 group versus 15% in placebo group (p=0.3)

Low severity: mostly grade 1 and 2

Infrequently lead to discontinuation: 1 patient (0.2%) in each group

No increased risk in patients with a history of psychiatric disorders

Abnormal dreams/nightmares in 5 patients (0.8%) in each group and no episodes of hallucinations, suicidal ideation or manic symptoms with TMC125

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Hepatic AEs and Laboratory Abnormalities

20

0

–20

–400 8 16 24 32 40 48

ALT

Ch

ang

e f

rom

b

asel

ine

(U/L

)

Week

20

0

–20

–400 8 16 24 32 40 48

AST

Week

TMC125 group Placebo group

ALT = alanine aminotransferase; AST = aspartate aminotransferase

Hepatic AEs, %TMC125 group


(n=604)

Any cause or severity 5.3 5.1Grade 3/4 3.8 3.1

Grade 3/4 in hepatitis coinfected patients 4.2 4.4

Leading to discontinuation 0.7 0.7

Laboratory abnormalities

ALT elevated (grade 3 or 4) 1.9 and 0.7 1.3 and 0.3

AST elevated (grade 3 or 4) 2.0 and 0.5 1.3 and 0.3

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Treatment-emergent Laboratory Abnormalities

Parameter, %TMC125 group


(n=604)

At least one laboratory abnormality 98 100

Grade 1/2 93 93

Grade 3/4 32 32

Most common (>2% in TMC125 group) grade 3/4 laboratory abnormalities

Amylase (>2x ULN) 7.5 7.9

Triglycerides (>750mg/dL) 7.0 4.3

Total cholesterol (>300mg/dL) 5.8 4.1

Increased LDL-cholesterol (190mg/dL)

5.2 5.4

Decreased neutrophils (<750mg/dL) 3.7 6.3

Increased glucose (>250mg/dL) 2.5 2.0

Increased ALT (>5x ULN) 2.5 1.7

Increased AST (>5x ULN) 2.5 1.7

Abstract 1210

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal

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-200

-150

-100

-50

0

50

0 8 16 24 32 40 48

-5

0

5

10

15

20

0 8 16 24 32 40 48

0

20

40

60

80

100

0 8 16 24 32 40 48

HDLLDL calculated

Lipid Changes over Time

Total cholesterol/HDL Triglycerides

-100-80-60-40-20

02040

0 8 16 24 32 40 48

TMC125 group Placebo group

HDL = high density lipoprotein; LDL = low density lipoprotein

Ch

ang

e f

rom

b

asel

ine

(mg

/dL

)C

han

ge

fro

m

bas

elin

e (m

g/d

L)

Week Week

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Hospitalizations

0

5

10

15

20

Pat

ien

ts h

osp

ital

ized

at

leas

t o

nce

b

y 24

wee

ks (

%)

16%

11%

Placebo groupTMC125 group

p=0.0031

0

500

1000

1500

2000

1700

1105

Cu

mu

lati

ve d

ays

ho

spit

aliz

ed

by

24 w

eeks

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Safety Conclusions from DUET

Assessing safety/ tolerability of this new agent in a complex background was facilitated by the placebo-controlled design

Safety and tolerability of TMC125 was similar to placebo

Rash, the only AE to occur more frequently with TMC125 generally mild to moderate often resolved with continued treatment associated with low discontinuation (2% versus 0% with placebo)

Overall, most AEs were of low severity and infrequently led to discontinuation 6% vs 4% in the TMC125 vs placebo groups

TMC125 was not associated with any increase in laboratory abnormalities, including hepatic and lipid parameters

TMC125 provides a tolerable new option for treatment-experienced patients not associated with common NNRTI side effects

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TMC125 Safety and Tolerability: 24-week Results of the Pooled DUET-1 and -2 Trials

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