A Phase II, open-label trial in treatment-na

1
A Phase II, open-label trial in treatment-naïve,
HIV-1-infected patients who received DRV/r as
induction monotherapy

• Patricia Patterson,1 Alejandro Krolewiecki,1
  Frank Tomaka,2 Sabrina Spinosa-Guzman,3 Diego
  Miralles4 and Pedro Cahn1

1Fundacion Huesped, Buenos Aires, Argentina
2Tibotec Inc, Yardley, PA, USA 3Tibotec BVBA,
Mechelen, Belgium 4PRD West Coast Research
Center, San Diego, CA, USA
2
Pedro Cahn Disclosures

• Investigator Abbott Avexa Boehringer-Ingelheim
  BMS GSK Myriad Merck Pfizer Pharmasset
  Tibotec Schering-Plough
• Speaker Abbott BMS Gilead Merck Pfizer
  Tibotec
• Scientific Advisor Avexa GSK Myriad Merck
  Pfizer Tibotec, Schering-Plough

3
Background

• Simplifying ARV therapy for HIV-infected patients
  is important to ensure long-term treatment
  adherence, minimise toxicities and reduce costs.
  Strategies could include
• induction monotherapy
• maintenance monotherapy
• Maintenance monotherapy data with once-daily
  DRV/r in virologically suppressed patients have
  shown encouraging results
• MONET 48-weeks HIV-1 RNA lt50 copies/mL1 DRV/r
  800/100mg qd monotherapy (84.3) was non-inferior
  to DRV/r 800/100mg qd 2 NRTIs (85.3)

1. Squires et al, 5th IAS 2009. Abstract
TUAB106-LB Ripamonti et al, 12th EACS 2009.
Abstract PS4/1
4
TMC114-C227 pilot study in ARV treatment-naïve
patients objectives

• TMC114-C227 was an exploratory pilot study
  designed to evaluate once-daily DRV/r induction
  monotherapy in treatment-naïve patients
• stringent inclusion/exclusion criteria were
  applied to decrease the risk of virological
  failure
• virological responses were closely monitored
• rigorous criteria were applied to discontinue
  treatment immediately if there was evidence that
  treatment did not result in complete viral
  suppression

5
TMC114-C227 pilot study design

• Pilot, open-label, uncontrolled, Phase II trial
  to investigate the sustained antiretroviral
  activity of DRV/r induction monotherapy in 24
  treatment-naïve, HIV-1-infected adult patients
  over 48 weeks

• ARV-naïve, HIV-1-infected adult patients ?18yrs
  old
• Screening HIV-1 RNA 10,000100,000 copies/mL
  (Panel A)
• CD4 cell count gt100 cells/mm3 at screening
• No resistance mutations at screening
• N11 (initial enrolment Panel A followed by
  enrolment of 13 additional patients Panel B)

Treatment phase (up to 48 weeks)
4 week follow-up period
DRV/r 800/100mg qd monotherapy

• Primary endpoints
• Week 4 HIV-1 RNA decrease from baseline of gt1.0
  log10 copies/mL
• Week 8 HIV-1 RNA lt400 copies/mL in ?7 patients
• Weeks 24 and 48 HIV-1 RNA lt50 copies/mL

The following polymorphisms were allowed as
they have no known effect on DRV susceptibility
I13V, K20I/M/R, M36I/V, D60E, I62V, L63P, A71T/V,
V77I and I93L.
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TMC114-C227 stopping rules
N11 (Panel A) (BL VL10,000100,000
copies/mL)
After 8 weeks of treatment
?7/11 patients achieve HIV-1 RNA lt400 copies/mL
7
TMC114-C227 patient demographics and baseline
characteristics
N7
Baseline demographics
Male, n 6
Median age, years (range) 39 (3059)
Caucasian/Hispanic, n 6/1
Disease characteristics
Median (range) baseline HIV-1 RNA, copies/mL 52,183 (20,882145,002)
Median CD4 cell count, cells/mm3 (range) 145 (64353)
Mean duration of known HIV infection, years ( SD) 5.9 (4.32)

• 3 patients had HIV-1 RNA 100,000 copies/mL at
  baseline (all 3 had HIV-1 RNA lt100,000 at
  screening, required for eligibility)
• 2 patients had CD4 cell count lt100 cells/mm3 at
  baseline (both patients had CD4 cell count gt100
  cells/mm3 at screening as required for
  eligibility)

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TMC114-C227 patient disposition

• 38 excluded (due to 1 failing criteria)
• 21 due to failure to meet screening HIV-1 RNA
  criteria (16 with HIV-1 RNA gt100,000 copies/mL 5
  with HIV-1 RNA lt10,000 copies/mL)
• 22 due to failure to meet screening resistance
  criteria
• 5 due to CD4 lt100 cells/mm3
• 2 due to acute hepatitis HAV IgM and HBsAg
• 2 withdrew consent

45 patients screened
Screening
7 patients received DRV/r monotherapy
0
All 7 patients reached Week 12
12
Week
24
Trial terminated at Week 32 3 patients reached
the Week 32 visit. Decision to terminate trial
based on difficulties meeting inclusion criteria
and trend to insufficient number of patients
achieving virological endpoints at Week 32
36
9
TMC114-C227 observed change in log10 plasma
HIV-RNA from baseline individual patient data
6
100,000 copies/mL
5
4
HIV-1 RNA (log10 copies/mL)
3
400 copies/mL
2
50 copies/mL
1
0
2
32
0
4
8
12
16
20
24
Screening
1
D/C001, 002, 003
D/C004
D/C005, 006
D/C007
Time (weeks)
HIV-1 RNA lt50 copies/mL was imputed as 49
copies/mL
10
TMC114-C227 post-trial period individual
patient data

• Post-trial, all 7 patients received combination
  therapy with DRV/r, lamivudine plus zidovudine.
  One patient was switched to tenofovir plus
  lamivudine due to anaemia
• All patients achieved HIV-1 RNA lt50 copies/mL by
  12 weeks after intensification

6
5
4
HIV-1 RNA (log10 copies/mL)
3
2
50 copies/mL
1
D/C001, 002, 003
D/C004
D/C005, 006
D/C007
0
32
Screening
0
4
8
12
16
20
24
Time (weeks)
HIV-1 RNA lt50 copies/mL was imputed as 49
copies/mL
11
TMC114-C227 post-trial period individual
patient data

• Post-trial, all 7 patients received combination
  therapy with DRV/r, lamivudine plus zidovudine.
  One patient was switched to tenofovir plus
  lamivudine due to anaemia
• All patients achieved HIV-1 RNA lt50 copies/mL by
  12 weeks after intensification

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Post-trial intensification
5
4
HIV-1 RNA (log10 copies/mL)
3
2
50 copies/mL
1
D/C001, 002, 003
D/C004
D/C005, 006
D/C007
0
32
48
Screening
0
4
8
12
4
12
16
20
24
16
24
32
0
Time (weeks)
Follow-up time (weeks)
HIV-1 RNA lt50 copies/mL was imputed as 49
copies/mL
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TMC114-C227 resistance determinations

• Post-screening resistance data were available for
  two patients with viraemia and paired
  baseline/endpoint genotypes
• no DRV RAMs developed
• no IAS-USA major PI mutations developed

Baseline HIV-1 RNA (copies/mL) Endpoint Endpoint Developing mutations at endpoint Developing mutations at endpoint
Patient Baseline HIV-1 RNA (copies/mL) Visit HIV-1 RNA (copies/mL) PI mutations RT mutations
001 145,002 Week 32 1,369 I13V, K14R, I64L, I72V -
005 125,502 Week 12 1,113 - E138Q, T200A, Q207H
none of these mutations correspond to DRV RAMs
or IAS-USA major PI mutations
Resistance testing was performed locally only 2
samples were received for post screening testing
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TMC114-C227 summary of safety

• Most common adverse events (AEs, all grades,
  regardless of causality and occurring in gt2
  patients) were
• nasopharyngitis (n6)
• diarrhoea (n4)
• asthenia (n3)
• No grade 3 or 4 AEs or laboratory abnormalities
  were reported
• There were no serious AEs or discontinuations due
  to AEs
• No new safety information emerged compared with
  the safety profile of once-daily DRV/r from
  larger trials

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TMC114-C227 overall summary

• Only 7 of the 11 patients planned for the first
  phase could be enrolled
• At Week 4, all 7 patients achieved ?1 log10 HIV-1
  RNA reduction from baseline and maintained it
  during the treatment phase
• The trial was discontinued at Week 32 as it was
  unlikely that it would reach its predetermined
  virological endpoints and had a high screening
  failure rate
• Dosing with once-daily DRV/r was generally
  well-tolerated
• Patients with paired baseline/endpoint genotypes
  did not develop DRV mutations or IAS-USA major PI
  mutations on failure
• All patients subsequently achieved HIV-1 RNA lt50
  copies/mL following intensification with NRTIs

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TMC114-C227 study limitations

• TMC114-C227 was a small pilot study
• an insufficient number of patients could be
  enrolled due to restrictive inclusion/exclusion
  criteria
• Only 7 of the 11 planned patients in Panel A
  could be enrolled
• The pre-planned stopping rules may have been too
  stringent
• although all enrolled patients met the HIV-1 RNA
  screening criterion, at the time of the baseline
  visit 3 of the 7 patients had HIV-1 RNA gt100,000
  copies/mL

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TMC114-C227 conclusions

• All patients achieved gt1 log10 HIV-1 RNA
  reduction by Week 4 but complete viral
  suppression was not consistently achieved on
  induction monotherapy
• Due to study limitations, definitive conclusions
  cannot be drawn from this pilot study
• After the study, all patients achieved HIV-1 RNA
  lt50 copies/mL with intensification of therapy

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Acknowledgements

• The authors express their gratitude to the
  patients who participated in the study, as well
  as the study centre staff and the TMC114-C227
  study team
• The authors would also like to thank Sandra De
  Meyer, Tom Van De Casteele and Vanitha Sekar from
  Tibotec for their contributions to the data
  analyses and interpretation and Eric Lefebvre,
  Ralph DeMasi, Gaston Picchio and Andrew Hill for
  their important contributions to the presentation
• Editorial support was provided by Catherine
  Elliott of Gardiner-Caldwell Communications,
  Macclesfield, UK this support was funded by
  Tibotec