Transcript Document

"Beginning to Cross the
Rectal Rubicon"
Clinical Trials with UC781 & Tenofovir
Peter A. Anton MD
NIAID IP/CP U19
UCLA / University of Pittsburgh / CONRAD / MTN
an NIH IP/CP for Topical Microbicides
NIH IP/CP
Overview
• MDP: U19 funded (5 years) 8/04-7/09 for topical rectal microbicide work
• Structure: 4 Projects, 4 Cores
• Project 1: Preclinical/NHP
• Project 3: Behavioral/Acceptability
• Project 4: Pre/Phase 1 Human trials
• Project 5: Human Pharmacodymanics and Rectal Formulations
• Core A: Administrative
• Core B: Regulatory
• Core C: Data Management and Biostatistics
• Core D: Formulation Science
• Plans: new U19 submission (5 years) 7/08 to hopefully start 7/10
• Today: Review mainly Phase 1 Trials and future plans
NIH IP/CP
Related MDP achievements with
UC781 & Tenofovir
• Project 1: explant data: alone and in combination
• Project 1: exciting macaque prevention data
• Core D: developing formulations miscible with UC781, tenofovir
• Project 3: acceptability data will help guide carrier
• Project 4: acceptability data helps with formulations and carrier
• Project 5: test various formulations for distribution, permeability
NIH IP/CP
PMPA/UC781 combinations are more active than
the individual compounds
1- In cellular models (luciferase reporter cell line TZM-bl and activated
PBMCs) the IC50 values for PMPA and UC781 were reduced, on average, by
65.55 % and 55.90 %, respectively, when used in combination against a
panel of R5 and X4 HIV-1 isolates.
2- In the colorectal explant model the PMPA/UC781 combination was also
more active than the individual compounds with reductions of 82.86 % for
PMPA and 36.88 % for UC781 of the IC50 values.
3- The PMPA/UC781 combination was active against
- an NNRTI-escape mutant, A17, fully resistant to UC781, and
- an NRTI-resistant isolate with the K65R mutation
when tested in cellular and colorectal explant models.
NIH IP/CP
Clinical Trials
RMP-01: A PHASE 1 SAFETY AND ACCEPTABILITY
STUDY OF THE UC781 MICROBICIDE GEL
APPLIED RECTALLY IN HIV SERONEGATIVE
ADULTS
RMP-02 / MTN-006: A TWO-SITE, PHASE I, DOUBLEBLIND, PLACEBO-CONTROLLED SAFETY AND
PHARMACOKINETIC TRIAL OF TOPICAL,
VAGINALLY-FORMULATED 1% TENOFOVIR GEL
APPLIED RECTALLY IN HIV
SERONEGATIVE
ADULTS
NIH IP/CP
Always more questions than answers
• New?
• definition of ‘safety’? what to compare to? What’s “normal”
• first populations to study?
• where to look: anus, rectum, rectosigmoid, colon, SI??
• what assays?
• how to interpret changes that have clinical relevance?
NIH IP/CP
Pivotal: HPTN 056
• first effort to try to define these normative ranges…“immnuotoxicity”
• for primarily financial and some scientific reasons, limited to men
• HPTN 056 (McGowan PI) attempted to quantify these ranges in 4
groups (N = 4/group); each subject seen every 2 weeks for 6
weeks to evaluate reproducibility and stability of readouts.
Groups:
HIV- men, no hx of RAI
HIV- men, + hx RAI
HIV+ men, undetectable PVL
HIV+ men, PVL >5000 copies/ml
Indices…at 2 sites (10cm and 30 cm):
 Histology (quantitative & qualitative)
 secreted IgG and IgA
 cytokine mRNA from tissue
 MMC phenotypes
 not endoscopic appearance
McGowan et al JAIDS 2007
NIH IP/CP
What did we learn from HPTN 056?
• at least at this stage, not a huge difference in readouts
between 10cm and 30cm (being tested in RMP-01)
• quantitative histology far too variable in health
• HIV+ have some (predictable) baseline differences from HIV• HIV- with/without RAI no different (? frequency)
• rectal Ig readouts have large intra-subject, intra-group
variability
• cytokines and cell phenotypes quite stable
• caveats to 056: not very sexually-active population, older, men
• GOAL: to continue weaning/assessing mucosal assays
NIH IP/CP
1st trial: UC781 RM (MDP-01)
• first effort: as first RM trial, many potholes to avoid
• first effort, interventional test of HPTN 056 indices
• preferential assays for ‘safety’? Others (calprotection, fluid
cytokines)?
• how interpret findings without “positive control”?
• IND study; great collaboration with Biosyn, now CONRAD
• Pre-PSRC very helpful in preparation for PSRC
• Critical first steps by NIAID to adapt toxicity tables for AE
reporting to enable efforts to distinguish anticipated
procedure-related findings
NIH IP/CP
A PHASE 1 SAFETY AND ACCEPTABILITY
STUDY OF THE UC781 MICROBICIDE GEL
APPLIED RECTALLY
IN HIV SERONEGATIVE ADULTS:
A SAFETY REPORT
AT 100% COMPLETION (!!!)
P Anton, T Saunders, A Adler, C Siboliban, E Khanukhova, C Price,
J Elliott, K Tanner, D Cho, EJ Johnson, J Klein, A Dominquez, S Watson,
Ana Ventuneac,Alex Carballo-Dieguez, J Boscardin, Y Zhao, AM Corner, C Mauck,
I McGowan
UCLA, NIH, CONRAD
an NIH IP/CP for Topical Microbicides
1st Rectal Microbicide IND Trial
• blinded analysis at 100% completion of safety data only
• Sponsored by Biosyn, now CONRAD with NIAID’s U19 IP/CP
• Single site: UCLA
• NNRTI: UC781 evaluated in 36 seronegatives (men & women)
• 3 Groups: 0.1% gel vs. 0.25% gel vs. placebo gel (Universal, not
excipient; same as vaginal trials)
• Single and 7d exposures (subset enrolled in 24 hour pK)
• Using: vaginal formulation of the reverse-transcriptase inhibitor
UC781 gel applied rectally with vaginal applicator
NIH IP/CP
Trial Objectives and Indices
• Primary Objective:
To evaluate the safety and acceptability
of 0.1% and 0.25% UC781 vaginal
microbicide gel versus placebo when
applied rectally.
Indices:
• Frequency of ≥Grade 2 adverse events
• Acceptability assessments
NIH IP/CP
Trial Objectives and Indices
• Secondary Objectives: Using very detailed, sensitive
assays, to determine whether use is associated with rectal
mucosal damage (immunotox):
Epithelial sloughing
Histopathology
Mucosal mononuclear cell phenotype (flow)
Mucosal cytokine mRNA (tissue)
Mucosal cytokines (secreted)
Mucosal immunoglobulins
Fecal calprotectin
Explants- ex vivo susceptibility to HIV infection
*(Many compared to baselines established in HPTN 056..McGowan JAIDS 2007)
NIH IP/CP
NEW: Amended Toxicity Tables for AE
(1° endpoint)
 DAIDS EAE Reporting Manual and DAIDS Toxicity Tables
 Clarifications/Additions to avoid inaccurate AE reporting:
“diarrhea”
“hematochezia” (from NCI, not in DAIDS)
“bloody diarrhea”
“Proctitis” (stricter definition than DAIDS; used by NIDDK)
“bruising” (to cover AE related to applicator injury)(NCI)
 Protocol team to review q 2-4 weeks; DSMB on call
 Trial suspended if 2 or more subjects have ≥ Grade 3
NIH IP/CP
Applicator (vaginal form) issues
• Not optimal for rectal application,
but tolerated.
• Acceptability portion of UC781
trial asking lots of questions
regarding applicator; pilot amFAR
study underway with prototype
NIH IP/CP
Study Outline
• Study Population: HIV negative men and women with a history of
RAI (in order to give context to applicator use and acceptability
assessments)
• Study Size: 36 participants (men and women) in 3 arms
• Accrual: 9-12 months
• Duration: 14 months (First subject screened on 12/20/07 and the last
subject completed study on 04/03/08
NIH IP/CP
Inclusion Criteria
Men who meet the following 10 criteria and women who meet the following 12 criteria
are eligible for inclusion in the study:
1.
 Age of 18
2.
HIV-1 status antibody negative as documented at screening
3.
Understands and agrees to local STI reporting requirements
4.
Able and willing to communicate in English
5.
Able and willing to provide written informed consent to take part in the study
6.
Able and willing to provide adequate information for locator purposes
7.
Availability to return for all study visits, barring unforeseen circumstances
8.
A history of consensual RAI at least once in lifetime*
*Required to assure that subjects have a context for the acceptability assessments.
9.
Willing to abstain from insertion of anything per rectum other than the study gel for the
1 week prior to treatment, 1 week prior each flexible sigmoidoscopy (i.e. during
week of study gel use), and 1 week after each flexible sigmoidoscopy.
10. Willing to use condoms for the duration of the study
In addition to the criteria listed above, female participants must meet the following
criteria:
11. Negative pregnancy test
12. Post-menopausal or using an acceptable form of contraception.
Exclusion Criteria
1.
HIV positive at baseline
2.
History of inflammatory bowel disease
3.
Active inflammatory condition of the GI tract at baseline
4.
Active rectal infection at baseline
5.
≥Grade 2 laboratory abnormality at baseline
6.
Allergy to methylparaben, propylparaben, sorbic acid
7.
History of alcoholism or IV drug abuse
8.
Unwillingness to refrain from chronic use of aspirin and NSAIDs.
9.
Use of warfarin or heparin
10. Use of systemic immunomodulatory medications within 4 weeks of Visit 2
11. Use of rectally administered medications, with the exception of over the counter
enemas, within 4 weeks of Visit 2
12. Use of product containing nonoxynol-9 rectally within 4 weeks of Visit 2
13. Use of any investigational products within 4 weeks of Visit 2
14. Any other clinical condition or prior therapy that, in the opinion of the investigator,
would make the patient unsuitable for the study.
In addition to the criteria listed above, female participants will be excluded if they
meet any of the following criteria:
15. Pregnancy
16. Breastfeeding
17. Female of child-bearing potential unwilling to use acceptable form of contraception
RM Phase 1 Trial Design
Randomization: 0.1% UC781, 0.25% UC781, or placebo
flex
<4 wk
flex
 1 wk
Week 0
Visit 1
Visit 2
Screening
Baseline Behav
Questionnaire
Baseline
flex
 1 wk
Week 2
Visit 3
Single-dose
exam
~ 8 days
Week 5 Week 6
Visit 4
Visit 5
Safety;
Given
7 daily
doses
7-day
exam
Acceptability
questionnaire
Week 8
Visit 6
Phone
interview
In depth tel
interview
NIH IP/CP
UCLA IRB # 02-05-001;
approved for 30 bx per visit
Multiple publications,
Near 100% adherence
No AE
‘post-biopsy’ appearance
Indices/Assays used in UC781 RM safety trial
• “routine” clinical sn/sx and laboratories
• rectal swabs for STI, microflora
• rectal sponges for secreted IgG, IgA and cytokines *
• stool calprotectin *
• rectal lavage for epithelial sloughing *
• tissue at 10cm and 30cm for:
Histology (qualitative)(quantitative dropped)
Cytokine mRNA
MMC for phenotype by FACS
Explant infection studies *
• plasma pK (to 24 hours)
* Not in HPTN 056
NIH IP/CP
Clinical Results at 100% Completion: Blinded
• Recruit/Enroll: CFAR/IPCP Trial Registry has helped.
 146 volunteers
 55 screened
 36 enrolled (entered V2)
 36 completed
 26 men (72%) and 10 women (28%)
 no withdrawals (including due to procedures)
 average of 80 phone calls/emails to get each
subject recruited and through trial
 1 year, 3 months
NIH IP/CP
Safety Conclusions at 100% completion
• Appears safe and well-tolerated
• Subjects highly compliant with demanding protocol
• Procedures well tolerated
• No Drop outs/withdrawals
• No Grade 3 or 4 AE
• No procedure related AE
• 84 Grade 1 AE reported
• 8 Grade 2 AE reported in 5 of 36 individuals completing
(4 from one individual at V3; not at V5)
• New NIAID RM toxicity tables are useful in RM clinical
trials where biopsy procedures produce findings that
might otherwise be reported as “possibly-related’
• 36 subjects completed from 55 screened (66%)
NIH IP/CP
Ex Vivo HIV-challenge of in vivo exposed colorectal
explants may be an important predictor of
microbicidal effectiveness
Explant infectivity results from a
Phase 1 Rectal Microbicide Trial of UC781
(blinded data from 75% completed)
an NIH IP/CP for Topical Microbicides
Explants: process
• Samples acquired (large-cup forceps): 14 biopsies at each site
(10cm and 30cm)
• NO procedure-related AE; no withdrawal / loss to follow-up
• NO Microbicide DRUG ADDED (except at V2): all drug is applied IN VIVO
• To laboratory and set up within 2 hours max.
• HIV applied and left incubating for 2 hours: all washed and then
incubated for 12-14 days. Controls: media (uninfected control);
UC781 at baseline visit only to demonstrate in vitro efficacy
• Supernatants for p24 taken every 3 days; each time point is mean
of 2 biopsies pooled; cumulative profile graphed
NIH IP/CP
Colorectal explants (10 cm and 30 cm)
Endoscopic biopsies
+
Absorbable gelatin sponge
= Happy Explants
NIH IP/CP
Explants: (i) prior experience with UC781
(ii) specifics of design plan
• EXPLANTS are proven/published model:
•
•
•
Margolis et al. J Clin Invest 1998
Fletcher et al. J Virol. 2005
Fletcher et al. AIDS 2006
• UC781 has been shown to suppress/reduce explant HIV infection in
vitro, ex vivo:
•
•
•
•
•
Fletcher et al. J Virol. 2005 (UC781 inhibits infection in cervical explant model)
Abner et al. J Infect Dis. 2005 (UC781 inhibits infection in cervical explant model)
Gupta et al. AIDS Res Hum Retroviruses. 2006 (frozen/fresh explants with UC781)
Van Herrewege et al. Antiviral Res. 2007 (cell line/chamber model with UC781)
Cummins et al. Antimicrob Agents Chemother. 2007 (cervical explant model: inhibition with UC781)
• Explants from 2 sites (10 cm and 30 cm)
• Explants from 3 visits: Baseline, post single exposure, post 7-day exposure
• Each exposed to same laboratory viral strain: only R5 HIVbal
• Two viral concentrations used to ensure infectivity and assess threshold:
TCID50: 104 and 102
• CONTEXT: in our hands, 104 always causes infection (no intra-subject
variability) while 102 can vary
NIH IP/CP
Presentation Focus
Due to short presentation time AND still blinded nature of data:
Only most controlled data will be presented now.
• Data at 10 cm (clinically relevant)
• Data at Visit 3: single dose exposure (controlled)
• Data from 104 viral infection ex vivo (ensure baseline infection)
NIH IP/CP
RM Phase 1 Trial Design
Randomization: 0.1% UC781, 0.25% UC781, or placebo
flex
<4 wk
flex
 1 wk
Week 0
Visit 1
Visit 2
Screening Baseline
flex
 1 wk
Week 2
Visit 3
Single-dose
exam
~ 8 days
Week 5 Week 6
Visit 4
Visit 5
Safety
7-day
exam
Week 8
Visit 6
Phone
interview
NIH IP/CP
At Baseline (V2), 26/27 of subject’s explants infectible with
HIVBaL104 TCID50 (10 cm)
Cumulative P-24 of Visit 2 samples
(Viral_Inoculum =10000, Biopsy_location=10cm , Visit_code=V2)
1
2
11000
3
4
10000
5
6
9000
7
Cumulative P-24 (pg/ml)
8
8000
9
10
11
7000
12
13
6000
14
15
5000
16
17
18
4000
19
20
3000
21
22
2000
23
24
1000
25
26
27
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14
Days Post Explant Infection
NB: All data recoded so PI/Team blinded from Laboratory identification
NIH IP/CP
Explant infectibility at each visit
Baseline
Post single dose
TCID50 104
TCID50 102
TCID50 104
% infected (N)
at 10 cm
96%
(26/27)
63%
(17/27)
66%
(18/27)
% infected (N)
at 30 cm
96%
(26/27)
66%
(18/27)
74%
(20/27)
TCID50 102
Post 7-day
TCID50 104
TCID50 102
30%
(8/27)
96%
(26/27)
44%
(12/27)
33%
(9/27)
78%
(21/27)
63%
(17/27)
NIH IP/CP
Visit 3 Results (single dose; samples acquired at 30’)
• 18/27 (66%) subject’s explants infectible, to some degree, with HIVBaL104 TCID50
• 9/27 (33%) subject’s explants unable to establish infection with HIVBaL104 TCID50
• One subject (#19) never established infection (FACS shows +CCR5)
Cumulative P-24 of explants at V3
(Viral_Inoculum =10000, Biopsy_location=10cm , Visit_code=V3)
1
2
7000
3
4
5
6000
6
7
Cumulative P-24 (pg/ml)
8
9
5000
10
11
12
4000
13
14
15
16
3000
17
18
19
20
2000
21
22
23
1000
24
25
26
27
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14
Days Post Explant Infection
NIH IP/CP
Visit 3 Results (single dose; samples acquired at 30’)
Cumulative P-24 of explants at V3
(Viral_Inoculum =10000, Biopsy_location=10cm , Visit_code=V3)
1
2
7000
3
4
5
6000
6
Cumulative P-24 (pg/ml)
7
No
change
5000
8
• 33% with NO INFECTION
• 33% with NO CHANGE
• 33% in MIDDLE
9
10
11
12
4000
13
14
15
16
3000
BLINDED
17
18
19
20
2000
21
22
23
1000
Middle
24
25
1 non-responder
in “NO infection”
group
26
NO
infection
0
1
2
3
4
5
6
7
8
9
27
10 11 12 13 14
Days Post Explant Infection
NIH IP/CP
BLINDED Data UC781 RM Trial:
Expanded view of 33% subjects showing “No infection”
and 33% subjects showing “No change” (Visit 3)
A
B
V3 -No Change
V3 - No infection
7000
19
2
21
5000
22
Cumulative P-24 (pg/ml)
Cumulative P-24 (pg/ml)
20
6000
23
4000
3000
2000
1
7000
24
25
26
27
1000
6000
3
5000
4
5
4000
6
3000
7
8
2000
9
1000
0
0
1 2 3 4
5 6 7 8 9 10 11 12 13 14
Days Post Explant Infection
1 2
3 4 5
6 7 8 9 10 11 12 13 14
Days Post Explant Infection
NIH IP/CP
No differences appreciated at Baseline between the
33% “no infection”and the 33% “no change” groups
V2 -1/3 with NO CHANGE at V3
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
19
20
Cumulative P-24 (pg/ml)
Cumulative P-24 (pg/ml)
V2 - 1/3 with NO INFECTION at V3
21
22
23
24
25
26
27
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Days Post Infection
1
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
2
3
4
5
6
7
8
9
1
2
3
4 5
6
7
8
9 10 11 12 13 14
Days Post Infection
NIH IP/CP
Following 7 days of daily dosing (V5),
no emerging pattern of response yet evident.
V5 - No infection at V3
Cumulative P-24 on samples post 7-Day use
(Viral_Inoculum =10000, Biopsy_location=10cm , Visit_code=V5)
2
3
4
5
6000
6
7
9
5000
10
11
4000
20
6000
21
5000
22
23
4000
24
3000
25
2000
26
27
1000
0
12
1 2 3 4 5 6 7 8 9 10 11 12 13 14
13
Days Post Infection
14
15
16
3000
17
V5 -No Change group at V3
18
19
2000
20
22
23
1000
24
25
26
27
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14
Days Post Infection
1
7000
21
Cumulative P-24 (pg/ml)
Cumulative P-24 (pg/ml)
8
Cumulative P-24 (pg/ml)
1
7000
19
7000
2
6000
3
5000
4
5
4000
6
3000
7
2000
8
9
1000
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14
Days Post Infection
NIH IP/CP
Interpretations
•
•
•
•
Data (75% reported here) all still blinded
Nearly all explants infectible at Baseline (26/27; 96%)
3 study groups: placebo, high-dose UC781, low-dose UC781
Important observation: Not all results the same after single exposure
• Convenient to anticipate that high drug dose are group that showed no
response to 104 HIV infection ex vivo; even MIDDLE group
demonstrated some reduction in infection…need to await unblinding.
• If so: (i) potentially important biomarker, especially for Phase 1 trials
(ii) remarkable that a “clinically-safe”, in vivo rectally-applied drug
dose could retain efficacy in assay of ex vivo tissue infection, using
clinically excessive doses of laboratory viral strain (R5 only)
NIH IP/CP
Data Presentation: Other assays
• Blinded data presented with laboratory numbers
recoded to maintain blind…numerical sequence #
• Data presented as box plot showing 25-75% range
(Interquartile range=IQR) with median identified;
‘whiskers’ reflect 1.5xIQR. “Outliers” are small circles
• Data presented as “grouped” at each visit
• Data next presented according to explant ‘responders’,
‘non-responders’ or ‘middle’
• When available, HPTN 056 data presented to give
context and evidence of reproducibility at baseline
NIH IP/CP
MMC phenotypes by FACS: Does CCR5 on CD4 change?
CCR5 expression on CD4+ MMC does not seem to change in group as a whole after
single or 7-day exposure; Subset analysis based on explant responders: no changes.
Mean similar to HPTN 056
U19 (Non-resp)
U19 (Med)
U19 (Responder)
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
HPTN056
(n=8,v=24)
60
40
20
0
% CCR5+on CD4+
80
100
U19 (All)
Group
NIH IP/CP
MMC phenotypes by FACS: Do ‘double +s’ on CD4 change?
U19 (All)
U19 (Non-resp)
U19 (Med)
U19 (Responder)
HPTN056
(n=27)
(n=9)
(n=9)
(n=9)
(n=8,v=24)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
60
40
20
0
% CCR5+ X4+on CD4+
80
100
CCR5/CXCR4 dual expression on CD4+ MMC does not seem to change in group as a
whole after single or 7-day exposure; Subset analysis based on explant responders: no
changes. Mean similar to HPTN 056
Group
NIH IP/CP
MMC phenotypes by FACS: Does activation on CD4 change?
U19 (All)
U19 (Non-resp)
U19 (Med)
U19 (Responder)
HPTN056
(n=27)
(n=9)
(n=9)
(n=9)
(n=8,v=24)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
6
4
2
0
DR+CD38+ CD4+
8
10
While trends in CD38 and HLA-DR on CD4 MMC may be suggested, there is no difference
over time compared to baseline changes. HPN 056 data not immediately available.
Group
NIH IP/CP
Collection of rectal secretions
for cytokines/chemokines
with surgical sponges
Luminal cytokines by Luminex™: IL-1b or IL-6
No appreciable differences over time or within subgroups of IL-1b or IL-6.
In general, IQR reasonably tight for whole group at baseline.
100
U19 (All)
Boxplots of IL-6
U19 (NON) U19 (Med) U19 (RESP)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
U19 (NON) U19 (Med) U19 (RESP)
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
0
20
40
IL-6
60
60
40
20
0
IL-1b
U19 (All)
80
(n=27)
80
100
Boxplots of IL-1b
Group
Group
Luminal cytokines by Luminex™: IL-12 or IFN-g
No appreciable differences over time or within subgroups of IL-12 or IFN-g.
IQR reasonably tight for IL-12; broad for IFN-g.
U19 (Low) U19 (Med) U19 (High)
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
U19 (All)
200
U19 (All)
Boxplots of Ing-gamma
U19 (Low) U19 (Med) U19 (High)
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
150
50
100
Ing-gamma
20
15
10
0
5
0
IL-12(p-40)
25
30
Boxplots of IL-12(p-40)
Group
Group
Luminal cytokines by Luminex™: TNF-a or RANTES
No appreciable differences over time/within subgroups of TNF-a or RANTES.
IQR reasonably tight for TNF-a; broad for RANTES.
U19 (All)
U19 (Low) U19 (Med) U19 (High)
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
400
U19 (All)
Boxplots of RANTES
U19 (Low) U19 (Med) U19 (High)
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
300
Group
0
100
200
RANTES
40
20
0
TNF-Alpha
60
80
Boxplots of TNF-Alpha
Group
Luminal cytokines by Luminex™: MIP-1a
No appreciable differences over time or within subgroups of MIP-1-a.
In general, more variable IQR.
U19 (All)
U19 (Low) U19 (Med) U19 (High)
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
300
200
100
0
MIP-1 Alpha
400
500
Boxplots of MIP-1 Alpha
Group
“Blinded” Interpretations
• MMC phenotypes: Based on FACS data, there appears to be no
difference among the all subjects in the 3 groups (placebo, highdoes, low-dose) over all visits on co-receptor expression or
activation status.
• Rectal fluid cytokines: Using Luminex™ data from rectal sponges
eluates, there does not appear to be any trend/significant differences
among 7 measured cytokines/chemokines after single or 7 day
exposure.
• Based on these still blinded data, if these assays (MMC phenotype and
‘secreted’ cytokines) are relevant and sensitive enough to assess
early/mild immunoreactive changes to topical UC781 exposure, we are
not detecting such changes
NIH IP/CP
Boxplots of IgA
UC-781 (All) U19 (Low) U19 (Med) U19 (High) HPTN056
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
(n=8,v=24)
150000
50000
0
IgA (ng/ml)
250000
350000
Boxplots comparing range of IgA at UC781 baseline (V2) with HPTN 056
Group
NIH IP/CP
Boxplots comparing range of IgG at UC781 baseline (V2) with HPTN 056
U19 (All)
U19 (Low) U19 (Med) U19 (High) HPTN056
(n=27)
(n=9)
(n=9)
(n=9)
V2 V3 V5
V2 V3 V5
V2 V3 V5
V2 V3 V5
(n=8,v=24)
40000
20000
0
IgG (ng/ml)
60000
80000
Boxplots of IgG
Group
NIH IP/CP
Findings thus far in UC781..still blinded
• safe
• intensive recruiting/scheduling (~80 phone
calls/emails per subject): HIGH adherence
• no significant AE or procedure problems
• most immunoassays: no difference seen across 36
• explant data: exciting. May be potential bio-indicator
• lessons from blinded results that have guided next trial:
 no apparent difference between 10cm and 30cm;
therefore, only 10cm in next trial. Can anal bx
with stool and sponges suffice?
 Ig variabilty even greater in this trial that in HPTN
056..therefore, dropped as future
immunotox/safety assay in next trial
NIH IP/CP
RMP-02 / MTN-006:
A TWO-SITE, PHASE I, DOUBLE-BLIND, PLACEBO-CONTROLLED
SAFETY AND PHARMACOKINETIC TRIAL OF
TOPICAL, VAGINALLY-FORMULATED 1% TENOFOVIR GEL
APPLIED RECTALLY
WITH AN EXPLORATORY PHARMACOKINETICS STUDY
COMPARING TOPICAL WITH ORAL TENOFOVIR LEVELS
IN RECTAL TISSUE, RECTAL FLUID, AND BLOOD
IN HIV SERONEGATIVE ADULTS
 NOVEL: Sponsored by CONRAD, MTN, Gilead, NIAID’s U19 IP/CP
 2 Sites: UCLA & McGee/U Pitt
 Tenofovir (oral/topical) evaluated in 18 seronegatives
 Oral: all get 300 mg tablet (single exposure only)
 Topical: Randomized 2:1 (1% drug: Universal placebo)(single; 7-day)
 pilot PK: plasma
 exploratory pK: 5 (maybe 6) compartments (includes intracellular)
NIH IP/CP
Study points
INDs: Oral and topical help by DAIDS with cross-referencing letters, will
complement MTN efforts. CONRAD singly supporting animal tox.
Protocol development: Outline completed (CONRAD/UCLA) enough to
submit initial questions to FDA. Need MTN input now and then
NIH PO/MO review/support prior to DAIDS PSRC. Then, FDA
topical IND submitted in parallel with IRBs.
Practical start/end dates: First enrolled 1/09; end enroll 6/09
Endpoints:
• Primary: Safety & Immunotoxicity
• Secondary: Drug concentrations in plasma and rectal compartments
• Tertiary: Preliminary efficacy
Study: each subject with total of 8 flex sigs (10cm only); 5 compartments
sampled for pK over 2 weeks; oral IC c/w topical IC of PBMC &
MMC
NIH IP/CP
Indices/Assays used in UC781 Tenofovir RM safety trial
• “routine” clinical sn/sx and laboratories
• rectal swabs for STI, microflora
• rectal sponges for secreted IgG, IgA and cytokines *
• stool calprotectin *
• rectal lavage for epithelial sloughing *
• tissue at 10cm and 30cm for:
Histology (qualitative)
Cytokine mRNA
MMC for phenotype by FACS
* Not in HPTN 056
Explant infection studies *
• plasma pK (to 24 hours); tissue/fluid pK (to day 14)
NIH IP/CP
Oral/Topical Tenofovir RM trial
Baseline
Week:
0
1
Visit:
1
2
Screen Flex
Single
Topical
Oral
2
3
34
4
5
5A/B 6A/B
Flex 50%
Flex
Flex 50%
6
9
10
7 8 9A/B 10A/B 11
12
Flex
7
7-day
Topical
8
Flex 50%
Flex 50%
F/U Safety
Phone call
Flex
Randomization: 2:1 (drug:placebo)-but ALL subjects get oral Tenofovir
1:1 (for biopsies: Group A:Group B)
Group A flex sigs: Baseline, ORAL: 30’, d 1-3, 7-9; TOPICAL (single): 30’, d 1-3, 7-9; TOPICAL (7-day): 30’= 8 flex sigs
Group B flex sigs: Baseline, ORAL: 30’, d 4-6, 10-12; TOPICAL (single): 30’, d 1-3, 7-9; TOPICAL (7-day): 30’= 8 flex sigs
Future Plans
•
•
•
•
•
Break blind on UC781 trial 6/1/08
Start oral/topical tenofovir trial
Continue formulation work with eye toward combinations
Develop rectal-specific formulations
Develop rectal-specific applicators
• Trial of rectally formulated UC781
• Trail of rectally formulated tenofovir
• Meet FDA needs for:
 trial of rectally formulated combination
NIH IP/CP
•NIH NIAID U19 IP/CP #AI060614: “Microbicide Development Program”
Biosyn, Inc
Anne Marie Corner
Linda Knapp
Linda Kristekas
CONRAD
Henry Gabelnick
Christine Mauck
Tim McCormick
Marianne Callahan
UCLA
Ian McGowan (U Pitt)
Chomchay Siboliban
Amy Adler
Terry Saunders
Elena Khanukhova
Charlie Price
Julie Elliott
John Boscardin
Ying Zhao
Daniel Cho
Karen Andrews
Elizabeth Johnson
Alexis Dominguez
Julia Klein
NIH
Jim Turpin
Jeanna Piper
Cherylnn Mathias
Grace Chow
MTN
Consultants
Alex Carballo-Dieguez
Ana Vetuneac
VOLUNTEERS!
an NIH IP/CP for Topical Microbicides
Numbering of Clinical Trials
RMP-01: Project 4: The current P4A1 trial with UC781
RMP -02/MTN-006: Project 4: The next RM trial with
oral/topical tenofovir
RMP-03: Project 3's Aim 1 and 2 study of 880 subjects
RMP-04: Project 3's Aim 3 acceptability study
RMP-05: Project 5, Aim 1 enema study
RMP-06: Project 5, Aim 2 rectal formulation study
NIH IP/CP