an nih ip/cp for topical microbicides "beginning to cross the rectal rubicon" clinical...

an NIH IP/CP for Topical Microbicides

"Beginning to Cross the Rectal Rubicon"

Clinical Trials with UC781 & Tenofovir

Peter A. Anton MD

NIAID IP/CP U19UCLA / University of Pittsburgh / CONRAD / MTN

NIH IP/CP

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

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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

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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.

PMPA/UC781 combinations are more active than the individual compounds

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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, DOUBLE-BLIND, PLACEBO-CONTROLLED SAFETY AND PHARMACOKINETIC TRIAL OF TOPICAL,

VAGINALLY-FORMULATED 1% TENOFOVIR GEL APPLIED RECTALLY IN HIV SERONEGATIVE ADULTS

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• 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?

Always more questions than answers

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• 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/mlIndices…at 2 sites (10cm and 30 cm):

Histology (quantitative & qualitative) secreted IgG and IgA cytokine mRNA from tissue MMC phenotypes not endoscopic appearance

Pivotal: HPTN 056

McGowan et al JAIDS 2007

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• 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

What did we learn from HPTN 056?

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• 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

1st trial: UC781 RM (MDP-01)


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

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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

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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

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Trial Objectives and Indices• Secondary Objectives: Using very detailed, sensitive

assays, to determine whether use is associated with rectal mucosal damage (immunotox):

Epithelial sloughingHistopathologyMucosal mononuclear cell phenotype (flow)Mucosal cytokine mRNA (tissue)Mucosal cytokines (secreted)Mucosal immunoglobulinsFecal calprotectinExplants- ex vivo susceptibility to HIV infection

*(Many compared to baselines established in HPTN 056..McGowan JAIDS 2007)

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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

• Not optimal for rectal application, but tolerated.

• Acceptability portion of UC781 trial asking lots of questions regarding applicator; pilot amFAR study underway with prototype

Applicator (vaginal form) issues

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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

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 Criteria1. 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

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RM Phase 1 Trial Design

Randomization: 0.1% UC781, 0.25% UC781, or placebo

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6

Screening Phone interview

Single-doseexam

Safety;Given 7 daily doses

7-day examBaseline

<4 wk 1 wk 1 wk~ 8 days

Week 0 Week 2 Week 5 Week 6 Week 8

flex flex flex

Baseline Behav Questionnaire In depth tel

interviewAcceptabilityquestionnaire

‘post-biopsy’ appearance

UCLA IRB # 02-05-001; approved for 30 bx per visit

Multiple publications,Near 100% adherenceNo AE

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• “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 mRNAMMC for phenotype by FACSExplant infection studies *

• plasma pK (to 24 hours)

Indices/Assays used in UC781 RM safety trial

* Not in HPTN 056

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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

• 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%)

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Safety Conclusions at 100% completion


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)

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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

Colorectal explants (10 cm and 30 cm)

Endoscopic biopsies + Absorbable gelatin sponge

= Happy Explants

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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

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Presentation Focus

Due to short presentation time AND still blinded nature of data:

Only most controlled data will be presented now.

• Data at Visit 3: single dose exposure (controlled)

• Data from 104 viral infection ex vivo (ensure baseline infection)

• Data at 10 cm (clinically relevant)

NIH IP/CP

RM Phase 1 Trial Design

Randomization: 0.1% UC781, 0.25% UC781, or placebo

Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6

Screening Phone interview

Single-doseexam

Safety 7-day exam

Baseline

<4 wk 1 wk 1 wk~ 8 days

Week 0 Week 2 Week 5 Week 6 Week 8

flex flex flex

Cumulative P-24 of Visit 2 samples (Viral_Inoculum=10000, Biopsy_location=10cm, Visit_code=V2)

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Days Post Explant Infection

Cu

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/ml)

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At Baseline (V2), 26/27 of subject’s explants infectible with HIVBaL104 TCID50 (10 cm)

NB: All data recoded so PI/Team blinded from Laboratory identification

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Explant infectibility at each visit

Baseline Post single dose

Post 7-day

TCID50 104 TCID50 102 TCID50 104 TCID50 102 TCID50 104 TCID50 102

% infected (N)

at 10 cm

96%

(26/27)

63%

(17/27)

66%

(18/27)

30%

(8/27)

96%

(26/27)

44%

(12/27)

% infected (N)

at 30 cm

96%

(26/27)

66%

(18/27)

74%

(20/27)

33%

(9/27)

78%

(21/27)

63%

(17/27)

Cumulative P-24 of explants at V3 (Viral_Inoculum=10000, Biopsy_location=10cm, Visit_code=V3)

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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)

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Cumulative P-24 of explants at V3 (Viral_Inoculum=10000, Biopsy_location=10cm, Visit_code=V3)

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27NO infection

No change

Middle

Visit 3 Results (single dose; samples acquired at 30’)

• 33% with NO INFECTION• 33% with NO CHANGE • 33% in MIDDLE

BLINDED

1 non-responder in “NO infection”

group

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V3 - No infection

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V3 -No Change

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BLINDED Data UC781 RM Trial: Expanded view of 33% subjects showing “No infection”

and 33% subjects showing “No change” (Visit 3)

A B

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V2 - 1/3 with NO INFECTION at V3

0100020003000400050006000700080009000

1000011000

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days Post Infection

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V2 -1/3 with NO CHANGE at V3

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No differences appreciated at Baseline between the 33% “no infection”and the 33% “no change” groups

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Following 7 days of daily dosing (V5), no emerging pattern of response yet evident.

Cumulative P-24 on samples post 7-Day use (Viral_Inoculum=10000, Biopsy_location=10cm, Visit_code=V5)

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V5 -No Change group at V3

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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)

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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

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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

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Group

% C

CR

5+

on

CD

4+

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

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MMC phenotypes by FACS: Do ‘double +s’ on CD4 change?

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

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Group

% C

CR

5+

X4

+o

n C

D4

+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

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MMC phenotypes by FACS: Does activation on CD4 change?

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.

02

46

81

00

24

68

10

Group

DR

+C

D3

8+

CD

4+

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

Collection of rectal secretions for cytokines/chemokines

with surgical sponges

02

04

06

08

01

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Boxplots of IL-1b

Group

IL-1

b

U19 (All) U19 (NON) U19 (Med) U19 (RESP)(n=27) (n=9) (n=9) (n=9)

V2 V3 V5

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V2 V3 V5 V2 V3 V5 V2 V3 V5

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Boxplots of IL-6

Group

IL-6

U19 (All) 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

Luminal cytokines by Luminex™: IL-1 or IL-6

No appreciable differences over time or within subgroups of IL-1 or IL-6.In general, IQR reasonably tight for whole group at baseline.

05

10

15

20

25

30

05

10

15

20

25

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Boxplots of IL-12(p-40)

Group

IL-1

2(p-

40)

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 V50

50

10

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Boxplots of Ing-gamma

Group

Ing

-ga

mm

a


V2 V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5

Luminal cytokines by Luminex™: IL-12 or IFN-

No appreciable differences over time or within subgroups of IL-12 or IFN-.IQR reasonably tight for IL-12; broad for IFN-.

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04

06

08

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20

40

60

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Boxplots of TNF-Alpha

Group

TN

F-A

lph

a


V2 V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5 01

00

20

03

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40

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30

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Boxplots of RANTES

Group

RA

NT

ES


V2 V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5

Luminal cytokines by Luminex™: TNF- or RANTES

No appreciable differences over time/within subgroups of TNF- or RANTES.IQR reasonably tight for TNF-; broad for RANTES.

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Boxplots of MIP-1 Alpha

Group

MIP

-1 A

lph

aU19 (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

Luminal cytokines by Luminex™: MIP-1

No appreciable differences over time or within subgroups of MIP-1-.In general, more variable IQR.

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“Blinded” Interpretations

• MMC phenotypes: Based on FACS data, there appears to be no difference among the all subjects in the 3 groups (placebo, high-does, 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

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Group

IgA

(ng

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UC-781 (All) U19 (Low) U19 (Med) U19 (High)(n=27) (n=9) (n=9) (n=9)

HPTN056(n=8,v=24)

V2V3 V5 V2 V3 V5 V2 V3 V5 V2 V3 V5

NIH IP/CP

Boxplots comparing range of IgA at UC781 baseline (V2) with HPTN 056

Boxplots of IgA

02

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Boxplots of IgG

Group

IgG

(n

g/m

l)

U19 (All) U19 (Low) U19 (Med) U19 (High) HPTN056(n=27) (n=9) (n=9) (n=9) (n=8,v=24)

V2V3 V5 V2V3 V5 V2V3 V5 V2V3 V5

NIH IP/CP

Boxplots comparing range of IgG at UC781 baseline (V2) with HPTN 056

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

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

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

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

• “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 mRNAMMC for phenotype by FACSExplant infection studies *

• plasma pK (to 24 hours); tissue/fluid pK (to day 14)

Indices/Assays used in UC781 Tenofovir RM safety trial

* Not in HPTN 056

Week: 0 1 2 3 4 5 6 7 8 9 10

Visit: 1 2 3 4 6A/B 7 9A/B 10A/B

11 12

F/U Safety Phone call

Baseline Oral Single Topical

7 - da y Topical

Screen Flex Flex 50% Flex 50% Flex Flex 50% Flex 50%

Flex Flex

Randomization: 2:1 (drug:placebo)-but ALL subjects get oral Tenofovir 1:1 (for biopsies: Group A:Group B)

5A/B 8

Oral/Topical Tenofovir RM trial

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 sigsGroup 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

NIH IP/CP

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 NIAID U19 IP/CP #AI060614: “Microbicide Development Program”

Biosyn, Inc Anne Marie CornerLinda KnappLinda Kristekas

UCLAIan McGowan (U Pitt)Chomchay Siboliban Amy AdlerTerry SaundersElena KhanukhovaCharlie PriceJulie ElliottJohn BoscardinYing ZhaoDaniel ChoKaren AndrewsElizabeth JohnsonAlexis DominguezJulia Klein

NIHJim TurpinJeanna PiperCherylnn MathiasGrace Chow

ConsultantsAlex Carballo-DieguezAna Vetuneac

CONRADHenry GabelnickChristine MauckTim McCormickMarianne Callahan

VOLUNTEERS!

MTN

NIH IP/CP

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

an nih ip/cp for topical microbicides "beginning to cross the rectal rubicon" clinical...

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