IRMWG TCRectal Safety Update7th December 2006

Ian McGowan MD PhD FRCP

Center for Prevention Research

David Geffen School of Medicine at UCLA

Los Angeles, California

Recent Microbicide Meetings

�HPTN Microbicide Safety Meeting,

March 2006

�DAIDS Toxicity Table Meeting,

Washington DC, November 2006

Background

� Increasing awareness of RAI in general

population

� Several microbicide candidates in late stage

development

� Post licensure vaginal microbicides will be

used rectally

� Extensive non-human primate rectal safety

data

� More limited non-human primate efficacy data

– Cyanovirin-N and PMPA

Human Rectal Phase 1 Studies

UK MRC MDP

STI CTG

� UCLA/UPMC

DAIDS

� UCLA U-19 (V)

� UCLA U-19 (R)

University of Washington

Site

Under designPro-2000

Approved for protocol development

VivaGel™

Q4 2006

Q1 2008

UC-781

CompletedNonoxynol-9

StatusStudy

HPTN Microbicide Safety Meeting, March 2006

HPTN Microbicide Safety Meeting, March 2006

� Lecture sessions

�Break-Out Sessions

– Preclinical safety

– Phase 1/2 vaginal microbicide safety

– Phase 2B/3 vaginal microbicide safety

– Community issues

– Viral resistance

– Rectal safety

The Delegates

� HIV Networks– HPTN

– MTN

– SCHARP

� Federal agencies– DAIDS

– DMID

– FDA

– CDC

� Regulatory– EMEA

– WHO

� Sponsors– CONRAD

– IPM

– FHI

– UK MRC MDP

� Pharmaceutical Industry

– GSK

– Indevus

� Community

� Academic centers & investigators

Key Findings from the Rectal Group

� No current FDA guidelines for rectal microbicide (RM) development

� RMs will probably need two approaches

– Vaginal products used rectally

– Rectal specific products

� Sequence of studies

– Phase 1 / sexually abstinent / HIV negative

– Phase 1 / sexually active / HIV negative

– Phase 1 / sexually active / HIV positive

Safety Measurements

� Required

– Signs & symptoms of rectal irritation

– Endoscopy

– Safety labs

– Pharmacokinetics

� Strongly encouraged

– Acceptability

– Rectal lavage

– Histology

– Assessment of immunological toxicity

– Tissue viral load and viral shedding in HIV+ participants

RM Phase 1 Trial Design

Randomization: 0.1% UC-781, 0.25% UC-781, or placebo

Visit 1 Visit 2 Visit 3 Outpatient Visit 4 Visit 5

ScreeningPhone

interviewSingle-dose

Clinical Eval

7 daily

dosesClinical EvalBaseline

<4 wk ≥≥≥≥ 1 wk ≥≥≥≥ 1 wk~ 8 days

Week 0 Week 2 Week 5 Week 6 Week 8

Flex Flex Flex

RM Phase 1 Endpoints

�Primary endpoints:– Frequency of ≥ Grade 2 adverse events

– Acceptability assessments

�Secondary endpoints:– Epithelial sloughing

– Histopathology

– Mucosal mononuclear cell phenotype (flow)

– Mucosal cytokine mRNA (tissue)

– Mucosal immunoglobulins

– Fecal calprotectin

– Explant susceptibility to HIV infection

Product Labeling Issues

� No products licensed yet

� Will first vaginal product have labeling

about rectal use?

� FDA said they could not imagine labeling a

vaginally product as rectally safe on the

basis of one Phase 1 study

DAIDS Toxicity Table Meeting

What is a Toxicity Table?

+

An Example

GradeSymptom

Life threatening

> 6 over BL

4-6 over BL

< 4 over BL

Diarrhea

(Stool frequency)

G4G3G2G1

Scope of Meeting

� Vaginal Toxicity– Colposcopy

– Pregnancy

– Masses

– Pain

– Dysplasia / Malignancy

– Bleeding issues etc.

� Penile Toxicity

� Rectal toxicity– Anal

– Rectal

– Other

The Rectal Team

� Ian McGowan

� Amy Adler

� Peter Anton

� Larry Allan

� Charlene Brown

� Ross Cranston

� Cherlynn Mathias

� David Phillips

� Sharof Tugizov

� Yvonne Cosgrove Sweeney

� Ita Yuen

Prevalence of Anorectal Symptoms

� Benign anal conditions highly prevalent in the general population

� 1.5 million anorectal preparations dispensed by prescription each year in US

� 80% of US population with anal symptoms

self-medicate

Janicke 1996, Nagle 1996, Nelson 1995

Anorectal Anatomy

Ryan et al. N Engl J Med. 2000 16;342(11):792-800.

Anorectal Diagnosis and Presentation

Pain, swelling, dischargeAbscess

Itch, painDermatophyte

Itch, painPsoriasis

Itch, pain, dischargeEczema

Itch, pain, massHemorrhoids

Itch, pain, discharge, swellingFistula

Pain, bleedingFissure

Symptom/sDiagnosis

Anorectal STD Diagnosis and Presentation

Mass, painSyphilis

Itch, massHPV

Pain, itchLGV

Pain, itch, systemic/autonomicHerpes simplex

Discharge, pain, tenesmusChlamydia

Discharge, pain, tenesmusGonorrhea

Symptom/sSTD

High-Resolution Anoscopy and Image Capture

� Rectum

� Anorectal

transition zone

� Anal canal

� Perianal area

� Lesion/s

HRA Clinical Signs/Diagnoses

Skin tagSwelling

AbscessFissure

ErythemaLeukoplakia

Condylomata lataCondyloma accuminata

BlisteringDischarge

BruisingExcoriation

Piercing/tattooUlceration

Fistula openingHemorrhoids

MolluscumBleeding

Diagnosis

Colorectal Key Issues

� AIM of toxicity tables:accurately report change from baseline and/or any findings?

� ‘Terms’ vary greatly between individuals

� Less ‘inter-reporter’ variability with sign

� Detection and reporting of symptoms vary with subject

� High prevalence of underlying IBS

� Many patients will have abnormal mucosal and

perianal signs with no symptoms

� Many patients will have not-normal (but not diseased) mucosal findings with no symptoms.

Irritable Bowel Syndrome (IBS)

� Common!

� Functional, not anatomic

� Few objective criteria but reliable history-based/symptom-based indices (Rome Criteria)

� Often present with abdominal pain, altered bowel habits, diarrhea, constipation, systemic symptoms,

urgency, fullness, bloating etc

� Often hyper-responsive to intra-rectal introductions (scope, balloon, DRE)

Goals of Rectal Toxicity Table

� Comprehensive:

– Anal

– Colorectal

– Other

– STIs

� Relevant for Phases 1-3 of RM

development

� Easy to use at site level

Anal

Colorectal

Other

Sexually Transmitted Infections

Topics Not Addressed

�Histological toxicity scales

�Emerging endpoints of uncertain

validity:

– Cytokines

– Immunological toxicity

– Fecal calprotectin

– ESR, CRP

Questions?