Safety and Pharmacokinetics of Dapivirine Vaginal Ring in Post-menopausal Women

Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted
diamino- pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1.
Dapivirine is chemically described as 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-
pyrimidinyl]amino]benzonitrile.6 The dapivirine matrix VR is a flexible ring containing 25
mg of drug substance dispersed in a platinum-catalyzed-cured silicone matrix. Dapivirine is
known to be well-suited for delivery via VR, as evidenced by favorable safety and
pharmacokinetic data to date described below.

Inclusion Criteria:

1. Age 45 through 65 years (inclusive) at Screening, verified per site SOPs

2. Per participant report, postmenopausal at Screening, defined as amenorrheaic for the
past 12 months (minimum) or at least 6 months status post-bilateral oophorectomy

3. Follicle-stimulating hormone (FSH) level at 40 mIU/ml or higher at Screening

4. Able and willing to provide written informed consent to be screened for and enrolled
in MTN-024/IPM 031

5. Able to communicate in spoken and written English

6. Able and willing to comply with all study procedural requirements

7. Willing to only use study provided and/or approved vaginal products throughout the
duration of study participation.

8. Willing to abstain from inserting study approved lubricant into the vagina for 72
hours prior to each visit

9. Willing to abstain from vaginal intercourse for 72 hours prior to each visit

10. In general good health as determined by the Investigator of Record (IoR)/designee at
Screening and Enrollment

11. Able and willing to provide adequate locator information, as defined in site SOPs

12. HIV-uninfected based on testing performed at Screening (per protocol algorithm in
Appendix II)

13. Per participant report at Screening and Enrollment, agrees to use male latex condoms
for sexual intercourse

14. Per participant report at Screening and Enrollment, states a willingness to refrain
from inserting any non-study vaginal products or objects into the vagina including,
but not limited to spermicides, female condoms, diaphragms, topical or systemic
hormone replacement therapy, including vaginal estrogens, and/or hormonal
contraceptives, vaginal medications, menstrual cups, cervical caps (or any other
vaginal barrier method), vaginal douches, lubricants and moisturizers, sex toys
(vibrators, dildos, etc.), for the duration of the study participation.

Note: Use of study approved lubricant is permitted.

15. At Screening and Enrollment, agrees not to participate in other research studies
involving drugs, medical devices, vaginal products, or vaccines for the duration of
study participation

Participants in the biopsy subset must also meet the following criteria at Screening
to be eligible for inclusion:

16. Willing to abstain from inserting anything into the vagina for 72 hours following the
collection of biopsies, including abstaining from vaginal intercourse

17. Anatomy sufficient for the collection of cervical biopsies

Exclusion Criteria:

1. Per participant report at screening:

1. Plans to relocate away from the study site during study participation

2. Plans to travel away from the study site for more than 4 consecutive weeks
during study participation

2. Pregnant at screening Note: A documented negative pregnancy test performed by study
staff is required for inclusion; however a self-reported pregnancy is adequate for
exclusion from the study.

3. Diagnosed with urinary tract infection (UTI) at Screening or Enrollment Note:
Otherwise eligible participants diagnosed with UTI during screening are offered
treatment and may be enrolled after completing treatment and all symptoms have
resolved.

If treatment is completed and symptoms have resolved within 45 days of obtaining
informed consent for screening, the participant may be enrolled.

4. Diagnosed with pelvic inflammatory disease, an STI or reproductive tract infection
(RTI) requiring treatment per current Centers for Disease Control and Prevention
(CDC) guidelines at Screening or Enrollment Note: Otherwise eligible participants
diagnosed during screening with pelvic inflammatory disease or STI/RTI requiring
treatment per CDC guidelines — other than asymptomatic bacterial vaginosis (BV) and
asymptomatic candidiasis — are offered treatment and may be enrolled after completing
treatment and all symptoms have resolved. If treatment is completed and symptoms have
resolved within 45 days of obtaining informed consent for screening, the participant
may be enrolled. Genital warts requiring treatment also must be treated prior to
Enrollment. Genital warts requiring therapy are defined as those that cause undue
burden or discomfort to the participant, including bulky size, unacceptable
appearance, or physical discomfort.

5. Has a clinically apparent Grade 2 or higher pelvic exam finding (observed by study
staff) at Screening or Enrollment, as per the Division of AIDS Table for Grading the
Severity of Adult and Pediatric Adverse Events Version 1.0, December, 2004
(Clarification dated August 2009), Addendum 1-Female Genital Grading Table for Use in
Microbicide Studies Note: Cervical bleeding associated with speculum insertion and/or
specimen collection judged to be within the range of normal according to the clinical
judgment of the Investigator of Record (IoR)/designee is considered expected
non-menstrual bleeding and is not exclusionary.

Note: Otherwise eligible participants with exclusionary pelvic exam findings may be
enrolled/randomized after the findings have improved to a non-exclusionary severity
grading or resolved. If improvement to a non-exclusionary grade or resolution is
documented within 45 days of providing informed consent for screening, the
participant may be enrolled.

6. Participant report and/or clinical evidence of any of the following:

1. Known adverse reaction to any of the study products (ever)

2. Known adverse reaction to latex (ever)

3. Chronic and/or recurrent vaginal candidiasis

4. Topical or systemic hormone replacement therapy and/or hormonal contraception
within the 6 months prior to Enrollment

5. Non-therapeutic injection drug use in the 12 months prior to Enrollment

6. Post-exposure prophylaxis (PEP) for HIV exposure within the 6 months prior to
Enrollment

7. Pre-exposure prophylaxis (PrEP) for HIV prevention within the 6 months prior to
Enrollment

8. Last pregnancy outcome 6 months or less prior to Enrollment

9. Gynecologic or genital procedure (e.g., tubal ligation, dilation and curettage,
piercing) 90 days or less prior to Enrollment

10. Currently breastfeeding

11. At Screening, severe pelvic relaxation such that either the vaginal walls or the
uterine cervix descend beyond the vaginal introitus with valsalva maneuver

12. Participation in any other research study involving drugs, medical devices,
vaginal products, or vaccines, in the 45 days prior to Enrollment

7. As determined by the IoR/designee, any significant uncontrolled active or chronic
cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric,
endocrine, respiratory, immunologic disorder or infectious disease

8. Has any of the following laboratory abnormalities at Screening Visit:

1. Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or
higher*

2. Creatinine Grade 2 or higher*

3. Hemoglobin Grade 2 or higher*

4. Platelet count Grade 1 or higher*

5. Pap result Grade 2 or higher** Note: Otherwise eligible participants with an
exclusionary test may be re-tested during the screening process.

Note: Women with a documented normal result within the 12 months prior to Enrollment
need not have a Pap smear during the screening period. Women with a Grade 1 abnormal
Pap smear can be enrolled upon completion of the initial phase of evaluation if no
current treatment is indicated (based on local standard of care for management of
abnormal cervical cytology). Need for a repeat Pap within 6 months does not preclude
Enrollment prior to that result becoming available. If the participant has had a
hysterectomy for reasons not related to cervical dysplasia, a Pap smear need not be
performed.

9. Has any other condition that, in the opinion of the IoR/designee, would preclude
informed consent, make study participation unsafe, complicate the interpretation of
study outcome data, or otherwise interfere with achieving the study objectives
*Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse
Events Version 1.0, December, 2004 (Clarification dated August 2009) **Female Genital
Grading Table for Use in Microbicide Studies Addendum 1 to the Division of AIDS
(DAIDS) Table for Grading Adult and Pediatric Adverse Events, Version 1.0, December
2004 (Clarification dated August 2009)