The HIV Prevention Product Pipeline for Adolescents

The HIV Prevention Product Pipeline for Adolescents

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  The HIV Prevention ProductPipeline for Adolescents SYBIL HOSEK, PHD DEPARTMENT OF PSYCHIATRY, STROGER HOSPITAL OF COOK COUNTY INTER-CFAR ARV FOR PREVENTION WORKING GROUP WEBINAR JANUARY 8TH, 2018
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  Conflicts of Interest Ihave no conflicts to report
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  Overview 1) Need forbiomedical prevention options that are licensed for adolescents 2) Inclusion of children in research – funder perspective 3) Inclusion of children in research – regulatory perspective 4) Review of current pipeline for biomedical HIV prevention products and corresponding adolescent data (or lack thereof) 5) Conclusions
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  AVERT, 2017
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  Currently Available Productsfor Adults ✓Condoms ✓HIV Testing ✓Home self-test kits ✓Medical Male Circumcision ✓HIV Treatment ✓Pre-Exposure Prophylaxis (TDF/FTC PrEP)
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  When to BeginAdolescent Studies for New Biomedical Products?
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  The goal… CONCURRENT licensureof adult and pediatric HIV prevention and treatment products “The ability of adolescents to access safe and effective new products for HIV prevention and treatment is optimised by adolescent licensure at the same time these products are approved and marketed for adults. Many adolescent product development programmes for HIV prevention or treatment products may proceed simultaneously with adult Phase III development programmes.” Hume, Lewis & Nelson, 2017
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  Policy for theInclusion of Children in NIH Research (NIH NOT 98-024) ▪ The goal was to increase the participation of children in research so that adequate data would be developed to support treatment modalities for disorders and conditions that affect adults as well as children. ▪ Medical treatments applied to children were often based upon testing done only in adults; thus, evidence-based treatments less available to children due to their exclusion from studies. ▪ These concerns were specifically articulated in Congressional directives to the NIH as reflected in language from the FY 1996 House and Senate Appropriations Committee reports ▪Update: Applications submitted after January 25, 2016, for the purposes of inclusion policy, the age of a child will be defined as individuals under 18 years old
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  Code of FederalRegulations §46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. HHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject's well-being, only if the IRB finds that: (a) The risk is justified by the anticipated benefit to the subjects; (b) The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and (c) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in §46.408.
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  Regulatory Perspective Pediatric ResearchEquity Act (2003): for new drugs, assessments of safety and effectiveness are required for all relevant pediatric sub-populations ◦ Safety CANNOT be extrapolated ◦ PK/dosing not usually extrapolated for children, but may be OK for adolescents ◦ Efficacy MAY be extrapolated depending on a number of criteria When should pediatric trials begin? ◦ Proof of concept for prospect of direct benefit from human adult studies or animal disease models; varies by severity of disease and adequacy of available treatments ◦ For HIV prevention, evidence of antiviral activity must be available ◦ Once sufficient adult and/or animal data exist, pediatric development should begin “The level of adult data necessary to support a prospect of direct benefit determination is less than the level of evidence required to establish efficacy.” (Hume, Lewis & Nelson, 2017)
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  To wait foradult efficacy or not? If YES, then an efficacious product may be available which adolescents cannot access (e.g. PrEP). If NO, then adolescents may be exposed to a SAFE but non- efficacious product (e.g. vaginal gel).
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  Product dependent ▪ Productuse history ▪ Previously used for treatment? ▪ New formulation of old drug? ▪ Intended use of new product
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  Antibody-Mediated Prevention
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  Adolescent IND Studies onPrEP
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  Oral Pre-Exposure Prophylaxis(PrEP) ▪ July 2012: TDF/FTC approved as PrEP based on efficacy data from iPrEx, Partners PrEP & TDF2 trials ▪But US youth are under-represented in studies ▪No PrEP data available on adolescent males or females under age 18
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  Adolescent PrEP Studies ▪5+years post-approval for adults and no adolescent indication ▪Additional safety and behavioral data in adolescents will be required to support a supplemental PrEP indication under age 18 ▪ATN 110/113: PrEP demonstration projects and safety studies for young MSM ages 15-22 in the US ▪PlusPills: A demonstration open label study to assess the acceptability, safety and use of Truvada PrEP in healthy, HIV- uninfected South African adolescents, 15-19 years of age
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  ATN 113 StudyDesign Hosek et al., JAMA Pediatrics, 2017
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  Baseline Demographics 29% 21% 14% 33% 3% Black Hispanic/Latino WhiteOther/Mixed Asian/PI Mean age 16.5 Sexual Identity Gay – 58% Bisexual – 28% Questioning – 6% Completed high school 18.4% Currently living with parents/family 88.5% Received public aid 76.9% Kicked out of house for being gay 15% Ever been paid for sex 17% Partners in past mo 2 CRAI w/last partner 60% Any positive STI test 15.4%
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  Safety Well-tolerated overall ◦ Nodocumented discontinuations due to side effects Adverse Events ◦ Three Grade 3 adverse events (weight loss) in 2 participants deemed related to study drug ◦ Grade 3 weight loss = 10-19% No abnormal laboratory results
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  STI Diagnoses 0 2 4 6 8 10 12 14 0 1 2 3 4 5 6 7 8 9 Baseline Week24 Week 48 Number of Diagnoses Rectal Gonorrhea Rectal Chlamydia Syphilis Any STI “Any STI” count
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  HIV Incidence 3 seroconversionsthrough week 48 HIV incidence = 6.41 per 100 person-years (95% CI: 4.9-25.8) TFV- DP Level Study Week 0 200 400 600 800 1000 1200 Wk 4 Wk 8 Wk 12 Wk 24 Wk 36 Wk 48 PT 1 (wk 32) PT 2 (wk 36) PT 3 (wk 48) TFV- DP level 4+ doses
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  Adherence: TFV-DP inDBS
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  PlusPills Study Design Gillet al., IAS 2017
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  Baseline Demographics
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  Safety Well-tolerated overall 11 %(n= 16) participants experienced a grade 2 or 3 related side effect Grade 2: ◦ 4 headaches ◦ 4 nausea and vomiting ◦ 2 abdominal pain ◦ 2 diarrhea ◦ 2 skin rash Grade 3 ◦ Two Grade 3 adverse events (weight loss) in 2 participants deemed related to study drug ◦ Grade 3 weight loss = 10-19% No abnormal Creatinine / LFT’s
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  STI Diagnoses
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  Plasma TDF Levels
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  Conclusions (ATN 113/PlusPills) ▪Adolescentsmales and females are still at high risk for HIV ▪ In ATN 113, HIV incidence was high compared to other open label PrEP studies ▪PrEP was well tolerated with minimal safety concerns ▪Acceptability of PrEP, the overall study, and HIV testing and counseling was high ▪Adherence to daily medications notoriously difficult for adolescents worldwide. ▪PrEP usage and adherence diminished over time with less frequent visits ▪ Adolescent implementation of PrEP needs developmentally-appropriate strategies, such as enhanced visit schedules and/or more frequent interactions (in-person or via mobile technology) ▪In PlusPills, young women were not less adherent than young men ▪STI diagnoses remained constant or dropped over the course of these studies ▪sNDA based on ATN 113 data submitted to FDA on November 16th, 2017!!
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  Implementation of PrEPfor Adolescents Progress: ◦ Over 25 countries have PrEP approved for adults ◦ The EU just granted approval for PrEP for adolescents down to age 12 Significant barriers remain: ◦ Lack of prescriber knowledge, comfort ◦ Issues of parental/guardian consent ◦ Undesired disclosure of sexual activity, sexual orientation ◦ Insurance, cost, lack of access to medication assistance programs Best practices for implementation and improving adherence being studied across populations in many countries
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  Adolescent-focused PrEP Studiesin US Studies currently underway or in development within the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN)…
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  Prevention Products Under Regulatory Review
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  Dapivarine Vaginal Ring ▪Similarto vaginal rings commonly used for contraception except that it contains an antiretroviral (ARV) drug, dapivirine, instead. ▪Dapivirine belongs to a class of ARVs called non- nucleoside reverse transcriptase inhibitors that bind to and disable a key protein that HIV needs to make copies of itself. ▪The ring, which is made of a flexible material, sits high inside the vagina, where it slowly releases the drug over the course of the one month the ring is worn. Women can insert and remove it themselves.
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  ASPIRE/The Ring Study
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  However… ▪In ASPIRE, HIVprotection differed by age ▪In fact, the ring was not effective among younger women ages 18-21 who used the ring least regularly. ▪Higher levels of protection were seen in women who used the ring most regularly.
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  Adolescent Studies on theDapivirine Ring
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  MTN 023 Bunge etal., IAS 2017
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  Study Design
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  Demographics
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  Safety
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  Adherence ▪Dapivirine plasma drugconcentration > 95 pg/mL ▪87% of plasma samples with levels suggestive of adherence to study product in the day prior to visit ▪Dapivirine residual drug levels in used rings <23.5 mg ▪95% of returned vaginal rings with levels suggestive of adherence over the past month ▪Self report ▪42% (95% CI, 32, 52) of participants reported that they never removed the ring except to replace it monthly. ▪Most removals were brief
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  Conclusions ▪The dapivirine vaginalring is safe and acceptable in 15-17 year old US girls ▪Both plasma and residual vaginal ring drug levels indicated high adherence ▪Consistency between dapivirine plasma levels and residual dapivirine levels in used rings supports appropriate study product use
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  Next Steps ▪Dapivirine licensurepackage has been submitted to the European Medicines Agency; SA MCC and FDA to follow ▪Safety data among adolescents are still needed ▪MTN-034 (REACH) to begin in mid-2018 ▪A Phase 2a crossover trial evaluating the safety of and adherence to a vaginal matrix ring containing dapivirine and oral emtricitabine/tenofovir disoproxil fumarate in 16-21 year olds ▪4 sites: S Africa, Uganda, Kenya, Zimbabwe
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  Prevention Products Currently inEfficacy Trials
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  Cabotegravir (GSK1265744) ▪Experimental, long-actingintegrase inhibitor ▪Well-suited for injectable formulation ▪High genetic barrier to resistance ▪PK profile – half life of 21-50 days -- allows once-daily oral or 1-3 month injectable dosing using nanosuspension formulation ▪Being evaluated currently as injectable PrEP and HIV treatment
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  HPTN 083/084
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  Adolescent Trials of PreventionProducts Being Studied
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  HPTN 086: AdolescentCAB-LA Study ▪Purpose: To establish the minimum safety, tolerability and acceptability data needed to allow expansion of the anticipated FDA indication for LA CAB to include youth down to age 15, potentially transforming the field of HIV prevention for youth and adolescents. ▪A single arm, open label study using an enrollment design of sequential cohorts of decreased age ▪~100 youth (50 males, 50 females) ages 15-18 ▪US and South Africa ▪Timeline Goal: To submit adolescent data with adult package for concurrent licensure
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  Other Products inthe Prevention Pipeline
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  AVAC, 2016
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  Possible Study Designs •Bridgingstudies •Inclusion of adolescents in large Phase 3 trials ◦ Part of original protocol ◦ Sub-study •Key Components: ◦ Pediatric/Adolescent expertise ◦ Adolescent-competent staff ◦ Adequate resources to give youth the time that they need
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  Conclusions ▪Adolescents need accessto powerful new biomedical prevention strategies ▪The timeline for adolescent-approved products needs to be expedited - - concurrent licensure of adolescent and adult products is the goal! ▪There is ethical and regulatory support for concurrent adolescent and adult trials ▪When to launch an adolescent trial and what data are needed may be product dependent
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  Thank You!