The Protective Barrier of SYMTUZA®

SYMTUZA® is the only STR with the protective barrier of darunavir

Zero

Zero treatment-emergent darunavir, primary PI, or TAF mutations across clinical trial populations1,2*

Only 1 patient receiving SYMTUZA® was found to have M184I/V; this patient also had a transmitted K103N mutation at screening. M184V was detected pretreatment by deep sequencing (Illumina MiSeq) as a minority variant (9.4%).3

Molecular Properties of Darunavir

molecular properties

SYMTUZA® has the Ability to Adapt to HIV-1 Protease Mutations4

SYMTUZA® contains darunavir, which quickly and tightly binds to HIV-1 protease4-7

Molecular flexibility

Fits tightly into the viral protease pocket and forms an extensive network of long-lasting hydrogen-bonding interactions

Molecular flexibility allows for adaptation to mutant HIV-1 protease, maintaining these bonds and preserving antiretroviral activity

  • SYMTUZA® should not be used in patients with known DRV RAMs (V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V, and L89V) or mutations to tenofovir

The clinical implications of these data have not been established.

molecular properties

Darunavir Kinetic Profile Results in Strong Protease Binding4

Darunavir has a fast association rate, slow dissociation rate, and high binding affinity

Fast Association Rate

(kon) = (2.2 + 0.8) x 106

  • Association Rate (kon) = The degree of recognition a molecule has for HIV

Slow Dissociation Rate

(koff) = (7.8 + 0.5) x 10-7

  • Dissociation Rate (koff) = The binding stability of the interaction between a molecule and HIV

Dissociative half-life >240 hours

High Binding Affinity

(kD) = (4.1 + 1.7) x 10-13

  • Binding Affinity (kD) = The ratio of kon to koff

    Calculation: koff/kon = KD

The clinical implications of these data have not been established.

molecular properties

SYMTUZA® Maintains Therapeutic Darunavir Plasma Concentrations1,8

33X greater than EC50 at 24 hours1,8

Clinical Implications

The clinical implications of these data have not been established.

Infographic is for graphical representation only.

 

The clinical implications of these data have not been established.

*In the AMBER trial, of 362 treatment-naïve patients taking SYMTUZA®, 8 met the criteria for VF and 7 patients experiencing VF were analyzed for resistance.1,3

†In the EMERALD trial, of 763 virologically suppressed patients taking SYMTUZA®, 6 met the criteria for VF and 1 patient experiencing VF was analyzed for resistance.1,9

‡Measurements were assessed using wild-type virus.

 

Extensive Experience

Duration Over Time

Protective Barrier

that has been proven over time10,11

1 in 4 Patients

>1 in 4 Patients

diagnosed and living with HIV-1 who were on treatment received a darunavir-based regimen in 20178

>5500 patients*

treated with darunavir in 14 clinical trials, with data up to 192 weeks1,2,12-20

6.4 Million

>6 Million Prescriptions

with darunavir in the United States since approval8

 

The clinical implications of these data have not been established.

*AMBER (n=362): AMBER CONTROL (n=363): EMERALD (n=763): EMERALD CONTROL (n=266): DIAMOND (n=109): STUDY 130 (n=313): ARTEMIS (n=343): ODIN QD (n=294); ODIN BID (n=296): POWER 1 (n=65): POWER 2 (n=66): POWER 3 (n=336): METABOLIK (n=34): GRACE (n=429): DUET (n=599): DUET CONTROL (n=604): TITAN (n=298): PHASE 2 (n=l03): PHASE 2 CONTROL (n=SD) = 5693.

Protective Barrier That Has Been Proven Over Time
In 2 extensive retrospective analyses of isolates, darunavir RAMs decreased over time10,11**††

The absence of darunavir RAMs does not imply clinical results.

**Study Design 1: the aim of this analysis was to assess potential changes in the frequency trends of darunavir RAMs over time in the United States. Clinical isolates (N=78,843) submitted to Monogram Biosciences for routine clinical resistance testing (PhotoSense GT®) between January 2006 and June 2012 were analyzed. The proportion of samples with 0, 1, 2, and ≥3 RAMs were evaluated at yearly intervals between 2006 and the first half of 2012.

††Study Design 2: the aim of this analysis was to evaluate DRV and primary Pl RAMs and phenotypic resistance among clinical samples in the United States. Clinical isolates (N=60,760) submitted to Monogram Biosciences for routine clinical resistance testing (PhotoSense GT®) between January 2010 and December 2017 were analyzed. The proportion of samples with 0, 1, 2, and ≥3 RAMs were evaluated at yearly intervals.

‡‡Darunavir RAMS=V11I, V32I, L33F, I47V, I50V, I54L or M, T74P, L76V, I84V and L89V.

§§Statistical trend analysis demonstrated a significant upward trend, P=0.0008.

¶¶Statistical trend analysis demonstrated a significant downward trend, P=0.002.

BID=twice daily; CO=mean trough plasma population; DRV=darunavir; EC50= half maximal effective concentration; Hl=first half; PI=protease Inhibitor; PK=pharmacokinetlcs; QD=daily; RAMs=resistance-assoclated mutations; STR=slngle-tablet regimen; TAF=tenofovir alafenamlde; VF=virologlc failure.

References: 1. SYMTUZA® [package insert]. Titusville, NJ: Janssen Therapeutics, Division of Janssen Products, LP. 2. Huhn G, Crofoot G, Ramgopal M, et al. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) rapid initiation for HIV-1 infection: primary analysis of the DIAMOND study. Poster presented at: 13th Annual American Conference for the Treatment of HIV (ACTHIV); April 11-13, 2019; Miami, Florida. 3. Eron JJ, Orkin C, Gallant J, et al. A week-48 randomized phase-3 trial of darunavir/cobicistat /emtricitabine/tenofovir alafenamide in treatment-naïve HIV-1 patients. AIDS. 2018;32:1431-1442. 4. Dierynck I, De Wit M, Gustin E, et al. Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral acti vity and high genetic barrier. J Viral. 2007;81:13845-13851. 5. Ghosh AK, Anderson DD, Weber IT, Mitsuya H. Enhancing protein backbone binding-a fruitful concept for combating drug-resistant HIV. Angew Chem Int Ed. 2012;1778-1802. 6. Tremblay CL. Combating HIV resistance-focus on darunavir. Ther Clin Risk Manag. 2008;4:759-765. 7. King NM, Prabu-Jeyabalan M, Nalivaika EA. et al. Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. J Viral. 2004;78:12012-12021. 8. Data on file. Janssen Therapeutics, Division of Janssen Products, LP. 9. Orkin C, Molina J-M, Negredo E, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2017. http://dx.doi.org/10.1016/S2352-3018(17)30179-0. 10. Lathouwers E, Gupta S, Haddad M, et al. Trends in darunavir resistance-associated mutations and phenotypic resistance in commercially tested United States clinical samples between 2006 and 2012. AIDS Res Hum Retroviruses. 2015;31:628-635. 11. Brown K, Stewart L, Whitcomb J, et al. Prevalence of darunavir resistance in the United States from 2010 to 2017. [published online ahead of print August 27, 2018]. AIDS Res Hum Retroviruses. doi:10.1089/AID.2018.0100. 12. Mills A, Crofoot G Jr, McDonald C, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-1 therapy: a randomized Phase 2 study. J Acquir Immune Defic Syndr. 2015;69(4):439-445. 13. Tashima K, Crofoot G, Tomaka FL, et al. Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a Phase IIIb, open-label single-arm trial. AIDS Res Ther. 2014;11:39.14. Cahn P, Fourie J, Grinsztejn B, et al. 48-week analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients. AIDS. 2011;25:929-939. 15. Arastéh i K, Yeni iP, Pozniak A, et al. Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antivir Ther. 2009;14:859-864. 16. Aberg JA, Tebas P, Overton ET. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type-1 infected subjects over 48 weeks. AIDS Res Hum Retroviruses. 2012;28:1184-1195. 17. Currier J, Bridge DA. Hagins D, et al. Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial. Ann Intern Med. 2010;153:349-357 18. Katlama C, Clotet B, Mills A. Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials. Antivir Ther. 2010;(15):1045-1052. 19. Madruga JV, Berger D, McMurchie M, et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase Ill trial. Lancet. 2007;370(9581):49-58. 20. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive patients in the ARTEMIS trial. HIV Med. 2013;14:49-59.