Safety Information of SYMTUZA – Neurologic/Psychiatric Adverse Effects

SUMMARY  

• In the AMBER, DIAMOND, and EMERALD studies, the only neurologic or psychiatric adverse event (AE) reported in more than 5% of patients was headache.^1-3 Incidence of drug-related headache in each study was:
  • AMBER (week 96): 3.3%¹
  • DIAMOND (week 48): 1.8%²
  • EMERALD (week 96): 1.4%³
• A subgroup analysis of the two Phase 3 studies AMBER and EMERALD found that patients with baseline neuropsychiatric comorbidities (NPCs) did not experience higher rates of study-drug related AEs compared to those without baseline NPCs.^{4, 5}

CLINICAL DATA

Treatment-Naïve Patients

AMBER

The AMBER study was a phase 3, randomized, active-controlled, double-blind, noninferiority study to evaluate efficacy and safety of SYMTUZA vs PREZCOBIX (darunavir [DRV]/cobicistat [COBI]) fixed dose combination co-administered with emtricitabine/ tenofovir disoproxil fumarate (FTC/TDF) in antiretroviral (ARV) treatment-naïve HIV-1-infected adults (N=725).⁶

Study Design/Methods

• Patients were stratified by screening viral load (VL; < / ≥100,000) and by screening CD4+ cell counts (< / ≥200 cells/mm³) and then randomized to a single-tablet regimen (STR) of SYMTUZA (DRV 800 mg, COBI 150 mg, FTC 200 mg, and tenofovir alafenamide [TAF] 10 mg) with matching PREZCOBIX + FTC/TDF placebo or the active-control regimen of PREZCOBIX + FTC/TDF with a matching SYMTUZA placebo.
• After week 48, patients continued to take their blinded study drug until the last subject had reached week 48 and treatment assignments were unblinded.
• After unblinding, all patients entered the open-label, single-group treatment phase with continued SYMTUZA use in the SYMTUZA group and switch to SYMTUZA in the control group up to week 96.
• A subgroup analysis was conducted to assess the prevalence of preexisting NPCs and to compare outcomes in patients with and without baseline NPCs.^{4, 5}
  • NPCs were based on verbatim medical history terms and were defined as those within the Medical Dictionary for Regulatory Activities (MedDRA) v22 entire system organ classes of Nervous System Disorders or Psychiatric Disorders.
  • For psychiatric disorders, the terms sexual dysfunctions/disturbances, gender identity disorders, and eating disorders/disturbances were excluded.

Results

• At week 48, the only neurologic or psychiatric AE reported in more than 5% of patients was headache (n=47 [13.0%] in the SYMTUZA arm and n=32 [8.8%] in the control arm).
  • Of these, 12 cases (3.3%) and 6 cases (1.7%) were thought to be drug-related in the SYMTUZA and control arms, respectively.⁷
• There were 88/362 patients with baseline NPCs and 274/362 without baseline NPCs.⁵
  • Neurologic comorbidities were present in 38/88 (43%); the most common were headache (18/88; 20%) and migrane (5/88; 6%).
  • Psychiatric comorbidities were present in 56/88 (64%); the most common were depression (31/88; 35%), anxiety (16/88; 18%), sleep disorder (8/88; 9%), and insomnia (6/88; 7%).
• Through week 48, patients with vs. without baseline NPCs reported a higher incidence of new or worsening neurologic and/or psychiatric AEs overall; however, they did not experience a higher incidence of neurologic or psychiatric AEs related to SYMTUZA (Table: Summary of Neurologic and Psychiatric AEs Through Week 48).⁴
• The specific neurologic and psychiatric study drug-related AEs reported during the study are noted in Table: Study Drug-related Neurologic and Psychiatric AEs (Specific Terms) Through Week 48.

• Through week 96, the only neurologic or psychiatric AE reported in more than 5% of patients in the SYMTUZA group was headache (n=54, 14.9%).¹
  • No additional patients had drug-related headache between weeks 48-96.
• Between weeks 48-96, there was one additional drug-related nervous system AE (insomnia) in a patient without baseline NPCs in the SYMTUZA group.⁵
• Through week 96, there were no drug-related neurologic/psychiatric AEs classified as serious and none leading to discontinuation of therapy.¹

DIAMOND

The DIAMOND study was a phase 3, single-arm, open-label, multicenter study to evaluate the safety and efficacy of SYMTUZA in newly diagnosed, HIV-1 infected, treatment-naïve patients in a rapid initiation model of care over 48 weeks (N=109).⁸

Study Design/Methods

• Eligible patients were enrolled and started on SYMTUZA once daily (QD) as soon as within 24 hours of the screening/baseline visit and before results of the baseline safety and resistance laboratory tests were available.

Results

• At week 48, the only neurologic or psychiatric AE reported in more than 5% of patients was headache (n=10, 9.2%). Of these, 2 cases (1.8%) were thought to be drug-related.²
• At week 48, there were no drug-related neurologic/psychiatric AEs classified as serious and none leading to discontinuation of therapy.²

Treatment-Experienced Patients

EMERALD

The EMERALD study was a phase 3, randomized, active-controlled, open-label noninferiority study to evaluate the efficacy, safety, and tolerability of switching to SYMTUZA vs continuing the current regimen consisting of a boosted protease inhibitor (bPI) combined with FTC/TDF in virologically-suppressed, HIV-1-infected adults (N=1141).⁹

Study Design/Methods

• Patients were stratified according to bPI (PREZISTA [DRV]/ritonavir [r] or PREZCOBIX QD, atazanavir [ATV]/r or ATV/COBI QD, or LPV/r twice daily [BID]) and then randomized 2:1 to switch to SYMTUZA or to continue their bPI regimen.
• At week 52, patients in the SYMTUZA arm could continue on current therapy and patients in the control arm could switch to SYMTUZA in an extension phase until week 96.
• A subgroup analysis was conducted to assess the prevalence of preexisting NPCs and to compare outcomes in patients with and without baseline NPCs.⁵
  • NPCs were based on verbatim medical history terms and were defined as those within the Medical Dictionary for Regulatory Activities (MedDRA) v22 entire system organ classes of Nervous System Disorders or Psychiatric Disorders.
  • For psychiatric disorders, the terms sexual dysfunctions/disturbances, gender identity disorders, and eating disorders/disturbances were excluded.

Results

• At week 48, the only neurologic or psychiatric AE reported in more than 5% of patients was headache (n=58 [7.6%] in the SYMTUZA arm and n=16 [4.2%] in the control arm).
  • Of these, 10 cases (1.3%) and 0 cases (0%) were thought to be drug-related in the SYMTUZA and control arms, respectively.¹⁰
• There was 1 nervous system AE leading to permanent discontinuation of therapy in each arm at week 48, both of which (headache in the SYMTUZA arm and tunnel vision in the control arm) were thought to be drug-related.¹⁰
• There were 2 psychiatric AEs leading to permanent discontinuation of therapy in the SYMTUZA arm at week 48, only 1 of which (depression/suicidal) was thought to be drug-related.¹⁰
• At week 96, the only neurologic or psychiatric AE reported in more than 5% of patients in the SYMTUZA arm was headache (n=79, 10.4%).³
  • Only one case of drug-related headache occurred after week 48.
• At week 96, there were no drug-related neurologic/psychiatric AEs classified as serious.³
• Between weeks 48-96, there were no additional neurologic/psychiatric AEs leading to permanent discontinuation of therapy in the SYMTUZA arm.³
• There were 294/763 patients with baseline NPCs and 469/763 without baseline NPCs.⁵
  • Neurological comorbidities were present in 125/294 (43%); the most common were headache (37/294, 13%), peripheral neuropathy (27/294; 9%), and migrane (17/294; 6%).
  • Psychiatric comorbidities were present in 241/294 (82%); the most common were depression (126/294; 43%), insomnia (100/294, 34%), anxiety (81/294; 28%), and attention deficit/hyperactivity disorder (16/294; 5%).
• Overall, patients with (n=294) vs. without (n=469) baseline NPCs reported a higher incidence of neurologic and psychiatric AEs; however, the incidence of drug-related AEs did not differ between groups (18% vs 24%, respectively).⁵

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 21 September 2021.