SUMMARY

• The GRIPHON phase 3 study (Prostacyclin [PGI₂] Receptor agonist In Pulmonary arterial HypertensiON) was a multicenter, double-blind, parallel group, placebo-controlled, event-driven trial evaluating the efficacy and safety of oral UPTRAVI in patients with World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH; N=1156).¹
• In GRIPHON, over a median duration of 70.7 weeks, 142 treatment interruptions were reported in 111 (19.3%) patients on UPTRAVI. The majority of interruptions occurred during the titration phase (76/142) and the most common reason for treatment interruptions were adverse events (AEs). During the interruption, approximately onethird of patients reported an AE and 2 reported serious adverse events (SAEs).²
• AEs leading to treatment discontinuation were also observed in a post hoc analyses and the open label extension (OLE) of the GRIPHON study.^3,4
• In an exploratory analysis of the GRIPHON data, a total of 192 (33.4%) patients on UPTRAVI and 127 (22.0%) on placebo experienced 213 and 134 episodes, respectively, of either discontinuation or interruption of study drug for at least 2 days without reintroduction of study drug within 7 days in the absence of a recent clinical worsening event. Of these, 3 patients treated with UPTRAVI, and 2 patients treated with placebo experienced an SAE suggestive of PAH worsening within this timeframe. Two of the 3 events in the UPTRAVI group (right ventricular failure in both cases) were deemed associated with UPTRAVI withdrawal compared to none of the 2 events in the placebo group.⁵

CLINICAL DATA

Phase 3 GRIPHON Study

The GRIPHON phase 3 study (Prostacyclin [PGI₂] Receptor agonist In Pulmonary arterial HypertensiON; AC-065A302) was a multicenter, double-blind, parallel group, placebocontrolled, event-driven trial evaluating the efficacy and safety of oral UPTRAVI in adult patients with WHO Group 1 PAH.¹ Patients with symptomatic PAH (N=1156) were randomized 1:1 to receive UPTRAVI (n=574) or placebo (n=582) twice daily (BID). The median duration of study treatment was 70.7 weeks and 63.7 weeks for patients who received UPTRAVI or placebo, respectively. The study design is presented in the Figure: GRIPHON Study Design. Please visit http://www.clinicaltrials.gov for more information on the inclusion and exclusion criteria for GRIPHON (identifier NCT01106014).⁶

Dosing of UPTRAVI or placebo in GRIPHON was initiated at 200 mcg BID and increased weekly in steps of 200 mcg BID, as tolerated, up to a maximum dose of 1600 mcg BID. This dose adjustment phase spanned the first 12 weeks of treatment. To determine the highest tolerable dose, this phase employed dose reduction by 200 mcg BID when an intolerable dose was reached.^1,7 After 12 weeks, patients entered the maintenance phase of the study. Starting at week 26, doses could be increased at scheduled visits; dose reductions were allowed at any time. For each patient, the individualized maintenance dose (IMD) was the dose the patient received for the longest duration until end of treatment (i.e., last intake of double-blind treatment with UPTRAVI or placebo plus 7 days; EOT). For the majority (81.7%) of UPTRAVI treated patients, the IMD represented the highest tolerated dose in the titration phase.⁸

Temporary Treatment Interruptions in GRIPHON

In GRIPHON, study treatment could be interrupted or permanently discontinued if it was in the patient’s best interests or for administrative reasons. If treatment was interrupted for <3 days, UPTRAVI could be reintroduced at the highest tolerated dose achieved before the interruption. If treatment was interrupted for ≥3 days, subsequent retitration from 200 mcg BID was required.²

Of the 1156 patients in the GRIPHON study, 169 (14.6%) had at least 1 treatment interruption: 58 of 582 patients (10.0%) in the placebo group and 111 of 574 patients (19.3%) in the UPTRAVI group. Baseline characteristics of patients with an interruption were generally similar to those of patients without an interruption. Consistent with the overall GRIPHON population, most of the patients with a treatment interruption were receiving background PAH therapy: 94 of 111 patients (85%) in the UPTRAVI group and 48 of 58 patients (83%) in the placebo group.²

Characterization of Treatment Interruptions

The titration phase was from randomization (day 1) up to day 87. The median (quartile [Q1Q3]) duration of UPTRAVI treatment during the maintenance phase was 463 (258-775) days. Among patients receiving UPTRAVI, 142 treatment interruptions were reported, with 72 (51%) lasting ≥3 days. Overall, 76 UPTRAVI interruptions (54%) occurred during the titration phase, and 66 (46%) occurred during the maintenance phase (Figure: Distribution of the Frequency of UPTRAVI Treatment Interruptions by Interruption Start Day). In the titration phase, 58% (44 of 76) of the UPTRAVI interruptions were <3 days’ duration, whereas in the maintenance phase, 61% (40 of 66) were of ≥3 days’ duration. A similar distribution was observed among the 71 placebo interruptions.²

Among UPTRAVI interruptions that lasted for ≥3 days, the median (Q1-Q3) duration was 6.0 (4.0-9.0) days in the titration phase and 10.5 (6.0-18.5) days in the maintenance phase. In the placebo group, for interruptions ≥3 days, the median (Q1-Q3) duration was 5.5 (5.0-11.0) days and 8.0 (6.0-34.0) days in the titration and maintenance phases, respectively.²

Reasons for Treatment Interruptions

AEs were the most common reason for UPTRAVI interruptions, accounting for 87% (124 of 142) of the reasons for interruption; this was the case in both the titration (93% [71 of 76 interruptions]) and the maintenance (80% [53 of 66 interruptions]) phases, regardless of the interruption duration. The remaining UPTRAVI interruptions were attributed to administrative/other reasons. In the placebo group, AEs were the most common reason for interruptions during the titration phase and both AEs and administrative/other contributed equally to reasons for interruptions during the maintenance phase.²

Of the UPTRAVI interruptions for which the reason was reported as an AE, 55% in the titration phase were those typically associated with prostacyclin therapy, and 32% in the maintenance phase were prostacyclin-type AEs (Table: Summary of the Reasons for UPTRAVI Treatment Interruptions and Table: Summary of AEs Listed as the Reason for UPTRAVI Treatment Interruptions). For placebo interruptions, most of the AEs were those not typically associated with prostacyclin therapy.²

Post hoc analyses of the GRIPHON study explored the effect of UPTRAVI in patients with PAH and cardiovascular comorbidities. Patients were divided into subgroups A (<3 comorbidities and hemodynamic criteria met; n=962) and B (≥3 comorbidities and/or hemodynamic criteria not met; n=144). A higher proportion of patients treated with UPTRAVI vs placebo had an AE leading to treatment discontinuation in both subgroups (subgroup A, 13.2% vs 6.0%; subgroup B, 21.3% vs 13.2%). When grouped by comorbidity count, the proportion of patients with an AE leading to treatment discontinuation in both the UPTRAVI and placebo groups generally increased in those with a higher number of comorbidities.³

In the OLE of the GRIPHON study that aimed to assess the long-term safety and tolerability of UPTRAVI in patients with PAH, 305 (32.0%) patients experienced an AE leading to treatment discontinuation in the safety/tolerability set (N=953). The most common AEs leading to treatment discontinuation included PAH worsening (12.9%), headache (3.4%), right ventricular failure (2.9%), diarrhea (2.0%), dyspnea (1.5%), nausea (1.4%), and pain in extremity (1.0%).⁴

Dose Before and After Treatment Interruption

In the subset of patients with an interruption <3 days during the maintenance phase, the median UPTRAVI dose before and after the interruption was similar (Table: Summary of Dose Before and After Treatment Interruption During the Maintenance Phase). Of these patients, 87% reached similar doses before and after the interruption (individual mode dose within 200 mcg BID). For the subset of patients with an interruption ≥3 days in the maintenance phase, the median pre-interruption UPTRAVI dose was higher than the post-interruption dose; 68% of these patients reached similar doses pre- and post-interruption (individual mode dose within 200 mcg BID). For the 13 UPTRAVI interruptions caused by administrative or other reasons in the maintenance phase, the dose pre- and post-interruption was similar in 92.3% of cases (individual mode dose within 200 mcg BID). This proportion was 66.0% for the 53 interruptions caused by AEs during the maintenance phase.²

Among patients with UPTRAVI interruption of ≥3 days in the maintenance phase, 27 (79%) restarted UPTRAVI at 200 mcg BID (per protocol). For the remaining 7 patients, 5 restarted UPTRAVI at the dose they had received before the interruption and 2 restarted at a lower dose (not 200 mcg BID).²

AEs During Treatment Interruption

The frequency of AEs reported during treatment interruptions was low in both treatment groups (Table: Most Frequent AEs and SAEs That Began During UPTRAVI Interruption). During the 142 UPTRAVI interruptions, 50 AEs and 11 SAEs were reported, of which 17 AEs and 3 SAEs were considered by the investigator to be related to the study drug. Of the 11 SAEs, 9 were reported on the first day of the interruption (2 considered to be drugrelated: dizziness and hyponatremic syndrome) and are likely to have been the reason for the interruption. There were no reports of acute deterioration during temporary UPTRAVI interruption, assessed up to reinstitution of treatment or 14 days into the interruption, which ever came first. In 138 of 142 cases (97.2%), background PAH therapy remained unchanged during the treatment interruption.²

AEs After Treatment Reintroduction

Among patients who restarted treatment at the same dose as before treatment interruption, very few AEs and SAEs were reported within the 3 days of restarting treatment. Only 2 AEs denoting PAH progression were reported within the first 3 days of treatment reintroduction: PAH (placebo group) and peripheral edema (UPTRAVI group).²

Withdrawal and Rebound in GRIPHON

An exploratory analysis of GRIPHON data was performed to assess whether rebound effects were associated with the interruption or discontinuation of UPTRAVI for at least 2 days (without re-introduction within 7 days of the last administered dose), in patients who had not experienced a clinical worsening event within the previous 4 weeks. Cases in which SAEs suggestive of PAH worsening occurred within 2-7 days following drug interruption/discontinuation were identified. These cases underwent blinded review by an internal medical expert. Adjudication was provided as to whether the SAE was associated with study drug discontinuation.⁵

A total of 192/575 (33.4%) patients in the UPTRAVI group and 127/577 (22.0%) in the placebo group experienced 213 and 134 episodes, respectively, of either discontinuation or interruption of study drug for at least 2 days without re-introduction of study drug within 7 days in the absence of a recent clinical worsening event. Of these, 3 patients treated with UPTRAVI, and 2 patients treated with placebo experienced a SAE suggestive of PAH worsening within this timeframe. Two of the 3 events in the UPTRAVI group (right ventricular failure in both cases) were deemed associated with UPTRAVI withdrawal compared to none of the 2 events in the placebo group (Table: Treatment Emergent SAEs Suggestive of a Rebound Effect in Patients Who Discontinued or Interrupted UPTRAVI for At Least 2 Days).⁵

As the adjudicated cases represented <1% of the total cases of abrupt UPTRAVI interruption/discontinuation and there was a short-term low-dose exposure to UPTRAVI (exposure duration, 11 days) for the first case and uncertainty of the temporal relationship and reported moderate worsening in the second case, the results of the analysis did not indicate an association between UPTRAVI interruption/discontinuation and any AE suggestive of a rebound effect.⁵

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 29 March 2024.