Relative exposure Relative exposures to ACT-333679/selexipag were calculated relative to estimated AUC024 h values from population PK analysis of data from PAH patients steady-state selexipag doses of 1600 µg bd. Relative exposures to ACT-333679, at the No observable adverse effect level (NOAEL) dose, were moderately high for rodents (approximately40 for daily dosing of mice for 2 years and approximately15 for daily dosing of rats for 6 months) and very high for dogs (approximately140 for daily dosing for 9 months) (see Table 2). 2: Relative exposure in repeat-dose toxicity and carcinogenicity studiesa Study Study day of TK Dose Sex h µg∙h/mLc Exposure ratioc, d 13 weeks (91) 100e, 300, 500 ♂ 12.40, 51.50, 71.50 (12.20, 52.10, 90.00) 34, 141, 195 (110, 469, 811) ♀ 9.990, 39.80, 58.00 (10.10, 44.40, 74.00) 27, 109, 158 (91, 400, 667) 2 years (181) 125, 250, 500f ♂ 13.90, 31.70, 67.50 (11.60, 36.80, 84.40) 38, 87, 184 (105, 332, 760) ♀ 16.00, 30.80, 65.50 (18.60, 36.70, 91.70) 44, 84, 179 (168, 331, 826) Rat (SD) 4 weeks (28) 20, 60, 180 ♂ 12.20, 38.79, 137.3 (0.3176, 2.148, 8.770) 33, 106, 375 (3, 19, 79) ♀ 9.541, 36.28, 303.5 (0.5100, 26, 99, 829 (5, 26, 223) b e
Rat SD Fertility and early embryo (T-08.287 (R-950)) ♂ = 2 weeks + 2-weeks mating; ♀ = 2 weeks during mating, and till GD7 (15) 6e, 20, 60e ♂ 3.65, 12.3, 48.9 (0.160, 0.709, 4.30) 10, 34, 134 (1.4, 6.4, 39) ♀ 3.00, 8.62, 47.8 (0.107, 0.502, 2.88) 8.2, 24, 131 (1.0, 4.5, 26) (T-08.288 (R-951)) GD7‒17 (GD17) 2, 6f, 20 ♀ 0.920, 3.35, 12.9 (0.0406, 0.156, 1.16) 2.5, 9.2, 35 (0.4, 1.4, 10) (T-12.054 (R-1048)) (dams) (PND21) 2, 6, 20 ♀ 0.236, 2.46, 9.56 (‒, 0.193, 1.17) 0.6, 6.7, 26 (‒, 1.7, 11) NZW (T-08.289 (R-952)) (GD18) 3, 10, 30 ♀ 1.15, 4.09, 13.7 (0.0228, 0.144, 1.56) 3.1, 11, 37 (0.2, 1.3, 14) Dog beagle Juvenile (T-12.357 26 (starting PND 27‒32) (181) 1, 3 ♂ 20.90, 55.20 (2.360, 8.270) 57, 150 (21, 75) ♀ 14.30, 52.80 (2.330, 7.190) 39, 144 (21, 65) 39 weeks (starting PND 27‒32) (272) 1, 3, 6/4 ♂ 16.40, 44.70, 48.80 (2.920, 7.270, 12.50) 45, 122, 133 (26, 65, 113)
of the AEs associated with their use and also of those associated with selexipag, particularly headache, diarrhoea and nausea. Despite multifactorial reasons for patients treated with none, one or two PAH-specific medications prior to entry into GRIPHON, a trend for a more severe baseline disease state in patients with combination therapy compared to treatment-naïve patients is evident. The treatment effect of selexipag in the primary endpoint was consistent across categories of background treatment. In line with published data in PAH patients, the treatment effect on exercise capacity was larger in treatment-naïve patients compared to those pre-treated. The AE safety profile of each sub-group appears to be driven largely by the individual contributions of the respective PAH-specific medications. The use of selexipag on top of existing PAH background therapy targeting endothelin and nitric oxide pathways, as well as in monotherapy, is in line with current PAH treatment guidelines. The mentioned references are provided in updated Module 5.4 Literature References. Given the limited evidence could be provided by clinical trials for this first in class product, the sponsor should consider the need to further characterise the safety profile through additional pharmacovigilance activities. The sponsor will provide further long-term safety information through routine pharmacovigilance (PV) monitoring and submission of PBRERs in accordance with the ICH guideline E2C (R2). In addition, further long-term safety data will emerge from the GRIPHON and NS-304/-03 studies. A CSR will be provided once the studies are completed. As an additional PV activity, Actelion is in discussion with the Committee for Medicinal Products for Human Use (CHMP) regarding setting up a long-term, multicenter, prospective, real-world, (observational) Uptravi (selexipag) safety study. The evaluator has noted that two planned safety study (PASS) studies have been included in the updated One is the study referred by the sponsor and the other is to monitor the occurrence of the important potential risk - medication error, and to measure the effectiveness of the additional risk minimisation activities. It is noted that neither studies are referred in