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1. Safety
1.1.1. Adverse Events (AEs)
In both studies, the most frequent AEs were in the Body System Nervous System Disorders and the most frequent CNS AEs were headache and dizziness. In the bitopertin study, several cases of back pain were reported, which were mostly considered to be unrelated to treatment as there was a relationship to the CSF procedures. In the RG7118 study, no severe AE, and in the bitopertin study, 3 severe AEs (headache, nausea and syncope) occurred. One subject under 10 mg suffered from headache and nausea, which were reversible under treatment. Another subject under 60 mg had syncope on Day 3 lasting for approximately 20 seconds, treatment was continued and no re-occurrence was reported.
1.1.2. Visual Assessments
As GlyT1 is localised on amacrine cells in the retina [Pow, 2011], regular visual assessments were performed in both studies. In the bitopertin study, there were no relevant changes in pupil size, near vision (Rosenbaum chart), color vision (Ishihara plates), or confrontation field testing. For distance vision (ETDRS chart), one subject on 10 mg experienced reversible bilateral reduction of visual acuity (change from baseline: 0.38 LogMAR) two hours postdose on day 5 with concurrent blurred vision and another subject on 60 mg experienced reversible unilateral reduction 4 hours postdose on Day 5 (change from baseline : 0.48 logMAR).
In the RG7118 study, no drug-related deteriorations were observed in pupil size, distance vision (ETDRS chart), color vision (Farnsworth-Munsell 100 Hue), or visual field. At the higher dose of 30 mg, statistically significant increase in the distance of convergence break and improvement in contrast sensitivity (both eyes) was observed.
1.1.3. Haematological Assessments
GlyT1 is expressed on pre-erythrocytes [Schranzhofer et al., 2011]. As the first step in heme synthesis is the condensation of glycine with succinyl-CoA by ALAS to form δ-aminolevulinic acid, inhibition of GlyT1 leads to reduction in haemoglobin synthesis.
In the RG7118 study, several haematological parameters showed a tendency for a dose dependent pattern, i.e. decrease in haemoglobin, haematocrit, MCV, MCH, reticulocytes MCV, and reticulocytes MCH and increase in reticulocytes. MCH in reticulocytes decreased rapidly with a minor additional decrease between 7 and 28 days (absolute change from baseline, mean ± SD: 15 mg: -4.94 ± 1.56 and -6.16 ± 1.23 pg/cell after 7 and 28 days, respectively; 30 mg: -6.36 ± 2.17 and -8.19 ± 3.00 pg/cell). In contrast, MCH in RBCs decreased gradually (Day 28: -1.30±0.66 and -2.10±0.52 pg/cell after 15 and 30 mg, respectively) and did not reach a plateau. This is compatible with the life span of 1-2 days for reticulocytes and 120 days for RBC. Haemoglobin decreased dose-dependently and with high variability (Day 28: -3.0±6.3 and -11±9.5 g/L after 15 and 30 mg, respectively).
1.1.4. Other Safety Assessments
In the bitopertin study, no relevant changes in vital signs, ECGs, and laboratory parameters were observed. In the RG7118 study, no relevant changes in vital signs or ECGs were detected. Two cases of reversible changes in laboratory parameters occurred in the 30 mg dose group, which were considered to be an adverse event by the Investigator: a case of neutropenia and a case of increased ALAT (3.9-fold above upper limit of normal). For all other non-haematological laboratory parameters no clinically relevant changes were observed.
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