Inhaled levodopa in Parkinson's disease patients with OFF periods: A randomized 12-month pulmonary safety study

Introduction: CVT-301 is an orally inhaled levodopa therapy approved for the intermittent treatment of OFF episodes in Parkinson's disease patients who are taking a standard oral levodopa regimen. This open-label, randomized, controlled study over 12 months characterizes the safety, including pulmonary safety, of CVT-301 84 mg (nominal respirable levodopa fine-particle dose, 50 mg). Methods: Patients experiencing motor fluctuations were randomized 2:1 to CVT-301 or an observational cohort (OC) receiving oral standard of care. Pulmonary safety was assessed using spirometry and carbon monoxide diffusion capacity (DLCO). Exploratory efficacy endpoints, assessed only for CVT-301, included change in Unified Parkinson's Disease Rating Scale Part III (UPDRS-III), patients achieving ON within 60 min and remaining ON at 60 min, Patient Global Impression of Change (PGIC) scale, and total daily OFF time. Results: Of 408 patients randomized, 310 completed the study (204 in CVT-301 and 106 in OC). Mean 12-month changes from baseline for CVT-301 were −0.105 L (FEV1) and −0.378 mL/min/mm Hg (DLCO), and for OC were −0.117 L and −0.722 mL/min/mm Hg, respectively. Between-group comparisons were not statistically significant. For FEV1/FVC the 12-month change was −0.3 and −1.6, respectively, which was a significant between-group difference. However, between-group differences were not significant at 3 and 9 months and all changes from baseline were small (<2.0%). UPDRS-III scores improved from predose to 60 min postdose at all assessments; 80%–85% of patients switched ON within 60 min and remained ON; and >75% reported improvement in PGIC. OFF time decreased by 1.32–1.42 h/day. Conclusion: CVT-301 84 mg induced no clinically significant differences in pulmonary function compared with the OC. Improvements in motor scores, OFF time, and patient-reported outcomes support clinical efficacy for up to 12 months

Pulmonary Safety and Tolerability of Inhaled Levodopa (CVT-301) Administered to Patients with Parkinson\u27s Disease

BACKGROUND: CVT-301, an inhaled levodopa (LD) formulation, is under development for relief of OFF periods in Parkinson\u27s disease (PD). Previously, we reported that CVT-301 improved OFF symptoms relative to placebo. In this study, we evaluate pulmonary function in patients treated with a single dose of CVT-301 or placebo for 3 hours, or received multiple doses/day for 4 weeks. METHODS: As part of two phase 2 studies, pulmonary safety and tolerability of CVT-301 were evaluated in PD patients experiencing motor fluctuations (≥2 hours OFF/day), Hoehn and Yahr stage 1-3, and forced expiratory volume in 1 second/forced vital capacity ratio ≥75% of predicted (in ON state). In study A, patients received single doses of oral carbidopa/LD and each of the following via the inhaled route: placebo and 25 and 50 mg LD fine particle dose (FPD) CVT-301. In study B, patients received up to 3 inhaled doses/day of 35 mg (weeks 1-2) and 50 mg LD FPD CVT-301 (weeks 3-4) versus placebo. Assessments included spirometry and treatment-emergent adverse events (TEAEs). RESULTS: In study A, (n = 24) mean age ± standard deviation was 61.3 ± 7.4 years, mean time since diagnosis was 10.5 ± 4.6 years, and mean duration of LD treatment 8.4 ± 3.7 years. Assessment of pulmonary function (predose to 3 hours postdose) showed that spirometry findings were within normal ranges, regardless of treatment groups, or motor status at screening. In study B, (n = 86) mean age was 62.4 ± 8.7 years, time since PD diagnosis was 9.4 ± 3.9 years, and duration of LD treatment 7.8 ± 3.9 years. Longitudinal assessment of pulmonary function over 4 weeks showed no significant difference in spirometry between CVT-301 versus placebo groups. In both studies, the most common CVT-301 TEAE was mild-to-moderate cough (study A: 21%; study B: 7% vs. 2% in placebo). Other common TEAEs in study B were dizziness and nausea. CONCLUSION: Acute and longitudinal assessment of pulmonary function showed that CVT-301 treatment was not associated with acute airflow obstruction in this population. CVT-301 was generally safe and well tolerated

Inhaled levodopa (CVT-301 84mg) significantly improves motor function during off periods in Parkinson\u27s disease (PD) subjects: A phase 3 study (SPAN-PD™)

Objective: To evaluate efficacy and safety of CVT-301 vs placebo in PD subjects during OFF periods. Background: CVT-301, an investigational, inhaled therapy that delivers levodopa to the lungs, is intended to treat OFF periods for patients on a dopa-decarboxylase inhibitor/levodopa regimen. Methods: A 12-week, double-blind, placebo-controlled study of PD subjects experiencing motor fluctuations. Subjects were randomized to placebo, CVT-301 84mg or 60mg (1:1:1). Treatment was up to 5 times daily. Efficacy analyses were performed using a prespecified hierarchical testing. Primary efficacy endpoint: change in UPDRS part III score at 30min from pre-to postdose with CVT-301 84mg vs placebo at week 12 evaluated during an OFF period. Key secondary endpoints: ON responders within 60min; change in UPDRS part III score at 20min postdose; improvement in PGIC; change in UPDRS part III score at 10min postdose; and total daily OFF time. Safety profile, including pulmonary function, was assessed. Nominal P-values are presented for key secondary endpoints that were not statistically significant due to the hierarchy. Results: 339 randomized subjects received at least 1 dose of CVT-301 or placebo; 290 completed the study (mean age 63.3years, mean PD duration 8.3years, mean total OFF time 5.5hours). Primary endpoint was 29.8 for 84mg vs 25.9 for placebo (P50.009). At week-12, 58% on 84mg vs 36% on placebo were ON responders within 60min (P\u3c0.05), and 71% on 84mg vs 46% on placebo reported improvement in PGIC (nominal P\u3c0.05). 84mg vs placebo improved in UPDRS part III at 10min, which was sustained for 1hour. Most common AE for 84mg vs placebo was cough (14.9% vs 1.8%). Spirometry data showed no significant pulmonary safety indicators. Conclusion: Findings confirmed that compared with placebo, CVT-301 84mg showed a clinically meaningful response in the treatment of OFF periods, based on the Shulman criteria. CVT-301 was generally well tolerated

Changes of lipid peroxidation and antioxidant protection in spontaneously hypertensive rats during experimental treatment by Ramipril and Candesartan

Background: As Parkinson’s disease progresses, levodopa treatment loses efficacy, partly through the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC). In the phase I PD-1101 study, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced Parkinson’s disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements. Objectives: This substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01administration. Methods: Participants received 2-hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01. Infusion order was randomized and double blinded. Unified Parkinson’s Disease Rating Scale motor scores, finger-tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and ≥3 hours after start of levodopa infusion. Results: Of 15 PD-1101 patients, 13 participated in the sub-study. Unified Parkinson’s Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and67%, respectively, after VY-AADC01; finger-tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY-AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre–VY-AADC01 and 2 participants post–VY-AADC01administration. Conclusions: VY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and findings from the parent study support further clinical development of AADC gene therapy for people with Parkinson’s disease

Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson\u27s disease: a randomised, double-blind, placebo-controlled phase 3 trial

BACKGROUND: Patients with Parkinson\u27s disease chronically treated with levodopa commonly have delayed or unpredictable onset of its benefits after oral intake. In this study, we assessed the safety and efficacy of CVT-301, a self-administered levodopa oral inhalation powder, for the treatment of patients with Parkinson\u27s disease during off periods. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, patients were recruited at 65 sites in Canada, Poland, Spain, and the USA. Eligible participants were patients with Parkinson\u27s disease aged 30-85 years, who had daily off periods of 2 h or longer and showed an improvement of 25% or greater in the Unified Parkinson\u27s Disease Rating Scale (UPDRS) motor score from off to on state after use of an oral levodopa plus a dopa-decarboxylase inhibitor combination. Patients were assigned (1:1:1) with a computer-generated randomisation code, in fixed blocks of six, to either CVT-301 60 mg, CVT-301 84 mg, or placebo. Spirometry results and modified Hoehn and Yahr disease stage at screening were used for stratification of treatment groups. Patients, the sponsor, and site personnel were masked to treatment assignment. Each study dose consisted of two capsules administered with an inhaler. Patients were instructed to use the study drug as needed for off periods, and could self-administer up to five doses per day. The primary endpoint was the change in UPDRS motor score from predose to 30 min postdose, assessed at week 12 during an in-clinic off period, in the CVT-301 84 mg group compared with the placebo group. Analysis was by intention to treat. Safety was assessed in all patients who received at least one dose of experimental treatment. This trial is registered with ClinicalTrials.gov, number NCT02240030. FINDINGS: Between Dec 4, 2014, and Aug 26, 2016, 351 patients were enrolled and randomly assigned to receive CVT-301 60 mg (115 patients), CVT-301 84 mg (120 patients), or placebo (116 patients). Of these, 339 received the assigned study treatment (CVT-301 60 mg, n=113; CVT-301 84 mg, n=114; placebo, n=112) and 290 completed the study (CVT-301 60 mg, n=96; CVT-301 84 mg, n=97; placebo, n=97). The least-squares mean difference in UPDRS motor score change from predose to 30 min postdose was -5·91 (SE 1·50, 95% CI -8·86 to -2·96) for the placebo group and -9·83 (1·51; -12·79 to -6·87) for the CVT-301 84 mg group (between-group difference -3·92 [-6·84 to -1·00]; p=0·0088). Treatments were safe and well tolerated. Severe adverse events were reported by 2 (2%) of 112 patients in the placebo group, 7 (6%) of 113 in the CVT-301 60 mg group, and 5 (4%) of 114 in the CVT-301 84 mg group, with no severe adverse event occurring in more than one patient in any treatment group. 11 (3%) of 339 patients had 19 serious adverse events (three [3%] of 112 patients in placebo, six [5%] of 113 in CVT-301 60 mg, and two [2%] of 114 in CVT-301 84 mg). Of these, hypotension and atrial fibrillation were assessed by investigators to be possibly related to the study drug. INTERPRETATION: CVT-301 can improve UPDRS motor scores of patients with Parkinson\u27s disease during in-clinic off periods, with few severe or serious adverse events. The long-term safety and efficacy of CVT-301 need to be investigated in future studies. FUNDING: Acorda Therapeutics

A phase Ib/II study of olutasidenib in patients with relapsed/refractory IDH1 mutant gliomas: Safety and efficacy as single agent and in combination with azacitidine

2505 Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in >70% of patients with Grade II/III gliomas resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent, brain penetrant (Kpuu=0.4 in intact rodent), and selective inhibitor of mutated IDH1 protein. Methods: Patients (pts) with relapsed/refractory (R/R) mIDH1 gliomas received olutasidenib 150 mg BID, orally either as single agent (SA) or in combination (CO) with azacitidine in a dose confirmation phase Ib followed by efficacy evaluation phase II study (NCT: 03684811). Results: As of 31-Oct-2019, 29 pts with R/R mIDH1 glioma were treated with olutasidenib as SA (n=24) or CO (n=5). The median age was 45 yrs (range: 23-64) & 62% were male. WHO Glioma Grade (Gr) at study entry was: II (17%), III (52%) & IV (31%). Median number of prior treatments was 2 (1-5); 86% had received prior temozolomide. mIDH1 status was locally determined (IHC, NGS or PCR): R132H (86%), R132L (7%), R132C (3.5%) & unspecified (3.5%). The median duration of olutasidenib treatment for SA & CO was 4.8 (1-11.4) & 1 (0.2-2.3) months, respectively. Fifteen pts discontinued (disease progression [n=12], AE [n=1], withdrew consent [n=1], other [n=1]). For SA, the most common (>25%) TEAEs (all grades, regardless of attribution) were: fatigue (50%), nausea (50%), diarrhea (33%), ALT increase (29%) & headache (29%). For CO, TEAEs that occurred in ≥ 2 pts were: nausea (n=4), fatigue (n=2), neutropenia (n=2), ALT increase (n=2) & AST increase (n=2). There were 2 protocol defined DLTs in the CO cohort, 1 pt with Gr 4 ALT, Gr 3 AST & Gr 3 GGT elevations & 1 pt with Gr 3 ALT elevation. No pts experienced a TEAE of QTcF prolongation. SA best responses are shown in Table; CO pts are too early for response assessment. The median PFS for SA was 8.3 months. Twenty (87%) and 11 (48%) pts were alive and progression-free at 6 & 12 months, respectively. Conclusions: SA olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in glioma pts. Evaluation of CO is ongoing. Updated safety and clinical activity, as well as evaluations of serum/CSF PK/PD will be provided. Clinical trial information: NCT03684811 . [Table: see text

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: a multicenter, open-label, phase 1b/2 trial

Olutasidenib (FT2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1  R132X mutation.This was an open-label, multicenter, non-randomized, phase 1b/2 clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1  R132Xmutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase 1 and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase 2.Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase 2 dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each).Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1  R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population

Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: a multicenter, open-label, phase 1b/2 trial

BACKGROUND: Olutasidenib (FT2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1 R132X mutation. METHODS: This was an open-label, multicenter, non-randomized, phase 1b/2 clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1 R132Xmutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase 1 and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase 2. RESULTS: Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase 2 dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each). CONCLUSIONS: Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1 R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population