Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials

Background Elexacaftor–tezacaftor–ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. Methods We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor–tezacaftor–deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor–tezacaftor–deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor–deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)–tezacaftor–deutivacaftor or tezacaftor–ivacaftor active control for 4 weeks, following a 4-week tezacaftor–ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. Findings In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI –0·8 to 7·0) and 2·7 percentage points (–1·0 to 6·5) from baseline at week 12, respectively, versus –0·8 percentage points (–6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)–tezacaftor–deutivacaftor (n=9), vanzacaftor (10 mg)–tezacaftor–deutivacaftor (n=19), vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (−1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (−4·1 to 8·0), respectively, in sweat chloride concentration of −42·8 mmol/L (–51·7 to –34·0), −45·8 mmol/L (95% CI –51·9 to –39·7), −49·5 mmol/L (–55·9 to –43·1), and 2·3 mmol/L (−7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (−10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=18) and tezacaftor–ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor–ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and −0·1 percentage points (−6·4 to 6·1), respectively, in sweat chloride concentration of −45·5 mmol/L (−49·7 to −41·3) and −2·6 mmol/L (−8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and −5·0 points (−16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor–tezacaftor–deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. Interpretation Once-daily dosing with vanzacaftor–tezacaftor–deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor–tezacaftor–deutivacaftor in phase 3 clinical trials compared with elexacaftor–tezacaftor–ivacaftor. Funding Vertex Pharmaceuticals

Multiple Si–H Bond Activations by ^<i>t</i>Bu₂PCH₂CH₂P^<i>t</i>Bu₂ and ^<i>t</i>Bu₂PCH₂P^<i>t</i>Bu₂ Di(phosphine) Complexes of Rhodium and Iridium

Reactions of the di­(<i>tert</i>-butylphosphino)­ethane complex (dtbpe)­Rh­(CH₂Ph) with Ph₂SiH₂ and Et₂SiH₂ resulted in isolation of (dtbpe)­Rh­(H)₂(SiBnPh₂) (<b>1</b>; Bn = CH₂Ph) and (dtbpe)­Rh­(H)₂(SiBnEt₂) (<b>2</b>), respectively. Both <b>1</b> and <b>2</b> feature strong interactions between the rhodium hydride and silyl ligands, as indicated by large ²<i>J</i>_SiH values (44.4 and 52.1 Hz). The reaction of (dtbpm)­Rh­(CH₂Ph) (dtbpm = di­(<i>tert</i>-butylphosphino)­methane) with Mes₂SiH₂ gave the pseudo-three-coordinate Rh complex (dtbpm)­Rh­(SiHMes₂) (<b>3</b>), which is stabilized in the solid state by agostic interactions between the rhodium center and two C–H bonds of a methyl substituent on the mesityl group. The analogous germanium compound (dtbpm)­Rh­(GeHMes₂) (<b>4</b>) is also accessible. Complex <b>3</b> readily undergoes reactions with diphenylacetylene, phenylacetylene, and 2-butyne to give the silaallyl complexes (dtbpm)­Rh­[Si­(CPhCHPh)­Mes₂] (<b>5</b>), (dtbpm)­Rh­[Si­(CHCHPh)­Mes₂] (<b>7</b>), and (dtbpm)­Rh­(Si­(CMeCHMe)­Mes₂) (<b>8</b>) via net insertions into the Si–H bond. The germaallyl complexes (dtbpm)­Rh­[Ge­(CPhCHPh)­Mes₂] (<b>6</b>) and (dtbpm)­Rh­[Ge­(CMeCHMe)­Mes₂] (<b>9</b>) were synthesized under identical conditions starting from <b>4</b>. The reaction of (dtbpm)­Rh­(CH₂Ph) with 1 equiv of TripPhSiH₂ yielded (dtbpm)­Rh­(H)₂[5,7-diisopropyl-3-methyl-1-phenyl-2,3-dihydro-1<i>H</i>-silaindenyl-κ<i>Si</i>] (<b>11</b>), and catalytic investigations indicate that both (dtbpm)­Rh­(CH₂Ph) and <b>11</b> are competent catalysts for the conversion of TripPhSiH₂ to 5,7-diisopropyl-3-methyl-1-phenyl-2,3-dihydro-1<i>H</i>-silaindole. A dtbpm-supported Ir complex, [(dtbpm)­IrCl]₂, was used to access the dinuclear bridging silylene complexes [(dtbpm)­IrH]­(μ-SiPh₂)­(μ-Cl)₂[(dtbpm)­IrH] (<b>12</b>) and [(dtbpm)­IrH]­(μ-SiMesCl)­(μ-Cl)­(μ-H)­[(dtbpm)­IrH] (<b>13</b>). The reaction of [(dtbpm)­IrCl]₂ with a sterically bulky primary silane, (dmp)­SiH₃ (dmp = 2,6-dimesitylphenyl), allowed isolation of the mononuclear complex (dtbpm)­Ir­(H)₄(10-chloro-1-mesityl-5,7-dimethyl-9,10-dihydrosilaphenanthrene-κ<i>Si</i>), in which the dmp substituent has undergone C–H activation

Highly efficient large bite angle diphosphine substituted molybdenum catalyst for hydrosilylation

Treatment of the complex Mo(NO)Cl3(NCMe)2 with the large bite angle diphosphine, 2,2′-bis(diphenylphosphino)diphenylether (DPEphos) afforded the dinuclear species [Mo(NO)(P∩P)Cl2]2[μCl]2 (P∩P = DPEphos = (Ph2PC6H4)2O (1). 1 could be reduced in the presence of Zn and MeCN to the cationic complex [Mo(NO)(P∩P)(NCMe)3]+[Zn2Cl6]2–1/2 (2). In a metathetical reaction the [Zn2Cl6]2–1/2 counteranion was replaced with NaBArF4 (BArF4 = [B{3,5-(CF3)2C6H3}4]) to obtain the [BArF4]− salt [Mo(NO)(P∩P)(NCMe)3]+[BArF4]− (3). 3 was found to catalyze hydrosilylations of various para substituted benzaldehydes, cyclohexanecarboxaldehyde, 2-thiophenecarboxaldehyde, and 2-furfural at 120 °C. A screening of silanes revealed primary and secondary aromatic silanes to be most effective in the catalytic hydrosilylation with 3. Also ketones could be hydrosilylated at room temperature using 3 and PhMeSiH2. A maximum turnover frequency (TOF) of 3.2 × 104 h–1 at 120 °C and a TOF of 4400 h–1 was obtained at room temperature for the hydrosilylation of 4-methoxyacetophenone using PhMeSiH2 in the presence of 3. Kinetic studies revealed the reaction rate to be first order with respect to the catalyst and silane concentrations and zero order with respect to the substrate concentrations. A Hammett study for various para substituted acetophenones showed linear correlations with negative ρ values of −1.14 at 120 °C and −3.18 at room temperature