Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial.

opticinumab, optic neuritis, RENEW, michael duplessie

Lancet Neurol. 2017 Mar;16(3):189-199. doi: 10.1016/S1474-4422(16)30377-5. Epub 2017 Feb 15.
Safety and efficacy of opicinumab in acute optic neuritis (RENEW): a randomised, placebo-controlled, phase 2 trial.
Cadavid D1, Balcer L2, Galetta S2, Aktas O3, Ziemssen T4, Vanopdenbosch L5, Frederiksen J6, Skeen M7, Jaffe GJ8, Butzkueven H9, Ziemssen F10, Massacesi L11, Chai Y12, Xu L12, Freeman S12; RENEW Study Investigators.
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Abstract
BACKGROUND:
The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode.
METHODS:
This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18-55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3-5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161.
FINDINGS:
The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was -3·5 ms (17·3 vs 20·8 [95% CI -10·6 to 3·7]; 17%; p=0·33) in the ITT population, and -7·6 ms in the PP population (14·7 vs 22·2 [-15·1 to 0·0]; 34%; p=0·050) at week 24 and -6·1 ms (15·1 vs 21·2 [-12·7 to 0·5]; 29%; p=0·071) in the ITT population and -9·1 ms (13·2 vs 22·4 [-16·1 to -2·1]; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL [SD 0·21] for placebo vs 0·20 mL [0·52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0·4 [SD 0·79 for the placebo group and 0·85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group.
INTERPRETATION:
Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation.

Aqueous Humor Penetration and Biological Activity of Moxifloxacin 0.5% Ophthalmic Solution Alone or with Dexamethasone 0.1.

J Ocul Pharmacol Ther. 2017 Mar;33(2):98-102. doi: 10.1089/jop.2016.0126.
Aqueous Humor Penetration and Biological Activity of Moxifloxacin 0.5% Ophthalmic Solution Alone or with Dexamethasone 0.1.
Gomes RL1,2, Viana RG2, Melo LA Jr1,2, Cruz AC3, Suenaga EM3, Kenyon KR4, Campos M1,2.
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Abstract
PURPOSE:
To compare aqueous humor concentrations of topically applied moxifloxacin 0.5% ophthalmic solution alone or in combination with dexamethasone 0.1% and to correlate these concentrations with the minimum inhibitory concentrations (MICs) for common endophthalmitis-causing organisms.
METHODS:
Sixty-eight patients undergoing routine phacoemulsification with intraocular lens implantation received either moxifloxacin 0.5% alone or moxifloxacin 0.5% combined with dexamethasone. For both groups, 1 drop of the test solution was instilled 4 times daily 1 day preoperatively and 1 drop 1 h preoperatively. An aqueous humor sample obtained immediately before paracentesis was submitted to high-performance liquid chromatography-tandem mass spectrometry to determine the moxifloxacin concentration.
RESULTS:
The mean concentrations of moxifloxacin were 986.6 ng/mL in the moxifloxacin with dexamethasone group and 741.3 ng/mL in the moxifloxacin group (P = 0.13). Moxifloxacin concentrations of all samples exceeded the MICs for Staphylococcus epidermidis, S. aureus, and Streptococcus pneumoniae. All samples in the moxifloxacin with dexamethasone group and 94% in the moxifloxacin group achieved the MIC for Enterococcus species. For quinolone-resistant S. aureus, the MIC was achieved in 29% in the moxifloxacin with dexamethasone group and 9% in the moxifloxacin group (P = 0.06).
CONCLUSION:
Aqueous humor moxifloxacin concentrations were higher when topically administrated in combination with dexamethasone compared to the moxifloxacin alone. However, this difference was not statistically significant. Nevertheless, the MICs of the most common pathogens associated with endophthalmitis were exceeded in both study groups.
KEYWORDS:
antibiotics; aqueous humor; corneal permeability; fluoroquinolone ophthalmic solutions; steroids

One-Year Outcomes of Intravitreal Aflibercept Injections in Macular degeneration

Ophthalmologica. 2017 Feb 24. doi: 10.1159/000461785.
One-Year Outcomes of 1 + pro re nata versus 3 + pro re nata Intravitreal Aflibercept Injection for Neovascular Age-Related Macular Degeneration.
Takayama K1, Kaneko H, Sugita T, Maruko R, Hattori K, Ra E, Kawano K, Kataoka K, Ito Y, Terasaki H.
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Abstract
PURPOSE:
We compared 1-year outcomes of 1 + pro re nata (PRN) versus 3 + PRN of intravitreal aflibercept injection (IAI) for age-related macular degeneration (AMD).
METHODS:
Forty-two eyes with naïve AMD received 3 + PRN IAI treatment and 47 eyes with naïve AMD received 1 + PRN IAI treatment. Visual acuity (VA), central retinal thickness (CRT), and central choroidal thickness (CCT) and number of administered IAIs during 12 months were compared.
RESULTS:
VAs improved, and CRTs reduced significantly at any given month from baseline in both groups (p < 0.01, respectively). CCT reduced significantly at 3 months in the 3 + PRN group (p = 0.024) but not in the 1 + PRN group. The 1 + PRN group received fewer injections than the 3 + PRN group (p < 0.01).
CONCLUSIONS:
Aflibercept leads to equivalent VA and morphologic retinal improvement without administering 3 injections.

One-Year Outcomes of 1 + pro re nata versus 3 + pro re nata Intravitreal Aflibercept Injection for Neovascular Age-Related Macular Degeneration.
Takayama K1, Kaneko H, Sugita T, Maruko R, Hattori K, Ra E, Kawano K, Kataoka K, Ito Y, Terasaki H.
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Abstract
PURPOSE:
We compared 1-year outcomes of 1 + pro re nata (PRN) versus 3 + PRN of intravitreal aflibercept injection (IAI) for age-related macular degeneration (AMD).
METHODS:
Forty-two eyes with naïve AMD received 3 + PRN IAI treatment and 47 eyes with naïve AMD received 1 + PRN IAI treatment. Visual acuity (VA), central retinal thickness (CRT), and central choroidal thickness (CCT) and number of administered IAIs during 12 months were compared.
RESULTS:
VAs improved, and CRTs reduced significantly at any given month from baseline in both groups (p < 0.01, respectively). CCT reduced significantly at 3 months in the 3 + PRN group (p = 0.024) but not in the 1 + PRN group. The 1 + PRN group received fewer injections than the 3 + PRN group (p < 0.01).
CONCLUSIONS:
Aflibercept leads to equivalent VA and morphologic retinal improvement without administering 3 injections.