Horacio Kaufmann is Professor of Neurology, Medicine and Pediatrics and holds the Axelrod Chair for Neurological Research at New York University School of Medicine where he also Heads the Division of Autonomic Disorders and the Dysautonomia Center at NYU Langone Health. He received his Medical Degree from the National University of Buenos Aires, Argentina. He trained in Internal Medicine and completed Neurology residency and fellowship at Mount Sinai School of Medicine in New York City. His research focuses on the autonomic nervous system and its abnormalities in neurological disorders. His research is funded by the National Institute of Health (NIH, NINDS), the US Food and Drug Administration (FDA), The Michael J. Fox Foundation,The MSA Coalition and the Dysautonomia Foundation, Inc.

Background: The neurogenic orthostatic hypotension (nOH) is due to failure of the autonomic nervous system to adequately increase synaptic norepinephrine to maintain upright blood pressure (BP). Norepinephrine reuptake inhibitors (NRI) could augment local synaptic concentrations of tonically released norepinephrine, resulting in increased BP and reduced symptoms of OH. Ampreloxetine is a novel NRI being investigated for the treatment of symptomatic nOH.

 

Methods: This was a phase 2 multicenter, single and multiple-dose study of subjects with nOH. After a single dose escalation phase, responders were enrolled in an open label phase, treated with ampreloxetine taken orally once daily for up to 20 weeks, and followed for 4 weeks thereafter. The primary endpoint was the improvement from baseline in the validated symptom questionnaire OHSA#1 on day 29.

 

Results: 21 subjects were enrolled (mean age 64yrs), 16(76%) completed day 29. The mean [SD] improvement from baseline in OHSA#1 was 2.4[4.5] in all subjects and 3.8[3.1] in symptomatic subjects (OSHA#1 >4 at baseline). OHSA and OHDAS composite scores improved by 1.0(2.8) and 1.1(2.9), respectively. The most frequently reported adverse events (AE) were urinary tract infection (24%), hypertension (19%) and headache (14%). 2(10%) discontinued treatment due to AE and 5(24%) reported SAEs, none considered related to the study medication.

 

Conclusion: In subjects with nOH, ampreloxetine demonstrated clinically meaningful improvements in OHSA#1, OHSA and OHDAS composite scores at week 4. Th e improvement in OHSA#1 was maintained through week 20, with a regression to baseline levels during the 4 week follow-up. Ampreloxetine was generally well-tolerated.

Amin Hajitou completed his PhD at the University of Liege, Belgium, where he acquired extensive experience in delivery technologies for therapeutic nucleic acids. Then he did his Postdoctoral training in the world leading MD-Anderson Cancer Center in Texas-USA, where he gained expertise in bacteriophage

(phage)-guided gene delivery and phage display technologies in vitro and in vivo. Importantly, he designed a novel hybrid phage vector for targeted nucleic acid transfer to cancer. The hybrid phage, published in Cell 2006, showed first success of systemic gene targeting to cancer in vivo. His team and independent groups reported efficacy of intravenous cancer gene therapy in rodents and pet dogs with naturally occurring cancers. In 2008, he established his research team, as a Lecturer, at Imperial College, then became Senior Lecturer in 2013 and Reader in 2016. His research team has become a leading authority in phage-guided delivery systems to cancer including brain tumours. His leadership in the field has resulted in various awards for his research and a Royal Decoration by his Majesty the King of Morocco, in 2015.

Current treatments for brain tumours have faced major challenges including lack of tumour selectivity and the bloodbrain barrier (BBB). Development of a selective delivery system for brain tumours would play a major advance in the treatment of these tumours. For instance, successful exploitation of numerous therapeutic agents depends, essentially on the development of non-invasive nucleic acid delivery platforms. Indeed, gene therapy is promising in this disease and brain tumours were the first to be treated by clinical gene therapy but success has been limited by the inefficiency of vectors and by the BBB. We have used bacteriophage (phage), bacteria virus, to develop tumour targeted systemic vectors. Phages have a historic safety profile as they have been administered to human over many years to treat infectious diseases. Importantly, the filamentous M13 phage is able to traverse the BBB. However, phage has no strategies to deliver genes to human cells. We reported a bacteriophage vector, as hybrid genome between two single-stranded DNA of human adenoassociated virus (AAV) and filamentous M13 phage, termed AAV phage or AAVP, in which gene expression is under the control of AAV genome. We and independent groups reported efficacy of selective intravenous cancer gene therapy, with the RGD4C-AAVP displaying RGD4C ligand to target the tumour specifi c αvβ3 integrin receptor. To validate our systemic delivery platform for brain tumours, we showed the ability of the phage vector administered intravenously to home selectively to human glioblastoma (GBM), in preclinical models, through the BBB by binding the αvβ3 integrin, subsequently delivering a recombinant rAAV genome that delivers a suicide gene therapy in tumour cells, angiogenic endothelial cells and GBM-derived stem cells. Combination with a low dose of temozolomide (TMZ) enhanced gene delivery/therapy by using a tumour specific promoter from an endogenous gene associated with GBM resistance to TMZ chemotherapy. These findings provide evidence that bacteriophage is a promising delivery platform for use in targeted treatment in neuro-oncology.

Manoj Malhotra received his Medical Degree from Wayne State University in Detroit, Michigan. He completed his Neurology residency and two fellowships at The Cleveland Clinic in Cleveland, Ohio. He is the Vice President, Head of Medical Affairs for the Neurology Business Group at Eisai Inc. He is responsible for Medical Affairs activities for the Americas and is Global Medical Lead for Epilepsy. He holds six neurology board certifications (neurology, epilepsy, sleep medicine, clinical neurophysiology, vascular neurology and electrodiagnostic medicine) and has extensive experience in neurodegenerative diseases, rare diseases and epilepsy. His industry experience includes working at Novartis, Takeda and Mallinckrodt.

Perampanel is a once-daily oral anti-seizure drug for partial-onset seizures and primary generalised tonic-clonic seizures. We report the second interim analysis of the multicentre, non-interventional, Phase IV retrospective Study 506 (NCT03208660), to assess retention rate, safety and dosing experience of perampanel administered to patients with epilepsy during routine clinical care. Data were obtained from medical records of patients initiating perampanel after 1 January 2014. Primary endpoint is retention rate (proportion of patients remaining on perampanel; Safety Analysis Set [SAS]). Safety, effi cacy and dosing experience are secondary objectives. Th e interim SAS comprised 605 patients (55.9% female). At data cut-off (5 March 2018), 317 (52.4%) patients remained on perampanel; 285 (47.1%) had discontinued, primarily due to adverse event (AE; n=157 [26.0%]) and inadequate therapeutic effect (n=86 [14.2%]). Mean (standard deviation [SD]) cumulative duration of exposure to perampanel was 15.4 (13.9) months. Mean (SD) maximum perampanel dose was 6.5 (3.2) mg. Retention rates at 3, 6, 12, 18 and 24 months were 80.2% (n=479/597), 69.0% (n=392/568), 58.1% (n=288/496), 52.7% (n=216/410) and 49.8% (n=154/309), respectively. At Months 22-24: median reduction in seizure frequency per 28 days was 93.3% (n=27); 50% responder rate was 77.8% (n=21/27); 40.7% (n=11/27) of patients achieved seizure freedom. Treatment-emergent AEs (TEAEs) occurred in 304 (50.2%) patients, including dizziness (10.2%), aggression (6.1%) and irritability (5.0%). Serious TEAEs occurred in 14 (2.3%) patients, including 3 (0.5%) deaths. Favourable retention rates and sustained efficacy of perampanel for ≤2 years were demonstrated in patients with epilepsy treated during routine clinical care.