NeuroVia, NV1205 Clinical Trials Developing a safe and effective treatment for children with Childhood Cerebral Adrenoleukodystrophy Masoud Mokhtarani MD Chief Medical Officer ALD Life Family Weekend Meeting, London, 6 May 2018 14:25 Dr Masoud Mokhtarani- NeuroVia NV1205 clinical trial 1
NeuroVia Founded in 2013; a venture-backed company in San Francisco Based on work from Oregon Health Science University with sobetirome in X-ALD animal model Two ongoing studies: PEDALS an interventional study with NV1205 in CCALD SADDLE an observational study in X-ALD children 2 NeuroVia is a small company in San Francisco founded in 2013. 2 active programmes: 1 intervention for cerebral ALD patients and one in the US. 2
Upregulation of ABCD2 By NV1205 Restores Peroxisome s Ability to Degrade VLCFA ABCD2 gene promoter has a thyroid hormone response element and is regulated by thyroid hormone NV1205 is thyroid hormone receptor modulator capable of upregulating the ABCD2 gene 3 NV1205 (Subitorol) creates a sister gene to ABCD1, called ABCD2, which creates a similar protein taking VLCFAs into peroxisomes. It is hoped that the drug will correct the basic physiology of all phenotypes of the disease. 3
NV1205 Upregulates ABCD2 gene in Patients Fibroblasts Thyroid hormone and NV1205 upregulate ABCD2 gene in all phenotypes Maximum effect seen in CCALD Sob: Sobetirom NV1205; *p<0.05 Hartley, Kirkemo, et al. Endocrinology (2017) 4 The drug works on the region of the gene with a hormone receptor element. The first step is to see if the drug works on different phenotypes, so it has been tested on those with cerebral ALD, AMN and on female carriers. 4
NV1205 Upregulates ABCD2 Gene and Lowers VLCFA in Brains ABCD2 Expression in Brain after 2 Weeks Systemic Tx VLCFA Reduction after 12 weeks of oral administration in ABCD1 KO mice * NV1205 enters into CNS and upregulates ABCD2 gene within 2 weeks VLCFA is reduced significantly in brain after 12 weeks of oral treatment with NV1205 Sob 0.4: NV1205 80ug/kg; Sob 2.0: NV1205 400 ug/kg; Hypo: Hypothyroid mice; WT: wild type mice; *p,0.05 Hartley, Kirkemo, et al. Endocrinology (2017) 5 A significant increase in the ABCD2 gene happens in all of these phenotypes in a similar way after 3 days in vitro. 5
NV1205 Lowers VLCFA in Serum, Adrenal Glands, and Testes of ABCD1 KO Mice Oral treatment of ABCD1 Knock out mice with vehicle, T3/T4, or NV1205 (Sob 0.4: NV1205 80ug/kg; Sob 2.0: NV1205 400 ug/kg) and wild type mice (WT) for up to 12 weeks ; * p<0.05 6 Hartley, Kirkemo, et al. Endocrinology (2017) The next and most important step looks at if systemic administration of the drug will get in to CNS and if it successfully creates the ABCD2 gene. Tests on mice showed that levels of ABCD1 gene did not change, but levels of ABCD2 gene rose. This showed further evidence that the concept works. Does prolonged administration lead to a reduction in VLCFAs? The experiment was carried out in mice with no ABCD1 gene, so with high levels of VLCFAs. Systemic administration of the drug results in a significant reduction in VLCFAs and CNS. Systemic administration is effective in getting the drug into the target organ and reducing VLCFAs. 6
www.ccald.com PEDiatric AdrenoLeukodystrophy Study NV1205-009: Phase I/II, Open-Label, Dose Escalation Study of the Safety, Pharmacokinetics and Pharmacodynamics of NV1205 in Pediatric Male Subjects with Childhood Cerebral Adrenoleukodystrophy (CCALD) 7 The next step is a paediatric study, for children with cerebral ALD who cannot access or are not eligible for bone marrow transplants. The most important objective is safety, while other effects of the drug are explored looking at MRI scans and neurological function 7
NV1205-009 Study Objectives PRIMARY OBJECTIVE To evaluate the safety and pharmacokinetics of NV1205 in pediatric subjects diagnosed with CCALD EXPLORATORY OBJECTIVE To assess the effect of NV1205 on expression of the ABCD2 gene, levels of VLCFA, brain lesions, and neurological function score 8 8
NV1205-009 Study Design Cohorts of 3 subjects receive 4 weeks of treatment with multiple safety checks Subsequent cohorts to receive higher doses after safety check by the data safety monitoring board (DSMB) Subjects will roll into long term treatment for up to 2 years An expanded access study will be offered after the 2-yr is complete Up to 25 patients may be enrolled 9 This is a very conventional study design, taking a small group of paediatric patients and giving them a low dose of the drug for 4 weeks. An independent person will look at the data and authorise the next cohort to be involved with higher doses. 3 cohorts are planned, receiving the drug for at least 12 weeks to ensure safety before this develops in to long term treatment. An increase in sample size to 25 is planned, after 2 years the treatment will be expanded for all patients in the study until treatment is stopped or the drug comes to the market. 9
Major Inclusion Criteria and Procedures Eligible Patients Pediatric patients with MRI evidence Loes score of <15 No access/ineligible for transplant No prior transplant No Lorenzo s oil or other VLCFA lowering agents Procedures 7 visits during the first 3 months; q3 months thereafter Long term treatment under DSMB supervision Brain MRI Neurological assessment VLCFA Travel assistance (transport, lodging, expenses) available for out of area families 10 Targeting: paediatric patients with no access/eligibility for bone marrow transplant, with a Loes score of up to 15. There is a safety period of 3 months of monitoring to establish a baseline and safety assessment. These patients are based around the country, so assistance with travel and lodging will be provided. 10
PEDALS is a Global Study United Kingdom Ukraine Russia France Colombia Chile Argentina Australia 11 This is a global study: in the UK, sites are in London and Manchester and hopes to begin in June. Australia are hoping to start at the end of this month, there are also programmes in Russia, Ukraine and Latin America among others. 11
w w w. c c a l d. c o m NV1205-008: A Non-Interventional Study to Prospectively Assess Baseline Status and Disease Progression in Male Children with X-Linked AdrenoLEukodystrophy Identify markers of disease status and disease progression Asymptomatic, symptomatic and transplanted patients up to 13y VLCFA, NFS, MRI every 6 months Current US sites: Stanford, UPMC, MGH, U of Florida, Seattle Expanding globally 12 Observational study in the US: Looking for up to 100 untreated patients who are symptomatic and asymptomatic to monitor and understand the progression of the disease alongside the interventional study, as a control group. This has begun in the US, and hopefully will be expanded globally. 12