Daniel S Ory1, Elizabeth A Ottinger2, Nicole Yanjanin Farhat3, Kelly A King4, Xuntian Jiang1, Lisa Weissfeld5, Elizabeth Berry-Kravis6, Cristin D Davidson7, Simona Bianconi3, Lee Ann Keener3, Ravichandran Rao8, Ariane Soldatos9, Rohini Sidhu1, Kimberly A Walters5, Xin Xu2, Audrey Thurm10, Beth Solomon11, William J Pavan12, Bernardus N Machielse8, Mark Kao13, Steven A Silber14, John C McKew2, Carmen C Brewer4, Charles H Vite15, Steven U Walkley7, Christopher P Austin2, Forbes D Porter16. 1. Washington University School of Medicine, St Louis, MO, USA. 2. National Center for Advancing Translational Sciences, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. 3. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD USA. 4. National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. 5. Statistics Collaborative, Washington, DC, USA. 6. Rush University Medical Center, Chicago, IL, USA. 7. Albert Einstein College of Medicine, Bronx, NY, USA. 8. Vtesse Inc, Gaithersburg, MD, USA. 9. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services Bethesda, MD, USA. 10. National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. 11. Mark O Hatfield Clinical Research Center, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. 12. National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. 13. Preclinical Development and Safety, Janssen R&D, Raritan, NJ, USA. 14. Global Public Health, Johnson & Johnson, Philadelphia, PA, USA. 15. School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. 16. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD USA. Electronic address: fdporter@mail.nih.gov.
Abstract
BACKGROUND: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD. METHODS: In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. FINDINGS: Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423). INTERPRETATION: Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD. FUNDING: National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson.
BACKGROUND: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPβCD. METHODS: In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPβCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPβCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPβCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. FINDINGS: Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPβCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPβCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPβCD were increased about two fold (p=0·0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1·22, SEM 0·34 points per year compared with 2·92, SEM 0·27 points per year (p=0·0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0·0622), cognition (p=0·0040) and speech (p=0·0423). INTERPRETATION: Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPβCD. FUNDING: National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson.
Authors: Nicole M Yanjanin; Jorge I Vélez; Andrea Gropman; Kelly King; Simona E Bianconi; Sandra K Conley; Carmen C Brewer; Beth Solomon; William J Pavan; Mauricio Arcos-Burgos; Marc C Patterson; Forbes D Porter Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2010-01-05 Impact factor: 3.568
Authors: Charles C Pontikis; Cristin D Davidson; Steven U Walkley; Frances M Platt; David J Begley Journal: J Inherit Metab Dis Date: 2013-02-15 Impact factor: 4.982
Authors: Charles H Vite; Jessica H Bagel; Gary P Swain; Maria Prociuk; Tracey U Sikora; Veronika M Stein; Patricia O'Donnell; Therese Ruane; Sarah Ward; Alexandra Crooks; Su Li; Elizabeth Mauldin; Susan Stellar; Marc De Meulder; Mark L Kao; Daniel S Ory; Cristin Davidson; Marie T Vanier; Steven U Walkley Journal: Sci Transl Med Date: 2015-02-25 Impact factor: 17.956
Authors: Benny Liu; Stephen D Turley; Dennis K Burns; Anna M Miller; Joyce J Repa; John M Dietschy Journal: Proc Natl Acad Sci U S A Date: 2009-01-26 Impact factor: 11.205
Authors: Cristin D Davidson; Nafeeza F Ali; Matthew C Micsenyi; Gloria Stephney; Sophie Renault; Kostantin Dobrenis; Daniel S Ory; Marie T Vanier; Steven U Walkley Journal: PLoS One Date: 2009-09-11 Impact factor: 3.240
Authors: Kanagaraj Subramanian; Darren M Hutt; Samantha M Scott; Vijay Gupta; Shu Mao; William E Balch Journal: J Biol Chem Date: 2020-04-30 Impact factor: 5.157
Authors: Jessica Davidson; Elizabeth Molitor; Samantha Moores; Sarah E Gale; Kanagaraj Subramanian; Xuntian Jiang; Rohini Sidhu; Pamela Kell; Jesse Zhang; Hideji Fujiwara; Cristin Davidson; Paul Helquist; Bruce J Melancon; Michael Grigalunas; Gang Liu; Farbod Salahi; Olaf Wiest; Xin Xu; Forbes D Porter; Nina H Pipalia; Dana L Cruz; Edward B Holson; Jean E Schaffer; Steven U Walkley; Frederick R Maxfield; Daniel S Ory Journal: Biochim Biophys Acta Mol Cell Biol Lipids Date: 2019-04-30 Impact factor: 4.698
Authors: Fabrizio Vacca; Stefania Vossio; Vincent Mercier; Dimitri Moreau; Shem Johnson; Cameron C Scott; Jonathan Paz Montoya; Marc Moniatte; Jean Gruenberg Journal: J Lipid Res Date: 2019-02-01 Impact factor: 5.922