- Email: [email protected]
An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations
Alzheimer’s & Dementia: Translational Research & Clinical Interventions - (2017) 1-6 1 2 3 4 5 6 7 8 9 10Q9 11 12 13 14 15 16 17Q1 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Q3 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
Neurodegenerative
An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations Sharon J. Shaa,*,1,2, Zachary A. Millera,1, Sang-won Minb,3, Yungui Zhoub, Jesse Browna, Laura L. Mitica,c, Anna Karydasa, Mary Koestlera, Richard Tsaia, Chiara Corbetta-Rastellia,4, Sophie Lina,5, Emma Harea,6, Scott Fieldsd, Kirsten E. Fleischmanne, Ryan Powersa, Ryan Fitcha, Lauren Herl Martensf,7, Mehrdad Shamloog, Anne M. Faganh, Robert V. Farese, Jr.f,8, Rodney Pearlmanc, William Seeleya, Bruce L. Millera, Li Ganb, Adam L. Boxera a
Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA b Gladstone Institute of Neurodegenerative Disease, San Francisco, CA c Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA d Investigational Drug Service, UCSF Medical Center, San Francisco, CA e Division of Cardiology, University of California, School of Medicine, San Francisco, CA f Gladstone Institute of Cardiovascular Disease, San Francisco, CA g Institute for Neuro-Innovation and Translational Neurosciences, Stanford, CA h Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO
Abstract
Introduction: Frontotemporal lobar degeneration–causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration–approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. Methods: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. Results: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of 25.2 6 10.9% in plasma and 210.2 6 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period. Discussion: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.
Dr A.L.B. receives grant support from the NIH (U54NS092089, R01AG038791, and U01AG045390), the Tau Research Consortium, CBD Solutions, The Bluefield Project to Cure FTD, and the Alzheimer’s Association; research support from Avid, BMS, Biogen, C2N, Cortice, Eli Lilly, Forum, Genentech, and TauRx for conducting clinical trials; personal compensation for consulting for Asceneuron, Ionis Pharmaceuticals, Janssen, Merck, and Novartis and serving on a DSMB for Neurogenetics; stock/options for serving on a scientific advisory board for Alector and Delos. Dr S.J.S. receives research support from Alkahest, Biogen, Genentech, and Merck for conducting clinical trials and personal compensation for consulting with Guidepoint Global. Dr A.M.F. is on the Scientific Advisory Boards of IBL International, Roche, and AbbVie and consults for DiamiR and LabCorp.
Dr Z.A.M. receives grant support from the NIH (K23AG048291). These authors contributed equally.2Current address: Stanford Center for Memory Disorders, Stanford University, Stanford, CA.3Current address: Genentech, Inc, South San Francisco, CA.4Current address: University of California, School of Medicine, San Francisco, CA.5Current address: Johns Hopkins School of Medicine, Baltimore, MD.6Current address: Michigan State University, College of Osteopathic Medicine, East Lansing, MI.7Current address: Dementia Discovery Fund, Boston, MA.8Current address: Harvard School of Public Health, Boston, MA. *Corresponding author. Tel.: 11 650 725 6563; Fax: 11 650 725 7459. E-mail address: [email protected] 1
http://dx.doi.org/10.1016/j.trci.2017.08.002 2352-8737/Ó 2017 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). SCO 5.5.0 DTD TRCI108_proof 30 August 2017 3:58 am ce
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110 Ó 2017 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access 111 article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 112 Frontotemporal dementia; Progranulin; Genetics; Nimodipine 113Q2 Keywords: 114 115 116 117 Participants were enrolled from March 2013 until January 1. Introduction 118 2015. Inclusion and exclusion criteria are listed in 119 Mutations in the progranulin gene (GRN) are a common Supplemental Materials. 120 cause of inherited frontotemporal dementia (FTD). GRN muBecause nimodipine is a Food and Drug Administration– 121 tations cause haploinsufficiency, with only one functional 122 approved drug at a dose of 360 mg per day, we chose a titracopy of the gene remaining. Progranulin protein (PGRN) 123 tion to 360 mg or maximum tolerated dose. Nimodipine was 124 levels are less than 50% from birth [1–3]. Thus, therapeutic titrated every week as follows: 30 mg orally TID, 60 mg 125 approaches have focused on increasing PGRN levels, either TID, 90 mg TID, and 90 mg QID and maintained at this 126 by increasing transcription from the normal allele [4,5] or dose for 4 weeks. All subjects attempted to titrate to the 127 by modulating posttranslational mechanisms [6,7]. 128 full 360 mg per day dose (Supplemental Fig. 3). Promising preclinical data in heterozygous Grn mice sug129 130 gested that nimodipine might restore PGRN levels in hu2.3. Outcomes 131 mans with GRN mutations. As PGRN levels are stable 132 over both short and long periods (1 week to 2 years) in Primary outcomes were safety and tolerability of 133 GRN mutation carriers [8] as well as various disease and nimodipine and identification of the optimal nimodipine 134 control populations [9], PGRN levels alone are suitable enddose for long-term efficacy studies in GRN mutation 135 136 points for trials. We tested the effects of modulators of calcarriers. Safety was measured by the number of treatment 137 cium homeostasis on PGRN levels in cultured cells and emergent adverse events (listed by detailed MedDRA 138 found that reducing intracellular calcium by blocking calterm [www.meddra.org]), routine clinical, laboratory, and 139 cium channels increased PGRN secretion. We focused on nielectrocardiogram assessments. Secondary outcomes were 140 modipine, a Food and Drug Administration–approved change from baseline concentration of plasma PGRN or 141 142 L-type calcium channel blocker that crosses the bloodCSF PGRN, plasma PGRN-related inflammatory markers 143 brain barrier, as it is relatively well tolerated and, in a (CRP, ESR), CSF neurodegeneration proteins (neurofila- Q4 144 placebo-controlled trial, it improved overall status and ment light chain [NfL], amyloid b 42 [Ab42], tau), blood 145 cognitive function in patients with dementia [10]. and CSF cytokines (interleukin-10 [IL-10], IL-2, IL-6, 146 We report the effects of nimodipine on PGRN levels in IL-8, and tumor necrosis factor a [TNFa]), and volumetric 147 148 plasma and central nervous system tissues in correlative magnetic resonance imaging (MRI). 149 studies on animals and humans carrying GRN mutations. In 150 a phase 1, 8-week open-label clinical trial, we sought to deter2.4. Plasma and CSF sampling and analysis 151 mine the safety and tolerability of oral nimodipine treatment in 152 PGRN was measured by A&G Pharma (Columbia, MD) GRN mutation carriers and the best dose of nimodipine for 153 using a proprietary enzyme-linked immunosorbent assay Q5 154 long-term efficacy studies. As secondary objectives, we investhat detects full-length PGRN. TNFa was measured by 155 tigated the effects of nimodipine on PGRN levels in plasma 156 Quanterix (Lexington, MA). Tau, phospho-tau181, and and cerebrospinal fluid (CSF), a subset of inflammatory and 157 Ab levels were analyzed using the xMAP multiplex immu42 neurodegeneration-associated proteins, and in brain volumes. 158 noassay/Luminex analyzer (INNO-BIA AlzBio3; Fujire159 bio). NfL levels were measured using the 160 2. Methods UmanDiagnostics kit (Ume a, Sweden). Proinflammatory cy161 162 tokines were measured in plasma and CSF using a V-PLEX 2.1. Study oversight 163 human proinflammatory 10-Plex kit from Meso Scale Dis164 This study was approved under local institutional review covery (Rockville, MD). Nonparametric measures (Mann165 board’s supervision, registered at ClinicalTrials.gov Whitney U) were used to compare mean baseline versus 166 (NCT01835665). Informed consent was obtained from pa8-week or early termination values of the secondary clinical 167 tients and, when applicable, caregivers. 168 and laboratory measures. 169 170 2.2. Study design and enrollment 2.5. Brain imaging 171 172 The target enrollment was eight asymptomatic and/or MRI was performed at screening and completion of the 173 symptomatic carriers of known FTD-causing GRN mutastudy using a 3T Siemens scanner [11]. MP-RAGE scans 174 tions (Supplemental Fig. 2). Participants were required for both time points for a given subject were registered to 175 176 to be aware of their mutation status before screening. one another using the serial longitudinal anatomical MRI SCO 5.5.0 DTD TRCI108_proof 30 August 2017 3:58 am ce
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Clinical Clinical phenotype (clinicians’ impression) CDR-SB MMSE Completed 8 weeks? Max dose achieved (mg) Plasma GRN ng/mL, (% change) ESRmm/hour, (% change) CRP mg/L, (% change) CSF GRN ng/mL, (% change) NfL pg/mL, (% change) Ab42 pg/mL, (% change) Tau pg/mL, (% change) P-tau pg/mL, (% change) IL-10 pg/mL, (% change) IL-2 pg/mL, (% change) IL-6 pg/mL, (% change) IL-8 pg/mL, (% change) TNFa pg/mL, (% change)
Subject 1
Subject 2
Subject 3
Subject 4
nfvPPA
Asymptomatic
Asymptomatic
bvFTD
bvFTD
Asymptomatic
bvFTD
Asymptomatic
0 29 Yes 360
0.5 29 Yes 360
0 30 Yes 360
12 Yes 360
4 22 Yes 180–270
0 30 Yes 360
2 25 Yes 360
0 30 No 180
1.1 (21) 2 (40) 0.4 (14)
1.4 (19) nd 20.1 (21)
212.6 (253) 0 (0) 1.2 (92)
20.2 (22) 0 (0) 21.7 (39)
20.07 (213) 211.8 (5) 28.7 (21) 4.2 (7) 21.7 (27) 0.03 (6) 0.01 (10) 0.11 (6) 3.82 (5) 0.00 (0)
0.06 (27) 239.5 (212) 281.6 (215) 24.2 (214) 5.8 (31) 0.001 (21) 0.01 (31) 20.15 (211) 1.24 (4) 20.05 (238)
20.15 (218) 27.4 (0) 76.8 (11) 20.4 (21) 20.8 (23) 0.005 (25) 0.03 (62) 20.04 (23) 20.38 (21) 0.02 (14)
20.2 (227) 750.6 (5) 19.7 (4) 25.8 (25) 23.0 (213) 0.01 (11) 20.02 (233) 0.07 (7) 6.74 (9) 20.07 (216)
Subject 5
4.9 (23) 19 (91) 6.8 (145) 20.28 (241) 2654.5 (28) 246.3 (214) 10.0 (12) 2.0 (17) 20.01 (215) 0 (9) 0.14 (13) 4.65 (11) 0.04 (42)
Subject 6
Subject 7
21.5 (216) 24 (500) 5.9 (590)
23.4 (227) 25 (231) 0.1 (6)
0.06 (15) 71.4 (9) 235.4 (26) 26.7 (216) 28.0 (234) -
20.05 (212) 2499.9 (25) 258.3 (212) 2.2 (23) 7.8 (89) 0.003 (4) 0.03 (36) 0.11 (16) 21.72 (26) 0.00 (21)
Subject 8
20.08 (217) 277.9 (27) 2103.9 (219) 2.0 (5) 1.6 (13) 0.04 (65) 0.01 (14) 0.06 (8) 20.16 (0) 0.01 (9)
Mean 2.3 27.9 Mean 6 SEM 21.47 6 2.1 (25.2 6 10.9) 6 6 4.3 (99.9 6 81.8) Q7 1.8 6 1.2 (115.4 6 62.5) 20.09 6 0.04 (210.7 6 7.8) 230.68 6 151.8 (21.4 6 2.5) 229.70 6 20.5 (26.5 6 3.6) 3.59 6 3.7 (1.9 6 4.8) 0.48 6 1.8 (11.6 6 13.1) 0.00 6 0.1 (9.1 6 9.8) 0.01 6 0.01 (18.5 6 11.2) 0.04 6 0.04 (5.1 6 3.5) 2.0 6 1.17 (3.1 6 2.2) 0.01 6 0.02 (1.4 6 9.4)
Abbreviations: Ab42, amyloid b; CDR-SB, Clinical Dementia Rating–sum of boxes; CSF, cerebrospinal fluid; GRN, progranulin; MMSE, Mini–Mental State Examination; nd, not determined; NfL, neurofilament light chain; P-tau, phospho-tau; TNFa, tumor necrosis factor a. NOTE. Age and gender were not shown to maintain participant confidentiality.
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Table 1 Characteristics of study participants
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package in SPM12 [12], and the procedures outlined elsewhere [13]. 3. Results 3.1. Preclinical studies Cultured cellular models revealed that cytosolic calcium levels affected the secreted PGRN levels (Supplemental Fig. 1). Two-week treatment with nimodipine elevated hippocampal PGRN levels in both wild-type (P , .001) and Grn1/– mice (P , .05) compared to vehicle-treated mice (Supplemental Fig. 1). 3.2. Demographics Eight GRN mutation carriers were enrolled in the trial (Table 1), with a median age of 57.3 years; 50% were male. They included three behavioral-variant FTD (bvFTD), one nonfluent-variant primary progressive aphasia (nfvPPA), and four asymptomatic individuals. One selfreported asymptomatic participant had a 0.5 in judgment on the Clinical Dementia Rating–sum of boxes (CDR-SB) and thus fit into the classification of normal with concerns. 3.3. Safety and tolerability Two of the eight participants (25%) were unable to titrate to the maximum dose of 360 mg per day (Table 1). One participant discontinued treatment early at week 5 due to dizziness, palpitations, and malaise. Another discontinued due to edema. There were no serious adverse events. Forty-three adverse events were reported; the most common included edema (12 reports), headache (3), and dizziness (3). There were also two reports of arrhythmia and lassitude. There were single reports of upper respiratory infection, flu-like symptoms, syncope, redness on legs, depression, insomnia, worsening of asthma, and urinary tract infection. 3.4. Fluid biomarkers PGRN concentrations, in plasma and CSF, did not change from baseline after nimodipine treatment (percent changes of 25.2 6 10.9% [mean 6 standard error mean] in plasma and 210.2 6 7.8% in CSF) (Table 1 and Fig. 1A and 1B). CSF levels of three neurodegenerative disease–associated proteins, NfL, Ab42, and tau (both total tau and phospho-tau) did not change significantly after nimodipine treatment (Table 1). Levels of CSF NfL (P 5 .0002, Mann-Whitney U) and tau (P 5 .0002, Mann-Whitney U) at baseline correlated with disease severity as measured by CDR-SB, with the highest levels of NfL and tau observed in subjects with the highest CDR-SB score (Fig. 1C and 1D). Of 10 cytokines measured in CSF, five were detectable (IL-10, IL-2, IL-6, IL-8, and TNFa), and none exhibited a significant change following nimodipine treatment (Table 1).
3.5. Volumetric MRI Longitudinal structural MRI differences were determined by performing a one-sample t-test on the longitudinal Jacobian gray matter change maps. Six subjects were analyzed (mean age 5 56.2 years, range 32.5–69.0; 4 females; mean interscan interval 5 50.7 days, range 29–70). The resultant map was corrected with a joint height/extent threshold of P , .001 (no significant reductions were detected at a more stringent threshold of P , .05, familywise error corrected). There was one significant cluster of gray matter loss in the left middle frontal gyrus. The rate of change in this cluster revealed that the effect was driven by four subjects with annualized rates of gray matter loss between 1% and 2% (Fig. 1). 4. Discussion PGRN deficiency causes FTD; therefore, treatments that restore PGRN levels are of high therapeutic interest. We found that oral nimodipine increased mouse hippocampal PGRN concentrations but failed to increase human PGRN levels in plasma and CSF. In an 8-week, open-label trial, nimodipine was safe and well tolerated in GRN mutation carriers, but no effects of nimodipine were noted on secondary outcome measures, including concentrations of PGRN in blood and CSF, CSF NfL, CSF Ab42, CSF total tau, CSF phospho-tau, plasma ESR, plasma CRP, or CSF cytokines (IL-10, IL-2, IL-6, IL-8, and TNFa). Although there were no clear effects on volumetric MRI measurements by nimodipine, there was volume loss noted in severely affected patients. Reasons for the discrepancy between rodents and humans are unknown and may be related to many factors, including exposure, dose, timing, and interspecies difference in responsiveness. Of the six participants with MRIs conducted before and after treatment, three were asymptomatic and three were symptomatic. The most severely affected cases displayed the greatest decrease in volume over the trial period; a change that would extrapolate to a 1%–2% loss in the volume of the left frontal region annually, if constant. This rate is slightly less than reported for whole-brain atrophy in a comparably sized group of GRN mutation carriers assessed with MRI scans over 2 years [14]. Intermediate volume loss was observed in a mildly symptomatic individual and in an asymptomatic individual with a score of 0.5 on CDR-SB for judgment. The two asymptomatic cases revealed no change in brain volume. Given that nimodipine did not raise levels of PGRN, we propose this rate of decline may be comparable to untreated GRN mutation carriers. However, we cannot exclude a contribution of volume loss from treatment with nimodipine. If this rate of volume loss is confirmed in a larger cohort of mutation carriers, slowing or reversal of regional gray matter loss could be a viable endpoint in future FTD-GRN Q6 clinical trials.
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Fig. 1. Nimodipine had no effect on secondary outcome measures in humans, including plasma and CSF PGRN levels and brain volume loss. (A) The mean change in plasma PGRN between baseline (day 0) and the end of the trial (day 56 6 7) was 21.47 6 2.1 ng/mL. (B) The mean change in CSF PGRN between baseline (day 0) and the end of the trial (day 56 6 7) was 20.09 6 0.04 ng/mL. (C) Elevated neurofilament light chain correlated with disease severity. (P 5 .0002, Mann-Whitney) (D) Elevated tau correlated with disease severity (P 5 .0002, Mann-Whitney). (E) A significant cluster of gray matter loss was detected in the left middle frontal gyrus (yellow 5 20% loss) (cluster extent of 1431 voxels, peak MNI coordinate: 251, 28, 28). (F) The change in brain volume loss was driven by symptomatic mutation carriers.
This is the second reported trial to be completed in GRN mutation carriers [7]. There are a number of therapeutic targets in the development pipeline intended for GRN mutation carriers, and this study provides a framework for future bench-to-bedside proof of mechanism studies for FTDGRN. Acknowledgments Authors’ contributions: Drs S.J.S., Z.A.M., and A.L.B. had full access to all the data in the study and took the responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: A.L.B., L.G., S.J.S. Acquisition, analysis, or interpretation of data: A.L.B., L.G., W.S., S.J.S., Z.A.M., S.-w.M., Y.Z., L.L.M., J.B., M.K., R.T., M.S., A.M.F., and K.E.F. Drafting of manuscript: L.L.M., Z.A.M., S.J.S., A.L.B., L.G., and S.-w.M. Obtained funding: A.L.B., L.G., B.L.M., and W.S. Administrative, technical, or material support: A.K., C.C.R., S.L., E.H., R.P., R.F., S.F., L.H.M., R.V.F., and R.P. Study supervision: A.L.B. and L.G. Funding: This work was funded by The Bluefield Project to Cure Frontotemporal Dementia.
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Role of the Funder: Employees of The Bluefield Project to Cure Frontotemporal Dementia participated in the design and conduct of the study, analysis, interpretation of data, and preparation of the manuscript. Additional contributions: We are grateful to, and offer tremendous thanks to, the participants and their families who made this study possible. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.trci.2017.08.002.
RESEARCH IN CONTEXT
1. Systematic review: The authors reviewed the literature using traditional (e.g., PubMed) sources. Heterozygous loss of function mutations in the progranulin gene (GRN) lead to frontotemporal dementia (FTD) through decreased production of the normal progranulin protein (PGRN). Therapeutic approaches have focused on finding novel compounds that increase PGRN levels. In murine model systems, calcium channel blockers were discovered to increase PGRN levels. We launched a phase 1 trial of nimodipine in GRN mutation carriers to test safety and tolerability. 2 Interpretation: Nimodipine was safe and well tolerated but is unlikely to provide therapeutic benefit in GRN FTD. 3. Future directions: This trial demonstrated that a nimble, small-scale trial could arise entirely from, and be contained within, an academic center. From the initial target identification to the execution of human trials, this trial provides a framework for future bench-to-bedside proof of mechanism studies in FTD.
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[2] Gass J, Cannon A, Mackenzie IR, Boeve B, Baker M, Adamson J, et al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 2006;15:2988–3001. [3] Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916–9. [4] Cenik B, Sephton CF, Dewey CM, Xian X, Wei S, Yu K, et al. Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem 2011;286:16101–8. [5] Holler CJ, Taylor G, McEachin ZT, Deng Q, Watkins WJ, Hudson K, et al. Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia. Mol Neurodegener 2016;11:46. [6] Capell A, Liebscher S, Fellerer K, Brouwers N, Willem M, Lammich S, et al. Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase. J Neurosci 2011;31:1885–94. [7] Alberici A, Archetti S, Pilotto A, Premi E, Cosseddu M, Bianchetti A, et al. Results from a pilot study on amiodarone administration in monogenic frontotemporal dementia with granulin mutation. Neurol Sci 2014;35:1215–9. [8] Meeter LH, Patzke H, Loewen G, Dopper EG, Pijnenburg YA, van Minkelen R, et al. Progranulin levels in plasma and cerebrospinal fluid in granulin mutation carriers. Dement Geriatr Cogn Dis Extra 2016; 6:330–40. [9] Feneberg E, Steinacker P, Volk AE, Weishaupt JH, Wollmer MA, Boxer A, et al. Progranulin as a candidate biomarker for therapeutic trial in patients with ALS and FTLD. J Neural Transm (Vienna) 2016;123:289–96. [10] Lopez-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 2002;CD000147. [11] Bettcher BM, Wilheim R, Rigby T, Green R, Miller JW, Racine CA, et al. C-reactive protein is related to memory and medial temporal brain volume in older adults. Brain Behav Immun 2012;26:103–8. [12] Ashburner J, Ridgway GR. Symmetric diffeomorphic modeling of longitudinal structural MRI. Front Neurosci 2012;6:197. [13] Pankov A, Binney RJ, Staffaroni AM, Kornak J, Attygalle S, Schuff N, et al. Data-driven regions of interest for longitudinal change in frontotemporal lobar degeneration. Neuroimage Clin 2016;12:332–40. [14] Whitwell JL, Weigand SD, Gunter JL, Boeve BF, Rademakers R, Baker M, et al. Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN. Neurology 2011;77:393–8. [15] Minami SS, Min SW, Krabbe G, Wang C, Zhou Y, Asgarov R, et al. Progranulin protects against amyloid beta deposition and toxicity in Alzheimer’s disease mouse models. Nat Med 2014;20:1157–64. [16] Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134:2456–77. [17] Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 2003;54:S15–9. [18] Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, et al. Classification of primary progressive aphasia and its variants. Journal 2011;76:1006–14. [19] Coppola G, Karydas A, Rademakers R, Wang Q, Baker M, Hutton M, et al. Gene expression study on peripheral blood identifies progranulin mutations. Ann Neurol 2008;64:92–6.
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Neurodegenerative
An 8-week, open-label, dose-finding study of nimodipine for the treatment of progranulin insufficiency from GRN gene mutations Sharon J. Shaa,*,1,2, Zachary A. Millera,1, Sang-won Minb,3, Yungui Zhoub, Jesse Browna, Laura L. Mitica,c, Anna Karydasa, Mary Koestlera, Richard Tsaia, Chiara Corbetta-Rastellia,4, Sophie Lina,5, Emma Harea,6, Scott Fieldsd, Kirsten E. Fleischmanne, Ryan Powersa, Ryan Fitcha, Lauren Herl Martensf,7, Mehrdad Shamloog, Anne M. Faganh, Robert V. Farese, Jr.f,8, Rodney Pearlmanc, William Seeleya, Bruce L. Millera, Li Ganb, Adam L. Boxera a
Memory and Aging Center, Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA b Gladstone Institute of Neurodegenerative Disease, San Francisco, CA c Bluefield Project to Cure Frontotemporal Dementia, San Francisco, CA d Investigational Drug Service, UCSF Medical Center, San Francisco, CA e Division of Cardiology, University of California, School of Medicine, San Francisco, CA f Gladstone Institute of Cardiovascular Disease, San Francisco, CA g Institute for Neuro-Innovation and Translational Neurosciences, Stanford, CA h Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO
Abstract
Introduction: Frontotemporal lobar degeneration–causing mutations in the progranulin (GRN) gene reduce progranulin protein (PGRN) levels, suggesting that restoring PGRN in mutation carriers may be therapeutic. Nimodipine, a Food and Drug Administration–approved blood-brain barrier-penetrant calcium channel blocker, increased PGRN levels in PGRN-deficient murine models. We sought to assess safety and tolerability of oral nimodipine in human GRN mutation carriers. Methods: We performed an open-label, 8-week, dose-finding, phase 1 clinical trial in eight GRN mutation carriers to assess the safety and tolerability of nimodipine and assayed fluid and radiologic markers to investigate therapeutic endpoints. Results: There were no serious adverse events; however, PGRN concentrations (cerebrospinal fluid and plasma) did not change significantly following treatment (percent changes of 25.2 6 10.9% in plasma and 210.2 6 7.8% in cerebrospinal fluid). Measurable atrophy within the left middle frontal gyrus was observed over an 8-week period. Discussion: While well tolerated, nimodipine treatment did not alter PGRN concentrations or secondary outcomes.
Dr A.L.B. receives grant support from the NIH (U54NS092089, R01AG038791, and U01AG045390), the Tau Research Consortium, CBD Solutions, The Bluefield Project to Cure FTD, and the Alzheimer’s Association; research support from Avid, BMS, Biogen, C2N, Cortice, Eli Lilly, Forum, Genentech, and TauRx for conducting clinical trials; personal compensation for consulting for Asceneuron, Ionis Pharmaceuticals, Janssen, Merck, and Novartis and serving on a DSMB for Neurogenetics; stock/options for serving on a scientific advisory board for Alector and Delos. Dr S.J.S. receives research support from Alkahest, Biogen, Genentech, and Merck for conducting clinical trials and personal compensation for consulting with Guidepoint Global. Dr A.M.F. is on the Scientific Advisory Boards of IBL International, Roche, and AbbVie and consults for DiamiR and LabCorp.
Dr Z.A.M. receives grant support from the NIH (K23AG048291). These authors contributed equally.2Current address: Stanford Center for Memory Disorders, Stanford University, Stanford, CA.3Current address: Genentech, Inc, South San Francisco, CA.4Current address: University of California, School of Medicine, San Francisco, CA.5Current address: Johns Hopkins School of Medicine, Baltimore, MD.6Current address: Michigan State University, College of Osteopathic Medicine, East Lansing, MI.7Current address: Dementia Discovery Fund, Boston, MA.8Current address: Harvard School of Public Health, Boston, MA. *Corresponding author. Tel.: 11 650 725 6563; Fax: 11 650 725 7459. E-mail address: [email protected] 1
http://dx.doi.org/10.1016/j.trci.2017.08.002 2352-8737/Ó 2017 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). SCO 5.5.0 DTD TRCI108_proof 30 August 2017 3:58 am ce
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110 Ó 2017 Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access 111 article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 112 Frontotemporal dementia; Progranulin; Genetics; Nimodipine 113Q2 Keywords: 114 115 116 117 Participants were enrolled from March 2013 until January 1. Introduction 118 2015. Inclusion and exclusion criteria are listed in 119 Mutations in the progranulin gene (GRN) are a common Supplemental Materials. 120 cause of inherited frontotemporal dementia (FTD). GRN muBecause nimodipine is a Food and Drug Administration– 121 tations cause haploinsufficiency, with only one functional 122 approved drug at a dose of 360 mg per day, we chose a titracopy of the gene remaining. Progranulin protein (PGRN) 123 tion to 360 mg or maximum tolerated dose. Nimodipine was 124 levels are less than 50% from birth [1–3]. Thus, therapeutic titrated every week as follows: 30 mg orally TID, 60 mg 125 approaches have focused on increasing PGRN levels, either TID, 90 mg TID, and 90 mg QID and maintained at this 126 by increasing transcription from the normal allele [4,5] or dose for 4 weeks. All subjects attempted to titrate to the 127 by modulating posttranslational mechanisms [6,7]. 128 full 360 mg per day dose (Supplemental Fig. 3). Promising preclinical data in heterozygous Grn mice sug129 130 gested that nimodipine might restore PGRN levels in hu2.3. Outcomes 131 mans with GRN mutations. As PGRN levels are stable 132 over both short and long periods (1 week to 2 years) in Primary outcomes were safety and tolerability of 133 GRN mutation carriers [8] as well as various disease and nimodipine and identification of the optimal nimodipine 134 control populations [9], PGRN levels alone are suitable enddose for long-term efficacy studies in GRN mutation 135 136 points for trials. We tested the effects of modulators of calcarriers. Safety was measured by the number of treatment 137 cium homeostasis on PGRN levels in cultured cells and emergent adverse events (listed by detailed MedDRA 138 found that reducing intracellular calcium by blocking calterm [www.meddra.org]), routine clinical, laboratory, and 139 cium channels increased PGRN secretion. We focused on nielectrocardiogram assessments. Secondary outcomes were 140 modipine, a Food and Drug Administration–approved change from baseline concentration of plasma PGRN or 141 142 L-type calcium channel blocker that crosses the bloodCSF PGRN, plasma PGRN-related inflammatory markers 143 brain barrier, as it is relatively well tolerated and, in a (CRP, ESR), CSF neurodegeneration proteins (neurofila- Q4 144 placebo-controlled trial, it improved overall status and ment light chain [NfL], amyloid b 42 [Ab42], tau), blood 145 cognitive function in patients with dementia [10]. and CSF cytokines (interleukin-10 [IL-10], IL-2, IL-6, 146 We report the effects of nimodipine on PGRN levels in IL-8, and tumor necrosis factor a [TNFa]), and volumetric 147 148 plasma and central nervous system tissues in correlative magnetic resonance imaging (MRI). 149 studies on animals and humans carrying GRN mutations. In 150 a phase 1, 8-week open-label clinical trial, we sought to deter2.4. Plasma and CSF sampling and analysis 151 mine the safety and tolerability of oral nimodipine treatment in 152 PGRN was measured by A&G Pharma (Columbia, MD) GRN mutation carriers and the best dose of nimodipine for 153 using a proprietary enzyme-linked immunosorbent assay Q5 154 long-term efficacy studies. As secondary objectives, we investhat detects full-length PGRN. TNFa was measured by 155 tigated the effects of nimodipine on PGRN levels in plasma 156 Quanterix (Lexington, MA). Tau, phospho-tau181, and and cerebrospinal fluid (CSF), a subset of inflammatory and 157 Ab levels were analyzed using the xMAP multiplex immu42 neurodegeneration-associated proteins, and in brain volumes. 158 noassay/Luminex analyzer (INNO-BIA AlzBio3; Fujire159 bio). NfL levels were measured using the 160 2. Methods UmanDiagnostics kit (Ume a, Sweden). Proinflammatory cy161 162 tokines were measured in plasma and CSF using a V-PLEX 2.1. Study oversight 163 human proinflammatory 10-Plex kit from Meso Scale Dis164 This study was approved under local institutional review covery (Rockville, MD). Nonparametric measures (Mann165 board’s supervision, registered at ClinicalTrials.gov Whitney U) were used to compare mean baseline versus 166 (NCT01835665). Informed consent was obtained from pa8-week or early termination values of the secondary clinical 167 tients and, when applicable, caregivers. 168 and laboratory measures. 169 170 2.2. Study design and enrollment 2.5. Brain imaging 171 172 The target enrollment was eight asymptomatic and/or MRI was performed at screening and completion of the 173 symptomatic carriers of known FTD-causing GRN mutastudy using a 3T Siemens scanner [11]. MP-RAGE scans 174 tions (Supplemental Fig. 2). Participants were required for both time points for a given subject were registered to 175 176 to be aware of their mutation status before screening. one another using the serial longitudinal anatomical MRI SCO 5.5.0 DTD TRCI108_proof 30 August 2017 3:58 am ce
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Clinical Clinical phenotype (clinicians’ impression) CDR-SB MMSE Completed 8 weeks? Max dose achieved (mg) Plasma GRN ng/mL, (% change) ESRmm/hour, (% change) CRP mg/L, (% change) CSF GRN ng/mL, (% change) NfL pg/mL, (% change) Ab42 pg/mL, (% change) Tau pg/mL, (% change) P-tau pg/mL, (% change) IL-10 pg/mL, (% change) IL-2 pg/mL, (% change) IL-6 pg/mL, (% change) IL-8 pg/mL, (% change) TNFa pg/mL, (% change)
Subject 1
Subject 2
Subject 3
Subject 4
nfvPPA
Asymptomatic
Asymptomatic
bvFTD
bvFTD
Asymptomatic
bvFTD
Asymptomatic
0 29 Yes 360
0.5 29 Yes 360
0 30 Yes 360
12 Yes 360
4 22 Yes 180–270
0 30 Yes 360
2 25 Yes 360
0 30 No 180
1.1 (21) 2 (40) 0.4 (14)
1.4 (19) nd 20.1 (21)
212.6 (253) 0 (0) 1.2 (92)
20.2 (22) 0 (0) 21.7 (39)
20.07 (213) 211.8 (5) 28.7 (21) 4.2 (7) 21.7 (27) 0.03 (6) 0.01 (10) 0.11 (6) 3.82 (5) 0.00 (0)
0.06 (27) 239.5 (212) 281.6 (215) 24.2 (214) 5.8 (31) 0.001 (21) 0.01 (31) 20.15 (211) 1.24 (4) 20.05 (238)
20.15 (218) 27.4 (0) 76.8 (11) 20.4 (21) 20.8 (23) 0.005 (25) 0.03 (62) 20.04 (23) 20.38 (21) 0.02 (14)
20.2 (227) 750.6 (5) 19.7 (4) 25.8 (25) 23.0 (213) 0.01 (11) 20.02 (233) 0.07 (7) 6.74 (9) 20.07 (216)
Subject 5
4.9 (23) 19 (91) 6.8 (145) 20.28 (241) 2654.5 (28) 246.3 (214) 10.0 (12) 2.0 (17) 20.01 (215) 0 (9) 0.14 (13) 4.65 (11) 0.04 (42)
Subject 6
Subject 7
21.5 (216) 24 (500) 5.9 (590)
23.4 (227) 25 (231) 0.1 (6)
0.06 (15) 71.4 (9) 235.4 (26) 26.7 (216) 28.0 (234) -
20.05 (212) 2499.9 (25) 258.3 (212) 2.2 (23) 7.8 (89) 0.003 (4) 0.03 (36) 0.11 (16) 21.72 (26) 0.00 (21)
Subject 8
20.08 (217) 277.9 (27) 2103.9 (219) 2.0 (5) 1.6 (13) 0.04 (65) 0.01 (14) 0.06 (8) 20.16 (0) 0.01 (9)
Mean 2.3 27.9 Mean 6 SEM 21.47 6 2.1 (25.2 6 10.9) 6 6 4.3 (99.9 6 81.8) Q7 1.8 6 1.2 (115.4 6 62.5) 20.09 6 0.04 (210.7 6 7.8) 230.68 6 151.8 (21.4 6 2.5) 229.70 6 20.5 (26.5 6 3.6) 3.59 6 3.7 (1.9 6 4.8) 0.48 6 1.8 (11.6 6 13.1) 0.00 6 0.1 (9.1 6 9.8) 0.01 6 0.01 (18.5 6 11.2) 0.04 6 0.04 (5.1 6 3.5) 2.0 6 1.17 (3.1 6 2.2) 0.01 6 0.02 (1.4 6 9.4)
Abbreviations: Ab42, amyloid b; CDR-SB, Clinical Dementia Rating–sum of boxes; CSF, cerebrospinal fluid; GRN, progranulin; MMSE, Mini–Mental State Examination; nd, not determined; NfL, neurofilament light chain; P-tau, phospho-tau; TNFa, tumor necrosis factor a. NOTE. Age and gender were not shown to maintain participant confidentiality.
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Table 1 Characteristics of study participants
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package in SPM12 [12], and the procedures outlined elsewhere [13]. 3. Results 3.1. Preclinical studies Cultured cellular models revealed that cytosolic calcium levels affected the secreted PGRN levels (Supplemental Fig. 1). Two-week treatment with nimodipine elevated hippocampal PGRN levels in both wild-type (P , .001) and Grn1/– mice (P , .05) compared to vehicle-treated mice (Supplemental Fig. 1). 3.2. Demographics Eight GRN mutation carriers were enrolled in the trial (Table 1), with a median age of 57.3 years; 50% were male. They included three behavioral-variant FTD (bvFTD), one nonfluent-variant primary progressive aphasia (nfvPPA), and four asymptomatic individuals. One selfreported asymptomatic participant had a 0.5 in judgment on the Clinical Dementia Rating–sum of boxes (CDR-SB) and thus fit into the classification of normal with concerns. 3.3. Safety and tolerability Two of the eight participants (25%) were unable to titrate to the maximum dose of 360 mg per day (Table 1). One participant discontinued treatment early at week 5 due to dizziness, palpitations, and malaise. Another discontinued due to edema. There were no serious adverse events. Forty-three adverse events were reported; the most common included edema (12 reports), headache (3), and dizziness (3). There were also two reports of arrhythmia and lassitude. There were single reports of upper respiratory infection, flu-like symptoms, syncope, redness on legs, depression, insomnia, worsening of asthma, and urinary tract infection. 3.4. Fluid biomarkers PGRN concentrations, in plasma and CSF, did not change from baseline after nimodipine treatment (percent changes of 25.2 6 10.9% [mean 6 standard error mean] in plasma and 210.2 6 7.8% in CSF) (Table 1 and Fig. 1A and 1B). CSF levels of three neurodegenerative disease–associated proteins, NfL, Ab42, and tau (both total tau and phospho-tau) did not change significantly after nimodipine treatment (Table 1). Levels of CSF NfL (P 5 .0002, Mann-Whitney U) and tau (P 5 .0002, Mann-Whitney U) at baseline correlated with disease severity as measured by CDR-SB, with the highest levels of NfL and tau observed in subjects with the highest CDR-SB score (Fig. 1C and 1D). Of 10 cytokines measured in CSF, five were detectable (IL-10, IL-2, IL-6, IL-8, and TNFa), and none exhibited a significant change following nimodipine treatment (Table 1).
3.5. Volumetric MRI Longitudinal structural MRI differences were determined by performing a one-sample t-test on the longitudinal Jacobian gray matter change maps. Six subjects were analyzed (mean age 5 56.2 years, range 32.5–69.0; 4 females; mean interscan interval 5 50.7 days, range 29–70). The resultant map was corrected with a joint height/extent threshold of P , .001 (no significant reductions were detected at a more stringent threshold of P , .05, familywise error corrected). There was one significant cluster of gray matter loss in the left middle frontal gyrus. The rate of change in this cluster revealed that the effect was driven by four subjects with annualized rates of gray matter loss between 1% and 2% (Fig. 1). 4. Discussion PGRN deficiency causes FTD; therefore, treatments that restore PGRN levels are of high therapeutic interest. We found that oral nimodipine increased mouse hippocampal PGRN concentrations but failed to increase human PGRN levels in plasma and CSF. In an 8-week, open-label trial, nimodipine was safe and well tolerated in GRN mutation carriers, but no effects of nimodipine were noted on secondary outcome measures, including concentrations of PGRN in blood and CSF, CSF NfL, CSF Ab42, CSF total tau, CSF phospho-tau, plasma ESR, plasma CRP, or CSF cytokines (IL-10, IL-2, IL-6, IL-8, and TNFa). Although there were no clear effects on volumetric MRI measurements by nimodipine, there was volume loss noted in severely affected patients. Reasons for the discrepancy between rodents and humans are unknown and may be related to many factors, including exposure, dose, timing, and interspecies difference in responsiveness. Of the six participants with MRIs conducted before and after treatment, three were asymptomatic and three were symptomatic. The most severely affected cases displayed the greatest decrease in volume over the trial period; a change that would extrapolate to a 1%–2% loss in the volume of the left frontal region annually, if constant. This rate is slightly less than reported for whole-brain atrophy in a comparably sized group of GRN mutation carriers assessed with MRI scans over 2 years [14]. Intermediate volume loss was observed in a mildly symptomatic individual and in an asymptomatic individual with a score of 0.5 on CDR-SB for judgment. The two asymptomatic cases revealed no change in brain volume. Given that nimodipine did not raise levels of PGRN, we propose this rate of decline may be comparable to untreated GRN mutation carriers. However, we cannot exclude a contribution of volume loss from treatment with nimodipine. If this rate of volume loss is confirmed in a larger cohort of mutation carriers, slowing or reversal of regional gray matter loss could be a viable endpoint in future FTD-GRN Q6 clinical trials.
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Fig. 1. Nimodipine had no effect on secondary outcome measures in humans, including plasma and CSF PGRN levels and brain volume loss. (A) The mean change in plasma PGRN between baseline (day 0) and the end of the trial (day 56 6 7) was 21.47 6 2.1 ng/mL. (B) The mean change in CSF PGRN between baseline (day 0) and the end of the trial (day 56 6 7) was 20.09 6 0.04 ng/mL. (C) Elevated neurofilament light chain correlated with disease severity. (P 5 .0002, Mann-Whitney) (D) Elevated tau correlated with disease severity (P 5 .0002, Mann-Whitney). (E) A significant cluster of gray matter loss was detected in the left middle frontal gyrus (yellow 5 20% loss) (cluster extent of 1431 voxels, peak MNI coordinate: 251, 28, 28). (F) The change in brain volume loss was driven by symptomatic mutation carriers.
This is the second reported trial to be completed in GRN mutation carriers [7]. There are a number of therapeutic targets in the development pipeline intended for GRN mutation carriers, and this study provides a framework for future bench-to-bedside proof of mechanism studies for FTDGRN. Acknowledgments Authors’ contributions: Drs S.J.S., Z.A.M., and A.L.B. had full access to all the data in the study and took the responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: A.L.B., L.G., S.J.S. Acquisition, analysis, or interpretation of data: A.L.B., L.G., W.S., S.J.S., Z.A.M., S.-w.M., Y.Z., L.L.M., J.B., M.K., R.T., M.S., A.M.F., and K.E.F. Drafting of manuscript: L.L.M., Z.A.M., S.J.S., A.L.B., L.G., and S.-w.M. Obtained funding: A.L.B., L.G., B.L.M., and W.S. Administrative, technical, or material support: A.K., C.C.R., S.L., E.H., R.P., R.F., S.F., L.H.M., R.V.F., and R.P. Study supervision: A.L.B. and L.G. Funding: This work was funded by The Bluefield Project to Cure Frontotemporal Dementia.
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Role of the Funder: Employees of The Bluefield Project to Cure Frontotemporal Dementia participated in the design and conduct of the study, analysis, interpretation of data, and preparation of the manuscript. Additional contributions: We are grateful to, and offer tremendous thanks to, the participants and their families who made this study possible. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.trci.2017.08.002.
RESEARCH IN CONTEXT
1. Systematic review: The authors reviewed the literature using traditional (e.g., PubMed) sources. Heterozygous loss of function mutations in the progranulin gene (GRN) lead to frontotemporal dementia (FTD) through decreased production of the normal progranulin protein (PGRN). Therapeutic approaches have focused on finding novel compounds that increase PGRN levels. In murine model systems, calcium channel blockers were discovered to increase PGRN levels. We launched a phase 1 trial of nimodipine in GRN mutation carriers to test safety and tolerability. 2 Interpretation: Nimodipine was safe and well tolerated but is unlikely to provide therapeutic benefit in GRN FTD. 3. Future directions: This trial demonstrated that a nimble, small-scale trial could arise entirely from, and be contained within, an academic center. From the initial target identification to the execution of human trials, this trial provides a framework for future bench-to-bedside proof of mechanism studies in FTD.
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