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Clinical Trial
. 2023 Jan;19(1):261-273.
doi: 10.1002/alz.12651. Epub 2022 Mar 31.

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease

Mark Brody  1 , Marc Agronin  2 , Brad J Herskowitz  3 , Susan Y Bookheimer  4 , Gary W Small  5 , Benjamin Hitchinson  6 , Kevin Ramdas  6 , Tyler Wishard  7 , Katalina Fernández McInerney  8 , Bruno Vellas  9 , Felipe Sierra  10 , Zhijie Jiang  11 , Lisa Mcclain-Moss  6 , Carmen Perez  8 , Ana Fuquay  1 , Savannah Rodriguez  3 , Joshua M Hare  6   12 , Anthony A Oliva Jr  6 , Bernard Baumel  8
Affiliations
Clinical Trial

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease

Mark Brody et al. Alzheimers Dement. 2023 Jan.

Abstract

Hypothesis: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action.

Key predictions: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints).

Strategy and key results: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments.

Interpretation: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

Keywords: Alzheimer disease; Lomecel-B; anti-inflammatory agents; biological therapy; bone marrow mesenchymal stem cell; clinical trial; cytokines; hippocampus; human bone marrow; inflammation; inflammation mediators; interleukins; medicinal signaling cell; mesenchymal stem cell; mesenchymal stromal cell; multipotent stem cells; neuroimaging; neuroinflammatory diseases; randomized controlled trial; regenerative medicine; vascular; vascular endothelial cell growth factor.

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Conflict of interest statement

This research was supported by two grants from the Alzheimer's Association awarded to Longeveron (AAO, principal investigator). AAO, BH, LM‐M, KR, and JH received partial salary support from these grants. MB, MA, BJH, and BB were clinical investigators on the clinical trial of this study, to which institutional payments were made by Longeveron, partially using funds from these grants. TW received a consulting fee from Longeveron that was pre‐approved by his institution to perform MRI analyses, and paid in part by one of these grants. FS, BV, SB, MB, MA, and BJH serve as members of Longeveron's Alzheimer's Disease Program Steering Committee, and for which no support was made from these grants. AAO, BH, LM‐M, KR, and JH are affiliated with Longeveron Inc., and receive salary support and stock options from Longeveron. In addition, the authors report the following over the past 36 months. MB has contracted with Biogen, Lilly Cerevel, UCB, AgeneBio, Cortexyme, Genentech, Roche, NIH, Cognito, BioIVT, Athira, Novartis, EISAI, ABBVIE, Cassava, Biohaven, Athira, Alector, GreenValley, Janssen, SAMUS, Vaccinex (institutional payments made). He also serves on advisory boards for both Lilly and Biogen, and has been a paid consultant for Biogen. MA has contracted with Biogen and Mededicus, and is President‐elect (2022) of the American Association for Geriatric Psychiatry. SB has received (in the form of institutional support) grants from the Alzheimer's Association (Zenith award), NICHD (2 center grants, 1 network), NIA (multi‐site, site PI), NIDA (multi‐site, site PI), and NIMH (multi‐site; site PI), which were not used for this study. Her institution has also received payments for patent from MS Cohen on a signal process algorithm unrelated to the current paper, and receives direct consulting fees on MRI research from the Pacific Neuroscience Institute, and received a speaker honorarium from the Society of Biological Psychiatry. GS has contracted or consulted for the AARP, Acadia, Allergan, Avanir, Biogen, Genentech, Gerontological Society of America, Handok, Herbalife, Home Care Assistance, Longeveron, McCormick Spice Institute, Medscape, Reckitt Benckiser, Roche, Theravalues, and WebMD. He has also received grant support from NIH (Columbia University Multi‐site Clinical Trials), and is on a UCLA patent for FDDNP‐PET. BH is a co‐investigator on a Maryland Stem Cell Research Fund grant unrelated to this study, and is a co‐inventor on a provisional patent related to Lomecel‐B. BV has received grants from the Ton Institution, Lilly, Pfizer, and Pierre Fabre Merci outside of the presented work and provided to the institution, has received consulting fees from Lily, Biogen, Roche, and Longeveron outside of this work. FS has received consulting fees from Indiana University, and from the Fisabio Conferences, all paid directly to him. JMH is a co‐founder, Chief Science Officer, and board member of Longeveron Inc. This relationship is reported to the University of Miami, and a management plan is in place. JMH is inventor of intellectual property licensed to Longeveron. Longeveron has paid license fees to the University of Miami through an Exclusive license fee, and as a university faculty member, he has received an institutionally designated share of these fees. He is a named co‐inventor on provisional patents submitted by Longeveron, and an investigator on grants from the National Institutes of Health and Department of Defense unrelated to this research (institutional payments made). He has also served on two DSMBs (one for the National Institutes of Aging; the other for the National Eye Institute), has received support for presentation at the American Heart Association (covered by an NIH grant to University of Miami), and is affiliated with the Heart Failure Society of America. AAO has received grant support as principal investigator from the National Institute of Aging (two awards) and Maryland Stem Cell Research Fund (three awards) that were unrelated to this research (institutional payments made). He has received travel/accommodations support from the National Institutes of Health for the Geroscience Summit III, and from the University of the West Indies (The Bahamas) for presentations (paid directly to him). He is also a co‐inventor on provisional patents submitted by Longeveron. The University of Miami is an equity owner in Longeveron, which has licensed intellectual property from the University of Miami.

Figures

FIGURE 1
FIGURE 1
Secondary and exploratory biomarker endpoints: changes in serum biomarkers related to inflammation and vascular functioning, and hippocampus volume. A to C, Declines in vascular‐related biomarkers occurred in the placebo arm, but not the Lomecel‐B arms. A, Vascular endothelial growth factor (VEGF) significantly decreased in the placebo arm versus the changes in the low‐dose Lomecel‐B arm (P < 0.0128) and the high‐dose Lomecel‐B arm (P < 0.0012). B, Interleukin (IL)‐4 was significantly higher in both the low‐dose and high‐dose Lomecel‐B arms versus placebo (P < 0.0054 and P < 0.0180, respectively). C, IL‐6 was significantly higher for the high‐dose Lomecel‐B arm versus placebo (P < 0.0014). D, D‐Dimer significantly increased in the high‐dose Lomecel‐B arm versus placebo (P < 0.0488). E to G, Significant increases in anti‐inflammatory biomarkers occurred in the Lomecel‐B arms versus the changes in placebo. E, Soluble IL‐2 receptor α (sIL‐2Rα) significantly increased in the high‐dose Lomecel‐B arm versus the change in placebo (P < 0.0049). A trending increase was seen in the low‐dose Lomecel‐B arm. F, IL‐10 significantly increased in the low‐dose Lomecel‐B arm versus placebo (P < 0.0349). G, IL‐12 significantly increased in the low‐dose Lomecel‐B arm versus placebo (P < 0.0015). A to G, P values indicate analysis of variance evaluation of change from baseline through week 26 for the indicated comparisons. Plotted are the means ± standard error of the mean. H, The left hippocampus showed an increase in volume in the high‐dose Lomecel‐B group versus the change in placebo at week 13 post‐treatment (*, P < 0.0311)
FIGURE 2
FIGURE 2
Secondary endpoints: changes in neurocognitive and neuropsychiatric assessments. A, The low‐dose Lomecel‐B arm showed significantly slower decline on the Mini‐Mental State Examination (MMSE) versus placebo. The MMSE showed no significant decline in the low‐dose Lomecel‐B arms versus baseline, whereas the placebo arm showed a significant decline (†, P = 0.034 at week 13). This change from baseline in placebo versus the low‐dose Lomecel‐B arm was also significant (*, P < 0.019 at week 13). In contrast, the high‐dose Lomecel‐B arm showed no significant change versus placebo. B, The Alzheimer's Disease Assessment Scale–Cognitive subscale‐11 (ADAS‐Cog‐11) showed no significant changes between any of the groups, although the placebo arm showed a worsening trend. C, The low‐dose Lomecel‐B arm improved on the patient version of the Quality of Life in Alzheimer's Disease (QOL‐AD) assessment. The QOL‐AD significantly increased from baseline in the low‐dose Lomecel‐B arm versus the change in placebo at week 26 (*, P = 0.0444). There was no significant difference between the high‐dose Lomecel‐B and placebo arms. D, At week 26, the placebo arm had significantly declined from baseline on the Alzheimer's Disease Cooperative Study‐Activities of Daily Living (ADCS‐ADL; †, P = 0.0211), and was statistically significant versus the change in the low‐dose Lomecel‐B arm (*, P = 0.0118). Neither Lomecel‐B arm showed a significant change from baseline. Plotted are the means ± standard error of the mean (SEM) for change from baseline for each arm. The inset on each graph shows the raw means ± SEM
FIGURE 3
FIGURE 3
Consort diagram for trial enrollment, randomization, and trial completion. Subject screening consisted of a three‐tiered process starting with a clinical assessment for probable mild Alzheimer's disease (AD), followed by magnetic resonance imaging (MRI) to rule out other potential etiologies and confounding complications, and finally a positron emission tomography (PET) scan using an amyloid tracer to confirm the mild AD diagnosis. Six of the withdrawals after the 26 week follow‐up visit occurred during the COVID‐19 pandemic. One subject in the placebo arm was unable to make the 26 week follow‐up due to COVID‐19 self‐isolation, but returned for the other follow‐ups. MMSE, Mini‐Mental State Examination; NIA‐AA, National Institute on Aging–Alzheimer's Association; TSH, thyroid stimulating hormone
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