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Enasidenib treatment in two individuals with D-2-hydroxyglutaric aciduria carrying a germline IDH2 mutation

Nature Medicine volume 29, pages 1358–1363 (2023)Cite this article

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Abstract

D-2-hydroxyglutaric aciduria type II (D2HGA2) is a severe inborn disorder of metabolism caused by heterozygous R140 mutations in the IDH2 (isocitrate dehydrogenase 2) gene. Here we report the results of treatment of two children with D2HGA2, one of whom exhibited severe dilated cardiomyopathy, with the selective mutant IDH2 enzyme inhibitor enasidenib. In both children, enasidenib treatment led to normalization of D-2-hydroxyglutarate (D-2-HG) concentrations in body fluids. At doses of 50 mg and 60 mg per day, no side effects were observed, except for asymptomatic hyperbilirubinemia. For the child with cardiomyopathy, chronic D-2-HG inhibition was associated with improved cardiac function, and for both children, therapy was associated with improved daily functioning, global motility and social interactions. Treatment of the child with cardiomyopathy led to therapy-coordinated changes in serum phospholipid levels, which were partly recapitulated in cultured fibroblasts, associated with complex effects on lipid and redox-related gene pathways. These findings indicate that targeted inhibition of a mutant enzyme can partly reverse the pathology of a chronic neurometabolic genetic disorder.

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Fig. 1: Clinical features of patient 1 and patient 2 during enasidenib treatment.
Fig. 2: Metabolic and biological features that responded to enasidenib therapy in serum and fibroblasts of patient 1.

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Data availability

Data from this clinical trial are available from the authors and can be requested by completing the data request form for Gustave Roussy clinical trials at https://redcap.gustaveroussy.fr/redcap/surveys/?s=DYDTLPE4AM. The trial steering committee and the sponsor will review the requests on a case-by-case basis. A specific agreement between the sponsor and the researcher may be required before data transfer.

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Acknowledgements

We thank N. Garcia (Hôpital Robert Debré, Paris, France) for initial care and discussions on the patients; M. David, L. Delestre, P. Dessen (UMR INSERM U1170) and D. Farabos (Saint Antoine Hospital) for excellent technical assistance; A. Boutron and E. Lebigot (Hôpital Bicêtre, Le Kremlin Bicêtre, France) for providing primary fibroblasts; P. Rustin (UMR1141, Paris, France), G. Pierron (Gustave Roussy) and R. J. Morscher (Kinderspital Zurich, Switzerland) for discussions; A. Paci and J. Delahousse (Gustave Roussy) for 2-HG analysis; the team of the clinical research direction and statistics department at Gustave Roussy for sponsoring and running the AcSé-ESMART trial; and Celgene Corporation/Bristol Myers Squibb for providing the study drug and financial grant. The work is generated, in part, by members of the European Reference Network for Hereditary Metabolic Disorders (MetabERN). We are grateful to M. Touat and R. Maki for critical reading of the paper. AcSé-ESMART is supported by grants from the Institut National du Cancer (INCa) within the AcSé program, the Association Imagine for Margo, Fondation ARC and Celgene Corporation/Bristol Myers Squibb France. B.G. is supported by the ‘Parrainage médecin-chercheur’ of Gustave Roussy. N.D. is supported by the Swedish State Support for Clinical Research (ALFGBG-965049 and ALF-GBG-967240). The work was supported by the Paris Île-de-France Region under the ‘DIM Thérapie génique’ initiative (C.O., C.P. and A.L.). The funders had no role in study design, data collection and analysis, preparation of the manuscript or decision to publish.

Author information

Author notes

  1. Katharine Yen & Michael Su

    Present address: Auron Therapeutics, Cambridge, MA, USA

  2. David Schenkein

    Present address: GV, Cambridge, MA, USA

  3. These authors contributed equally: Chris Ottolenghi, Stéphane De Botton.

Authors and Affiliations

  1. Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France

    Birgit Geoerger & Pablo Berlanga

  2. INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France

    Birgit Geoerger

  3. Reference Center for Inborn Errors of Metabolism, Necker University Hospital, APHP and University of Paris Cité, Paris, France

    Manuel Schiff, Clarisse Duchon, Clément Pontoizeau & Chris Ottolenghi

  4. INSERM UMRS 1163, Institut Imagine, Paris, France

    Manuel Schiff, Clément Pontoizeau & Chris Ottolenghi

  5. INSERM 1170, Université Paris-Saclay, Equipe Labellisée Ligue Nationale Contre le Cancer, member of OPALE Carnot Institute The Organization for Partnerships in Leukemia, Villejuif, France

    Virginie Penard-Lacronique & Stéphane De Botton

  6. Department of Pediatrics, Institute of Clinical Sciences, University of Gothenburg and Queen Silvia Children’s Hospital at Sahlgrenska University Hospital, Gothenburg, Sweden

    Niklas Darin

  7. Department of Cardiology, Clinique du Diaconat, Mulhouse, France

    Selim-Maria Saad

  8. Clinical Metabolomic Department, Assistance Publique-Hôpitaux de Paris, Saint Antoine Hospital, Saint-Antoine Research Center, Sorbonne University, Paris, France

    Antonin Lamazière & Aurore Desmons

  9. Metabolomics Unit of the Department of Biology, Physiology and Genetics, Necker University Hospital, APHP and University of Paris Cité, Paris, France

    Clément Pontoizeau & Chris Ottolenghi

  10. Department of Pediatric Hemato-Oncology, CHU Bordeaux, Bordeaux, France

    Stéphane Ducassou

  11. Agios Pharmaceuticals, Cambridge, MA, USA

    Katharine Yen, Michael Su & David Schenkein

  12. Department of Hematology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France

    Stéphane De Botton

Authors
  1. Birgit Geoerger
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Contributions

B.G., M. Schiff., V.P.-L., N.D., S.D., C.O. and S.D.B. conceived the study, designed and conducted the experiments, provided and analyzed the data and wrote the paper. S.-M.S., C.D., A.L., A.D., C.P. and P.B. designed and conducted the experiments and analyzed the data. K.Y., M. Su and D.S. developed the study treatment. All authors approved the paper.

Corresponding author

Correspondence to Birgit Geoerger.

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Competing interests

D.S. is a current board member at Agios Pharmaceuticals and a current shareholder of Agios Pharmaceuticals. The other authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Anja Karlstaedt, Julie-Aurore Losman, Ross Levine and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Michael Basson, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Height and weight of patient 1 (a) and patient 2 (b).

Dots mark height and weight at indicated biological age in relevant growth charts for boys and girls respectively; green shaded area depicts enasidenib treatment duration since aged 7.1 years and 8.0 years, respectively.

Extended Data Fig. 2 Lipids that responded to therapy in serum of patient 1.

Phospholipid species included phosphatidylcholine (PC; a) and phosphatidylethanolamine (PE; b) plasmalogens as well as sphingomyelins (SM; c). Molecules are designated by the sums of acyl and alkyl residues (www.lipidmaps.org/data/classification/lipid_cns.html). For example, PC O-38:5 refers to several molecular species, notably PC O-18:0/20:5, PC O-16:0/22:5 and/or PC O-18:1/20:4.

Extended Data Fig. 3 Lipids showing significant patterns in serum, investigated in cultured fibroblasts (patient 1).

Lipids showing significant patterns in serum, investigated in cultured fibroblasts in patient 1. The lipids that were found to be associated with therapy (Fig. 2a and Extended Data Fig. 2a–c) were tested for differential enrichment in patient 1 fibroblasts at 1, 3 and 6 days of culture in the presence of mutant IDH2 inhibitor or vehicle. The lipids with statistically significant differences between inhibitor and vehicle conditions (two-sided t-test on log transformed data, p < 0.05) at one or more of the three time points of culture were as follows: PC 35:4, PC O36-3,PC O36-4, PE O36:3 (higher values for vehicle than inhibitor), and Sm d18:1/20:0, Sm d18:1/22:0,Sm d18:1/24:0, Sm d18:1/24:1, Sm d18:1/24:2 (higher values for inhibitor than vehicle). For readability purposes data are presented as mean values without standard deviations, except for phosphatidylserine, because of the complex kinetics shown by the large number of metabolites of all other subclasses. The number of biological replicates was 3 per condition (treatment and time of culture).

Extended Data Fig. 4 Metabolite levels in patient 1 cultured fibroblasts.

Metabolite levels in patient 1 fibroblasts cultured for 1-6 days in the presence of mutant IDH2 inhibitor relative to vehicle mean value from the corresponding time point (set to 100%, highlighted by a horizontal dotted line). a, 2-hydroxyglutaric acid (total levels); b, citric acid; c, oxidized/reduced glutathione ratio; d, 2-oxoglutaric acid. Two-sided t-test of inhibitor/vehicle ratios on log-transformed values (a,b,d) and on inhibitor/vehicle ratios from paired samples for the GSSG/GSH ratio (c); NS = statistically not significant (p > 0.05). Y-axis log-scaled except for the GSSG/GSH ratio. Data are presented as mean values +/− standard deviation. The data points represent the values of biological replicates from the inhibitor condition (N = 3 biological samples) relative to the ratio between the inhibitor and the control mean values (a,b,d) or to the mean of individual vehicle/control ratios from paired samples (c).

Extended Data Fig. 5 Patient 1 fibroblast transcriptome.

a. Transcript levels of selected genes of microarrays from patient 1 and control fibroblasts cultured for 3 days in the presence of mutant IDH2 inhibitor or vehicle (see Methods). Y-axis: fold-intensities are relative to the mean of control values in the vehicle condition (%). Transcript levels of 8 major antioxidant defense enzymes. NS = statistically not significant (two-sided t-test; p > 0.05). b, Transcript levels of 4 major enzymes involved in lipogenesis or fatty acid beta-oxidation. The large color bars show the mean values (blue for inhibitor, red for vehicle) and error bars show the standard error of mean (N = 3 biological replicates per condition). Two-sided t-test p-values are shown over horizontal thin bars that compare patient 1 and control fibroblasts (vehicle condition), or inhibitor and vehicle, for patient 1; NS: not significant (p > 0.05). c,d, The published fibroblast IL11-related 20 gene signature15 and e,f, an extended 192 gene signature (including the published signature) from our reanalysis of the same study are compared to our fibroblast transcriptomes by GSEA with default settings (see Methods). Of these lists, probes for 19 out of 20, and 173 out of 192 genes, respectively, were present in our dataset. In all 4 panels, the nominal GSEA p-value is 0. c, Published fibroblast IL11-associated gene shortlist is enriched in patient relative to control fibroblasts. d, Published fibroblast IL11-associated gene signature is suppressed by the inhibitor in patient fibroblasts. e, Extended IL11-negative cell gene list (N = 85 genes) is significantly induced by the inhibitor (two-sided t-test; p < 0.05). f, Extended IL11-positive cell gene list (N = 88 genes) is significantly suppressed by the inhibitor.

Extended Data Table 1 VABS-II before and on enasidenib treatment in patient 1
Full size table
Extended Data Table 2 Tests in patient 2 before and at 6 months and 12 months on enasidenib treatment
Full size table
Extended Data Table 3 Molecular Signatures Database hallmark GSEA on patient 1 fibroblasts
Full size table

Supplementary information

Supplementary Information

Supplementary Table 1: Main clinical milestones before and on enasidenib treatment in patient 1 and patient 2. Supplementary Table 2: Serum lipidomic data for patient 1. Supplementary Table 3: Lipidomic data from patient 1 fibroblasts. Supplementary Table 4: Gene pathway enrichment data corresponding to Fig. 2c.

Reporting Summary

Supplementary Video 1

Left: Before treatment start, patient needed manual support and encouragement from her father to walk 436 m. Top-right: After 6 months of enasidenib treatment, she walked 390 m independently without manual support next to parent. Lower-right: After 12 months, she walked 424 m completely unaided.

Supplementary Video 2

Left: Before treatment start, patient walked down stairs with two-handed support. Top-right: After 6 months of enasidenib treatment, she walked down stairs with one-handed support in 12.0 s. Lower-right: After 12 months, she walked down stairs with one-handed support in 10.9 s.

Supplementary Video 3

Left: Before treatment start, patient was unable to walk on a line. Top-right: After 6 months of enasidenib treatment, she was able to walk a short distance following a line on the floor. Lower-right: After 12 months, she was able to walk following a line and on tip-toe.

Supplementary Video 4

Left: Before treatment start, BOT-2 test: 4 points. Top-right: After 6 months of enasidenib treatment, BOT-2 test: 13 points. Patient used a better pen grip when drawing and had begun to imitate a circle and words, and her movements became more fluent and precise. Lower-right: After 12 months, BOT-2 test: 19 points. Drawing and imitating a circle and words and movements became more fluent and precise.

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Geoerger, B., Schiff, M., Penard-Lacronique, V. et al. Enasidenib treatment in two individuals with D-2-hydroxyglutaric aciduria carrying a germline IDH2 mutation. Nat Med 29, 1358–1363 (2023). https://doi.org/10.1038/s41591-023-02382-9

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