RTA 901: A C-Terminal Heat Shock Protein 90 (Hsp90) Modulator with Neuroprotective and Neuroregeneration Potential

Hsp90: A Molecular Chaperone That Regulates Hsp70 Expression

Hsp90 is a molecular chaperone that promotes correct protein folding and plays an important role in the heat shock response. Upon sensing cellular stress, Hsp90 activates the heat shock response pathway, which results in increased expression of Hsp70, another molecular chaperone.1 Hsp70 plays key roles in several processes including protein folding, mitochondrial function, and cellular homeostasis.2,3

Heat shock proteins are organized into several families (Hsp90, Hsp70, Hsp60, etc) based on molecular weight and function. Heat shock proteins play important roles in multiple aspects of the cellular stress response. A variety of stimuli—including thermal, oxidative, mechanical, chemical, and pathophysiological stresses—induce heat shock protein expression. Once induced, heat shock proteins prevent other proteins from misfolding and restore cellular homeostasis.1

Hsp70 and Hsp90 act as molecular chaperones and bind to those regions of proteins that become exposed when they are misfolded.1 Hsp70 is also critically involved in the transport of nuclear-encoded mitochondrial proteins across mitochondrial membranes,2 and it is required for normal mitochondrial function.3

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Consistent with these activities, recent insights have indicated a potentially profound role of Hsp70 activation in neuroprotection and neuronal regeneration.4,5 Inducing expression of Hsp70 is a promising strategy for treating neurodegenerative diseases, chronic inflammatory diseases, and other pathologies, and the development of selective heat shock protein modulators is an area of significant interest.

RTA 901: A C-Terminal Hsp90 Modulator with Hsp70-Dependent Activity

Reata has licensed several novel Hsp90 modulators. These molecules, including the lead product candidate RTA 901, are highly potent and selective C-terminal modulators of Hsp90 that address the mechanistic limitations of previous compounds in this category. The drug candidates in the Reata program have significant activity in several preclinical models of neurodegeneration and neuroprotection. In particular, RTA 901 has shown profound activity in animal models of insensate diabetic neuropathy, which is the numbness that occurs as a result of nerve damage from diabetes. This condition affects millions of people and has no effective therapy.

  • Reata’s Hsp90 modulators are efficacious in models of diabetic neuropathy, neural inflammation, Alzheimer’s disease, and demyelinating motor nerve diseases6-9
  • In these disease models, Reata’s Hsp90 modulators have been associated with significant rescue of nerve function, restoration of thermal and mechanical sensitivity, improvement in nerve conductance velocity, and improved mitochondrial function6,10,11
  • The efficacy of the Hsp90 modulators in many of these disease models has been demonstrated to be dependent on Hsp706,9,10
  • The preclinical effects of RTA 901 are achieved with once-daily oral dosing. RTA 901 has shown acceptable tolerability in early GLP toxicology studies12

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Development Program for RTA 901

Reata has completed a phase 1 clinical trial to evaluate the safety and pharmacokinetics of RTA 901 in healthy subjects. In this study, RTA 901 had an acceptable pharmacokinetic profile with no apparent safety or tolerability issues.

The trial was designed in 2 parts:

  • Part 1 (single ascending doses): 48 healthy subjects in six groups (eight subjects in each group) were randomized in a 3:1 ratio to receive a single dose of RTA 901 or placebo, respectively
  • Part 2 (multiple ascending doses): 30 healthy subjects in three groups (ten subjects in each group) were randomized in a 4:1 ratio to receive 14 daily doses of RTA 901 or placebo, respectively

Reata is the exclusive licensee of RTA 901 and has worldwide commercial rights to this agent.

RTA 1701: A Candidate for the Treatment of Autoimmune and Inflammatory Disorders

RORγt: A Master Transcription Factor That Regulates Th17 Cell Differentiation

RORγt, an orphan nuclear receptor selectively expressed in T lymphocytes, has been identified as the master transcription factor that regulates Th17 cell differentiation.13 RORγt is upstream in the differentiation process and is required for the expression of Th17 proinflammatory cytokines, including interleukin 17A (IL-17A). Inhibition of RORγt is a promising strategy to treat Th17-mediated inflammation in a broad range of autoimmune diseases, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, and multiple sclerosis.14

Naive CD4+ precursor T cells can differentiate into various lineages of effector T cells that are tailored to counteract specific types of pathogens. The T helper 17 (Th17) cell lineage plays a role in host defense but is also involved in the pathological immune response that occurs in many chronic inflammatory and autoimmune diseases.15

Th17 cells express a signature of proinflammatory cytokines, including the key effector cytokine IL-17A.16 The clinical significance of Th17 cells and IL-17A in autoimmune disease has been validated by recent Food and Drug Administration approvals of multiple injectable IL-17A-targeted therapies.

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RTA 1701: An Orally Administered Inhibitor of RORγt

RTA 1701, our lead product candidate, is an orally-bioavailable small molecule that selectively inhibits RORγT by a novel allosteric mechanism at low nanomolar concentrations.

Results from several in vitro, ex vivo, and animal disease models are consistent with the broad potential of RTA 1701 in the treatment of chronic inflammatory and autoimmune diseases.

  • In human CD4+ T cells, RTA 1701 potently inhibits Th17 cell differentiation and suppresses the expression of IL-17A and other Th17 signature cytokines17
  • RTA 1701 significantly reduces the amount of IL-17A produced by blood cells derived from patients with rheumatoid arthritis or psoriasis17
  • When dosed orally to nonhuman primates, RTA 1701 suppresses IL-17A production in blood cells stimulated ex vivo18
  • RTA 1701 is efficacious in animal models of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis17

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Development Program for RTA 1701

Reata is testing RTA 1701 in a phase 1, first in human study to evaluate the safety and pharmacokinetics of RTA 1701 in healthy subjects and to assess suppression of IL-17A production in blood cells stimulated ex vivo.

All rights to the RORγt inhibitors are retained by Reata and are not subject to any existing commercial collaborations.

  1. Saibil H. Chaperone machines for protein folding, unfolding and disaggregation. Nat Rev Mol Cell Biol. 2013;14(10):630-642.
  2. Craig EA. Hsp70 at the membrane: driving protein translocation. BMC Biol. 2018;16(1):11.
  3. Leu JI, Barnoud T, Zhang G, et al. Inhibition of stress-inducible HSP70 impairs mitochondrial proteostasis and function. Oncotarget. 2017;8(28):45656-45669.
  4. Brown IR. Heat shock proteins and protection of the nervous system. Ann N Y Acad Sci. 2007;1113:147-158.
  5. Turturici G, Sconzo G, Geraci F. Hsp70 and its molecular role in nervous system diseases. Biochem Res Int. 2011;1011:618127.
  6. Urban MJ, Li C, Yu C, et al. Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice. ASN Neuro. 2010;2(4):e00040.
  7. Li C, Ma J, Zhao H, Blagg BS, Dobrowsky RT. Induction of heat shock protein 70 (Hsp70) prevents neuregulin-induced demyelination by enhancing the proteasomal clearance of c-Jun. ASN Neuro. 2012;4(7):e00102.
  8. Ma J, Pan P, Anyika M, Blagg BS, Dobrowsky RT. Modulating molecular chaperones improves mitochondrial bioenergetics and decreases the inflammatory transcriptome in diabetic sensory neurons. ACS Chem Neurosci. 2015;6(9):1637-1648.
  9. Zhang X, Li C, Fowler SC, Zhang Z, Blagg BS, Dobrowsky RT. Targeting heat shock protein 70 to ameliorate c-Jun expression and improve demyelinating neuropathy. ACS Chem Neurosci. 2018;9(2):381-390.
  10. Ma J, Farmer KL, Pan P, et al. Heat shock protein 70 is necessary to improve mitochondrial bioenergetics and reverse diabetic sensory neuropathy following KU-32 therapy. J Pharmacol Exp Ther. 2014;348(2):281-292.
  11. Zhang L, Zhao H, Blagg BS, Dobrowsky RT. C-terminal heat shock protein 90 inhibitor decreases hyperglycemia-induced oxidative stress and improves mitochondrial bioenergetics in sensory neurons. J Proteome Res. 2012;11(4):2581-2593.
  12. Reata Pharmaceuticals, Inc., Data on file.
  13. Martinez GJ, Nurieva RI, Yang XO, Dong C. Regulation and function of proinflammatory TH17 cells. Ann N Y Acad Sci. 2008;1143:188-211.
  14. Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic potential of targeting the Th17/Treg axis in autoimmune disorders. Molecules. 2017;22(1):pii:E134.
  15. Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014;13(6):668-677.
  16. Xiao S, Yosef N, Yang J, et al. Small-molecule RORγt antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity. 2014;40(4):477-489.
  17. Dulubova I, Jian X, Trevino I, et al. RTA 1701 is an orally-bioavailable, potent, and selective RORγt inhibitor that suppresses Th17 differentiation in vitro and is efficacious in mouse models of autoimmune disease. J Immunol. 2018;200(1 suppl):121.14.
  18. Reisman SA, Lee CY, Proksch JW, et al. RTA 1701 is an oral RORγt inhibitor that suppresses the IL-17A response in non-human primates. J Immunol. 2018;200(1 suppl):175.22.
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