P-014 - Study design for testing safety, tolerability, and efficacy of NTM-006 against pain symptoms associated with Fragile X Tremor/Ataxia Syndrome (FXTAS)

Abstract Title: Study design for testing safety, tolerability, and efficacy of NTM-006 against pain symptoms associated with Fragile X Tremor/Ataxia Syndrome (FXTAS)

Background: Radiological criteria for the diagnosis of fragile x Tremor/Ataxia Syndrome (FXTAS) include the major findings of white matter lesions in the middle cerebellar peduncles or brainstem. The core features of FXTAS affects cognition and movement, including gait ataxia, intention tremor, parkinsonism, executive function deficits, neuropathy and dysautonomia (Hall et al, 2016). Individuals with FXTAS have high frequency of pain complaints, as well as comorbid conditions with chronic pain that often start prior to FXTAS onset. Both nociceptive (mechanical or chemical damage to a body tissue such as skin, muscles, joints, or fascia ) and neuropathic chronic pain are prevalent in individuals with FXTAS. The severity differs by sex, but peripheral neuropathy is common, including musculoskeletal and back pain (Salcedo-Arellano et al, 2020). Further, general muscle pain often manifests as fibromyalgia (Leehey et al, 2011). Migraine is also highly prevalent as are coexisting conditions related to pain such as psychiatric problems and executive function deficits (Hall et al, 2016). Previous research suggests that FMRP has a role in the development of nociceptive pain sensitization and chronic pain and is studied as a potential target for pain treatment.

Purpose/Objectives: FMRP is hypothesized to mediate translational control over allodynia and persistent nociceptive sensitization. The primary pathophysiology of FXTAS is thought to be through increased mRNA production and toxicity. Despite increased mRNA production, FMRP is paradoxically decreased as CGG repeats increase, likely secondary to less efficient translation due to excessive repeats. An effective non-opioid, non-steroidal anti-inflammatory therapeutic approach to pain management in FXTAS is highly warranted. The overarching hypothesis is that NTM-006 represents a safe medication for the treatment of pain and inflammation in patients with FXTAS. The Hagerman group was the first to identify FXTAS. The primary outcome will be safety of this treatment in those with FXTAS. The secondary objective is to assess the benefits of NTM-006 in improving the symptoms of FXTAS including pain, inflammation, neurocognitive features, molecular biomarkers and abnormalities on magnetic resonance imaging (MRI).

Methods: The proposed study would be a Phase 2/3 double-blind, placebo-controlled, randomized trial to determine if NTM-006 is effective in reducing pain and to determine the safety and tolerability of NTM-006 administered orally in male and female patients with pain with pain related to FXTAS. Twenty (20) patients/year diagnosed with FXTAS will undergo the following protocol: medical and neurological evaluation to assess FXTAS diagnosis, stage, and FMR1 molecular studies for CGG repeat size and mRNA level. A medical history will be taken at the time of visit to document FXTAS phenotype and symptoms including tremor and ataxia in addition to age of onset and severity, current and past medication use, self-reported anxiety and depression, musculoskeletal and autoimmune problems such as osteopenia, osteoporosis, osteoarthritis, rheumatoid arthritis, fibromyalgia, lupus, ANA positivity, and other immunological diseases.

Results: We will collect data on restless legs syndrome, severe cramps, disc/spine problems, and muscle pain. Migraine with and without aura, age of onset, and frequency will be collected along with symptoms of neuropathy, allodynia, back pain, and chronic pain in general. Activation ratio will be measured using ratios of signal intensity. Efficacy and tolerability will be assessed using standard measures.

Conclusions/Implications for future research and/or clinical care: FXTAS is associated with a variety of multiple pains of incompletely understood etiologies for which standard analgesics can be either ineffective of contraindicated. The presentation presents a plan to (1) investigate several hypothesized biochemical underpinnings of the pain symptoms associated with FXTAS, and (2) pilot-test the efficacy and tolerability of the mechanistically-novel analgesic agent NTM-006 currently in development.

References: Hall DA, Robertson E, Shelton AL, Losh MC, Mila M, Moreno EG, et al. Update on the clinical, radiographic, and neurobehavioral manifestations in FXTAS and FMR1 premutation carriers. Cerebellum. (2016) 15:578– 86.
Iwahashi CK, Yasui DH, An HJ, Greco CM, Tassone F, Nannen K, Babineau B, Lebrilla CB, Hagerman RJ, Hagerman PJ. Protein composition of the intranuclear inclusions of FXTAS. Brain. 2006 Jan;129(Pt 1):256-71.
Leehey MA, Legg W, Tassone F, Hagerman R. Fibromyalgia in fragile X mental retardation 1 gene premutation carriers. Rheumatology. (2011) 50:2233–2236.
Salcedo-Arellano MJ, Cabal-Herrera AM, Tassanakijpanich N, McLennan YA, Hagerman RJ. Ataxia as the major manifestation of fragile X-associated tremor/ataxia syndrome (FXTAS): case series. Biomedicines. (2020)8:136.