Safety and Efficacy of Etravirine in Friedreich Ataxia Patients
Condition: Friedreich Ataxia
MeSH terms: Ataxia; Cerebellar Ataxia; Friedreich Ataxia
Study type: Interventional
Phase: Phase 2

Summary: 
      A drug repositioning effort provided evidence supporting the possible use of Etravirine, a
      drug approved for the treatment of HIV infections in patients starting from 2 years of age,
      as a treatment for FA. We found that Etravirine is able to increase Frataxin protein both in
      vitro - in cells derived from FA patients - and in vivo - in the heart and skeletal muscle of
      Frataxin-deficient YG8 mice. Because of these findings, and since Etravirine displays a
      generally favorable safety profile, we plan to launch an open-label, phase 2 clinical trial
      aimed at assessing the safety and efficacy of Etravirine in FA patients. We aim at recruiting
      30 FA patients. 15 will be treated with Etravirine for 4 months at 200 mcg/day and 15 will be
      treated with Etravirine for 4 months at 400 mg/day. Efficacy primary endpoint will be
      represented changes in peak VO2 as measured by incremental cycle ergometer exercise test.
      Secondary endpoints will include maximal workload, SARA score, cardiac measures, Frataxin
      protein levels in peripheral blood mononuclear cells and molecular analysis of Frataxin mRNA
      translation efficiency. Complete sets of data will be collected 4 months before the start of
      the treatment (T -4), at the start (T0), after 2 months (T2), at the end of the treatment
      (T4) and 4 months after the termination of the treatment (T8).
    

Detailed description: 
      Friedreich ataxia is a rare progressive neurodegenerative disease presenting in childhood or
      late adolescence for which no treatment is currently available. The disease is caused by the
      defective synthesis of Frataxin, a mitochondrial protein synthesized by the FXN gene. Over
      95% of patients carry a homozygous intronic GAA expansion that impairs FXN gene transcription
      and translation. The persistence of an intact reading frame within the genome of most FRDA
      patients opens the way to treatment attempts that target FXN gene transcription and mRNA
      translation to increase endogenous Frataxin levels and balance the complex metabolic
      consequences of Frataxin deficiency. The disease is characterized by a relentless progression
      involving motor coordination (ataxia), heart function and structure (hypertrophic
      cardiopathy), exercise capacity (impaired bioenergetics with reduced aerobic capacity),
      endocrine function (diabetes) visual and auditory function (optic atrophy and hearing loss).

      By screening a library of 853 FDA-approved drugs, we found a few drugs that are capable to
      upregulate Frataxin in vitro. Among them, we selected and focused on Etravirine for its
      generally favorable safety profile. In Friedreich ataxia (FRDA) patients-derived cells, we
      found that Etravirine upregulates mature Frataxin protein, enhances the activity of aconitase
      and confers resistance to oxidative stress. Etravirine appears to upregulate Frataxin protein
      by a mechanism of action involving the redistribution of frataxin mRNA on heavy polysomes and
      consequent enhancement of Frataxin mRNA translation. Moreover, in collaboration with Dr. Mark
      Pook, Brunel University, London, we obtained evidence that Etravirine is able to upregulate
      Frataxin protein in the heart and in the skeletal muscle of YG8 mice dosed orally for 5 days
      with Etravirine (unpublished).

      Etravirine is a diarylpyrimidine that acts as a non-nucleoside reverse transcriptase
      inhibitor. It was approved in 2008 by the FDA (tradename Intelence) for the treatment of
      patients affected by HIV that are resistant to other drugs. In 2018 the label was extended to
      include patients 2 years of age and older. The FDA label reports no contraindications.
      Etravirine is administered orally in tablets.

      Preliminary Results

      In collaboration with Dr. Mark Pook, Brunel University, London, we tested whether Etravirine
      is able to upregulate Frataxin protein in tissues of YG8 mice. Five YG8 mice were dosed for 5
      days orally with Etravirine (10 mg/Kg) and five YG8 mice were dosed for 5 days orally with
      vehicle. Four hrs after last dosing, all the mice were sacrificed and protein extracts
      prepared from tissues. SDS-PAGE followed by immunoblotting revealed that Frataxin protein was
      significantly increased in the heart and in the skeletal muscle of Etravirine-dosed mice,
      compared to vehicle-dosed mice.

      Specific Aims

      Because of its ability to upregulate Frataxin protein and rescue phenotypic defects in FA
      patient-derived cells and because of its safety and approved use in children, Etravirine
      represents an attractive potential therapeutic for FA. Aim of the study, therefore, will be
      assessing the safety and efficacy of Etravirine in a small population of young FA patients.

      Experimental Plan Study design. The study will be a randomized open-label Phase 2 clinical
      trial, to investigate the safety and efficacy of Etravirine in FA patients.

      Study population. We aim at enrolling 30 FA patients, aged 10 to 40 years over a period of 6
      months. Enrollment will be done by advertising the study through the patients' associations
      and among FA patients currently followed at the Medea site (50 subjects at present time). The
      patients will be screened and evaluated in the tertiary care hospital setting where Dr
      Martinuzzi is active. Treatment will be carried on at home following the prescription given
      to the patients at each visit.

      Study Intervention. Recruited subjects will be randomized 1:1 by a computer-generated
      randomization sequence to either of the two dose regimens: Etravirine orally 200 mg/day (100
      mg cpr x 2, morning and evening) for 4 months or Etravirine 400 mg/day (one 200 mg cpr x 2
      morning and evening) for 4 months. Treatment will start only after the 4 months pre-treatment
      period will be completed and after the T0 evaluation visit.

      Withdrawal criteria. Failure to comply with the study follow-up visits or with the treatment
      protocol. Occurrence of a SUSAR (suspected unexpected severe adverse reaction) deemed related
      to the drug treatment.

      Stopping rules. The entire study will be interrupted: 1) When the third SUSAR occurs in
      different patients. 2) On the occurrence of the same SUSAR in two different patients. 3) Upon
      the occurrence of the first serious adverse event judged to be related to the investigational
      drug, which has endangered a patient's life or caused permanent damage. 4) Upon the exclusion
      of the third patient from the trial.

      Endpoints

        1. Safety. Hematochemical parameters (Blood cell count, glycaemia, BUN, Creatinine, AST,
           ALT, yGT, ferritin, Troponine) will be acquired 4 months before the start of the
           Etravirine treatment (T -4), at the start of the treatment (T0), after 2 months (T2), at
           the end of the treatment (T4) and 4 months after the termination of the treatment (T8).
           A physical evaluation including vital parameters assessment and skin inspection for
           possible rash will be completed at enrollment and at each follow up visit. A detailed
           questionnaire listing all known adverse events associated with Etravirine will be
           distributed to all patients and reviewed at each follow up visit. Any additional AE will
           be registered irrespective of its likely connection with the treatment.

        2. Efficacy Primary endpoint. Primary endpoint of the study will be the change in peak
           aerobic capacity (VO2 peak) achieved by participants during a standardized incremental
           exercise test by cycle ergometer. Peak VO2 normalized by weight, is a very stable
           objective measure of aerobic capacity. FA is associated with significant decrease
           (50-60% less) aerobic fitness as measured by standardized exercise testing and its
           measure has been employed as primary end point in FA intervention trials several times.

      Secondary endpoints. Secondary endpoints will include:

        -  clinical measures of the disease as quantitated by the Scale for the assessment and
           Rating of Ataxia (SARA); SARA is the most sensitive functional composite measure of
           performance developed specifically for ataxic disorders;

        -  Critical cardiac parameters (including interventricular septal wall thickness, left
           ventricular wall thickness, left ventricular ejection fraction, Sokolow-Lyon index);
           Heart is primarily affected in FA showing progressive mostly left ventricular
           hypertrophic. Cardiomyopathy is the main determinant of survival in this population. The
           ECG changes summarized by the Sokolow-Lyon index (∆%QRS-voltage) are reliable indicators
           of ventricular hypertrophy. Echocardiography can detect and measure very precisely the
           extent and severity of heart hypertrophic changes;

        -  Additional exercise indicators: maximal workload (W/Kg) reached at exhaustion during the
           incremental exercise test;

        -  WHO-DAS 2.0 is an internationally validated widely applied disease non-specific measure
           of disability developed by WHO within the framework of the biopsychosocial model of
           functioning and disability. It asks the subject to score in terms of severity and
           duration any difficulty experienced in the 30 previous days in 6 main life areas. The
           interview format will be used and the results will be computed as normalized scores.
           This measure has been validated only above age 16 and thus will be administered only to
           subjects >16 years of age.

        -  Frataxin protein levels as measured in peripheral blood cells. Frataxin protein will be
           quantitated by SDS-PAGE and immunoblotting in protein extracts from peripheral blood
           mononuclear cells. At the same time points, to assess the effect of Etravirine on
           Frataxin mRNA translation, the distribution of Frataxin mRNA in the translationally
           active heavy polysomal fraction, will be determined in extracts from peripheral blood
           mononuclear cells.

      Sample size calculation. Sample size was calculated considering the primary endpoint. VO2 at
      peak in controls subjects shows a value >16.2 with a test-retest variability of ± 4
      ml/min/Kg. Workload at peak is expected to be >3W/Kg in control subjects with a SD of ± 0.8.
      This parameter is reduced by approximately 50% in FA patients with similar SD values.
      Considering an alpha error of 0.05 and a statistical power of 80%, the needed number of
      participants is 30.

      Statistical analysis. Both primary and secondary endpoints will be analyzed using
      multivariate linear mixed models modeling timepoints as a repeated within-subject factor.
      Mixed models have the advantage of being able to account for heterogeneous distances between
      timepoints, missing data as well as unequal variances and covariances. In order to account
      for possible confounds due to inter-patient variability, all models will include sex, age at
      onset, disease duration, years of education and number of GAA1 repeats within the smaller FXN
      allele as covariates of no interest. When a statistically significant (p<0.05) overall effect
      of time is found, pairwise comparisons between timepoints were will be performed and
      corrected for multiple comparisons across pairs of timepoints using the Dunn-Šidák
      correction.
    

Intervention name(s): Etravirine Tablets
Intervention type(s): Drug
Intervention description(s): Daily etravirine BID with 100 or 200 tablets for 4 months
Intervention MeSH terms: Etravirine
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: dose comparison in open label pilot study
Masking: None (Open Label)
Primary purpose: Treatment