Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia

A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicentre Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia

Friedreich ataxia is the most frequent early-onset autosomal recessive hereditary ataxia. It is caused by a pathological expansion of a GAA repeat in the first intron of the frataxin gene (FXN) and results in decreased levels of FXN protein. FXN deficiency results in a relentlessly progressive neurodegenerative condition which frequently presents around puberty. Patients gradually lose coordination, become dysarthric and are frequently wheel-chair bound as adolescents. There is no disease modifying therapy and many patients die prematurely of cardiomyopathy. It was subsequently found that the FXN gene is silenced at the chromatin level by the formation of heterochromatin and that this heterochromatin formation can be antagonized by histone deacetylase inhibitors (HDACi) (Chan et al., 2013). A recent proof-of-concept clinical study on ten patients with Friedreich ataxia demonstrated that FXN levels can be restored to those seen in asymptomatic carriers using the class III HDACi nicotinamide at a dose that is well tolerated by patients (Libri et al., 2014). Since carriers are asymptomatic, this degree of restoration of FXN expression might be expected to halt disease progression. Nicotinamide readily crosses the blood brain barrier and has previously been given at high doses for long periods to normal individuals without serious adverse effects (Gale et al., 2004; Knip et al., 2000). This study will be the first to provide clinical evidence for the efficacy and safety of nicotinamide in patients with Friedreich´s ataxia.

Inclusion Criteria:

• Patients must have a molecular genetic diagnosis of Friedreich ataxia with a GAA- repeat expansion on both alleles of the FXN gene and a SARA Score >7 and <28 and age <50 years.
• Patients must be ≥18 years old and have a weight of at least 50kg.
• Written informed consent prior to study participation
• A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea or of childbearing potential and agrees to

Exclusion Criteria:

• Patients with any medical condition or illness that, in the opinion of the investigator would interfere with study compliance and/or impair the patient´s ability to participate or complete the study.

• Any uncontrolled medical or neurological/neurodegenerative condition (other than Friedreich ataxia).

• Clinically significant psychiatric illness (e.g., uncontrolled major depression, schizophrenia, bipolar affective disorder) within 6 months prior to screening.

• Patients with significant clinical dysphagia.

• Hypersensitivity to nicotinamide.

• Patients known to be positive for human immunodeficiency virus (HIV).

• Patients with a significant history of substance abuse (e.g. alcohol or drug abuse) within the previous six months before enrolment.

• Patients with a history of severe allergies to medications.

• Indication of impaired liver function as shown by an abnormal liver function profile at screening (e.g., repeated values of aspartate aminotransferase [AST], alanine aminotransferase [ALT] and bilirubin ≥3 × the upper limit of normal).

• History of malignancy or carcinoma. The following exceptions may be made after discussion with the Sponsor:

  • Subjects with cancers in remission more than 5 years prior to screening.
  • Subjects with a history of excised or treated basal cell or squamous carcinoma.
  • Subjects with prostate cancer in situ.

• History or evidence of an autoimmune disorder considered clinically significant by the Investigator or requiring chronic use of systemic corticosteroids or other immunosuppressants.

• The subject has a history of any other illness, which, in the opinion of the Investigator, might pose an unacceptable risk by administering study medication.

• History of clinically significant cardiac disease (ejection fraction < 40% [normal range 50-70%], cardiac insufficiency defined as New York Heart Association [NYHA] Class >2; clinically significant congenital or acquired valvular disease; symptomatic coronary disease such as prior myocardial infarction or angina, B-type natriuretic peptide (BNP) level increase more than 2 x of the normal age- and gender dependent range; history of unstable arrhythmias, history of atrial fibrillation).

• The subject received an investigational drug within 30 days prior to inclusion into this study.

• Patients taking sodium valproate, tranylcypromine or any other known histone deacetylase inhibitor.

• Use of vitamin B1 (thiamine), withdrawal should be at least 3 months prior screening or 5 half-lives, whichever is longer.

• Use of vitamin B3 (nicotinamide), withdrawal should be at least 3 months prior screening.

• If patients are taking idebenone or coenzyme Q10 (CoQ), this should be stable over the last three months and not changed during the study.

• The subject is unwilling or unable to provide written informed consent and to follow the procedures outlined in the protocol.

• For subjects who will undergo an MRI: Any contraindications to MRI such as, but not limited to cardiac pacemaker, implanted cardiac defibrillator, aneurysm clips, carotid artery vascular clamp, neurostimulator, implanted drug infusion devices, metal fragments or foreign objects in the eyes, skin or body, bone growth/fusion stimulator, cochlear, otologic implant, severe claustrophobia or any condition that would counterindicate an MRI scan.

• Patients participating at start or have been within 30 days before start of study in another pharmacological and non-pharmacological clinical trial, excluding natural history / observational studies.

• The subject is mentally or legally incapacitated.

• Pregnant females as determined by positive [serum or urine] hCG test at Screening or prior to dosing. Participants of child-bearing age should use adequate contraception as defined in the study protocol.

• Lactating females.