Ataxia-telangiectasia: Treating Mitochondrial Dysfunction With a Novel Form of Anaplerosis

Study design: Parallel group, placebo-controlled, dose-escalation each 2 months for 12 months. Dose based on percent (%) of calculated caloric intake. Thirty participants will be randomised in blocks on a 1:1:1 ratio into one of three groups stratified by age (\< 5 years, 5-10 years, \> 10 years of age). Group 1: 10%, 20%, 35%, 35%, 35% (no placebo). Group 2: placebo, 10%, 20%, 35%, 35% Group 3: placebo, placebo, 10%, 20%, 35%.

Primary endpoint: The percent cell death induced by glucose deprivation in cell culture. Secondary endpoints include: Scales for assessment and rating of ataxia, International Cooperative Ataxia Rating Scale, Ataxia Telangiectasia Neurological Examination Scale Toolkit, speech and language assessment, EyeSeeCam assessment, MRI lung imaging, Lung function, Upper respiratory microbiome, Faecal microbiome, Survival and inflammatory phenotype of airway epithelial cells, macrophages and in serum, Metabolomic biomarker discovery in serum and measurement of neuroflament light chain.

Ataxia Telangiectasia (A-T) is a rare, genetic, progressive, life-limiting, neuro-degenerative condition affecting a variety of body systems resulting in ataxia, immune deficiency, respiratory complications and a predisposition to cancer. Currently there is no cure for A-T. Over the years, a number of small clinical trials using steroids, antioxidants and anti-inflammatory agents have had little success. The disease natural history is relentless leading to early death. A-T generates a significant disease burden for the individuals, their extended families and on health care resources. With palliative care being the only current option for families, a treatment trial for A-T meets an unmet need. The investigators preliminary data provide compelling evidence of reversible mitochondrial dysfunction and preventable cell death in A-T patient cells and the beneficial effects of heptanoate (C7), the primary metabolite of triheptanoin. C7 corrects a defect in endoplasmic reticulum (ER)-mitochondrial signalling in A-T cells and has great potential for application in treating participants. C7 has been utilised with efficacy and safety over the last 15 years for inborn errors of metabolism (IEM) such as long chain fatty acid defects (LC-FAOD).

A-T is due to a genetic defect that results in a defective serine/threonine protein kinase, known as ATM. Normally, ATM, plays a central role in protecting the genome against damage. It is increasingly evident that ATM protects cells against oxidative stress. This protein is also present outside the nucleus, where it is activated by oxidative stress through a separate mechanism from DNA damage, providing an explanation why anti-oxidants have a protective role in A-T cells in culture and in animal models. From these and other studies, it is evident that mitochondrial abnormalities characterise ATM and it has been suggested that A-T should be considered, at least in part, as a mitochondrial disease. The Investigators have added substance to that claim by showing that ATM-deficient (B3) cells are exquisitely sensitive to inhibition of glycolysis by glucose deprivation, compared to controls (HBEC). The investigators have also shown this increased sensitivity to nutrient deprivation for primary epithelial cells from patients and in immortalised patient cells. Together these data point to a reduced capacity of A-T mitochondria to support energy metabolism and provide additional evidence for a mitochondrial defect in A-T cells. The investigators have recently demonstrated that this hypersensitivity to glucose deprivation can be explained by a novel mechanism involving defective signalling between the ER and the mitochondrion. The investigators demonstrated that this was caused by defective assembly of the VDAC1-GRP75-IP3R1 calcium channel and less ER-mitochondria contact points as determined by transmission electron microscopy. This in turn resulted in reduced calcium release from the ER and less transfer to mitochondria providing further evidence for mitochondrial dysfunction in A-T cells.

The investigators selected triheptanoin, a highly purified, synthetic medium odd-chain triglyceride that is catabolized to heptanoate and can traverse the mitochondrial membrane without the carnitine carrier. Free heptanoate is then metabolized by the medium chain fatty acid oxidation enzymes to yield both acetyl CoA and propionyl CoA that act as anaplerotics to replenish the TCA cycle and enhance energy metabolism by providing NADPH and generating ATP. The investigators demonstrated that heptanoate partially corrects the extreme sensitivity to glycolysis inhibition in both the ATM-deficient cell line as well as in primary epithelial cells from a patient with A-T. Excitingly, heptanoate also corrected all of the defects in ER-mitochondrial signalling including calcium uptake into mitochondria. Based on the importance of mitochondrial dysfunction in the A-T phenotype and our results revealing correction of mitochondrial function by heptanoate, the investigators consider that triheptanoin has excellent potential in correcting many aspects of the A-T phenotype including the progressive neurodegenerative phenotype.

Triheptanoin has been used for over 15 years to treat LC-FAOD, with demonstrated improvements in cardiac function and reductions in rhabdomyolysis episodes. Triheptanoin and heptanoate are known to protect against cell death in experimental conditions largely characterised by oxidative stress, such as stroke and motor neurone disease, adult polyglucosan body disease, alternating hemiplegia of childhood, Glucose-1 transporter deficiency, and mouse models and humans with epilepsy. Heptanoate protects cultured neurons against H2O2-induced cell death. Collectively these studies demonstrate that triheptanoin is well tolerated and is effective in treating a range of neurological conditions associated with neuronal energy deficiency.

Seamless Phase II to Phase III go/no-go criteria Interim monitoring for the intervention program in the A-T2020/01 trial will occur at the times of the two interim analyses (first, when the study cohort has completed the initial 2 months treatment, and second, after 6 months treatment when Group One has completed 2 months of the 35% dose). A blinded report will be presented to the iDSMB containing pertinent descriptive statistics of the groups, a standard between-group comparison for the primary and secondary outcomes, and a Bayesian estimation of the (posterior) probability that each of the three intervention groups is superior for the primary outcomes. The information to be presented to the iDSMB will be agreed with the iDSMB prior to the first iDSMB meeting, and will be updated at the time of the iDSMB meetings. Data will be presented to the iDSMB in a blind fashion, but the iDSMB can request unblinded data to confirm or ratify any reported interim results. The iDSMB may however make a recommendation about stopping current interventions if they show poor promise or futility.

The primary endpoints for interim iDSMB reports are the percent cell death induced by glucose deprivation in cell culture, and reversal/correction of their abnormal mitochondrial profile in primary epithelial cells resulting in cell death over the treatment period.

Secondary scales clinical neurological assessments assist formulating the go/no-go criteria and will include: SARA and ICARS. SARA is a validated cerebellar ataxia tool, measuring gait, stance, sitting, speech, finger-chase test, finger nose-test, fast alternating movements and heel-shin test. It has eight categories with accumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia); Gait (0-8 points), Stance (0-6 points), Sitting (0-4 points), Speech disturbance (0-6 points), Finger chase (0-4 points), Nose-finger test (0-4 points), Fast alternating hand movement (0-4 points), Heel-shin slide (0-4 points). ICARS is a scale recorded out of 100 with 19 items and 4 subscales and has been used in A-T. Disorders rated as subscales within the ICARS are: Postural and gait disturbances, (7 items, 0-34 points) Limb Ataxia (7 items, 0-52 points), Dysarthria (2 items, 0-8 points), and Oculomotor disorders (3 items, 0-6 points). Minimum Score: 0 Maximum score: 100.

go/no-go triggers

go triggers Seamless progress from Phase II to Phase III will be triggered under the following pre-set parameters;

* If clinically or statistically significant improvement in the primary study outcome is observed in combination with a measured improvement of at least ½ standard deviation in key clinical scales which includes either;
* significant improvement in total combined scores from the SARA and ICARS scales.
* And/or significant improvements any aspects of the SARA and ICARS scales individually, especially pertaining to; Postural and gait improvements, Speech disturbance, Improved fine motor skills, Fine motor disturbance, Kinetic functions

No-go triggers Seamless progress from Phase II to Phase III will not occur under the following pre-set parameters;

* Adverse events
* If no clinically significant improvement in the primary study outcome is observed
* If a clinically significant improvement in the primary study outcome occurs without any improvements in key secondary scales specifically the SARA and ICARS.

Eligibility Criteria:
Inclusion Criteria:

* Patients of either sex, of any age, with a confirmed diagnosis of A-T,
* Patients who are able to undertake the study procedures,
* Families who are able to comply with the protocol for its duration and who provide informed patient assent and consent signed and dated by parent/legal guardian or adult participant according to local regulations.

Exclusion Criteria:

* Patients whose parents/legal guardians are not able to provide consent
* Patients who have been in another randomised clinical intervention trial where the use of investigational medicinal product within 3 months or 5 half-lives, whichever is longer, before study enrolment
* Taking off label mediations or nutritional supplements that the PI consider would impact participant's safe participation.
* Patients who are pregnant and/or lactating, planning a pregnancy during the study. Contraception must be used for sexually active male and female participants
* Intestinal Malabsorption secondary to Pancreatic Insufficiency
* Liver enzymes (alanine aminotransferase \[ALT\]/aspartate aminotransferase \[AST\]) or total bilirubin \> 2 x the upper limit of normal at the time of screening.
* Renal insufficiency as defined by estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73m2 at the screening visit.
* Any comorbid medical condition that in the assessment of the PI that would impact participant's safe participation (e.g. active cancer requiring treatment)
* Evidence of dysphagia that places subject at risk of aspiration if orally fed.