A Phase 2A/2B Placebo-controlled Randomised Clinical Trial to Test the Ability of Triheptanoin to Protect Primary Airway Epithelial Cells Obtained From Participants With Ataxia-telangiectasia Against Death Induced by Glucose Deprivation

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.