Let’s tick some boxes. Summarising, trofenetide helps to correct...

Let’s tick some boxes.

Summarising, trofenetide helps to correct four of the hallmark pathological features of many central nervous system disorders: inflammation, over-activation of microglia, dysfunction of synapses and reduced levels of IGF-1. By simultaneously targeting multiple processes, trofenetide works to restore the natural balance of brain function.

“The outcome of this trial is very encouraging.

Safety, the primary goal, was achieved. As important and with broad implications, there was a clear clinical improvement covering several common symptoms in Rett syndrome, which are known to impair the quality of life of girls affected by the disorder. The variety of improved symptoms suggests that tro netide is a drug that targets mechanisms underlying the disorder rather than a symptomatic medication. Similar to the previous adult trial, the results are particularly signi cant because of the relatively short duration of the trial. The impact of the study goes beyond the suggested ef cacy of tro netide, since it shows the potential of neurobiologically- based drugs for the treatment of Rett syndrome and other neurodevelopmental disorders.”

During development, the brain and the cells that make it up change rapidly and
in complex ways. IGF-1 and GPE play a significant role in regulating these changes. In the mature brain, IGF-1 and GPE both play an important role in responding to disease, stress and injury. Whereas most drugs typically exert a specific effect on a specific target, trofenetide exerts diverse effects which can help to control or normalise abnormal biological processes in the brain.

Most Rett syndrome patients require life-long medical care and 24 hour supportive care. In addition to direct costs for medical and related services, costs for institutional and special education services as well as the  financial and emotional impact on families are very large.

Prior to commencing the Phase 3 trial in 2018, Neuren is completing signi cant investments in manufacturing processes and chronic toxicity studies that are required before the longer dosing in a Phase 3 trial and before a New Drug Application. These include the optimisation and scale up of the drug substance synthesis and development of the commercial  nished product presentation. The  first of two required chronic dosing toxicity studies has recently been completed and the second study is planned to conclude in the first half of 2018. These investments will benefit all potential clinical uses of trofenetide.

In March 2017 we announced the results of a profoundly important clinical study for the families affected by Rett syndrome. The results of the study in girls aged 5 to 15, which built on the clinical data generated from our  rst Rett syndrome study, were deeply encouraging and have greatly increased the confidence of Neuren and the Rett syndrome clinical experts, with whom we are working to develop this therapy. Taken together, the data from
our trials have provided a strong basis to move forward with the remaining steps
in trofenetide development.

Working in close collaboration with rettsyndrome.org, the clinical experts and the many Rett families, we conducted the study across 12 clinical sites in the US.

The very nature of these studies places an additional set of demands upon families,
so it is noteworthy that the motivation and rate of subject enrolment remained high at all times throughout the study.

This enabled us to recruit an additional 20 girls into the study, which served to further strengthen the  nal data set. The fact that only one subject discontinued from the study illustrates that compliance throughout the study was very high. This speed of enrolment and level of compliance are very important as we plan a larger Phase 3 study.

The objective of the Phase 2 pediatric study was to assess drug safety as well as a range of different ef cacy measures in younger patients, at a dose 2-3 times higher than previously administered. Following detailed analysis of the data, the Rett syndrome clinical experts were unanimous in their view that safety and tolerability of tro netide is not presenting as a limitation or concern and that the ef cacy results are strongly supportive of tro netide having a clinically meaningful effect on many of the core signs and symptoms of Rett syndrome. With these latest results in hand, including the valuable insights we have gained regarding a clear relationship between exposure to drug and ef cacy, as well as the suitability of ef cacy measures across both pediatric and adult patients, we are moving as quickly as possible to con rm with the FDA our development plans for an anticipated start of Phase 3 in 2018.

Three efficacy measures in the study demonstrated a statistically signi cant bene t of tro netide over placebo. We
are con dent that two of those, the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinician Global Impression of Improvement (CGI-I), provide appropriate and well validated measures for a pivotal Phase 3 study and we look forward to discussing the Phase 3 trial design with the FDA Division of Neurology Products
in coming months. The Motor Behavior Assessment (MBA) was shown in the pediatric study to be a less sensitive tool in this younger patient group compared with adults. It is important to understand that there is no gold-standard ef cacy measure for Phase 3 clinical trials in Rett syndrome. Our previously communicated intention to use the MBA resulted from Neuren’s proposal and was not a directive from the FDA.

In order to support the future plans for Rett syndrome and other indications, the Neuren Board is currently giving careful attention to a range of possible funding and partnering options, guided by two principles – speed to market for the families affected by these conditions and value for our shareholders.
I look forward to updating shareholders as we reach conclusions on those options.

Dr T.