NeuroSTAT for TBI – preparing for Phase IIb
NeuroSTAT is NeuroVive’s innovative, patent-protected formulation of ciclosporin without the use of Cremophor or ethanol, hence differentiated from other formulations of ciclosporin in the market (see our initiation report for detailed analysis of NeuroSTAT’s competitive edge). There is still no neuroprotective treatment available for TBI. In May 2017, NeuroVive announced positive findings from both the preclinical and clinical studies it had been conducting at that time and started preparations for the proof-of-concept Phase IIb.
One of these, the Phase IIa Copenhagen Head Injury Ciclosporin (CHIC) study, explored NeuroSTAT in severe TBI patients. The trial was conducted at Rigshospitalet in Copenhagen, Denmark and was complemented by an experimental large animal (piglets) study conducted in collaboration with the University of Pennsylvania, US. The purpose of both studies was to accumulate pharmacokinetic/pharmacodynamic (PK/PD) data, confirm safety and understand which factors are important in designing efficacy trials. TBI varies significantly in each case and can be characterised as ‘no two similar cases exist’. Therefore, defining a target patient population and which measures are the best to evaluate efficacy need careful consideration before starting efficacy trials.
The Phase IIa CHIC trial was an open-label study. It aimed to recruit 20 severe TBI patients and explore PK/PD, safety and exploratory outcomes tests, such as electroencephalography changes. Two dosing regimens were used: 5mg/kg/day and 10mg/kg/day. Preliminary disclosed findings show that dose-dependent concentration levels can be measured in the blood and that NeuroSTAT reaches the CNS (target tissue), which means it passes the blood-brain barrier. The safety profile was confirmed.
On 4 October 2018, NeuroVive, in collaboration with researchers at the University of Florida released a biomarker analysis from this study, which appeared to provide initial signs of NeuroSTAT’s effect on the secondary brain injury cascade. Four novel biomarkers, GFAP (Glial fibrillary acidic protein), UCH-L1 (Ubiquitin carboxy-terminal hydrolase L1), NF-L (Neurofilament Light) and Tau, were analysed in cerebrospinal fluid samples taken from the severe brain trauma patients in the CHIC study. The results showed that the administration of NeuroSTAT had a positive longitudinal effect on the levels of these biomarkers potentially alleviating secondary brain injury.
This was a non-controlled and open-label study; therefore, no concrete conclusions can be made at this point. On the other hand, it was a Phase IIa study with representative patients and CSF samples were taken on several occasions during the trial, so it represents a good starting point to understand how to best use the biomarkers in upcoming randomised trials, in our view. Having biochemical markers in the trial could lead to better understanding as to which patients NeuroSTAT is best suited to (patient stratification: mild, moderate, severe brain trauma). They also provide a sensitive way to evaluate NeuroSTAT’s treatment effect (follow-up) and make prognosis more accurate (outcomes). Detailed data from the CHIC study will be published at a future date.
All four biomarkers analysed in the study come from cutting-edge research, and recently the FDA approved GFAP and UCH-L1 blood tests for diagnosis of mild TBI. Until recently, no biochemical measures existed in practice to evaluate TBI patients; this mainly depended on physical examination and imaging studies. Given that NeuroSTAT’s mechanism of action is to limit secondary injury to brain tissue, the availability of biochemical biomarkers adds a new dimension of patient evaluation.
Experimental study results published
Until recently, only headline findings have been released from the experimental preclinical study with large animals (piglets), but a new peer-reviewed paper published in the Journal of Neurotrauma in July 2018 described the findings in detail. The importance of this study is that, while it is preclinical, it was carried out in a highly controlled manner similar to clinical trials, ie blinded and placebo controlled. There is a high degree of translatability of findings into humans due to the substantial structural, anatomical similarities between human and pig brains (similar gyral pattern and distribution of grey and white matter). In addition, the outcome was measured using MRI and the upcoming Phase IIb trial is likely to use same method.
The model involved standardised focal cranial impact resulting in a brain injury while the piglets were sedated. The study consisted of three different sub-studies, all of which were randomised. The first two sub-studies established the PK/PD profile, proving that NeuroSTAT reaches the CNS in a dose-dependent manner and established the recommended dose of 20mg/kg/day for the efficacy part of the trial.
The third sub-study evaluated the efficacy of the recommended dose after five days of treatment (randomized, blinded). A total of 37 animals underwent randomisation, of which 24 received the full dose (n=11 NeuroSTAT; and n=13 placebo; the remaining 13 animals did not receive the full dose due to various technical issues, such as failed intubation or anaesthesia). The findings include:
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The volume of brain injury was reduced by 35% in the NeuroSTAT group compared to the placebo group five days after TBI (measured with MRI; Exhibit 5).
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Brain tissue metabolism and mitochondria biomarkers. The researchers measured various neurotransmitters, neuronal and mitochondrial activity biomarkers, and reported a consistent trend towards positive improvements in brain metabolism and mitochondrial function in the brain tissue around the contusion area.
Exhibit 4: NeuroSTAT demonstrated a reduced neuronal injury volume of 35% compared to placebo (n=10 NeuroSTAT; n=13 placebo)
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Next steps: Positive FDA and EMA opinions on Phase IIb design
NeuroVive is making preparations for the Phase IIb trial and has now received positive opinions from both the FDA and EMA. The details of the trial design have not yet been released, but important elements include novel biomarker endpoints and a subpopulation of TBI patients with defined trauma. The latter is especially beneficial for NeuroVive, in our view, as TBI can present a very diverse pathology. The ability to select patients with similar trauma-features greatly improves the consistency of the study. NeuroVive appears to be the first company to adopt a precision medicine approach in the TBI field, also highlighted by the recent partnerships with University of Florida for biomarker development and the TRACK-TBI consortium.
Submission of the IND application is the next step. The precise timing of the start of the study has not been announced yet. We believe NeuroVive’s current cash position is sufficient to continue the preparations, but it will need new funds or a partner to start and run the study. Our model includes patient enrolment start in 2019. Enrolment rate is inherently unpredictable in acute treatment studies, but NeuroVive has indicated plans for a multi-centre design in Europe and the US. We expect data readout to be possible by 2021, which can be a substantial value trigger for the programme and enable progress to a confirmatory Phase III trial thereafter.