Clinical Trials

• On August 4, 2016, ReNeuron, a UK-based global leader in the development of cell-based therapeutics, announced the publication of long term follow up data from its PISCES I stroke clinical trial in The Lancet. The PISCES I study was the first clinical trial of ReNeuron's CTX cell therapy candidate for patients with motor disability as a consequence of ischaemic stroke. The Lancet paper describes two-year follow up clinical data relating to the eleven stroke patients treated in the study.   The study was designed primarily to determine the safety of the CTX cell therapy candidate in patients with stable motor disability following their stroke. A number of secondary endpoints were also monitored to investigate possible signals of efficacy in the participants taking part in the study. Patients in the study were treated from twelve to fifty one months after stroke onset. As previously reported at the 2015 European Stroke Conference, improvements in neurological status and limb function compared with pre-treatment baseline performance were observed within three months of treatment and maintained throughout long term follow up. Improvements in the National Institutes of Health Stroke Scale ("NIHSS") were seen in all dose groups.  The NIHSS is a scale used to measure the neurological impairment caused by a stroke.  For all subjects, the mean baseline score was 7.45.  This improved to 5.09 at three months and was sustained at two years follow up with a mean score of 4.91 (p=0.002). Improvements in other measures of neuromuscular disability were supportive of the NIHSS results.  Ashworth Scale scores, a measure of limb spasticity, showed sustained improvement over the course of the two year study in both the affected arm and leg (mean improvement of 2.5 and 3.7 points).  Scores on the Barthel Index, a measure of activities of daily living, also demonstrated improvement over the course of the study with a median improvement of 2 points at two years after treatment. There were no cell-related or immunological adverse events reported in any of the patients treated in the PISCES I study across the four ascending dose levels.  • On April 17, 2015, ReNeuron provided a further and final update on the PISCES Phase I clinical trial of its CTX stem cell therapy for disabled stroke patients. Long term follow-up data out to at least 24 months in all patients treated in the PISCES study are being presented by the clinical team from Glasgow’s Southern General Hospital on 19th April in a platform presentation at the 2015 European Stroke Organisation Conference (ESOC), taking place in Glasgow. The data are being presented ahead of submission for publication in a peer-reviewed clinical journal later this year. There have been no cell-related or immunological adverse events reported in any of the eleven patients treated in the study (across the four ascending dose levels). Adverse events reported were related only to the implantation procedure or the patient’s underlying medical condition. Improvements in neurological status and limb function compared to pre-treatment baseline performance were observed within three months of treatment and maintained throughout long term follow-up. Improvements in the National Institutes of Health Stroke Scale (NIHSS) were seen in all dose groups. The NIHSS is a measure used to objectively quantify the impairment caused by a stroke. For all subjects, the median baseline score was 7. This improved to 5 at 3 months and was sustained at 2 years follow up with a median score of 5 (p=0.002). Other measures of neuromuscular disability were supportive of the NIHSS improvement. Mean Ashworth Scale scores, a measure of limb spasticity, were 18.1 and 9.7 (affected upper and lower limb, respectively) at baseline, which improved to 15.7 and 7.8 at 3 months and 16.1 and 6.5 at 2 years. Improvements in scores on the Barthel Index (a measure of activities of daily living) were also consistent with the neuromuscular score changes with a median value of 12 at baseline, 14 at 3 months and 14 at 2 years. The Company is currently conducting a UK multi-site Phase II clinical trial (PISCES II) to examine the efficacy of its CTX stem cell treatment in patients disabled by an ischaemic stroke (NCT02117635). As a result of observed good safety profile of the treatment, the highest cell dose from the PISCES study is being used in the ongoing Phase II study. As with the PISCES study, the Phase II clinical trial involves a single, one-off injection of CTX cells into the brain. Subject to patient recruitment, initial data from this study are expected around the end of this year. * On May 7, 2014, ReNeuron has provided a further update on the PISCES Phase I clinical trial of its ReN001 stem cell therapy for disabled stroke patients ahead of the commencement of a Phase II efficacy study for which patient enrolment has now opened. Long term follow-up data out to 12 months in all patients treated in the PISCES study are being presented in two platform presentations by the clinical team from Glasgow’s Southern General Hospital at the 23rd European Stroke Conference, taking place in Nice, France this week. There were no cell-related or immunological adverse events reported in any of the eleven patients treated in the study. Adverse events were related only to the implantation procedure or underlying co-morbidities. Sustained reductions in neurological impairment and spasticity were observed in most patients compared to their stable pre-treatment baseline performance, reflected in the summary evaluation scores below (n=11 patients): · National Institutes of Health Stroke Scale (measure of neurological deficit): o Trial inclusion criteria require a score of 6 or more, representing stable moderate to severe disability (total of 2 or more for motor arm and leg scores) o Median pre-treatment score = 7 o Post-treatment scores improved by median 2 points at 3 months and 3 points at 12 months · Barthel Index (measure of independence in performing activities of daily living, rated 0-20): o Median pre-treatment score = 12 o Post-treatment scores improved by median 1 point at 3 months and 3 points at 12 months · Summated Ashworth Score (aggregated measure of spasticity in affected limbs, rated 0-40 arm, 0-25 leg): o Mean pre-treatment aggregate score = 29 o Post-treatment scores improved by mean 5 points at 3 months and 7 points at 12 months · Modified Rankin Score (overall measure of disability and handicap, rated 0-6): o Median pre-treatment score = 3 o Score improved by 1 grade in n=4/11 patients at 12 months, with n=7/11 patients unchanged · EuroQOL score (quality of life outcome measure, rated 0-100): o Median pre-treatment score = 45 o Post-treatment scores improved by median 18 points at 12 months. Preliminary functional MRI data in seven of the treated patients at resting state show, at a group level, evidence of increased short-term connectivity between the cell-implanted region of the brain (the putamen) and the other deep brain regions that are concerned with sensory motor control, although relevance to functional outcomes in the patients requires further evaluation. The Company recently announced that it had received unconditional approval to conduct a UK multi-site Phase II clinical trial to examine the efficacy of ReN001 in patients disabled by an ischaemic stroke. This Phase II study is now open for patient enrolment at the Glasgow clinical site, with other UK centres expected to follow, as required, over the coming weeks and months. The study will involve the treatment of up to 41 patients between 8 and 12 weeks after their stroke. Patients will be monitored on a number of validated stroke efficacy measures up to six months post-treatment. The treatment window in the Phase II clinical trial is regarded as optimal in terms of the potential efficacy of the ReN001 therapy and differs from the treatment window in the PISCES Phase I clinical trial where patients were treated at least 6 months after their stroke.   * On May 28, 2013, ReNeuron has announced that interim data from the first nine patients treated in the PISCES study are being presented by the clinical team from Glasgow’s Southern General Hospital at the 22nd European Stroke Conference, taking place in London. There were no cell-related or immunological adverse events reported in any of the patients treated. Sustained reductions in neurological impairment and spasticity were observed in most patients compared with their stable pre-treatment baseline performance, reflected in the summary evaluation scores below:

• National Institutes of Health Stroke Scale (neurological deficit): improved by median 1 point at 1 month post-treatment (n=9) and 3 points at 1 year (n=5)

• Barthel Index (functional outcome): improved by median 1 point at 3 months (n=8) and 4 points at 1 year (n=5)

• Modified Rankin Score (disability and handicap): improved by median 1 grade at 1 year (n= 5)

• Summated Ashworth scores for affected limbs (spasticity): improved by mean 4.5 at 3 months (n=9) and 7.2 at 1 year (n=5).

Since the above data were collated, the remaining patients in the PISCES study have been treated, with no subsequent cell-related or immunological adverse events reported.  As previously announced, the Company has cleared all points arising from the regulatory review of its proposed UK multi-site Phase II clinical trial to examine the efficacy of ReN001 in patients disabled by an ischaemic stroke. Reneuron has also announced that this Phase II study has been adopted by the NHS National Institute for Health Research Stroke Research Network (SRN). This endorsement will enable the Company to work closely with the SRN to optimise performance against defined targets regarding site set-up, patient recruitment and monitoring activities across the various sites participating in the study. The company will seek final regulatory and ethical approvals for the Phase II stroke study by submitting a data package including three month follow-up data on the final dose cohort in the PISCES study to the UK regulatory authorities in early July and, assuming approvals are granted, expects to commence recruitment into the Phase II study shortly thereafter.

* On March 27, 2013, ReNeuron has provided an update on progress with its ReN001 stem cell therapy for disabled stroke patients. Following a further positive assessment from the independent Data Safety Monitoring Board (DSMB) for the study earlier in March, the final dose cohort in the ongoing PISCES Phase I clinical trial with ReN001 has now been treated and the final patient dosed in the study has been discharged from hospital. No cell or immune-related adverse events have been reported in any of the patients treated to date. Last year, interim data from the first five patients treated in the PISCES study were presented by the clinical site team, with sustained reductions in neurological impairment and spasticity observed in all five patients compared with their stable pre-treatment baseline performance (see below). Further and longer term data from the study will be presented at a scientific conference later this year.

As previously announced, the Company has submitted an application to the UK regulatory authority to commence a multi-site Phase II clinical trial to examine the efficacy of ReN001 in patients disabled by an ischaemic stroke. This trial is designed to recruit from a well-defined population of patients between two and four months after their stroke, which the Company and its clinical collaborators currently believe will be the optimum treatment window for the therapy. ReNeuron has now cleared all points arising from the regulatory review of the Phase II application, assuming a continuing positive safety read-out from the ongoing PISCES study in the short term. The regulatory authority has also agreed with the Company’s proposal to curtail recruitment into the PISCES study at eleven patients rather than the twelve originally planned, with a consequent additional short-term safety assessment to be added for the first patient treated in the Phase II study. This change is in response to the Company’s contract cell manufacturer for the PISCES study recently entering into administration. Prior to this, the Company had contracted CTX cell supply for future clinical studies in both stroke and critical limb ischaemia with an additional contract manufacturer and is currently in the process of validating a third supplier.

In line with plan, the Company will therefore seek final regulatory and ethical approvals for the Phase II study by submitting a data package including three month follow-up data on the final dose cohort in the PISCES study to the regulatory authority in early July and, assuming approvals are granted, expects to commence recruitment into the Phase II study shortly thereafter.

* On January 29, 2013, ReNeuron has provided an update on progress with the PISCES clinical trial of its ReN001 stem cell therapy for disabled stroke patients. In this open label, dose-ranging Phase I safety study, taking place in Scotland, ReNeuron’s ReN001 stem cell therapy is being administered in ascending doses to a total of 12 stroke patients who have been left disabled by an ischaemic stroke, the most common form of the condition. The independent Data Safety Monitoring Board (DSMB) for the study has reviewed the three month follow-up data on the penultimate dose cohort and has cleared the study to proceed to dosing of the final dose cohort of three patients. Subsequently, and as planned, the first patient in this final dose cohort has been treated with ReN001 and discharged from hospital.

The PISCES study continues to run to plan, with no cell-related adverse events reported in any of the patients treated to date. Subject to DSMB approval and as previously announced, the remaining two patients are scheduled to be treated in March of this year. Last year, interim data from the first five patients treated in the PISCES study were presented by the Glasgow clinical team, with sustained reductions in neurological impairment and spasticity observed in all five patients compared with their stable pre-treatment baseline performance. Further and longer term data from the PISCES study are expected to be presented in scientific conference later this year.

As previously announced, the Company has submitted an application to the UK regulatory authority to commence a multi-site Phase II clinical trial to examine the efficacy of ReN001 in patients disabled by an ischaemic stroke. This trial is designed to recruit from a well-defined population of patients between two and four months after their stroke, which the Company and its clinical collaborators currently believe will be the optimum treatment window for the therapy. In line with the Company’s expectations, the regulator has confirmed that three month follow-up data on the final dose cohort in the PISCES study will be required as a pre-requisite for commencement of a Phase II study. On this basis, and subject to continuing positive progress with the PISCES study and the necessary regulatory and ethical approvals, the Company is continuing its preparations to commence the Phase II stroke study, on schedule, in the middle part of this year.

* On June 28, 2012, ReNeuron has announced that six patients have been treated in PISCES Phase I clinical trial, with remaining patients expected to be recruited and dosed by early 2013. The company expects to submit an application for a Phase II clinical study with ReN001 mid-2013.

* On June 14, 2012,ReNeuron has announced the presentation of interim data from the PISCES (Pilot Investigation of Stem Cells in Stroke) clinical trial of its ReN001 stem cell therapy for disabled stroke patients. In this open label, dose-ranging Phase I safety study, ReNeuron’s ReN001 stem cell therapy is being administered in ascending doses to a total of 12 stroke patients who have been left disabled by an ischaemic stroke, the most common form of the condition. To date, six patients have been treated in the PISCES stroke study, representing the first two of four dose cohorts. The interim data being presented are from the first five patients treated, at 2 x 12 month, 1 x six month and 2 x three month follow-up points. No cell-related adverse events or adverse immune-related responses were reported in any of the patients treated to date. A number of the patients experienced minor procedure-related adverse events such as asymptomatic bleeds or superficial scalp infections at the implantation wound site. Reductions in neurological impairment and spasticity were observed in all five patients compared with their stable pre-treatment baseline performance and these improvements were sustained in longer term follow-up.

Neurological deficits were measured using the National Institutes of Health Stroke Scale (NIHSS), a higher score representing a worse deficit. Patients are required to have a NIHSS score of at least 6 to participate in the study. The pre-treatment median score for the first five patients was 8 (range 6 to 10) and the three month posttreatment median score was 4 (range 3 to 9).

Spasticity was measured using the Summated Ashworth Scale for affected upper and lower limbs, a higher score representing a higher degree of spasticity. The pretreatment mean score for the first five patients was 28.6 (range 12 to 55) and the three month post-treatment mean score was 21.8 (range 5 to 42).

Functional magnetic resonance imaging (fMRI) data were also collected pre- and post-treatment to identify potential biomarkers of change in neurological function in the brains of the treated patients. Some longitudinal changes in motor activation fMRI were seen, consistent with the observed improvements in neurological measures.

* On March 3, 2011, Reneuron indicated that the first two patients treated in the clinical trial are both well. Both patients were successfully treated with ReN001 with no acute safety issues arising. Both patients were discharged two days after their respective treatments and are back in their local communities in the Greater Glasgow area. The first patient treated has now been assessed at three months post-treatment and has experienced no adverse reactions or effects relating to the therapy. The final patient in the first dose cohort has consented to treatment and, assuming a successful pre-treatment evaluation period, is expected to be dosed in May. On this basis, the Data Safety Monitoring Board would be expected to review data from the first dose cohort in August and, all being well, give approval for the trial to move on to a higher dose cohort at that time. The Company therefore expects that this higher dose cohort of three further patients would have been treated by the end of this year assuming no significant recruitment delays.

The remaining dose cohorts in the PISCES trial are expected to be treated in 2012, at which point Reneuron intends to have discussed and agreed its subsequent clinical development strategy for ReN001 with the relevant regulatory authorities both in the UK and beyond. The company is also exploring the clinical potential of its lead CTX stem cell line in other categories of the stroke patient population and in other neurological conditions where the mechanisms of action of the cells may be relevant. This is with a view to commencing further clinical trials in these indications as quickly as possible, based on the very significant pre-clinical safety and efficacy data already in existence with the CTX cells, as well as the emerging early clinical data from the PISCES trial.

* On September 1 , 2011, the independent Data Safety Monitoring Board (DSMB) for the clinical trial has recommended that the trial advances to the evaluation of a higher dose of ReN001. In arriving at this recommendation, the DSMB reviewed safety data from the first dose cohort of three patients treated with ReN001. The first patient treated in the cohort was assessed at nine months post-treatment, the second patient at six months and the third patient at three months. No cell-related adverse events have been reported in the clinical trial and data from the laboratory safety tests, neurological examinations and neurofunctional tests conducted thus far indicate that the ReN001 treatment is safe and well-tolerated at the initial dose. Although preliminary in nature, these data have also enabled some early progress to be made regarding the secondary objective of the trial, namely the evaluation of appropriate clinical measurements for use in the design of future proof-of-concept clinical trials with ReN001. Reneuron expects that the next dose cohort of three further patients will have been treated by the end of this year assuming no significant recruitment delays. The remaining dose cohorts in the PISCES trial are expected to be treated in 2012, at which point ReNeuron intends to have discussed and agreed its subsequent clinical development strategy for ReN001 with the relevant regulatory authorities both in the UK and beyond.