B4711001 Stem cell transplantation in wet AMD
Research type
Research Study
Full title
PHASE 1, OPEN-LABEL, SAFETY AND FEASIBILITY STUDY OF IMPLANTATION OF PF-05206388 (HUMAN EMBRYONIC STEM CELL DERIVED RETINAL PIGMENT EPITHELIUM (RPE)LIVING TISSUE EQUIVALENT) IN SUBJECTS WITH ACUTE WET AGE RELATED MACULAR DEGENERATION AND RECENT RAPID VISION DECLINE
IRAS ID
96163
Contact name
Lyndon da Cruz
Contact email
Sponsor organisation
Moorfields Eye Hospital NHS Foundation Trust
Eudract number
2011-005493-37
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 5 months, 0 days
Research summary
Research Summary:
Pfizer Global Research & Development in collaboration with University College London and Moorfields Eye Hospital are developing an advanced therapy medicinal product based on human embryonic stem cells (hESC) known as the SHEF 1 cell line. The proposed product (PF 05206388) comprises SHEF 1 cells differentiated to form Retinal Pigment Epithelium (RPE) cells fixed to a vitronectin coated polyester membrane and will be surgically implanted subrtinally using a surgical device. PF 05206388 will replace RPE in the eyes of patients with acute, declining untreatable or treatment failing wet age-related macular degeneration (AMD).
The target population of PF-0506388 in this exploratory study is patients with wet AMD with significant recent decline in vision who are deemed ineligible for, or for whom treatment with anti VEGF therapeutic agents (e.g Lucentis) is failing.
It is anticipated that RPE transplantation may eventually be indicated in many atrophic and neovascular macular diseases, including inherited, inflammatory and age-related wet and dry degenerations.Lay summary
I would like to begin this summary of the trial by thanking all of the participants who took part. It is of enormous benefit to science and medicine that people offer to take part in research studies with significant unknowns and real risks. The time they give, their co-operation with the study protocols and their commitment to increasing knowledge for patients in the future is commendable.Study title
Phase 1/2, open-label, safety and feasibility study of Implantation of TLPCB-05206388 (human embryonic stem cell derived retinal pigment epithelium (RPE) Living tissue equivalent) in subjects with acute wet age-related macular degeneration and recent rapid vision decline… Combined with… Phase 1/2, open-label, safety and feasibility study of The London Introducer, a delivery device for TLPCB – 05206388.Who carried out the research?
The research that is being described was carried out solely at Moorfields Eye Hospital NHS Foundation Trust (NHSFT), London. The research was carried out over two periods. The first period involved the recruitment of 2 patients who were enrolled in the trial in 2013. At that time the sponsor and funder of the trial was Pfizer Therapeutics Inc. The second period involved the recruitment of 7 patients commencing in 2020. During this second period of the trial the sponsor was Moorfields Eye hospital NHSFT and the funding was from the Sir Michael Uren Foundation. There was a device used to deliver the treatment called the London Introducer. This device was also under trial and the sponsor for the first period of the device trial was Evixaar Ltd, and for the second period Medical Device Management Ltd. The Principal Investigator (PI) throughout both periods of the trial was Professor Lyndon da Cruz, Consultant Ophthalmic Surgeon, Moorfields Eye Hospital NHSFT.The intellectual property of the trial was licenced to a spin out company called Tenpoint Therapeutics Ltd in 2020. The principal investigator Professor Lyndon da Cruz was a founder and shareholder of Tenpoint therapeutics. He therefore declared a financial interest in the treatment and the delivery device.
There were no financial incentives for recruiting to this study and there were no financial incentives for the completion or outcome of this study.
The outcome assessments for the study were made independently by the Moorfields Eye Hospital NHS Foundation Trust Clinical Trials Facility and the assessors had no financial connection with the company Tenpoint Therapeutics Ltd.Who took part in the study?
Five (5) male and four (4) female subjects aged between 60 to 88 years were enrolled in this study and received study treatment. All 9 patients had a diagnosis of wet Age-related Macular Degeneration (wAMD) and suffered from rapid vision loss within the 6 weeks prior to enrolment, 7 due to a large bleed and 2 patients due to poor response to standard injection treatment.
All subjects completed the study and were included in the outcome and safety analysis.Why was the research needed?
Wet AMD is a rapidly progressing condition that leads to severe vision loss. It is caused by abnormal ‘new’ blood vessels growing into the nerve layer of the eye. There is a good current treatment for this condition that involves injecting a drug into the eye that stops blood vessel growth and leaking. However, in certain cases the abnormal blood vessels bleed, or the vision declines despite the drug being present and the vision starts to rapidly decline. There is no treatment for those who fall into these two groups. In cases of bleeding, it is possible to remove the blood. However, during removal of the blood, a critical layer of the retina - the Retinal Pigment Epitehlium (RPE), is damaged so the vision remains lost. In cases where vision is declining despite standard injection treatment, it is thought to be due to loss of function of the RPE as well. This research aimed at making and transplanting RPE cells back into the retina after the vision was lost in these two conditions to see if vision could be improved and sustained.What were the main questions studied?
The main questions were:
1. Is transplantation of RPE, made from embryonic stem cells, into the macula feasible and safe
2. Can transplantation of RPE, made from embryonic stem cells, into the macula be used to improve and sustain vision in severe forms of wAMD.What treatments or interventions did the participants take/receive?
Each patient underwent transplantation of a layer of RPE cells made from embryonic stem cells on a polyester membrane measuring 3mm x 6 mm. The combination of RPE cells and the polyester membrane is referred to as the ‘patch’. The patch was delivered using a specially made tool called the London Introducer. This tool was also being studied for safety and efficiency in this combined trial.
The RPE patch was placed beneath the macula, which is the area of the nerve layer – the retina, at the centre of vision responsible for the highest quality vision. The transplanted RPE replaced the damaged or failing natural RPE of the patient. Immunosuppression was used to stop rejection of the transplant. For the first 6 weeks after the transplant surgery this was by tablets and then after this, a pellet of long-acting steroid was put in the eye that lasted 2-3 years and the tablets were stopped.What medical problems (adverse reactions) did the participants have?
There were no deaths or permanent discontinuations due to TEAEs reported in this study. Overall, 9 subjects experienced 69 TEAEs after the surgery and 3 TEAEs were treatment related. There were 13 SAEs experienced by 8 subjects, all of which were considered as not treatment related (Table 8).What were the results of the study?
As a reminder the main questions in this study were:
1. Is transplantation of RPE, made from embryonic stem cells, into the macula feasible and safe
2. Can transplantation of RPE, made from embryonic stem cells, into the macula be used to improve and sustain vision in severe forms of wAMD.Question 1. Feasibility and safety:
In all 9 patients the patch was successfully transplanted into the eye by the London Introducer into the correct place under the central retina - the macula. In three cases there was damage to the RPE cell layer due to the delivery device, but it was felt that the damage was minor, and the patch was not removed or replaced. The independent Data Monitoring Committee (iDMC) assessed that it did not affect the scientific or safety assessments of the study.In terms of safety, there were no deaths associated with the study. Furthermore, there were no tumours, or severe immune reactions associated with the use of stem cell derived tissue (the RPE cells). At no time did the iDMC stop the study for safety or other reasons.
All patients in the study experienced at least one adverse event in the study and 8 out of 9 patients had a serious adverse event.
The serious safety effects of the study overall were:
i. Retinal detachments in 2 patients that were treated with further surgery
ii. Reactivation of the original disease in 4 patients treated with conventional injections where the vision was good
iii. Major systemic illness in 3 patients that were not related to the study
iv. A retinal tear in 1 patient treated with surgery
v. A reopening of a surgical wound in 1 patient treated with surgeryThe iDMC felt that none of the serious safety effects were related to the RPE patch or the London Introducer.
There were 69 minor adverse events of which 3 were possibly associated with the treatment patch in the treatment trial. They were distortion of vision (1 patient) and changes in the electrical response of the operated eye (2 patients). The other most common minor adverse events were 22 eye disorders, 9 infections, 4 cardiac disorders and 4 vascular disorders. These and all of the other non-serious adverse events resolved without the need for admission or long-term medication.In the Introducer trial there were also 3 minor events related to the introducer. All three were damage to the cell layer due to the push rod of the introducer riding over the patch, rather than pushing it from the back edge. In no cases was it assessed by the iDMC that the damage to the cell layer was sufficient to affect the outcome of the trial.
Question 2. Effectiveness and outcome
The main vision endpoint of this study was the change in vision from before to 6 months after the transplantation surgery. Specifically, the study wanted to find out what proportion of patients had an improvement of 10 letters or more at 24 weeks (6 months) after the surgery. A total of three subjects showed more than 15 letters improvement in vision at Week 24 in their study eyes. All three of these were from the group of patients with vision loss due to hemorrhage. Neither of the 2 patients from the group who had vision decline despite treatment for wet AMD, improved at any timepoint. However, one of the 2 patients remained stable through to week 24 before experiencing substantial vision loss subsequently.
Overall, at the end of the study, by week 52, 4 patients (44%) still had improved or stable vision 1year after the transplantation operation. There were 2 patients with an improvement of 10 letters or more and 2 patients who remained stable without vision loss. The remaining five patients had a visual decline over the first year after transplantation of 14 to 54 letters. On average, the vision declined after this intervention for all of the subjects as a group.How has this study helped patients and researchers?
Transplantation of retinal cells, or any other type of cell in the body, made from embryonic stem cells is a completely new type of treatment. This study has shown that transplantation of cells such as our RPE cells is safe, feasible and may help some people restore sight or other functions in the future. Thus, we have achieved a proof of principle as we now know it is possible to create a retinal cell layer from embryonic stem cells, transplant it into the eye after vision is lost, and recover and sustain vision. This is important as it allows scientists to explore this whole new area of research and create new treatments for currently untreatable blinding conditions that will help patients in the future.Details of any further research planned
Currently this research is being taken forward by Tenpoint Therapeutics. They are looking to manufacture cells at a greater scale and volume to regulatory level, which would allow delivery appropriate for the number of cases that may require treatment. They are also exploring further clinical trials in AMD and inherited retinal disease to better evaluate the potential safety and effect of the treatment based on learnings from this trial.
Academic continuation of this research proceeds in terms of improving the delivery tool, examining other cell types to transplant including blood vessel cells for vascular diseases such as diabetes and photoreceptor cells for inherited diseases such as retinitis pigmentosa and Stargardt’s disease.REC name
London - West London & GTAC Research Ethics Committee
REC reference
GTAC194
Date of REC Opinion
8 May 2013
REC opinion
Further Information Favourable Opinion