Date: 2016-10-10
Type of information: Publication of results in a medical journal
phase: 1
Announcement: publication of results in Human Gene Therapy
Company: Oxford BioMedica (UK)
Product: RetinoStat®
Action
mechanism: gene therapy. RetinoStat® delivers two anti-angiogenic genes, endostatin and angiostatin, directly to the retina and aims to preserve and improve the vision of patients through anti-angiogenesis which blocks the formation of new blood vessels. In April 2014, Oxford BioMedica has regained the worldwide rights to RetinoStat®. Sanofi has notified the company that due to pipeline prioritisation they will not be taking up the option to continue development of RetinoStat® beyond the currently ongoing Phase I study.
Disease: neovascular “wet” age-related macular degeneration (AMD)
Therapeutic area: Ophtalmological diseases
Country: USA
Trial
details: The on-going Phase I study will enrol 18 patients with wet age-related macular degeneration at the Wilmer Eye Institute at Johns Hopkins, Baltimore (USA). Led by Professor Peter Campochiaro, the study will evaluate three dose levels and assess safety, aspects of visual acuity and ocular physiology.
Latest
news: * On October 10, 2016, Oxford BioMedica announced the publication in Human Gene Therapy of the previously announced results from the RetinoStat® (OXB-201) Phase I study in patients with advanced wet age-related macular degeneration (AMD) on 6 May 2016 . The article is entitled“Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study” and Peter A. Campochiaro is the lead author. According to key published findings, RetinoStat® demonstrated a favourable safety profile and led to robust, reproducible sustained expression of endostatin and angiostatin in the eye. The Phase I study was primarily designed to evaluate the safety and tolerability of RetinoStat® for the treatment of severe wet AMD following a single subretinal injection and represented the first time a lentiviral based vector had been administered to the human eye. Twenty-one subjects with highly fibrotic retinas who were refractory to anti-VEGF therapy following a prior responsive history were treated. As previously announced the results of the Phase I study indicated that RetinoStat® met the primary endpoint of safety and tolerability. Importantly, therapeutic gene expression, measured in these patients as a secondary study endpoint, was found to be dose-dependent and maintained at the last measurement (2.5 years in 8 subjects and >4 years in two subjects). Oxford BioMedica is evaluating the optimal way to progress the clinical development for RetinoStat®. * On May 6, 2016, Oxford BioMedica announced that Dr Andreas Lauer gave an oral presentation on Oxford BioMedica’s LentiVector®-based treatment for neovascular age-related macular degeneration (wet AMD), at the Association for Research in Vision and Ophthalmology (ARVO) conference in Seattle, USA. Consistent with results previously announced at the ARVO conference, the new data presented demonstrates that LentiVector® gene expression was dose-dependent and continued without significant decline for more than four years. new data has been presented from two clinical studies indicating ground-breaking long-term four-year sustained and, in one of the studies, dose-dependent gene expression with the Company’s LentiVector® delivery platform. * On May 5, 2015, Oxford BioMedica announced that results from the 21 patients in its Phase I study of RetinoStat®, a lentiviral vector based treatment for severe wet age-related macular degeneration AMD, was selected as a “Hot Topic” at the Association for Research in Vision and Ophthalmology (ARVO) conference on 4 May 2015 in Denver, USA and presented via a poster. The Phase I study was primarily designed to evaluate the safety and tolerability of RetinoStat® for the treatment of severe wet AMD at six months post single injection. RetinoStat® was administered to 21 patients by subretinal injection, the first ever time a lentiviral vector has been administered to the human eye. The study consisted of a dose escalation phase and then an expanded final cohort at the highest tolerated dose, which was the maximum dose administered. The study enrolled subjects with high fibrotic retinas where there was a poor anti-VEGF response following a prior responsive history. Secondary endpoints to assess signs of clinical benefit were also measured. Additionally, aqueous tap samples were taken to quantify the expression of the transgenes at various time points and at each dose. Analysis of these samples showed that gene expression was dose-dependent and was stable over at least 12 months. (#2284 ? B0189. Results from the Phase I GEM study, evaluating safety and tolerability of subretinally? injected lentiviral vector (RetinoStat®) for the treatment of wet age?related macular degeneration(AMD). Simon Chandler) As previously announced, the results of the Phase I study demonstrated that RetinoStat® met the six month primary endpoints of safety and tolerability. Over the full forty eight week study, patients also showed signs of clinical benefit, with visual acuity stabilisation and a reduction in vascular leakage consistent with the mechanism of endostatin and angiostatin function in vivo in this severe wet AMD population.Oxford BioMedica will work in consultation with the Principal Investigators of the study as well as Key Opinion Leaders in the retinal field at the ARVO conference and, following review of the complete data set, will look at all the possible indications for the product going forward. The data from the Phase I study will be published in a peer reviewed journal in due course. * On April 7, 2014, Oxford BioMedica has announced that it has completed the planned recruitment of 21 patients into its Phase I trial of RetinoStat®, a lentiviral vector based treatment for neovascular wet AMD. Each patient has been treated with a single subretinal administration of RetinoStat® which leads to the production of two anti-angiogenic proteins - endostatin and angiostatin. On the basis of pre-clinical data, it is anticipated that RetinoStat® may require only a single administration. If confirmed, this would give the product a significant advantage over currently available treatments in the market that require frequent, repeated administration. * On October 17, 2013, Oxford BioMedica has announced that it has received agreement from the FDA and the French regulatory agency, ANSM, to resume recruitment into the RetinoStat® Phase I, StarGen™ Phase I/IIa and UshStat® Phase I/IIa studies using the existing clinical trial material. In June 2013, Oxford BioMedica announced that it had voluntarily paused recruitment into the aforementioned studies, as a precautionary measure, whilst the Company investigated the detection of very low concentrations of a potential impurity in its clinical trial material derived from a third party raw material. Oxford BioMedica has since performed extensive characterisation studies using its newly developed, state-of-the-art analytical methods to identify the impurity as highly fragmented DNA derived from foetal bovine serum, the most widely-used growth supplement for cell culture media. In light of these findings, Oxford BioMedica remains convinced of the safety, integrity and quality of its LentiVector® platform products and no safety concerns relating to any of the ocular products have been identified in any pre-clinical and clinical data generated to date. Following the submission of a comprehensive data package to FDA and ANSM, Oxford BioMedica has received agreement from both agencies to resume recruitment into its ocular clinical trials using the existing clinical trial material. The Company will continue to use highly sensitive, state-of-the-art analytical methods to ensure the quality and integrity of its lentiviral vector products and will work with FDA and ANSM to define the necessary specifications for future batches of clinical trial material. Oxford BioMedica is now working closely with the clinical trial centres to obtain the necessary ethics committee approvals in order to resume recruitment into the ocular clinical studies. * On June 3, 2013, Oxford BioMedica has announced that it has voluntarily paused recruitment into the RetinoStat® Phase I, StarGen™ Phase I/IIa and UshStat® Phase I/IIa studies, as a precautionary measure, whilst the company investigates the recent detection of very low concentrations of potential impurities derived from a widely-used third party raw material. A new, highly sensitive test method has recently been introduced into the Company’s wide range of analytical methods and quality assurance processes used for routine batch testing. Using this method, potential impurities have been detected at very low concentrations in clinical trial material. No safety concerns relating to any of the aforementioned products have been identified in any pre-clinical and clinical data generated to date and there is no reason to believe that the favourable safety profile of these products will be affected. Such precautionary measures are routine and Oxford BioMedica is working very closely with the regulatory authorities to complete its investigations. The Company is committed to resuming the clinical trials as soon as possible and will continue to keep the market informed as appropriate. * On November 20, 2012, Oxford BioMedica and its partner Sanofi have announced further data from the ongoing RetinoStat® clinical study. Highlights of ongoing RetinoStat® Phase I study in “wet” age-related macular degeneration: • Three patient cohorts complete (n=9, ascending dose levels 1, 2 and 3), treatment of final patient cohort ongoing (n=9, confirmatory dose level) across two clinical centres • Long-term safety profile now up to 19 months post-treatment (dose level 1) • Successful retinal transduction, as shown by substantial increase in expression and secretion of endostatin and angiostatin proteins measured in the anterior chamber of the eye following a single administration of RetinoStat® • Long-term protein expression1: now sustained for up to one year post-treatment at dose levels 1 and 2, and up to two months at dose level 3. Further preliminary data continue to show a dose response, with the escalation to dose levels 2 and 3 yielding an increase in average protein expression. First results about safety have been presented in June 2011 and previous results of an interim review have been disclosed in August 2012 (See below). * On August 8, 2012, Oxford BioMedica and Sanofi have announced a positive interim review of the RetinoStat® Phase I study in neovascular “wet” age-related macular degeneration by the Data Safety Monitoring Board (DSMB). DSMB highlights of ongoing RetinoStat® Phase I study: • Nine patients treated to date (n=3 at each of dose levels 1, 2 and 3) • No serious adverse events related to RetinoStat® or its method of administration • Long-term safety profile now up to 18 months post-treatment (dose level 1) • Successful retinal transduction, as shown by substantial increase in expression and secretion of endostatin and angiostatin proteins measured in the anterior chamber of the eye following a single administration of RetinoStat®. So far, expression is sustained for up to 12 months post-treatment at dose level 1 (n=3) and up to six months post-treatment at dose level 2 (n=3) DSMB support received to proceed to final patient cohort (n=9, confirmatory dose level). * On June 22, 2011, Oxford BioMedica has announced that the first dose level of RetinoStat® is safe and well-tolerated at one month following treatment. Three patients received the first dose level of RetinoStat® and one-month results have been assessed by the DSMB. The first patient cohort at one month has shown favourable safety profile with no serious adverse events related to RetinoStat® or its method of administration. No signs of inflammation in the eye has been detected. The trial received DSMB support to proceed to dose level 2 in the next patient cohort. This treatment uses Oxford BioMedica's proprietary LentiVector® gene delivery technology. It is the lead programme of the ocular agreement Oxford Biomedica signed with Sanofi in April 2009.
The ongoing open-label study is evaluating three dose levels, in four cohorts, to assess safety and aspects of biological activity in the eye. Analysis of patient samples has shown a substantial increase above baseline levels of both endostatin and angiostatin proteins in the eye following a single administration of RetinoStat®; protein expression has been sustained to 12 months (the longest time-point assessed to date in the first three cohorts); and a clear proportional dose response has been seen. All patients are being regularly followed up and indicative results from the study are expected towards the end of 2014.
RetinoStat® is the remaining development programme under Oxford BioMedica’s 2009 ocular collaboration with Sanofi. Sanofi has an option under the collaboration to enter a development and commercialisation license for RetinoStat®. In February 2014, Oxford BioMedica concluded a licence agreement with Sanofi for the development and commercialisation of StarGen™ and UshStat®, the two other products covered by the collaboration agreement.
