Juvista
Juvista (INN: Avotermin) is a therapeutic application of human recombinant Transforming Growth Factor Beta 3 (TGFβ3). Clinical trials have investigated the effects of intradermal injection of Juvista applied to skin wounds created either by surgical incision or excision, at or shortly after the time of surgery on the appearance of the subsequent scar. Prophylactic improvement of skin scarring is predicted (by Renovo and analysts) to be a multi-billion Dollar/Euro opportunity in the US and EU markets alone.
Juvista is a first in class pharmaceutical product candidate to address these large potential markets of unmet medical need. Market research funded by Renovo and published during 2009 (Plastic and Reconstructive Surgery vol 124(1):256-65) shows a high rate of patient dissatisfaction with scars from recent surgical procedures regardless of age, race or sex and an appreciation of improvements in scar appearance.
Early Phase clinical trial programme provided valuable information and learning for Phase 3.
Renovo has pioneered the development of Juvista as a new drug in the new therapeutic field of skin tissue regeneration/improvement of scar appearance. In order to optimise the design of its Phase 3 trials, Renovo conducted a comprehensive Phase 1 and 2 programme involving approximately 1,500 human subjects. Results from eight double-blind, placebo-controlled trials (1002, 1005, 1007, 1011, 0050, 0036, 1009 and 0042), which were designed to explore the safety and efficacy of Juvista in improving scar appearance, have provided valuable insights into safety and dose response in a variety of clinical settings. These trials included small (1-2 cm long) surgical incisions, small excisions, as well as and skin graft donor sites in human volunteers. Studies in patients have included bilateral varicose vein surgery (groin incision 1.4-10 cm long) and scar revision surgery (excision 5-25cm long at multiple body sites) in male and female patients aged 18-85 years. These trials met their pre-specified primary endpoints and some exploratory secondary endpoints were significant. Furthermore, the safety profile of Juvista continues to support its development. This information alongside practical learnings from the volunteer and patient studies has been integrated to inform the trial designs for phase 3.
The results from three early Juvista trials (1002, 1005 and 0036) for the improvement of skin scarring were published in The Lancet on 11 April 2009 (vol. 373, pages 1264-1274). The Lancet publication was also reported in the lay press. An editorial commentary on the publication was provided in the same issue of The Lancet by Dr Edward Tredget, Professor of Plastic Surgery at the University of Alberta (The Lancet, vol 373, pages 1226-1228). We have purchased a limited number of licences from the Lancet for controlled downloads of the article in pdf format. If you require a copy please click here.
Considered in totality, the data from the early Phase Juvista trials are consistent, and help us understand why two trials (1008 and 1010) did not meet their primary endpoints. It is now clear both of these Phase 2 trials used sub-optimal doses of Juvista (neither included 500ng for example), and/or a sub-optimal dosing regime (once only dosing). These important features were not known at the time the trials were designed. Furthermore in trial 1008, scars of different lengths and anatomical locations were directly compared. Scar length and location are significant covariates which when left uncontrolled, are likely to confound the outcome of a trial.
Phase 2 is about exploration and learning and in this respect Renovo believes it has incorporated significant learning into the design and execution of its first pivotal EU Phase 3 efficacy trial so as to increase the chances of a positive result.
First Juvista EU Phase 3 efficacy trial in scar revision surgery on schedule to Report H1 2011.
Renovo’s first EU Phase 3 trial for Juvista (“Revise”) in scar revision surgery is ongoing. Scar revision is an excisional procedure performed by Plastic Surgeons and Cosmetic Dermatologists for both patients wanting cosmetic improvements and those with disfiguring scars. This trial evaluates two doses (which provided the greatest efficacy signal in Phase 2) of Juvista (200ng and 500ng per 100µl per linear cm of wound margin) given twice (following wound closure and 24 hours later) to a total of 350 patients in approximately 55 centres, in ten countries: United Kingdom, France, Hungary, Germany, Italy, Poland, Spain, Denmark, Latvia and USA. The protocol design, power calculations and trial endpoints were submitted to, and discussed and agreed in principle with the EMEA as part of its written scientific advice to Renovo. The trial protocol was also granted approval by the regulatory authorities and ethical bodies in all ten countries. A dedicated call centre, advertising campaign and website (www.revisestudy.com) is being used to assist patient recruitment in those countries where they are permitted.
The primary efficacy endpoint of the trial is an assessment of standardised photographs of drug and placebo treated scars from the same patient by an independent clinical expert panel, twelve months following surgery. This improvement is to be measured using the Global Scar Comparison Scale which has been developed by Renovo incorporating EMEA scientific advice.
Other secondary endpoints include a patient based assessment of scar improvement, and an on the patient assessment by the investigating surgeon.
Renovo is on track to report data from this trial in H1 2011.
Agreed EU Phase 3 Programme
Renovo sought and obtained written scientific advice from the EMEA concerning the Juvista Phase 3 programme for the indication of "improvement in scar appearance of disfiguring scars". Renovo currently plans the programme to include:
- Two within patient design trials with a 12 month assessment endpoint to establish efficacy. The first of these Phase 3 trials is underway and is expected to report data in H1 2011. The second Phase 3 efficacy trial is expected to commence in H2 2011 and report data in 2013.
- One parallel group design study with a 6 month endpoint to confirm the safety profile of Juvista, and to be run concurrently with the second phase 3 efficacy trial.
- A study to confirm that the systemic bioavailability of Juvista following intradermal injection is low . This study will be guided by ongoing pre-clinical pharmacokinetic work.
The primary endpoint for the EU Phase 3 efficacy trials has been confirmed by the EMEA as part of their written scientific advice to Renovo and will be:
A clinical panel assessment of standardised photographs at 12 months after surgery, assessed for scar improvement by the proprietary Global Scar Comparison Scale (GSCS). A key secondary endpoint will be an assessment of scar improvement by the patient (directly on themselves) using the GSCS at 12 months after surgery. Other secondary endpoints include an assessment of scar improvement by the Investigator using the GSCS at 12 months after surgery.
Paediatric Development Plan
A paediatric development plan is required under EU legislation and Renovo’s dialogue with the EMEA concerning Juvista is nearing conclusion. Studies in children will start after the adult Phase 3 programme is complete. A new single dose formulation has been developed for children and its performance is being investigated and compared to the existing formulation in clinical trial 1006–0100. This is a double-blind, placebo-controlled, within subject design using matched 1cm surgical wounds on the upper inner arms of 84 healthy adult volunteers. The trial is fully recruited and reports data towards the end of 2010, with an earlier interim analysis (to indicate whether further formulation development might be required).
Developments in USA, Canada and Mexico
Shire licensing deal
In June 2007 Renovo signed an exclusive licensing agreement with Shire LLC to develop and commercialise Juvista for the reduction of scarring. This agreement was revised in March 2010. Under the terms of the Amended and Restated Development and Licensing Agreement:
• Shire has licensed Juvista for USA, Canada and Mexico with the right to sub-license in those territories
• Renovo retains the rights to Juvista in all countries of the world except the USA, Canada and Mexico, including the right to sub-license in any or all of these territories
• Renovo received an initial payment of US$125 million, consisting of a US$75 million upfront payment and US$50 million equity investment in Renovo Group Plc at a price of £2.00 per share, equating to 6.7% of the total outstanding shares in the Company immediately after the issue
• Once Shire commences a clinical trial, after the first EU Juvista Phase III trial reports (currently on schedule to report H1 2011) a milestone payment to Renovo from Shire of US$5 million
• On acceptance of a BLA filing with the FDA, Shire will pay Renovo US$25 million and on FDA approval, US$50 - US$150 million depending on the breadth of the indication on the approved product label
• On the successful commercialisation of Juvista, Renovo will be eligible for further sales-related milestone payments of up to US$525 million, giving a total deal size of up to US$830 million
• Renovo will receive escalating royalties on sales of Juvista by Shire
• Each party (Shire and Renovo) is responsible for its own development costs but future costs can be shared by agreement
• Shire can use the data from Renovo’s current EU Phase III trial to support its North American regulatory filings without any cost reimbursement to Renovo
• Renovo and Shire have free access to each other’s data to support regulatory filings in their respective territories
• A collaboration committee between Renovo and Shire oversees the development programmes
Trials in USA
There is an open IND with ongoing clinical trials in USA.
Scar Revision Trial
The Juvista EU Phase 3 trial has been filed to the IND and US patients have been enrolled into the trial.
Keloid Pilot trials
Prophylactic reduction of keloid scars presents an additional opportunity for Juvista. Keloid scars develop and grow beyond the margins of the original wound and result from an abnormal deposition of collagen and extracellular matrix. They are more common in coloured skin races, and are often triggered by wounding, burns, bites, acne, surgery and body piercing. Renovo has a series of exploratory single centre trials underway in the USA in keloid scars.
Renovo’s keloid trials are double-blind, within-patient, placebo-controlled randomised trials investigating the safety (after three months) of Juvista (50, 200 or 500ng/100µL/linear cm of wound margin) administered twice intradermally to 50 patients immediately following excision of earlobe keloids and 24 hours later.
Time to recurrence and improvement of keloid appearance are also being assessed at twelve months as secondary endpoints. These trials are ongoing in the USA under an Investigational New Drug (IND) Application.
Following the reporting of positive safety data for the 50ng and 200ng dose groups in December 2008, Renovo increased the number of patients in the 500ng dose group from ten originally planned to 30. Renovo is on track to report safety (for the 500ng dose group) and pilot efficacy data (for all doses) in H2 2010.
Background Science
TGFß3 is an important protein in the normal development of the skin. It is present at high levels in embryonic skin wounds which heal without a scar. TGFß3 affects many important processes in the wound healing cascade including: increasing the speed of migration of keratinocytes and fibroblasts, inducing filopodia and random migration of fibroblasts resulting in the restoration of the normal basket weave organisation of dermal collagen, decreasing the number and duration of myofibroblasts, modulating the inflammatory response, and modulating the synthesis and degradation of extracellular matrix molecules.
Reviews of the underlying science can be found in:
Ferguson MWJ and O'Kane S (2004) Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Phil.Trans.R.Soc.London B 359 839-850.
Occleston NL Laverty HG O'Kane S Ferguson MWJ (2008) Prevention and reduction of scarring in the skin by Transforming Growth Factor beta 3 (TGFß3): from laboratory discovery to clinical pharmaceutical. J.Biomater.Sci.Polymer.Edn 19(8) 1047-1063.
Occleston NL Fairlamb D Hutchison J O'Kane S Ferguson MWJ (2009) Avotermin for the improvement of scar appearance: a new pharmaceutical in a new therapeutic area. Expert.Opin.Investig.Drugs 18(8) 1231-1239.
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