Juvista

Juvista (INN: Avotermin) is a therapeutic application of human recombinant Transforming Growth Factor Beta 3 (TGFβ3). Clinical trials have demonstrated that intradermal injection of Juvista to skin wounds created either by surgical incision or excision, at or shortly after the time of surgery, results in improved subsequent scar appearance. 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.

Comprehensive Phase 1/2 clinical trial programme provides 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 and has reported, in approximately 1,500 human subjects dosed to date a favourable safety profile, and positive, statistically significant, results from eight double-blind, placebo-controlled trials (1002, 1005, 1007, 1011, 0050, 0036, 1009 and 0042) which demonstrated the efficacy of Juvista in improving scar appearance.

This programme confirmed the advantages of using within-patient comparisons where drug and placebo are given to anatomically matched wounds of similar lengths.

The results from three statistically significant 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 publication featured on the front cover of The Lancet, was the subject of a podcast by Prof Mark Ferguson available on The Lancet website, and was widely 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). Quoting from this independent editorial comment:

"Despite decades of investigation, the development of fibrosis in the skin and other parts of the human body remains incompletely understood, whereas the morbidity of hypertrophic scarring and keloids after traumatic and thermal injury, remains very high...Few, if any, accepted anti-fibrotic drugs or treatments are established to assist patients with these fibroproliferative disorders."

"The investigators are to be congratulated for successful completion of a well designed and carefully controlled study that used a previously validated outcome measure of clinical significance to a broad range of both patients and observers. Although the investigators have acknowledged their commercial interests in TGFΒ3, adherence to established standards in this translational investigation and the rigorous nature of the statistical analysis in a well powered series of studies provide strong evidence for the benefits of Avotermin (Juvista) in this setting."

"With these investigations, Ferguson and colleagues provide substantial optimism for new solutions to difficult fibrotic disorders in the future."

Considered in their totality, the data from the different Phase 2 Juvista trials are consistent, and explain why two trials (1008 and 1010) did not meet their primary endpoints. Renovo now knows that both of these Phase 2 trials used sub-optimal doses (neither included 500ng), a sub-optimal dosing regime (once only dosing) and in trial 1008 a sub-optimal trial design involving scars of different lengths and anatomical locations.

Phase 2 is about exploring 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 currently recruiting patients. 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 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 and validated by Renovo.

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 Phase 3 programme for the indication of "improvement in scar appearance of disfiguring scars". Renovo have agreed with the EMEA:

• 2 x within patient efficacy 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.
  
• 1 x parallel group design safety study with a 6 month endpoint to be run concurrently with the second phase 3 efficacy trial.
  
• a small Pharmokinetic (PK) study to confirm that the systemic bioavailability of Juvista following intradermal injection is approximately 0.1%. This will run concurrent with the second Phase 3 efficacy study.