Renovo Group plc the biopharmaceutical company developing drugs to reduce scarring, improve wound healing and enhance tissue regeneration, announces a successful outcome of its clinical trial designed to establish the safety and efficacy of a new formulation (Juvista Paediatric) of Juvista intended for use in children. The trial met its primary endpoint: once dosing (at the time of wound closure) with Juvista Paediatric statistically significantly improved the appearance of the subsequent scars when compared to placebo (p<0.0001).
The trial also met a number of secondary endpoints including confirming that for the existing adult formulation of Juvista used in the ongoing EU phase III trial the 500ng/100µL/linear cm of wound margin dose produces the most significant improvement in scar appearance compared to placebo treatment (p<0.0001).
Study Highlights: 84 healthy male and female subjects participated in a double blind, placebo controlled, within subject comparative study of the safety and efficacy of Juvista and Juvista Paediatric on scar appearance after 12 months using the Global Scar Comparison Scale (the primary endpoint agreed with the EMA for Renovo’s ongoing EU Phase III trial).
Single doses of Juvista Paediatric administered immediately after wound closure (500 and 1000 ng/100µl/linear cm of wound margin) significantly improved the appearance of surgical 1cm incision scars compared to placebo (p<0.0001) when assessed by an expert panel using the Global Scar Comparison Scale at 12 months. Statistically significant improvements were also observed for single doses of Juvista Paediatric (500 and 1000 ng/100µl/linear cm of wound margin) for the investigator’s assessment directly on the patient at 12 months using the Global Scar Comparison Scale (p<0.001, p<0.0001 respectively).
The current top dose of Juvista in the ongoing adult EU Phase III efficacy study (500 ng/100µl/linear cm of wound margin administered twice) was re-confirmed as the optimal dose for improvement of scar appearance (p<0.0001) as no further efficacy (in fact a slight decrease) was achieved after dosing 1000ng /100µl/linear cm of wound margin, either once or twice. From a questionnaire designed to elucidate different characteristics of the scars after 12 months, subjects identified scar width and scar colour as the features most improved by administration of Juvista or Juvista Paediatric, particularly by the twice dosing regimens.
There was no untoward safety findings, the most common adverse events recorded were nasopharyngitis (14%), upper respiratory tract infection (13%) and headache (8%) as expected in a population of healthy people monitored over time. As previously observed, administration of Juvista or Juvista Paediatric may be associated with transient erythema and oedema at the site of injection, compared to placebo.
Professor Mark WJ Ferguson, CEO, Renovo Group plc commented “This trial has been extremely successful. Not only have we established that we have a new formulation that is suitable for further evaluation in children, ideally as a single administration, but we have also reconfirmed that the 500ng/100µl/linear cm of wound margin dose of Juvista in our ongoing EU phase III trial (REVISE) was appropriately selected as it demonstrated the greatest level of efficacy”.
The first Juvista EU phase III trial in scar revision surgery is fully recruited (more than 350 patients) and should report data in H1 2011.
Juvista is in phase III of clinical development for the prophylactic improvement of disfiguring scar appearance in adults following scar revision surgery. In the adult programme Juvista is administered twice, once at the time of surgery and once 24 hours later. Agreement was reached with the European Medicines Agency (EMA), as part of the Paediatric Development Programme that Renovo would endeavour to develop a single dose formulation for use in children immediately following wound closure i.e. whilst still anaesthetised.
Clinical development of this new formulation: Juvista Paediatric (developed at Renovo) was initiated with an adult human volunteer trial to establish if it was safe and effective. A secondary objective of the trial was to further explore the dose response of the existing Juvista formulation for adults, to underpin the dose selection for the remainder of the adult phase III programme.
The trial was a within subject, double blind, placebo controlled safety and efficacy study of the existing adult formulation of Juvista and a novel formulation (Juvista Paediatric) developed by Renovo for single dose administration to children. The doses employed in the trial were 500 and 1000 ng /100µl/linear cm of wound margin administered once at the time of wound closure or twice, the second dose being administered 24 hours later. Drug or placebo was administered by intradermal injection to the wound margins of 1 cm, full thickness, and surgical wounds applied to the inner upper aspect of the arm, with 4 incisional wounds per arm.
As in previous Renovo trials, standardised photographs were taken and scars evaluated by Investigators using the Global Scar Comparison Scale (GSCS) at regular intervals out to 12 months post wounding. The pre-specified primary endpoint was that agreed with the EMA for the Juvista phase III study (REVISE) i.e. the GSCS score at 12 months, as assessed by a panel of experts from the standardised photographs. Secondary endpoints included the Investigator GSCS score from evaluation of scars directly on the subject. Also included in this trial was an exploratory scar questionnaire designed to evaluate various characteristics of the scars by the subjects themselves.
From the 84 subjects enrolled into the trial, 2 withdrew prematurely for reasons unrelated to the study, and hence 82 completed evaluations out to 12 months. There were two serious adverse events, neither of which was thought related to treatment. The most common non-serious adverse events were nasopharyngitis (14%), upper respiratory tract infection (13%) and headache (8%).
Adverse events local to the wound site were low (<10%) for all Juvista formulations and were similar in incidence to placebo. The most common local adverse events were wound dehiscence (5% overall) and itching (4% overall). Local tolerability was assessed for 14 days post wounding by the investigator who assessed erythema, oedema, exudate, itch, burning, pain, dehiscence, bleeding, and infection. Both formulations of Juvista exhibited significantly higher levels of erythema and oedema compared to placebo, which tended to be dose related. These symptoms were transient andresolved spontaneously, and no other local tolerability measures differed between Juvista and placebo. Transient local erythema and oedema have been observed previously in Juvista trials, especially at the higher doses.
With regard to efficacy, Juvista Paediatric was administered at two dose levels, 500 ng and 1000 ng/100µl/linear cm. Both doses were tested in one and two dose administration regimens. Juvista Paediatric was efficacious for the primary outcome measure, an expert panel Global Scar Comparison Scale score at 12 months, compared to placebo at both dose levels following both one and two administrations (p<0.0001).
In addition to the primary outcome measure, significant improvements were also observed for single doses of Juvista Paediatric (500 and 1000 ng/100µl/linear cm) for the investigator’s assessment on the patient at 12 months using the Global Scar Comparison Scale (p=0.0007, p<0.0001 respectively).
These results demonstrate that the new formulation, Juvista Paediatric, satisfies the requirement for a single administration dosage form for children, and is appropriate for further study in the paediatric population. The adult formulation of Juvista currently being utilised in phase III was maximally efficacious when compared to placebo at a dose of 500 ng /100µl/linear cm of wound margin administered twice (once at the time of wound closure and once 24 hours later). Both the primary (expert panel evaluating photographs) and the secondary (Investigator evaluating patient directly) outcome measures were statistically significantly superior to placebo at 12 months (p<0.0001).
A 1000 ng/100µl/linear cm of wound margin dose of Juvista was also tested in this trial given both once at the time of wound closure and twice at the time of wound closure and 24 hours later. While both were improved over placebo, they were both statistically (p<0.04) and numerically inferior to the 500 ng /100µl/linear cm dose given twice for the primary outcome measure, confirming that the choice of doses for the ongoing EU phase III trial in scar revision surgery (REVISE) include the optimal dose and dosing regimen of Juvista.
In addition to the expert panel and investigator assessments, a patient questionnaire was introduced into this trial as a pilot for future studies. The questionnaire examined aspects of scar appearance and invited subjects to choose the best scar with respect to each characteristic, or indicate if there was no difference. Scars treated by both formulations of Juvista were chosen as improved over placebo for scar width and scar colour for the majority of time-points over the 12 month period, particularly in the two times dose regimen.
Renovo is a biopharmaceutical product company and a leader in the discovery and development of drugs to reduce scarring, improve wound healing and enhance tissue regeneration. Renovo has a portfolio of products which exploit different novel mechanisms of action to reduce scarring at multiple body sites and improve healing. Renovo’s lead drug for the improvement of scar appearance in the skin, Juvista, has been generally well tolerated by around 1,500 human subjects.