Melbourne Australia – Starpharma Holdings Ltd (ASX:SPL; OTCQX:SPHRY) today announced the positive results of its exploratory Phase 2 study of VivaGel^® for the prevention of recurrent bacterial vaginosis (R-BV).  The results showed a reduced overall risk of R-BV during the study in patients using 1% VivaGel^® and time to first recurrence was delayed compared with placebo.

The results demonstrated the ability of VivaGel^® to inhibit BV recurrence, as was suggested by results of earlier clinical trials, and they provide strong support for the advancement to Phase 3 clinical trials of VivaGel^® for the prevention of R-BV.

“We are very pleased with these Phase 2 results. We have seen consistently lower recurrence rates with VivaGel^® by every measure and these clinically relevant findings, if replicated in an appropriately designed larger Phase 3 study, would yield a positive pivotal result,” said Starpharma Chief Executive Officer Dr Jackie Fairley.

“The commercial opportunity for recurrent BV is very attractive with an estimated market of more than $1 billion and following these results we have a high degree of confidence to move this product forward into Phase 3 clinical trials,” Dr Fairley added.

To put these results into context, if the risk reduction results seen with 1% VivaGel^® were applied more generally to all women with BV using published incidence data it is estimated that this would translate to the prevention of more than 10 million cases of R-BV annually in the US alone.

The Phase 2 study also showed high levels of user satisfaction, in line with earlier clinical trials of VivaGel^®.  In this study 79% of users of 1% VivaGel^® were either satisfied, very satisfied or extremely satisfied with the product’s effectiveness and overall satisfaction. 

In the study, 205 women were randomised to VivaGel^® containing either 1% or 3% SPL7013, or placebo following a course of conventional BV treatment (metronidazole).  Women used the product every second day for 16 weeks.  The primary objective of the study was to assess the efficacy of VivaGel^® in reducing the risk of R-BV compared with placebo. 

As an exploratory, dose ranging Phase 2 study for a new indication with no approved treatments, a number of different efficacy measurements were undertaken at various time points with a view to identifying the most appropriate endpoints and trial design for Phase 3 studies.  The primary clinical endpoint of recurrence of BV was assessed during the 16 week treatment period.  The following criteria were used to diagnose R-BV, either alone or in combination:  

1. the presence of clinical signs (Amsel criteria) as assessed by the investigator;
2. the presence of BV symptoms reported by the patients; and
3. the investigator’s own determination as to whether the patient had BV.

Summary of Results and Commentary

Detailed results are shown in the Appendix to this announcement.

By all efficacy measures, patients treated with 1% VivaGel^® demonstrated a reduced risk of recurrent BV compared with placebo.  The 1% VivaGel^® group also had a delayed time to first recurrence of BV with more than 80% of VivaGel^® users remaining BV free at 16 weeks. 

When R-BV was determined by the presence of three of the most clinically important Amsel criteria, as stipulated by FDA (abnormal discharge, whiff test and presence of clue cells), the risk of R-BV was reduced in the 1% VivaGel^® group (12%) compared with both the 3% VivaGel^® (23%) and placebo groups (28%).  This difference represents a relative risk reduction in R-BV with 1% VivaGel^® of 56% compared with placebo at the end of 16 weeks.  Using these key criteria, the difference between 1% and placebo groups was close to statistically significant (P=0.0588). 

When assessed according to a combination of criteria (i.e. presence of patient-reported BV symptoms and at least 3 Amsel criteria), the risk of R-BV was again shown to be reduced in the 1% VivaGel^® group (17%) compared with both the 3% VivaGel^® (26%) and placebo groups (28%).  This difference represents a clinically significant relative risk reduction in BV recurrence of 39% with 1% VivaGel^® compared with placebo, but by this measure the difference was not statistically significant.

Commenting on the trial results, expert clinical advisor to the program, Professor George Kinghorn, OBE, Clinical Director at NIHR Clinical Research Network, Department of Genitourinary Medicine, Royal Hallamshire and Sheffield Teaching Hospitals in the UK, said:

“As a clinician, I am very encouraged by the data for 1% VivaGel^®.  In this group of women, almost all would have been expected to experience recurrent BV during the study.  However, more than 80% of VivaGel^® users remained BV free at 16 weeks.  Given there are no other approved products for recurrent BV, I see this finding as highly promising – both for the management of women with this often difficult chronic condition and for recurrent BV sufferers.”

The time to the first case of R-BV in the patients using 1% VivaGel^® was 35 days, while in the patients using placebo, the first case of R-BV occurred after just 5 days.  At the Week 4 visit, the relative risk reduction of R-BV with 1% VivaGel^® was 77% compared with placebo, and this reduction was close to statistically significant (P= 0.0729, or 0.0489 when one patient with unknown R-BV status in each group was excluded). 

The data also showed that the rate of recurrence in the placebo group reached 20% between weeks 4 and 8 of the study, while the rate of recurrence in the 1% VivaGel^® group reached 20% only after cessation of treatment beyond week 16.  Furthermore, the proportion of women with BV symptoms of discharge and/or odour at the Week 16 visit was approximately 4-times lower in the 1% SPL7013 Gel group compared with placebo (4% vs. 17%) (P=0.0803).  In addition to R-BV, these data also feed into the symptomatic relief strategy currently being explored in parallel for VivaGel^®.

In a subgroup of women enrolled in the study, who had BV confirmed by presence of a Nugent score of 4-10 at Screening, time to R-BV was increased in the 1% VivaGel^® group compared with placebo at the end of the 16 week treatment period, and even with the reduced number of women in this subgroup this difference came close to statistical significance at the 0.05 level (P=0.0598). 

In addition, at each of the 4-weekly visits during treatment (Weeks 4, 8, 12 and 16), the number of women who reported experiencing BV signs and symptoms since their last visit was consistently lower in the 1% VivaGel^® group compared with placebo.  This difference was statistically significant at Week 4 (9% vs. 23%, P=0.0434) and Week 16 (2% vs. 14%, P=0.0507).

In the follow-up period, once use of study product stopped, there was no difference in the proportion of women in the 1% SPL7013 Gel and placebo groups reporting BV symptoms, indicating that the product concept, ie. on-going use of VivaGel^®, would be beneficial in reducing recurrence of BV symptoms.

The rate of adverse events in the 1% VivaGel^® group was comparable with placebo, and significantly lower than published data on metronidazole when used for extended periods of time.  The rate of candidiasis (19%) was also very low compared with that reported following long-term use of metronidazole (44%).

In general, 1% VivaGel^® performed best compared with placebo, while in general the 3% dose did not reduce the risk of R-BV.  These clinical findings correlate with the earlier Phase 2 dose ranging results and in vitro microbiological findings, which show that 1% SPL7013 achieves the best balance between activity against pathogenic BV bacteria and the beneficial Lactobacillus species.  These findings will be further explored including the observation that there was a higher level of patient drop-outs in the 3% group prior to the first post-baseline study visit at Week 4 (19%) compared with 1% group (4% drop-out) and placebo (11% drop-out).  Given the very early drop-out of these participants, and the very good safety profile of all products throughout the remainder of the study, it did not appear that this discontinuation was associated with any product-related effects or adverse events.

This study demonstrated consistent and clinically significant reduced risk of R-BV in the 1% VivaGel^® group and findings from this trial will prove invaluable to inform and optimise trial design parameters for pivotal Phase 3 studies. Given this was a relatively small, exploratory, dose ranging Phase 2 study for a new treatment where no other registered products exist, it is not unexpected that statistical significance would not be achieved on all efficacy measures. Statistical modelling indicates that if these results were replicated in an appropriately designed, larger Phase 3 study, it would yield a statistically significant result.   

Next Steps

On the basis of these very encouraging results, planning for the conduct of a pivotal Phase 3 trial program for VivaGel^® in R-BV has now commenced and discussions will be held in coming months with regulatory authorities, including the US FDA, on the most appropriate design of pivotal studies.  These positive results will also be advantageous in progressing discussions with commercial partners which will continue in parallel with Phase 3 planning activities.