Melbourne Australia:  Starpharma Holdings Limited (ASX: SPL, OTCQX SPHRY) today announced the results of its two phase 3 studies of 1% SPL7013 Gel (VivaGel^®) for the treatment of bacterial vaginosis (BV).  Both studies showed that VivaGel^® achieved statistically significant Clinical Cure and resolution of patient-reported symptoms of BV at the End of Treatment visit (EOT, 2-5 days post treatment).  However, the primary endpoint of Clinical Cure 2-3 weeks after the cessation of treatment (Test of Cure, TOC visit) was not met. 

 A new drug application (NDA) for VivaGel^® for the treatment of BV will not be filed with the FDA at this time due to the lack of statistical significance at TOC, although other claim strategies (e.g. symptomatic relief) and other regulatory jurisdictions may well be available and will be fully explored.

Importantly, although not sustained for the full 2-3 weeks after cessation of therapy, the highly statistically significant Clinical Cure achieved with VivaGel^® compared with placebo gel at the EOT time point, 2-5 days after the end of treatment, confirms, in these large scale clinical studies, that VivaGel^® can have a significant impact in the treatment and management of BV. 

 Each study (SPL7013-015 and SPL7013-016) enrolled approximately 250 women.  In each study 50% and 57% women, respectively, achieved Clinical Cure with VivaGel^® versus just 17% and 21% with placebo (p<0.001) at EOT.  At TOC, the Clinical Cure rates for VivaGel^® and placebo were 27% versus 21%, respectively, in SPL7013-015 and 28% versus 28% in SPL7013-016.

Vaginal discharge assessed by the clinician was resolved in 71% and 74% of women (statistically significant versus placebo, p<0.001), while 61% and 68% of participants reported absence of abnormal vaginal discharge (p=0.033 and p<0.001, respectively, versus placebo).  Vaginal odour, as assessed by the clinician (‘whiff’ test) was resolved in 72% and 70% of women (p<0.001) at EOT, while 76% and 72% of participants reported resolution of unpleasant vaginal odour (p<0.001). 

The results are entirely consistent with the strategy being pursued to address prevention of recurrence of BV, for which ongoing therapy every second day with VivaGel^® is intended to achieve a reduced risk of recurrence of the condition. 

 Indeed, the demonstration of statistically significant Clinical Cure at EOT, which was the key secondary endpoint of these studies, is highly supportive of VivaGel^® for prevention of recurrence of BV, and there is no negative impact of these phase 3 results on the investigation of the product for this indication.  The phase 2 study of VivaGel^® (SPL7013-014) for prevention of recurrence of BV is ongoing, and results are anticipated in Q1 2013. 

 These phase 3 results at TOC are in contrast to the results from the 2011 phase 2 BV treatment study in which highly statistically significant Clinical Cure was achieved for VivaGel^® 1% at both EOT and TOC.  There appear to be several potentially confounding factors in the phase 3 studies, including unusually high placebo Clinical Cure rates at some sites, and the fact that these placebo cure rates increased between the two time points (EOT to TOC), rather than decreased.  Both of these factors may have contributed to the inability to achieve the required primary endpoint and reproduce the phase 2 results.

 Other potentially confounding factors, all of which are known to impact BV, may include rate of condom use, decreased sexual activity in the placebo-treated groups due to ongoing symptoms, and the possibility of placebo participants with unresolved or ongoing symptoms changing their behavior or seeking other therapies to ameliorate their symptoms.  These potentially confounding factors are currently being thoroughly investigated and will be discussed at planned meetings with the US FDA and other regulatory authorities as soon as practicable.

While the primary endpoint in these studies was not met, these results do demonstrate efficacy of 1% SPL7013 Gel in treating BV, and are supportive of the hypothesis that recurrence of BV could be prevented by ongoing therapy (every second day), as is being investigated in the current phase 2 prevention of recurrence study, SPL7013-014.

 Patients treated with VivaGel^® also reported rapid resolution of their symptoms (discharge and odour) within just 2-3 days of starting treatment, and this symptomatic relief was sustained in a significant proportion of women at the later (TOC) time point.  This finding is another promising indicator for the performance of VivaGel^® in the prevention of recurrence indication as it shows that onset of the effect is rapid. This rapid onset of action in symptom control was matched by very encouraging patient feedback on acceptability (see below).

Dr Jackie Fairley, Starpharma Chief Executive Officer said: “We are surprised and disappointed in not meeting the phase 3 FDA endpoint for the treatment indication in these trials, given the phase 2 trial results; however, we are also greatly encouraged by the statistically significant efficacy and excellent symptomatic relief shown for VivaGel^® at the end of treatment in these studies and we do plan to fully explore the potential for regulatory filings based on these data. In addition we, and our expert clinical advisors, see the efficacy demonstrated with VivaGel^®, the excellent safety profile and patient feedback as very positive for the prevention indication,”

“With total global sales of ~$300-350M, the treatment market is significantly smaller and more competitive than the prevention of BV recurrence market. In that market – estimated to be at least 3 times larger – there are no approved products and VivaGel^® would be first in class.  Partner interest in the prevention of recurrence indication continues to be very strong,” Dr Fairley added.

 Due to its chronic nature and the high prevalence of recurrent BV (40-50% of BV sufferers), estimates by analysts, partners and Starpharma concur that the prevention of recurrence market is more than $1 billion (range 1-2 billion).

 Expert clinical advisor to the program, Professor George Kinghorn, OBE, who is Clinical Director at NIHR Clinical Research Network, Department of Genitourinary Medicine, Royal Hallamshire and Sheffield Teaching Hospitals in the UK, commented: “Unfortunately the primary endpoint of these studies was not met, but the results showing statistically significant Clinical Cure of BV at the end of treatment are important, and combined with high patient acceptability and an excellent safety profile for the product, are highly encouraging in terms of the demonstration of a clinical effect of VivaGel^®, and the potential utility of the product for prevention of recurrent BV, and as a potential adjunct in primary treatment using existing therapies.”

The safety profile of VivaGel^® in these phase 3 trials was excellent, with very low rates of both genitourinary and non-genitourinary adverse events, and was consistent with administration of a locally applied, non-systemically absorbed agent.  Importantly, there were very few instances of candidiasis reported in women taking VivaGel^®, with just 1.6% and 3.2% of women in 015 and 016, respectively, being diagnosed with the condition during the treatment and follow-up periods.  This finding is in significant contrast to other BV treatments for which published candidiasis rates are around 10-20%.  Following prolonged use of metronidazole, as many as 59% of women are reported to experience episodes of candidiasis, which result in further cost and inconvenience for women with BV.  The safety profile of VivaGel^® in these studies is, again, highly encouraging in terms of the prevention indication.

Given its good performance in symptom resolution in patients, not surprisingly, women rated VivaGel^® significantly higher than placebo in terms of effectiveness and overall satisfaction (p<0.001) in a treatment satisfaction questionnaire for medications (TSQM) undertaken at EOT.  Twice as many women were satisfied to extremely satisfied with VivaGel^® compared with the placebo (p<0.001).

In addition, formal market research undertaken with trial participants and key opinion leaders elicited substantial positive feedback on VivaGel^® both in terms of effectiveness, rapid onset of effect and desirability of the formulation compared to current products.  In this research, women with BV reported “constantly worrying” about “embarrassing” and “absolutely horrible” odour and discharge.  Women also report the existing therapies as tasting “horrible”, causing unpleasant side effects such as an “upset stomach”, candidiasis (thrush) and interfering with sexual intercourse.  The clear gel and localised nature of VivaGel^® use was preferred by women.  Women who used VivaGel^® reported very quickly noticing a “huge difference” in their BV.

 Ultimately, the inability to meet the primary endpoint in either SPL7013-015 or -016 means that an NDA for VivaGel^® for treatment of BV will not be submitted to the FDA as originally planned based on these data in Q1 2013.  However, because of the positive results at EOT, the beneficial impact of the product on patient-reported symptoms, and the potentially confounding factors, discussions with the FDA and other regulators are certainly warranted to investigate the product options which may be open based on these data. These interactions will be scheduled as soon as practicable.

 Partnering discussions are already underway for VivaGel^® with a significant number of parties and will continue.  Given that the majority of potential licensing partners have emphasized the importance and value of prevention of recurrence of BV indication for VivaGel^®, it is expected that the achievement of statistically significant Clinical Cure at EOT in two large phase 3 studies, along with symptomatic relief and the excellent side effect profile, will assist in advancing these discussions.

In addition, these phase 3 study results have no negative implications for the condom coating products, as the marketing claims being pursued for condoms relate to the potent antiviral activity of SPL7013, the active dendrimer ingredient in VivaGel^®.  Many of the phase 3 study findings, including the demonstration of significant control of unpleasant vaginal odour, may have potential commercial applications in some geographic markets, while the excellent safety data add to the increasingly large database on the safety of SPL7013.

“In conclusion, despite this disappointing result the fundamentals of Starpharma’s strategy have not changed. We have a platform technology that has broad applicability with the potential to generate multiple revenue streams. We have already demonstrated through our three development programs our ability to secure multiple partnerships with large, leading international companies.  Starpharma remains in a strong cash position, with a cash balance of $37.6M at 30 September 2012.  This balance excludes the newly announced $5.3M in estimated cash from R&D tax incentives and together these will allow Starpharma to continue to progress the multiple VivaGel^® programs, as well as drug delivery and agrochemical programs as planned.” Dr Fairley concluded.

Further details on the results of both trials are presented in the Appendix to the announcement.

Download ASX Announcement  VivaGel Phase 3 study results ( pdf file, 158kb)