Background and history
IVIX was incorporated in 2012 to develop and subsequently commercialize a promising drug candidate, BP101, for the treatment of female sexual dysfunctions.
Between 2012 and 2015 IVIX completed a preclinical pharmacology program for BP101, the results of which allowed IVIX to then proceed and initiate a first-in-human clinical study in early 2015.
In 2017 IVIX completed a Phase IIa proof-of-concept clinical study in 110 female patients with hypoactive sexual desire disorder (HSDD). The statistically and clinically significant results from that study demonstrated impressive efficacy and favourable safety profile in the target indication. To date, three clinical studies of BP101 have been completed, demonstrating BP101’s promising potential for the treatment of female sexual dysfunctions, including decreased desire and arousal disorders, as well as the drug’s safety for use.
These results have formed the basis for the upcoming Phase III confirmatory therapeutic clinical study in Russia. The Phase III clinical study will be undertaken with the intention of obtaining marketing authorization in Russia and Eurasian Economic Union (EEU) countries for Libicore. This step will be crucial for market access in and further commercialization of the BP101 in Russia and EEU countries.
In March 2016, IVIX had a pre-investigative new drug (IND) filing meeting with US Food and Drug Administration (FDA), where BP101 scientific and clinical data was discussed. Generally, the FDA positively assessed the data submitted by IVIX, but the Agency requested additional preclinical and clinical studies to confirm the safety of the drug and to study its toxic-kinetic profile. Additional Phase I clinical trial and toxic-kinetic research has been completed. Other preclinical studies will be completed in 2018.
The results of the BP101 development program are patent-protected by three patents in Russia and one in the USA with a validity period up to 2033. Additional patents are in national landing phases in key target pharmaceutical markets: Brazil, Canada, China, EU, Israel, India, South Korea, and Japan.
Product candidate overview
The product candidate of IVIX – Libicore – is a novel synthetic peptide, administrated through a nasal spray. The nasal spray delivers the drug to olfactory and trigeminal nerves in the nasal cavity where the drug accumulates in the olfactory bulb and then further in the brain. Clinical studies completed to date have demonstrated statistically significant efficacy in treatment of major forms of female sexual dysfunction. To demonstrate Libicore’s applicability in clinic, IVIX has conducted three clinical trials to date. Two Phase I clinical trials were conducted to estimate the drug’s safety and tolerability.
In a preclinical animal model, BP101 demonstrated statistically significant enhancement of sexual behaviour in rats with decreased libido due to low hormonal levels. The model consisted of rats with surgically removed ovaries, the main source of sex hormones. The rats were then injected with low doses of oestrogen and progesterone at five days interval to reproduce the natural oestrous cycle. In this model, the sexual activity of female rats directly depends on the level of sex hormones. BP101 was delivered intranasally to the rats injected with these minimal doses of hormones. Their behaviour was then compared to rats injected with a maximal (saturating) dose of sex hormones. To measure sexual behaviour, the females were then introduced to active males. Two parameters were measured – “proceptive” (courting) behaviour of females and “lordosis” - reflexive posture leading to arching of the back and raising of the head, facilitating copulation with males. The results of this test demonstrated that BP101 consistently enhanced the sexual behaviour of female rats. With a single dose, BP101 enhanced behaviour stronger than the saturating dose of sex hormones (high progesterone).
In an exploratory Phase IIa proof-of concept randomized, double-blind, placebo-controlled study in female patients with lack or loss of sexual desire, 110 premenopausal women were treated with either 2,54 mg of BP101 or a placebo in a 1:1 ratio. The drug administration regiment included daily intranasal puffs for 4 weeks with a subsequent off-treatment follow-up period for control of sustainability of the treatment effect and long-term safety. Study endpoints included change in different aspects of sexual relationship (measured via Female Sexual Function Index (“FSFI”[The FSFI is a questionnaire commonly used in the clinical and scientific practice for assessment of sexual function in women. The index enables to assess female sexual function taking into account its six main components: sexual desire, sensitivity and excitability, lubrication (vaginal moisture), orgasticity, satisfaction with sexual life, coital and/or post-coital discomfort/pain.])) and distress related with the lack of desire (measured via Female Sexual Distress Scale-revised (“FSDR-R”[The FSDS-R is a validated questionnaire commonly used in the clinical and scientific practice for assessment of a distress related to a sexual function in women.])), and also change in numbers of satisfying sexual events (SSEs) and number of orgasms (with an orgasm as a component of SSE), compared with baseline. The study demonstrated that treatment with BP101 significantly increased sexual desire and the number of SSEs and orgasms in premenopausal women compared with the placebo.
Safety data from all BP101 clinical trials showed a favourable safety profile and only mild-to-moderate adverse events related to the treatment, with slightly more prevalence of mild local irritation in the nose (route of administration), headache and irritability. There was no increase of safety problems on high doses of BP101, as well as no unacceptable adverse effects.
The drug is produced by contract manufacturing organisations (CMOs). IVIX does not have and does not intend to develop its own manufacturing facilities until significant revenues from sales are achieved. For drug manufacturing, IVIX has chosen CMOs with strong track records of quality assurance and regulatory compliance. In Russia, the drug is manufactured by Nativa LLC, a CMO which has numerous peptide drugs in its portfolio that have been successfully produced for the Russian market.
For the USA and EU clinical studies, two CMOs have been engaged to manufacture the drug. The active pharmaceutical ingredient, peptide BP101, is to be manufactured by Bachem AG. Bachem is one of the world’s leading independent manufacturers of peptide active pharmaceutical ingredients (APIs) and an established manufacturer of small molecule APIs. Each year, Bachem manufactures hundreds of batches of drug substance for projects in clinical trials and for products on the market. Bachem’s manufacturing facilities are located in Switzerland and the United States and are regularly inspected by the FDA and local authorities.
Juniper Pharma Services, located in Nottingham, UK, will fulfil the second part of the drug manufacturing cycle for IVIX, namely production of the final drug product. Juniper Pharma Services have strong experience in the manufacturing of ready dosage forms for clinical trials, under a Medicines and Healthcare Products Regulatory Agency (MHRA) license.
The glass vials and nasal spray pump for the drug product are manufactured by SGD (France) and Aptar (Germany) respectively, both established firms in their respective areas with strong track records of product quality assurance.
Female sexual dysfunction (“FSD”) is estimated to affect a significant portion of the female population in US and EU countries. Examples of FSD may include hypoactive sexual desire disorder (“HSDD”) and female sexual arousal disorder (“FSAD”). FSD prevalence has been assessed in a number of large population studies. In a research paper published by Berman, J.R. et al, [Berman J.R. et al, Female sexual dysfunction: incidence, pathophysiology, evaluation, and treatment options, Urology, 54(3), 1999, pp385-391.] FSD was estimated to be present in 30-50 per cent. of US women. According to the Women’s International Study of Health and Sexuality, the prevalence of HSDD ranged from 6–13 per cent. in Europe, and the proportion of women with low desire associated with distress was significantly higher in younger women in comparison with older women [Nappi RE, Martini E, Terreno E, et al. Management of hypoactive sexual desire disorder in women: current and emerging therapies. International Journal of Women’s Health. 2010; 2:167-175)].
Current treatment options
Current FSD treatment options mostly include non-specific treatment focused on addressing any identified underlying conditions or medication issues that are suspected of contributing to FSD. However, in many cases FSD is idiopathic – i.e. not caused by any other concomitant health or environment problems. In such cases, treatment strategies include patient education, psychotherapy and sexual therapy. Lifestyle changes such as stress management and sleep adjustments are also recommended.
Specific medical treatments in FSD patients are limited to various food supplements with unclear efficacy, and off-label hormonal and antidepressant therapy. There is currently one approved specific medical treatment – Addyi (flibanserin), produced by Sprout Pharmaceuticals.
Hormonal treatment options include topical (i.e. in transdermal patches, gels etc.) testosterone or estrogen therapies used off-label. A number of clinical trials in HSDD patients, mostly with testosterone-containing drugs, have taken place in recent years. The only hormonal treatment marketed for HSDD was the P&G drug Intrinsa, which was approved by the European Medicines Agency (EMA) for the treatment of HSDD in women who have had an oophorectomy (the surgical removal of an ovary or ovaries) and receiving hormone replacement therapy. Intrinsa was withdrawn from the EU market in 2010 due to commercial reasons. The safety profile of Intrinsa was typical for testosterone-containing drugs and included the following common side effects (seen in more than 1 patient in 10): hirsutism (increased hair growth, especially on the chin and upper lip) and reactions at the site of application of the patch (redness and itching).
Other off-label treatment approaches include the prescription of antidepressant medications, such as atypical antidepressant bupropion (Wellbutrin). This approach is more common in secondary HSDD due to selective serotonin reuptake inhibitors (SSRIs) intake. Bupropion, as well as other antidepressants, are not approved by the FDA and EMA for treatment of female sexual dysfunctions, and there is lack of evidence regarding their effectiveness. Side effects of antidepressant medications vary, depending on the individual mechanism of action and the individual characteristics of each drug, but common side effects include nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, rash, and nervousness.
Only one pharmaceutical treatment, Addyi (flibanserin, antidepressant with selective action at serotonin 5-HT receptors), is marketed in the US for HSDD. Flibanserin efficacy in large US-based clinical studies was statistically significant over placebo, but demonstrated concomitant safety problems, such as risk of severe hypotension and syncope when taken together with alcohol or even Addyi alone, or Central Nervous System (CNS) depression (e.g., somnolence, sedation) with Addyi alone. Other common side effects included dizziness, somnolence, nausea, fatigue, insomnia, and dry mouth. In October 2015, Valeant Pharmaceticals acquired Sprout Pharmaceuticals, the producer of Addyi, for an aggregate purchase price of $1.45 billion, which included cash plus contingent consideration. Subsequently, in December 2017, Valeant completed the sale of Sprout to a buyer affiliated with certain former shareholders of Sprout, in exchange for a 6% royalty on global sales of Addyi beginning June 2019. Valeant noted that the sale of Sprout provided it with the opportunity to divest a business that was not core to its objectives, while also allowing it to resolve an ongoing legal matter between it and former shareholders of Sprout relating to compliance with certain contractual terms of the 2015 acquisition agreement with respect to the use of certain diligent efforts by Valeant to develop and commercialize Addyi.