Introduction
Bacterial vaginosis (BV)
BV is a common vaginal condition characterised by odorous grey vaginal discharge which can be really distressing for women. It is known to be related with an imbalance of vaginal bacterial communities (vaginal microbiome). The normal vagina is normally dominated by various species of Lactobacillus which protect the vaginal ecosystem through the production of antimicrobial molecules that exclude and inhibit the growth and expansion of other microorganisms.
Live Biotherapeutic Products (LBPs)
New types of medicines intended to restore the balance of human microbiomes have increasingly been investigated for the treatment and prevention of diseases in recent years. Some of these consist of live microorganisms and are designated as Live Biotherapeutic Products (LBPs) in the regulatory frameworks of key regions such as the US and the EU, as per the FDA Guidance “Early Clinical Trials with Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information”[1] and the European Pharmacopoeia[2].
Various LBPs are being investigated in different diseases and conditions involving various organs of the body.
Understanding Bacterial Vaginosis
BV is associated with an overgrowth of mixed organisms such as Gardnerella, Mobiluncus, Ureaplasma, Prevotella. A homogeneous Lactobacillus-dominated microbiome has long been considered the hallmark of health in the female reproductive tract. With BV, there is a lack of lactobacillus ultimately leading to a rise in pH of vaginal secretions from 5.0 to 7.0. The exact cause of BV is not clear, but it seems to be linked to the overgrowth of exogenous organisms that overwhelm normal vaginal lactobacilli leading to a dysbiosis. A smelly greyish homogenous flour-paste-coating vaginal discharge is characteristic of BV which is typically diagnosed by clue cells on microscopy and a fishy (amine) odour when 10% potassium hydroxide is added to the vaginal discharge.
BV is not a sexually transmitted disease but has been associated with increased sexual activity, and douching. The risk of BV appears to be twice increased when intra-uterine devices (IUDs) are inserted or after termination of pregnancies, and hysterectomies. In pregnancies, BV has also been linked to preterm deliveries, post-partum infection, and miscarriages.
BV apparently affects up to 50% of reproductive-aged women worldwide and tend to reoccur in majority within 3 months[3].
Commonly BV is treated with antibiotics, but it should be emphasised that antibiotic-based treatments don’t restore or treat dysbiosis but rather are known to for their ineffectiveness in preventing the recurrence of the disease and even, as potential causes of dysbiosis. In addition, repeated and prolonged use of antibiotics can lead to antimicrobial resistances (AMR), which is identified as one of the bigger global public health threats, estimated to have been linked to 1.2 million in 2019 and an increase to approximately 10 million deaths per year anticipated by 2050[4].
By and large, there is a real need to develop effective and safe interventions for the treatment of BV that could restore the vaginal ecosystem.
The role of LBPs
Considering BV is caused by an imbalance in the vaginal flora and that normally constituted vaginal microbiome consists to a large extent of homogeneous Lactobacillus, it is sensible to aim to restore bacterial, including Lactobacillus, balance in the vagina by harnessing the potential of live microorganisms as LBPs. Investigating them for the treatment of this distressing condition is, thus, a priority.
The proof of concept for the use of LBPs to treat BV has been shown to a great extent in various studies over the years. For instance, in a study in which women were treated with either two dried capsules containing Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 administered intravaginally, an 90% recovery rate was shown[5]. In another study, vaginal tablets containing a combination of three strains of lactobacilli (Lactobacillus brevis, Lactobacillus salivarius and Lactobacillus plantarum) were administered to women with recurrent BV in a randomized, placebo-controlled study. The results showed that the product was 61% effective in eliminating BV and 50% effective in restoring ‘normal vaginal flora’[6].
When it comes to the use of LBPs for the treatment of BV, there are different types of products being investigated in different stages of development, with different approaches including single species – single strain LBPs and multi-strain LBPs (consortia). Another alternative approach involving comprehensive and complex consortia is through vaginal microbiome transplantation.
Potential benefits of LBPs
A single strain product is being evaluated for the treatment or prevention of the recurrence of BV LACTIN-V (Lactobacillus crispatus CTV-05). The results so far have been encouraging. It was shown in a randomized, double-blind, placebo-controlled, phase 2b study that the BV incidence was lower with the use of LACTIN-V when compared with placebo in the prevention of the recurrence of BV[7].
Microbiome products are approved for the prevention of recurrence of Clostridium difficile infection such as VOWSTTM and REBYOTA which are both Fecal Microbiota Products[8], but no LBP has been approved for the treatment of BV. Interestingly, approved products target the gut microbial environment, although vaginal microbiome ecosystem is better defined. This knowledge is of great importance to develop new products. By and large, to unlock potential benefit of an LBP for the treatment of BV, it will be essential that such a product is demonstrated to be effective and safe in line with regulatory requirements. Therefore, clinical studies should be designed in an innovative smart manner. The product manufacturing should be well controlled and capable to establish a standard that matches health authorities’ expectations for an LBP to be potentially commercialised. Manufacturing conditions should be such that allow the production of a consistent, well-defined LBP, minimising variation between generated batches. The formulation should also be anticipated and developed to accelerate the product development.
It should be pointed out that before moving into clinical development the proposed LBP should be adequately characterised and tested using relevant nonclinical models (e.g., in vitro, ex vivo, in silico and/or in vivo) when possible. There should be a deep understanding of the strains to be used from a genetic aspect but also from their biological activity point of view.
From the clinical and regulatory perspective, improvement in the distressing symptoms of BV such as the odorous vaginal discharge would be considered a clinically relevant primary endpoint and demonstrating the restoration of the vaginal microflora would be considered secondary and supportive.
In addition, since BV is a condition that affects the vagina, route of administration and dosing of the product will be important considerations. For example, an LBP may be combined with a device for sustained and controlled release in the vagina and can be associated with insertion devices for proper placement within the vagina – compatibility of an LBP with associated devices must be evaluated. On a safety point of view, interactions between the LBP and on one hand the patient’s cells and on the other hand the patient microbiota should be evaluated.
Conclusion
BV is a condition in which the vaginal ecosystem is altered. It affects women quite frequently and can be quite troublesome when symptomatic. Hence a product that can restore the balance of the vaginal ecosystem and eliminate the signs and symptoms of BV will be quite beneficial. LBPs are live microorganisms for which promising data has been variously generated showing that there is a strong possibility for their use in the treatment of BV. LBP hold promises for the field as they would also constitute a promising alternative to current treatments and their limitations.
The health and overall wellbeing of women remain a priority globally. In the US, the Executive Order to Advance Women’s Health Research and Innovation shine the light on this issue with policies that aim to promote Women’s Health by stimulating research in this field, increasing women’s participation in clinical trials, and supporting investments in biomedical research supporting breakthroughs in women’s health[9]. So, there is a real opportunity to utilize the growing awareness regarding women’s health by using the treatment of BV as a starting point for catapulting into other women’s health issues such as recurrent yeast infections. The considerations for BV and LBPs would equally be applicable i.e., smart innovative study designs utilizing clinically relevant endpoints.
References:
[2] European Pharmacopoeia Online (edqm.eu)
[3] Laurel A Lagenaur, Anke Hemmerling, Charles Chiu, Steve Miller, Peter P Lee, Craig R Cohen, Thomas P Parks, Connecting the Dots: Translating the Vaginal Microbiome Into a Drug, The Journal of Infectious Diseases, Volume 223, Issue Supplement_3, 15 June 2021, Pages S296–S306, https://doi.org/10.1093/infdis/jiaa676
[4] Tang KWK, Millar BC, Moore JE. Antimicrobial Resistance (AMR). Br J Biomed Sci. 2023 Jun 28;80:11387. doi: 10.3389/bjbs.2023.11387. PMID: 37448857; PMCID: PMC10336207.
[5] Anukam KC, Osazuwa E, Osemene GI, Ehigiagbe F, Bruce AW, Reid G. Clinical study comparing probiotic Lactobacillus GR-1 and RC-14 with metronidazole vaginal gel to treat symptomatic bacterial vaginosis. Microbes Infect. 2006 Oct;8(12-13):2772-6. doi: 10.1016/j.micinf.2006.08.008. Epub 2006 Sep 11. PMID: 17045832.
[6] P. Mastromarino, S. Macchia, L. Meggiorini, V. Trinchieri, L. Mosca, M. Perluigi, C. Midulla, Effectiveness of Lactobacillus-containing vaginal tablets in the treatment of symptomatic bacterial vaginosis, Clinical Microbiology and Infection, Volume 15, Issue 1, 2009, Pages 67-74, ISSN 1198-743X, https://doi.org/10.1111/j.1469-0691.2008.02112.x. (https://www.sciencedirect.com/science/article/pii/S1198743X14606017)
[7] Cohen CR, Wierzbicki MR, French AL, Morris S, Newmann S, Reno H, Green L, Miller S, Powell J, Parks T, Hemmerling A. Randomized Trial of Lactin-V to Prevent Recurrence of Bacterial Vaginosis. N Engl J Med. 2020 May 14;382(20):1906-1915. doi: 10.1056/NEJMoa1915254. PMID: 32402161; PMCID: PMC7362958.
[8] https://www.fda.gov/vaccines-blood-biologics/vowst; https://www.fda.gov/vaccines-blood-biologics/vaccines/rebyota
[9] https://www.whitehouse.gov/briefing-room/statements-releases/2024/03/18/fact-sheet-president-biden-issues-executive-order-and-announces-new-actions-to-advance-womens-health-research-and-innovation/?utm_source=link
Published on: Oct 9th, 2024
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