Bremelanotide for Treatment of Female Hypoactive Sexual Desire

Round 1

Reviewer 1 Report

This review article defines hypoactive sexual desire disorder (HSDD) and gives a summary of its current treatments with a focus on the drug bremelanotide. The authors argue that bremelanotide is currently the most promising treatment for HSDD. Overall, the article contains helpful information on the topic of HSDD; however, the delivery of this information is often unclear and biased towards the use of bremelanotide. Specifically, many pieces of information were contradictory, certain terms and abbreviations were not defined, and certain sentences were written too vaguely and were misleading. Below I ranked the most important issues that need to be addressed.

 

1. Missing Information:

-When assessing the use of HSDD treatments, it is important to mention the less promising aspects of the RECONNECT bremelanotide data. For example, this paper should mention that 32.4% of women discontinued the 24-week trial prior to completion. This number was largely driven by the presence of adverse events. Also, the paper should give more detail around the percent of satisfying sexual events vs the number of satisfying sexual events and which variable is more important; the former was not defined.

-What is the DSM-IV criteria for HSDD? It is mentioned without being defined.

-Discuss more about the hypothesized mechanism of menopause-related HSDD. Many treatments are mentioned, but which treatments are specific to pre-menopausal vs post-menopausal women and why is not discussed.

2. The language in the paper frequently sounds biased. For example:

-RECONNECT; paragraph 5; they say bremelanotide caused several TEAEs including nausea, flushing, and headache. The authors then go on to say “Only 1 TEAE was linked to bremelanotide use”.

-RECONNECT; paragraph 4; “there was a greater than two-fold increase in the percentages of satisfying sexual events”. What are the percentages of satisfying sexual events? And why is this variable important when there was no significant increase in the number of satisfying sexual events? It seems the number of events would be more pertinent.

-RECONNECT; paragraph 3; “it was demonstrated that bremelanotide showed significant efficacy and tolerability compared with placebo”. Clarify which statistical data the word “significant” is being used to describe.

-RECONNECT; paragraph 6; “the drug has demonstrated a high efficacy profile with minimal safety concerns”

3. Some areas of the paper need more explanation or are contradictory. Examples:

-Approved agents; lines 1-3; Flibanserin is a receptor agonist/antagonist that functions by decreasing serotonin levels and increasing dopamine and norepinephrine levels. Explain how this receptor agonist/antagonist increases or decreases neurotransmitter levels.

-Pharmacodynamics of bremelanotide; sentence 2; The paper says bremelanotide interacts with alcohol. However, the study they mentioned seems to assert that no synergistic effects occur from combining alcohol and bremelanotide.

-In the RECONNECT studies it specifies satisfying sexual events to be the secondary end point, but in the chart, it specifies satisfying sexual events as the primary end point.

4. The section that includes the headings Bremelanotide, Mechanism of Action, Pharmacodynamics of Bremelanotide, and Pharmacokinetics of Bremelanotide should be rewritten for clarity to assist in understanding of the paper.

 

4. The paper has too many abbreviations and this causes confusion. Additionally, in certain areas, abbreviations are either not defined or used inconsistently. Examples:

-“MC4R receptor” is redundant and the abbreviation is not properly defined.

-Does SSE stand for satisfying sexual events or sexual satisfying events? It is also used inconsistently.

Author Response

This review article defines hypoactive sexual desire disorder (HSDD) and gives a summary of its current treatments with a focus on the drug bremelanotide. The authors argue that bremelanotide is currently the most promising treatment for HSDD. Overall, the article contains helpful information on the topic of HSDD; however, the delivery of this information is often unclear and biased towards the use of bremelanotide. Specifically, many pieces of information were contradictory, certain terms and abbreviations were not defined, and certain sentences were written too vaguely and were misleading. Below I ranked the most important issues that need to be addressed.

 

1. Missing Information:

-When assessing the use of HSDD treatments, it is important to mention the less promising aspects of the RECONNECT bremelanotide data. For example, this paper should mention that 32.4% of women discontinued the 24-week trial prior to completion. This number was largely driven by the presence of adverse events. Also, the paper should give more detail around the percent of satisfying sexual events vs the number of satisfying sexual events and which variable is more important; the former was not defined.

            Answer:

-What is the DSM-IV criteria for HSDD? It is mentioned without being defined.

            Answer: I apologize that this was missed as it should be in there. I’ve added it to this revision. We would need to use the DSM 5 criteria instead of the IV.

-Discuss more about the hypothesized mechanism of menopause-related HSDD. Many treatments are mentioned, but which treatments are specific to pre-menopausal vs post-menopausal women and why is not discussed.

            Answer: There actually aren’t many approved treatments for postmenopausal women. This is why most of the treatments listed are for premenopausal women. A statement at the beginning of the current treatment section was added to highlight this.

1. The language in the paper frequently sounds biased. For example:

-RECONNECT; paragraph 5; they say bremelanotide caused several TEAEs including nausea, flushing, and headache. The authors then go on to say “Only 1 TEAE was linked to bremelanotide use”.

            Answer: This was corrected in the manuscript. Thank you for bringing that to my attention

-RECONNECT; paragraph 4; “there was a greater than two-fold increase in the percentages of satisfying sexual events”. What are the percentages of satisfying sexual events? And why is this variable important when there was no significant increase in the number of satisfying sexual events? It seems the number of events would be more pertinent.

            Answer: This was actually written incorrectly. It was the sexual desire not the number of sexually satisfying events which I could not find in the RECONNECT trial when I revisited it during the revisions

-RECONNECT; paragraph 3; “it was demonstrated that bremelanotide showed significant efficacy and tolerability compared with placebo”. Clarify which statistical data the word “significant” is being used to describe.

            Answer:  The significance was added with the revisions in the above point. This should clarify this point of it being it clinically significant. This sentence was edited for further clarity.

-RECONNECT; paragraph 6; “the drug has demonstrated a high efficacy profile with minimal safety concerns”

            Answer:  This sentence was revised. The study did say that the TEAEs were mild to moderate and that they were related to tolerability and not safety.

1. Some areas of the paper need more explanation or are contradictory. Examples:

-Approved agents; lines 1-3; Flibanserin is a receptor agonist/antagonist that functions by decreasing serotonin levels and increasing dopamine and norepinephrine levels. Explain how this receptor agonist/antagonist increases or decreases neurotransmitter levels.

            Answer: This has been clarified in the text in this revision.

-Pharmacodynamics of bremelanotide; sentence 2; The paper says bremelanotide interacts with alcohol. However, the study they mentioned seems to assert that no synergistic effects occur from combining alcohol and bremelanotide.

            Answer: This point has been removed from the paper.

-In the RECONNECT studies it specifies satisfying sexual events to be the secondary end point, but in the chart, it specifies satisfying sexual events as the primary end point.

            Answer: This was removed as sexual desire was what was studied along with the distress called by the low sexual desire.

1. The section that includes the headings Bremelanotide, Mechanism of Action, Pharmacodynamics of Bremelanotide, and Pharmacokinetics of Bremelanotide should be rewritten for clarity to assist in understanding of the paper.

Answer:  This was reviewed and revised.

 

1. The paper has too many abbreviations and this causes confusion. Additionally, in certain areas, abbreviations are either not defined or used inconsistently. Examples:

-“MC4R receptor” is redundant and the abbreviation is not properly defined.

-Does SSE stand for satisfying sexual events or sexual satisfying events? It is also used inconsistently.

            Answer: The term SSE is defined as sexually satisfying events. This has been revised in the text.

Reviewer 2 Report

I congratulate the authors for this interesting article. In their qualitative review on bremelanotide, they provide a timely, broad and accurate discussion on the topic. They address the risk factors and pathophysiology of HSDD and current off-label and approved treatments; the mechanism of action, pharmacodynamics and pharmacokinetics of bremelanotide; the clinical perspective, with an in-depth overview of early, phase 1 and phase 2 studies. A table focused on the main findings of efficacy and safety trials was also included.

In my opinion, the article presents an unbiased, detailed and complete summary of the available literature. The length, structure and flow are also adequate.

I have only some minor suggestions.

• Introduction: Please note that, while the prevalence of low sexual desire increases with age, distress associated with low desire is common in younger women. See for example Menopause. Jan-Feb 2006;13(1):46-56.
• Off-label treatment with testosterone. In a validated animal model, it has been recently demonstrated that DHT facilitates sexual behavior, supporting an independent role of androgens in female sexual desire and substantiating the use of testosterone for the treatment of HSDD (Psychoneuroendocrinology. 2020 May;115:104606.)
• Please, add a comment on the lack of approved therapies for HSDD in post-menopausal women.

Author Response

• Introduction: Please note that, while the prevalence of low sexual desire increases with age, distress associated with low desire is common in younger women. See for example Menopause. Jan-Feb 2006;13(1):46-56.
• Answer: This is a good point. This was point was added to the introduction.
• Off-label treatment with testosterone. In a validated animal model, it has been recently demonstrated that DHT facilitates sexual behavior, supporting an independent role of androgens in female sexual desire and substantiating the use of testosterone for the treatment of HSDD (Psychoneuroendocrinology. 2020 May;115:104606.)
• Answer: This is a great point and honestly some providers use testosterone implants in women for this reason. This has been added to the pathophysiology section as a short blurb.
• Please, add a comment on the lack of approved therapies for HSDD in post-menopausal women.
• Answer: This statement has been added to the beginning of the current treatment sections.

Round 2

Reviewer 1 Report

The authors have improved the manuscript, but non-trivial problems remain:

1. New problem: The results of the secondary end point in the RECONNECT study are not reported in this manuscript. Mention that the study found no increase in the number of satisfying sexual events. 
2. Comment not addressed: The RECONNECT study in the text says primary end point is a change in FSFI-D and FSDS-DAO. The RECONNECT study in the chart says primary end point is change in satisfying sexual events/month. To my knowledge, the primary endpoint is the FSFI-D and FSDS-DAO. 
3. Comment not addressed: Although the biased language has been rectified, it is still important to include the percentage of women that dropped out of the original 24-week RECONNECT study. This statistic is the best indicator of bremelanotide's tolerability and is important for assessing if bremelanotide will be successful in treating HSDD. 
4. Comment not addressed: page 6; line 3; mentions bremelanotide's interaction with alcohol as an adverse effect. If a synergistic (non-additive) effect of alcohol and bremelanotide on headaches does exist, it needs to be better explained in the text. Same with the results on flushing. 
5. Comment not addressed: Still problems with abbreviations that were not defined in the text (DSM-IV, CAD, FSDS-DAO) and typos (rates instead of rats, behaiors). "MC4R receptor" is still used and is redundant. 

Author Response

1. New problem: The results of the secondary end point in the RECONNECT study are not reported in this manuscript. Mention that the study found no increase in the number of satisfying sexual events. 
• Answer: This was mentioned that they said it didn't reach statistical significance but in a post hoc analysis they found differences in the percentages between the two groups. This was added to the manuscript. it was 25% vs. 9.8% with a p value of <0.001.
2. Comment not addressed: The RECONNECT study in the text says primary end point is a change in FSFI-D and FSDS-DAO. The RECONNECT study in the chart says primary end point is change in satisfying sexual events/month. To my knowledge, the primary endpoint is the FSFI-D and FSDS-DAO. 
• Answer: Thank you for pointing that out. This has been corrected.
3. Comment not addressed: Although the biased language has been rectified, it is still important to include the percentage of women that dropped out of the original 24-week RECONNECT study. This statistic is the best indicator of bremelanotide's tolerability and is important for assessing if bremelanotide will be successful in treating HSDD. 
• Answer: The only percentage presented in the trial as those that discontinued were due to nausea. This has been included in the manuscript with this revision. It was also noted that the response rate may be high because of the high placebo rate. This was included in the manuscript
4. Comment not addressed: page 6; line 3; mentions bremelanotide's interaction with alcohol as an adverse effect. If a synergistic (non-additive) effect of alcohol and bremelanotide on headaches does exist, it needs to be better explained in the text. Same with the results on flushing. 
• Answer: This has been removed from the manuscript. The reason is that the data is actually split where some say it interacts and some say it does not. The mechanism of flushing is also not stated in manuscripts so this was also removed.
5. Comment not addressed: Still problems with abbreviations that were not defined in the text (DSM-IV, CAD, FSDS-DAO) and typos (rates instead of rats, behaiors). "MC4R receptor" is still used and is redundant.
• Answer: The above has been corrected. However, the MC4R is the melanocorticotropin 4 receptor or MC4R. Its statement in the manuscript is not redundant as it is the receptor that this medication is thought to work on. This has not been removed as its removal would not benefit the manuscript.