Kisspeptin for Low Testosterone

Recruiting in Palo Alto (17 mi)

Overseen by Stephanie B. Seminara, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Stephanie B. Seminara, MD

Must be taking: Reproductive condition treatments

Must not be taking: Reproductive endocrine drugs

Disqualifiers: Illicit drugs, Excessive alcohol, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The goal of this study is to develop novel treatments for patients with a condition called hypogonadotropic hypogonadism (HH) through the use of exogenous kisspeptin.

Will I have to stop taking my current medications?

The trial requires that you stop taking any prescription medications known to affect reproductive endocrine function for at least 2 months or for 5 half-lives of the drug, whichever is shorter, unless they are used to treat your reproductive condition.

What data supports the effectiveness of the drug Kisspeptin for Low Testosterone?

Research shows that kisspeptin analogs, like TAK-448 and TAK-683, can effectively lower testosterone levels in male rats by initially increasing and then significantly reducing hormone levels. These effects were more rapid and profound than those of a common GnRH agonist, suggesting potential for treating hormone-related conditions. ^{1 2 3 4 5}

How is the drug kisspeptin 112-121 different from other treatments for low testosterone?

Kisspeptin 112-121 is unique because it works by modulating the release of gonadotropin-releasing hormone (GnRH), which in turn affects testosterone levels. Unlike traditional testosterone replacement therapies, kisspeptin analogues like TAK-448 and TAK-683 can rapidly and profoundly lower testosterone levels by acting on the KISS1 receptor, offering a novel approach for managing hormone-related conditions. ^{1 2 4 6 7}

Research Team

Stephanie B. Seminara, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Adults diagnosed with hypogonadotropic hypogonadism (HH) can join this trial if their condition is stable and they're not on meds affecting reproductive hormones, except for HH treatment. Women must not be pregnant or breastfeeding, and all participants need normal blood tests, hormone levels within certain ranges, no drug allergies needing emergency care, and no excessive alcohol use.

Inclusion Criteria

Women need to have a negative pregnancy test before starting the study.

I am 18 years old or older.

I have been diagnosed with hypogonadotropic hypogonadism and have low testosterone or estradiol levels.

Exclusion Criteria

No illicit drug use

You drink less than 10 alcoholic drinks per week.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive kisspeptin intravenous boluses and undergo blood sampling

52 hours

Inpatient stay with continuous monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-2 weeks

1 visit (in-person)

Treatment Details

Interventions

• GnRH (Peptide)
• kisspeptin 112-121 (Peptide)

Trial Overview The study is testing the effectiveness of kisspeptin 112-121 in treating low testosterone due to HH. It aims to develop new treatments by administering kisspeptin externally. Participants will receive either GnRH or kisspeptin as part of the trial interventions.

Participant Groups

Group I: Experimental: kisspeptin, GnRH Experimental Treatment 2 Interventions

• Intravenous administration of kisspeptin 112-121; 20 boluses in a 40-hour period. Intravenous administration of GnRH; one bolus.

Who Is Running the Clinical Trial?

Stephanie B. Seminara, MD

Lead Sponsor

Trials

10

Recruited

840+

Findings from Research

A new nonapeptide analog of metastin, named compound 26, shows improved stability in serum and retains strong binding affinity to the KISS1R receptor, which is important for regulating hormone secretion.

Compound 26 effectively reduces plasma testosterone levels in male rats and represents a promising candidate for treating hormone-dependent diseases, leading to further development of investigational analogs for clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design, synthesis, and biological evaluation of novel investigational nonapeptide KISS1R agonists with testosterone-suppressive activity. Asami, T., Nishizawa, N., Matsui, H., et al.[2017]

A new peptide analogue, Ac-[D-Tyr46,D-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46-54), demonstrated significantly enhanced testosterone-suppressive activity (10-50 times more potent) compared to earlier versions, indicating its potential for treating hormone-dependent diseases.

This compound showed improved metabolic stability and agonistic activity at the KISS1 receptor, suggesting that controlled release of these short-length agonists could effectively suppress testosterone levels by targeting the hypothalamic-pituitary-gonadal axis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physicochemically and pharmacokinetically stable nonapeptide KISS1 receptor agonists with highly potent testosterone-suppressive activity. Asami, T., Nishizawa, N., Matsui, H., et al.[2017]

Kisspeptin plays a crucial role in regulating reproductive functions by controlling the release of GnRH, but its therapeutic use is limited due to its susceptibility to degradation.

Investigational kisspeptin analogs have shown promise in clinical studies, causing initial increases in gonadotropin and testosterone levels, although these effects diminish over time, indicating a need for further research on their long-term efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects and therapeutic potentials of kisspeptin analogs: regulation of the hypothalamic-pituitary-gonadal axis. Matsui, H., Asami, T.[2022]

Investigational kisspeptin analogues TAK-448 and TAK-683 effectively suppress testosterone levels in male rats, demonstrating a rapid and profound reduction to castrate levels within 3-7 days of continuous administration, which is more effective than traditional GnRH agonists like leuprolide.

Both analogues showed strong receptor-binding affinity and agonistic activity, suggesting they could be promising therapeutic options for managing reproductive functions and hormone-related diseases, such as prostate cancer, as indicated by their ability to reduce plasma prostate specific antigen (PSA) levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacologic profiles of investigational kisspeptin/metastin analogues, TAK-448 and TAK-683, in adult male rats in comparison to the GnRH analogue leuprolide. Matsui, H., Masaki, T., Akinaga, Y., et al.[2017]

The study developed stable analogs of the metastin/kisspeptin decapeptide that maintain high receptor affinity and activity, crucial for regulating reproduction and cell migration.

One promising analog, D-Trp(47), demonstrated both high metabolic stability in mouse serum and effective activation of the KISS1R receptor, suggesting potential for improved therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides. Asami, T., Nishizawa, N., Ishibashi, Y., et al.[2017]

In a study measuring plasma kisspeptin levels in 11 males (4 with hypogonadism and 7 normal controls), it was found that kisspeptin levels varied significantly, with elevated levels in cases of Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism, suggesting a link between kisspeptin and the regulation of male reproductive function.

The findings indicate that measuring kisspeptin levels could provide valuable insights into the mechanisms of male hypogonadism, as elevated levels may reflect decreased negative feedback from gonadal steroids, particularly in conditions where the hypothalamic-pituitary-gonadal axis is affected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma kisspeptin levels in male cases with hypogonadism. Kotani, M., Katagiri, F., Hirai, T., et al.[2018]

In a study measuring plasma kisspeptin levels in 11 males (4 with hypogonadism and 7 normal controls), elevated kisspeptin levels were found in cases of Kallmann's syndrome, azoospermia, and hypergonadotropic hypogonadism, suggesting a link between these conditions and hypothalamic kisspeptin secretion.

The findings indicate that measuring kisspeptin levels could provide valuable insights into male hypogonadism, as elevated levels may reflect decreased negative feedback from gonadal steroids, particularly in cases where the lesions are downstream of the kisspeptin neurons.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma kisspeptin levels in male cases with hypogonadism. Kotani, M., Katagiri, F., Hirai, T., et al.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Design, synthesis, and biological evaluation of novel investigational nonapeptide KISS1R agonists with testosterone-suppressive activity. [2017]

2. United States pubmed.ncbi.nlm.nih.gov

Physicochemically and pharmacokinetically stable nonapeptide KISS1 receptor agonists with highly potent testosterone-suppressive activity. [2017]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Effects and therapeutic potentials of kisspeptin analogs: regulation of the hypothalamic-pituitary-gonadal axis. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Pharmacologic profiles of investigational kisspeptin/metastin analogues, TAK-448 and TAK-683, in adult male rats in comparison to the GnRH analogue leuprolide. [2017]

5. England pubmed.ncbi.nlm.nih.gov

Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides. [2017]

6. Japan pubmed.ncbi.nlm.nih.gov

Plasma kisspeptin levels in male cases with hypogonadism. [2018]

7. Japan pubmed.ncbi.nlm.nih.gov

Plasma kisspeptin levels in male cases with hypogonadism. [2019]