Subcutaneous Kisspeptin for Hypogonadotropic Hypogonadism

Overseen By Study Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stephanie B. Seminara, MD

Must not be taking: Hormonal replacements

Disqualifiers: Excessive alcohol, Illicit drugs, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 12

Duration: 2 weeks

36 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this study is to see whether kisspeptin, a naturally occurring hormone, can stimulate the release of other reproductive hormones in men and women with idiopathic hypogonadotropic hypogonadism (IHH). The investigators are also examining whether kisspeptin can help women release eggs from their ovaries. Kisspeptin will be administered SC for two weeks in a pulsatile fashion. Ultrasound monitoring of ovarian follicular growth (for women) and frequent blood sampling (every 10 minutes for up to 70 minutes) will be performed to assess the physiologic response to kisspeptin over time. Funding Source: FDA OOPD

Will I have to stop taking my current medications?

If you are using hormonal replacement or medications that affect reproductive hormones, you may need to stop them for a certain period before joining the trial. This period without medication is called a 'washout period.'

What data supports the effectiveness of the drug Kisspeptin for treating hypogonadotropic hypogonadism?

Research shows that kisspeptin, a hormone, plays a key role in controlling reproductive hormones. Studies have found that kisspeptin analogs can increase hormone levels like testosterone in men, suggesting potential benefits for treating hormone deficiencies. ^{1 2 3 4 5}

Is subcutaneous kisspeptin safe for humans?

In a study with dogs, Kisspeptin-10 showed no signs of toxicity when given daily for 14 days, suggesting a favorable safety profile. However, more research is needed to confirm its safety in humans. ^{2 6 7 8 9}

How is the drug Kisspeptin-10 different from other treatments for hypogonadotropic hypogonadism?

Kisspeptin-10 is unique because it directly stimulates the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which is not a feature of other treatments. This makes it particularly useful for identifying and addressing hypothalamic dysfunction in hypogonadotropic hypogonadism, offering a novel approach compared to traditional therapies that may not target this specific mechanism. ^{2 3 4 5 10}

Research Team

Stephanie B. Seminara, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for men and women with idiopathic hypogonadotropic hypogonadism (IHH) who have low sex hormones due to low gonadotropins. Participants should not be on hormonal replacement or willing to stop it temporarily, and must have normal blood pressure. Pregnant women, those breastfeeding, or with a history of severe medication reactions cannot join.

Inclusion Criteria

Your blood pressure should be within the range of 140/90 or lower.

I have been diagnosed with congenital IHH based on hormone levels.

No current or recent use of a medication that, in the opinion of a study investigator, can modulate the reproductive axis or willing to complete an appropriate washout for that particular medication and method of administration

Exclusion Criteria

You drink more than 10 alcoholic drinks a week or use illegal drugs.

I use marijuana and understand it may affect my participation in the study.

History of a medication reaction requiring emergency medical care

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Pre-Treatment

A single SC injection of leuprolide acetate may be administered approximately six days before kisspeptin administration. A pelvic ultrasound will be performed on women to assess baseline follicular size.

1 week

1 visit (in-person)

Treatment

Participants receive pulsatile SC kisspeptin for two weeks. Frequent blood sampling and pelvic ultrasounds for women are conducted to monitor response.

2 weeks

10 blood sampling sessions, 3 ultrasound sessions for women

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Kisspeptin 112-121

Trial Overview The study tests if kisspeptin can trigger reproductive hormone release in IHH patients and help women ovulate. It involves subcutaneous injections of kisspeptin for two weeks and GnRH for about six days, along with ultrasound monitoring in women and frequent blood sampling to measure the body's response.

Participant Groups

Group I: kisspeptin pump Experimental Treatment 2 Interventions

SC administration of kisspeptin for two weeks (pulsatile, every 60-240 minutes)

Who Is Running the Clinical Trial?

Stephanie B. Seminara, MD

Lead Sponsor

Trials

10

Recruited

840+

Findings from Research

A new class of small peptide drugs derived from kisspeptin analogs has been developed, showing potential for treating sex hormone deficiency, particularly by maintaining moderate testosterone levels in male rats.

The pentapeptide analog (19) demonstrated strong agonist activity for the KISS1R receptor and effectively increased luteinizing hormone levels without causing testosterone depletion, unlike previous nonapeptide analogs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new class of pentapeptide KISS1 receptor agonists with hypothalamic-pituitary-gonadal axis activation. Nishizawa, N., Asami, T., Nishibori, K., et al.[2020]

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]

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]

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]

The study identified a new metastin derivative, TAK-448, which effectively suppresses plasma testosterone levels in male rats at lower doses than the standard treatment leuprolide, indicating its potential as a more efficient therapeutic option.

TAK-448 not only demonstrated superior pharmacological activity but also improved water solubility and stability, avoiding gel formation in solution, which enhances its usability for clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility. Nishizawa, N., Takatsu, Y., Kumano, S., et al.[2018]

Kisspeptin-10 (KP-10) was found to have a favorable safety profile in a study involving dogs, with no signs of toxicity observed at doses up to 1,000 μg/kg administered intravenously for 14 days.

The study indicated that KP-10 effectively stimulated luteinizing hormone (LH) release, peaking at 5 minutes post-dose, suggesting its potential as a therapeutic agent for reproductive disorders without adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Evaluation of KP-10 (Metastin 45-54) Following once Daily Intravenous Administration for 14 Days in Dog. Terse, PS., Peggins, J., Seminara, SB.[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]

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-54 (KP54) effectively differentiates men with congenital hypogonadotropic hypogonadism (CHH) from healthy men, showing a significant difference in luteinizing hormone (LH) response, which was much lower in CHH patients (0.4 iU/L) compared to healthy men (12.5 iU/L).

KP54 demonstrated superior accuracy in identifying hypothalamic dysfunction compared to gonadotropin-releasing hormone (GnRH), with a perfect area under the curve of 1.0 for KP54, indicating its potential as a specific test for hypothalamic function in CHH patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism. Abbara, A., Eng, PC., Phylactou, M., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A new class of pentapeptide KISS1 receptor agonists with hypothalamic-pituitary-gonadal axis activation. [2020]

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

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

3. Japan pubmed.ncbi.nlm.nih.gov

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

4. Japan pubmed.ncbi.nlm.nih.gov

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

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility. [2018]

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

Safety Evaluation of KP-10 (Metastin 45-54) Following once Daily Intravenous Administration for 14 Days in Dog. [2022]

8. 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]

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

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

10. Switzerland pubmed.ncbi.nlm.nih.gov

Kisspeptin-54 Accurately Identifies Hypothalamic Gonadotropin-Releasing Hormone Neuronal Dysfunction in Men with Congenital Hypogonadotropic Hypogonadism. [2022]