madman
Super Moderator
I. INTRODUCTION
Kisspeptin-10 was nominated for inclusion on the list of bulk drug substances that can be used in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act).1 Kisspeptin-10 was evaluated for the treatment of secondary hypogonadism in men.2,3 Kisspeptin-10 products proposed in the nomination are: 1 mg/mL solutions for injection for subcutaneous (SC) and intramuscular (IM) administration.
There is no applicable United States Pharmacopeia (USP) or National Formulary (NF) drug substance monograph for kisspeptin-10, and kisspeptin-10 is not a component of an FDA approved drug.
We have evaluated publicly available data on the physicochemical characteristics, safety, effectiveness, and historical use in compounding of this substance. For the reasons discussed below, we believe the evaluation criteria weigh against placing kisspeptin-10 on the list of bulk drug substances that can be used to compound drug products in accordance with section 503A of the FD&C Act (503A Bulks List).
II. EVALUATION CRITERIA
A. Is the substance well-characterized, physically and chemically?
Conclusions
Kisspeptin-10 is a synthetic peptide consisting of ten amino acids. As reported in the literature, kisspeptin-10 as a powder is reportedly stable for one year under -20°C storage condition. Nevertheless, the nominated BDS, kisspeptin-10, is not well characterized from the physical and chemical characterization perspective because certain critical characterization data specific to the kisspeptin-10, such as likely impurities, were neither found in the publicly available scientific literature nor were provided in the CoA, which are offered as evidence to establishing identity, purity, and impurity profiles of kisspeptin-10. For example, we could not find information on the nature and control of individual peptide-related impurities, including aggregates, and variants, in the nomination or elsewhere in the scientific literature. The limited information related to critical characterization data is particularly important for immunogenicity. As discussed in Section II.C.2.d, FDA is concerned about the potential for immunogenicity of kisspeptin-10 when formulated in injectable dosage form for SC and IM administration due to the longer amino acid chain and potential peptide-related impurities as well as potential aggregates, as discussed in the impurities section. Injectable routes of administration may present a particular risk for immunogenicity. We also note that the stability, pharmacological activity, and immunogenic properties of peptides, as a class, are highly sensitive to the manufacturing process and quality attributes of the compounded/finished drug product.
B. Has the substance been used historically in compounding?
Conclusions
There is limited information about the length and extent of kisspeptin-10 use in the U.S. Kisspeptin was first studied in 2001 and kisspeptin-10 was first described as a novel paracrine/endocrine regulator in 2004. A FAERS case report indicated that a compounded injectable kisspeptin-10 product was being used for hypogonadotropic hypogonadism. The most common uses of kisspeptin products on several clinics’ websites are weight loss and fertility. Some compounding pharmacies reported compounding kisspeptin-10 products as an injectableand/or troche formulation. There is no approved product in any country containing kisspeptin-10 at this time, nor is kisspeptin-10 found in the European or Japanese Pharmacopeias.
C. Are there concerns about the safety of the substance for use in compounding?
Conclusions
According to nonclinical pharmacological studies, tachyphylaxis can develop when high doses of kisspeptin-10 are administered uninterruptedly for a long period. This is evidenced by the finding that an initial LH surge is detected soon after the beginning of a continuous IV infusion of monkeys with kisspeptin-10 (1200 or 4800 µg/kg/day) but lasts only 3 h, after which time LH levels decline to baseline values despite the continuous kisspeptin-10 infusion. From the pharmacology/toxicology perspective, although the pro-atherosclerotic effects of kisspeptin-10 are concerning, their clinical relevance remains unclear. In addition, nonclinical toxicity studies available at the time of this evaluation were too limited in scope and duration to inform safety considerations for potential clinical uses of kisspeptin-10.
2. Human Safety
a. Pharmacokinetic data
Conclusion
In healthy men, the half-life of kisspeptin-10 is 3.8 (±0.3) minutes. From the study by Jayasena et al. (2011), it appears that the concentration-time profiles are different for kisspeptin-10 when administered SC vs IV in women. In addition, from the study by Jayasena et al. (2011), it appears that kisspeptin-10 can stimulate gonadotropin release (LH and FSH) in men but cannot consistently stimulate testosterone (with the dosing protocols utilized in the study). Finally, from the Jayasena et al. (2015) study, we observe that IV infusions of kisspeptin-10, kisspeptin-54,and GnRH for 3-hours are associated with similar levels of gonadotropin secretion (LH and FSH) in healthy men; however, GnRH is more potent when compared to either of the kisspeptin isoforms.
b. Reported adverse reactions (FAERS, CAERS, and case reports and anecdotal cases assessing safety)
c. Clinical studies assessing safety
d. Other safety information
e. Therapies that have been used for the condition(s) under consideration
Conclusions
Based on available data, there is a lack of information about whether kisspeptin 10 can be safely used in the intended population, the appropriate dose range, and frequency and duration of dosing for the proposed routes of administration. We found no studies that administered kisspeptin-10 to humans via the IM ROA. We identified a single study that administered a single SC bolus of kisspeptin-10 to approximately 35 healthy women. Acute administration of IV kisspeptin-10 has not raised any major safety concerns in studies to date. However, we found no studies that assessed adverse events for the doses and frequencies of dosing in the context of treatment of diseases in men with reproductive disorders.
The safety profile of compounded drug products containing kisspeptin-10 can be negatively impacted by various factors that include but are not limited to the product formulation, peptide concentration, and conditions of storage favoring the generation of product-related impurities and/or peptide aggregates capable of inducing untoward immunogenic responses. As a peptide with 10 amino acids that is administered through a parenteral route of administration (SC and IM), kisspeptin-10 may pose a significant risk for immunogenicity, potentially amplified by aggregation as well as potential peptide-related impurities. The nomination did not include, and FDA is not aware of, information about kisspeptin-10 to suggest that this substance does not present these risks. At the time of this evaluation, there are several FDA-approved drug products indicated to treat secondary hypogonadism in men.
D. Are there concerns about whether a substance is effective for a particular use?
Secondary hypogonadism in men
a. Reports of trials, clinical evidence, and anecdotal reports of effectiveness, or lack of effectiveness, of the bulk drug substance
b. Whether the product compounded with this bulk drug substance is intended to be used in a serious or life-threatening disease
c. Therapies that have been used for the condition(s) under consideration
Conclusions
Secondary hypogonadism in men is a potentially serious medical condition that may result in reduced male fertility, sexual dysfunction, decreased muscle formation and bone mineralization, and disturbances of fat metabolism. There is insufficient evidence to make a conclusion on the effectiveness of kisspeptin-10 as a treatment option for men with secondary hypogonadism. It is not possible to draw any meaningful conclusions on effectiveness from the studies identified in this evaluation due to the small number of subjects included, the exploratory nature of the studies, and the dosing of kisspeptin-10 (ROA and frequency of administration) used in the studies. We are not aware of studies that administered kisspeptin-10 via the proposed routes of administration (IM or SC) in men with hypogonadism. In addition, it is unclear if chronic IV administration of kisspeptin-10 would confer any clinical benefit in this patient population. At the time of this evaluation, there are several FDA-approved treatments that are indicated to treat secondary hypogonadism in men.
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Kisspeptin-10 was nominated for inclusion on the list of bulk drug substances that can be used in compounding under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act).1 Kisspeptin-10 was evaluated for the treatment of secondary hypogonadism in men.2,3 Kisspeptin-10 products proposed in the nomination are: 1 mg/mL solutions for injection for subcutaneous (SC) and intramuscular (IM) administration.
There is no applicable United States Pharmacopeia (USP) or National Formulary (NF) drug substance monograph for kisspeptin-10, and kisspeptin-10 is not a component of an FDA approved drug.
We have evaluated publicly available data on the physicochemical characteristics, safety, effectiveness, and historical use in compounding of this substance. For the reasons discussed below, we believe the evaluation criteria weigh against placing kisspeptin-10 on the list of bulk drug substances that can be used to compound drug products in accordance with section 503A of the FD&C Act (503A Bulks List).
II. EVALUATION CRITERIA
A. Is the substance well-characterized, physically and chemically?
Conclusions
Kisspeptin-10 is a synthetic peptide consisting of ten amino acids. As reported in the literature, kisspeptin-10 as a powder is reportedly stable for one year under -20°C storage condition. Nevertheless, the nominated BDS, kisspeptin-10, is not well characterized from the physical and chemical characterization perspective because certain critical characterization data specific to the kisspeptin-10, such as likely impurities, were neither found in the publicly available scientific literature nor were provided in the CoA, which are offered as evidence to establishing identity, purity, and impurity profiles of kisspeptin-10. For example, we could not find information on the nature and control of individual peptide-related impurities, including aggregates, and variants, in the nomination or elsewhere in the scientific literature. The limited information related to critical characterization data is particularly important for immunogenicity. As discussed in Section II.C.2.d, FDA is concerned about the potential for immunogenicity of kisspeptin-10 when formulated in injectable dosage form for SC and IM administration due to the longer amino acid chain and potential peptide-related impurities as well as potential aggregates, as discussed in the impurities section. Injectable routes of administration may present a particular risk for immunogenicity. We also note that the stability, pharmacological activity, and immunogenic properties of peptides, as a class, are highly sensitive to the manufacturing process and quality attributes of the compounded/finished drug product.
B. Has the substance been used historically in compounding?
Conclusions
There is limited information about the length and extent of kisspeptin-10 use in the U.S. Kisspeptin was first studied in 2001 and kisspeptin-10 was first described as a novel paracrine/endocrine regulator in 2004. A FAERS case report indicated that a compounded injectable kisspeptin-10 product was being used for hypogonadotropic hypogonadism. The most common uses of kisspeptin products on several clinics’ websites are weight loss and fertility. Some compounding pharmacies reported compounding kisspeptin-10 products as an injectableand/or troche formulation. There is no approved product in any country containing kisspeptin-10 at this time, nor is kisspeptin-10 found in the European or Japanese Pharmacopeias.
C. Are there concerns about the safety of the substance for use in compounding?
Conclusions
According to nonclinical pharmacological studies, tachyphylaxis can develop when high doses of kisspeptin-10 are administered uninterruptedly for a long period. This is evidenced by the finding that an initial LH surge is detected soon after the beginning of a continuous IV infusion of monkeys with kisspeptin-10 (1200 or 4800 µg/kg/day) but lasts only 3 h, after which time LH levels decline to baseline values despite the continuous kisspeptin-10 infusion. From the pharmacology/toxicology perspective, although the pro-atherosclerotic effects of kisspeptin-10 are concerning, their clinical relevance remains unclear. In addition, nonclinical toxicity studies available at the time of this evaluation were too limited in scope and duration to inform safety considerations for potential clinical uses of kisspeptin-10.
2. Human Safety
a. Pharmacokinetic data
Conclusion
In healthy men, the half-life of kisspeptin-10 is 3.8 (±0.3) minutes. From the study by Jayasena et al. (2011), it appears that the concentration-time profiles are different for kisspeptin-10 when administered SC vs IV in women. In addition, from the study by Jayasena et al. (2011), it appears that kisspeptin-10 can stimulate gonadotropin release (LH and FSH) in men but cannot consistently stimulate testosterone (with the dosing protocols utilized in the study). Finally, from the Jayasena et al. (2015) study, we observe that IV infusions of kisspeptin-10, kisspeptin-54,and GnRH for 3-hours are associated with similar levels of gonadotropin secretion (LH and FSH) in healthy men; however, GnRH is more potent when compared to either of the kisspeptin isoforms.
b. Reported adverse reactions (FAERS, CAERS, and case reports and anecdotal cases assessing safety)
c. Clinical studies assessing safety
d. Other safety information
e. Therapies that have been used for the condition(s) under consideration
Conclusions
Based on available data, there is a lack of information about whether kisspeptin 10 can be safely used in the intended population, the appropriate dose range, and frequency and duration of dosing for the proposed routes of administration. We found no studies that administered kisspeptin-10 to humans via the IM ROA. We identified a single study that administered a single SC bolus of kisspeptin-10 to approximately 35 healthy women. Acute administration of IV kisspeptin-10 has not raised any major safety concerns in studies to date. However, we found no studies that assessed adverse events for the doses and frequencies of dosing in the context of treatment of diseases in men with reproductive disorders.
The safety profile of compounded drug products containing kisspeptin-10 can be negatively impacted by various factors that include but are not limited to the product formulation, peptide concentration, and conditions of storage favoring the generation of product-related impurities and/or peptide aggregates capable of inducing untoward immunogenic responses. As a peptide with 10 amino acids that is administered through a parenteral route of administration (SC and IM), kisspeptin-10 may pose a significant risk for immunogenicity, potentially amplified by aggregation as well as potential peptide-related impurities. The nomination did not include, and FDA is not aware of, information about kisspeptin-10 to suggest that this substance does not present these risks. At the time of this evaluation, there are several FDA-approved drug products indicated to treat secondary hypogonadism in men.
D. Are there concerns about whether a substance is effective for a particular use?
Secondary hypogonadism in men
a. Reports of trials, clinical evidence, and anecdotal reports of effectiveness, or lack of effectiveness, of the bulk drug substance
b. Whether the product compounded with this bulk drug substance is intended to be used in a serious or life-threatening disease
c. Therapies that have been used for the condition(s) under consideration
Conclusions
Secondary hypogonadism in men is a potentially serious medical condition that may result in reduced male fertility, sexual dysfunction, decreased muscle formation and bone mineralization, and disturbances of fat metabolism. There is insufficient evidence to make a conclusion on the effectiveness of kisspeptin-10 as a treatment option for men with secondary hypogonadism. It is not possible to draw any meaningful conclusions on effectiveness from the studies identified in this evaluation due to the small number of subjects included, the exploratory nature of the studies, and the dosing of kisspeptin-10 (ROA and frequency of administration) used in the studies. We are not aware of studies that administered kisspeptin-10 via the proposed routes of administration (IM or SC) in men with hypogonadism. In addition, it is unclear if chronic IV administration of kisspeptin-10 would confer any clinical benefit in this patient population. At the time of this evaluation, there are several FDA-approved treatments that are indicated to treat secondary hypogonadism in men.
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