madman
Super Moderator
Abstract
Background
Oral testosterone undecanoate (TU) formulations may provide effective, safe, and easily titratable testosterone replacement therapy.
Objective
Demonstrate efficacy and safety of a novel oral TU formulation.
Design
An open-label, single-arm, multi-center trial treated 155 hypogonadal men for 180 days. Treatment began at 200mg TU twice daily with meals; doses were titrated over two 28-day cycles to between 100 and 800 mg TU daily, measuring average testosterone (T Cavg) after 90 days. Ambulatory blood pressure monitoring (ABPM) occurred at baseline, 120, and 180 days.
Methods
Titrations used a randomized blood sample taken 3-, 4-, or 5-h post-morning dose. Outcomes used sodium fluoride/ethylenediaminetetraacetate plasma testosterone (T) values;serum results were also reported. Blood pressure (ABPM and in-clinic) was evaluated for change from baseline.
Results
After titration, 87.8% of KYZATREX™ treated participants (worse-case scenario) and 96.1% of 90-day completers achieved eugonadal mean plasma T values. Serum T Cavg was 452 ng/dL and maximum T concentrations (T Cmax) met all FDA criteria. Participant eugonada lpercentages were comparable across subgroups for age, weight, and body mass index. Diet had no effect on participant eugonadal percentages. KYZATREX was well tolerated, with no drug-related serious adverse events (SAE) and one adverse drug reaction (hypertension)observed in 2% or more of participants. Systolic ambulatory blood pressure increased 1.7mmHg (95% confidence interval: 0.3–3.1). At baseline, 36% of 155 participants were receiving anti-hypertensive medication and 22% were diabetic. No dose increases occurred in existing anti-hypertensive medication; five participants (3.2%) started anti-hypertensive medication.
Conclusion
KYZATREX provided safe and effective testosterone levels within the normal range in hypogonadal male study participants.
Several products have been approved for testosterone replacement therapy (TRT) in the United States of America (USA).1 They contain either T, a T prodrug (i.e. T ester), or an active derivative of T (i.e. methyl derivative). Testosterone and related substances are Schedule III non-narcotic controlled substances in the USA. Routes of administration include implantable pellets, intramuscular injections, transdermal, buccal, nasal,and oral formulations. T products are indicated for TRT in males with a deficiency or absence of endogenous T due to primary or secondary hypogonadism. Side effects common to all TRT products include increases in hematocrit and prostate-specific antigen (PSA), changes in lipid levels, sleep apnea, and increases in blood pressure. These side effects are well characterized in product labeling and scientific literature. Results of long-term cardiovascular safety of TRT in men 45–80years with hypogonadism and pre existing or a high risk of cardiovascular disease (TRAVERSE; NCT03518034) were recently published. Testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events(MACE).6
Five oral preparations are currently available in the USA. The two oldest, methyltestosterone and fluoxymesterone, are associated with liver toxicity.1,2 Three oral testosterone undecanoate (TU) preparations have recently received approval from the US FDA: JATENZO™ was approved in March2019, TLANDO™ was approved in March 2022, and KYZATREX™ was approved in July 2022.7–9
Drug product
KYZATREX (known as SOV2012-F1 during clinical evaluations) is a Self-Emulsifying Drug Delivery System containing propylene glycol monolaurate (Type II), polyoxyl 40 hydrogenated castor oil, phytosterol esters, DL-alpha-tocopheryl acetate, and TU enclosed in a soft gelatin capsule. The drug product was provided in strengths of 100, 150, and 200 mg TU per capsule.9
Study design and titration procedure
Participants were either newly recruited or participated in the previous 12-month study(MRS-TU-2019) of the same KYZATREX formulation which used different titration criteria and doses. All participants were completely washed out of any previously approved or investigational TRT for at least 2 weeks before the beginning of treatment (longer times for depot type TRT). Figure 1 outlines the disposition of participants for MRS-TU-2019EXT.
Prior to the beginning of treatment, all participants completed the National Institute of Health ASA24® dietary assessment tool to identify diet habits for meals to be consumed on trial days on which PK samples were obtained.14 Participants were classified into low-, moderate-, and high-fat categories for each of breakfast and dinner. Breakfast and dinner meals were designed t odeliver varying percentages of calories from fat: low-fat meals (⩽20% calories from fat), normal fat meals (>20–35%), and high-fat meals (>35%). All lunches were normal fat as no drug was administered with lunch. Meal consumption for breakfast and dinner was recorded for all PK collection visits. Participants were instructed to take KYZATREX capsules with water 30 (±5) min after the start of the morning and evening meals (breakfast only for the 100mg dose level).
Treatment was initiated with a starting dose of 400mg TU given as 200 mg twice daily with breakfast and the evening meal. After 14 days, a 6-h PK sampling period was used to collect plasma (and serum) samples from which a titration decision would be based on the T-concentration in either the 3-, 4-, or 5-h plasma sample according to a randomization schedule. The titration decision was implemented on the 28th day of dosing. A second titration cycle was conducted in the same manner on the 42nd and 56th days of treatment. All titration decisions were determined centrally and communicated through interactive web response technology.
The primary endpoint of percent of participants in the normal range was assessed by a 24-h PK measurement (T Cavg) using NaF/EDTA plasma samples after 90 days of treatment. Serum T was assessed in a sub-study group on Day 90 as well. After the two cycles of titration, participants could be at daily dose levels of 100 (morning only), 200, 400, 600, or 800 mg using capsule strengths of 100, 150, and 200mg. Participants continued at their Day 90 dose for the remainder of the study to 180 days.
The titration algorithm used is provided in Table 2, noting that all doses are taken with meals.
The day prior to treatment initiation, a 24-h ABPM and in-clinic assessment (SBP, DBP, HR, arterial pressure, and pulse pressure) was completed to establish the BP baseline. After 120 and 180days of treatment, the 24-h ABPM assessment was repeated. This design allowed assessment of whether treatment-related changes in BP and HR continued or plateaued between the Day120 and Day 180 treatment assessments. In-clinic BP and HR were collected at scheduled visits.
Pharmacokinetic and efficacy assessments
Efficacy assessment was based on the percent age of treated participants whose 24-h T Cavg was within the NaF/EDTA plasma normal range. The T Cavg was calculated using actual sample times,and the percentage of participants within the normal range calculated using a worse-case scenario(WCS) that treated study drop-outs as treatment failures. The percentage of participants achieving T Cavg within the normal range was also assessed as a function of the Day 42 sample time (3-, 4-, or 5-h post-dose) used for determination of the titration decision.
Sample times for PK assessment were chosen to maximize the density of sampling around the expected time of maximum T concentration. Samples for PK assessments were collected at 0, 1.5, 3, 4, 5, 6, 8, 12, 13.5, 15, 16, 17, 18, 20, and 24h after the Day 90 morning dose. On Days 14 and 42, samples (plasma and serum) were collected at 0, 1.5, 3, 4, 5, and 6h only; the 3-, 4-, or 5-h plasma sample was used for making the titration decision as described above. Free T concentrations were calculated according to Vermeulen.15
Serum sub-study
After initiation of the trial, a sub-study was added to the protocol for assessment of the Day 90 24-hPK of T and DHT by serum samples. Serum samples (in addition to NaF/EDTA plasma) were collected for 89 participants in the study and evaluated against the primary and secondary endpoints for T Cavg and C
Evaluation of food effects on efficacy
The effect of diet choice was explored in two ways: first, geometric least squares mean (GLSM) ratios were calculated for T Cavg and T Cmax across breakfast diet categories (low-, normal-,and high-fat); second, the percentage of participants achieving the normal range on Day 90 was evaluated for breakfast diet categories.
Hormonal parameters
The percentage of participants at Day 90 with DHT Cavg below the ULN was 41.3%. The percentage of Day 90 participants with DHT Cavg above 2× the ULN was 4.8%; one value was above 3× but less than 5× the ULN on Day 90. The DHT Cavg for 95% of participants was below 2× the ULN. The pre-dose values on Day 1 of plasma DHT and T were 14.2 and 231.5 ng/dL, respectively, for a pre-dose ratio (percent) of 6.1%. However, the limit of quantitation for DHT was 10ng/dL, and the standard deviation reported for pre-dose DHT was 10.4ng/dL; thus, the pre-dose ratio has significant uncertainty. At Day 90, the ratio of DHT to T increased to 21.0% (SD=7.7%).
Figure 5 shows mean SHBG (5a), FSH (5b) and LH (5c) decreased from baseline to Day 90 and to end of treatment (nominally Day 180). While TSH levels decreased slightly at Day 90, they returned to near-baseline levels by end of treatment. Estradiol increased from 2.3 ng/dL (single sample, pre-treatment) to a Cavg of 3.5ng/dL at Day 90. The estradiol/testosterone ratio at Day 90 remained unchanged from 1.00% at pre-treatment. The mean values of these hormones remained within the normal range.
Vermeulen postulated that the sum of free T plus T bound to albumin reflects the concentration available for androgenic activity more than total T. In place of direct measurement of free T, Vermeulen presented a simple method for calculation of free T using total T, SHBG, and albumin concentrations and showed good correlation of the calculated value versus measured free T.15 Using Vermeulen’s calculation, the mean free T (SD) in serum at baseline was 7.0 (3.1) ng/dL;after 90 days of treatment with KYZATREX, the calculated mean free T was 14.1 (4.5)ng/dL.
Adverse events
Table 12 categorizes TEAEs observed in MRSTU-2019EXT. The majority of TEAEs were of mild to moderate intensity. Treatment-related TEAEs occurring in more than 1 participant included (number of participants, percent of treated participants): Hgb increased (3, 1.9%), acne (2, 1.3%), and hypertension (2, 1.3%).There were six (3.9%) TEAE reports of hypertension or blood pressure increase; two were judged of moderate intensity and four of mild intensity. No cases of treatment-related SAE nor of treatment-related severe TEAE’s was reported for the MRS-TU-2019EXT trial. There were no deaths and no cases of MACE reported in this trial.
The two serious TEAE were atrial fibrillation and diverticular perforation, neither of which was judged to be treatment related. Three participants account for the four severe TEAE observed: atrial fibrillation (1, SAE), diverticulum (1, SAE), diverticular perforation (1, SAE), and tendon rupture (1). The TEAE leading to discontinuation was acne of moderate intensity.
Red blood cell mass
Mean Hgb was 14.7 g/dL at baseline, 15.1 g/dL at Day 90, and 15.2 g/dL at Day 180, for a mean increase of 0.5g/dL, appearing to plateau between 90 and 180 days of treatment. There were 21 (14.7%) study participants with Hgb values greater than the upper limit of the lab normal range (16.9 g/dL) at the final study visit. Three participants (1.9%) had a TEAE of increased Hgb, with maximum values of 18.7, 17.1, and 18.0g/dL. As noted earlier, Hgb was used as an index of red blood cell mass.
Results of liver enzymes and blood chemistry
There was no clinically significant change in mean values for LFTs throughout the study. There were also no trends over time in the percent of participants LFT values between 1–2×, 2–3×, or > 3× the ULN for alanine transaminase (ALT), aspartate trans-aminase (AST), alkaline phosphatase (ALP), or bilirubin. One participant had elevated LFT values prior to the start of dosing and withdrew at Day 120 because of persistent elevation (ALP, ALT, and AST).There were no clinically significant changes in blood urea nitrogen, creatinine, sodium, potassium, or calcium.
Results of lipid profiles
From baseline, total cholesterol decreased 11.1 mg/dL (−5.2%), low-density lipoprotein cholesterol decreased 4.0 mg/dL (−0.8%), high density lipoprotein (HDL) cholesterol decreased 6.9 mg/dL (−14.0%), and triglycerides decreased 18.6 mg/dL (−1.2%). The median decrease from baseline for triglycerides was 6.0 mg/dL (−6.1%).
PSA results, prostate, and physical examination
Mean PSA at baseline was 1.0 ng/mL. The mean change from baseline after 90 and after 180 days of treatment was an increase of 0.2 ng/mL. Two participants (1.5%) had an increase in PSA >1.4ng/mL, and the same two participants had a PSA ⩾4.0ng/mL. All participants had a normal digital rectal examination at baseline and end of treatment. No participants had clinically significant gynecomastia at any time point.
Discussion
Efficacy
This phase III study of KYZATREX demonstrated that a flexible titration window (samples taken 3- to 5-h after morning dose) approach coupled with a novel formulation met FDA standards for efficacy and Cmax. The KYZATREX dose range is wide enough to treat both super responders who require down-titration as well as poor responders requiring higher doses. Results show that for participants who completed two titration cycles and 90 days of treatment, the large majority (96.1%) achieved Cavg values within the normal range. The use of serum results (serum sub-study) gave very comparable results for the percent of participants within the normal range after 90 days of treatment (86.5% using WCS,lower bound of the 95% CI: 79.4%).
The trial participants were drawn from a geographically diverse population of men in the USA and included substantial sub-populations with respect to hypertension, diabetic status, weight, body mass index, ethnicity, and age. Representation from diverse racial groups was limited; about 16% of the participants identified as black, but significant participation from other racial groups was small.
Subgroup analyses showed that the percent of participants in the normal range was not affected by age, weight, and BMI subgroups (trends to lower Cavg were noted with weight >93kg and BMI >30 kg/m2). The logistic analysis showed a relationship of dose and baseline body mass: higher body mass was associated with higher KYZATREX doses. Similarly, dose and diabetic status were related: the presence of diabetes at baseline (HbA1c >6.5%) was associated with higher KYZATREX doses.
With respect to the time at which the blood sample is obtained for adjusting or maintaining the KYZATREX dose level, analysis of the percentage of participants achieving the normal range outcome after two titration cycles and 90 days of treatment showed that regardless of whether the 3, 4, or 5-h time point was used on Day 42, more than 84% of participants achieved Cavg in the normal range.
Diet choices in MRS-TU-2019EXT had little to no observable effect on the percent of participants in the normal range or on PK parameters of T. In contrast to single-dose food effect studies in which a food effect for the highly lipophilic TU is usually observed,18 the phase III results forKYZATREX show that patient diet choices have minimal or no effect on the percentage of participants achieving the normal range for T Cavg. This may be due to participants consuming enough lipids even in low-fat meals such that sufficient absorption of TU occurs. The Day 90 GLSM ratios have a narrow range, even when comparing the low-fat versus high-fat breakfast, indicating that patients can achieve Cavg within the normal range regardless of diet choices.
A direct approach was used in calculating titration thresholds for use of serum samples, rather than a model-based approach. The data set for this direct approach used serum and NaF/EDTA plasma samples collected simultaneously at both titration visits (0–6h collected, hours 3, 4, and 5 used in defining the relationship). A regression analysis using the 3-, 4-, and 5-h time points yields an empirical relationship between the serum and plasma values based on samples from 18 clinical sites and 139 participants. This empirical relationship incorporates the stability and bioanalytical factors that are modeled separately in other studies.12
Conclusion
The authors conclude that within the limits of the study reported here, KYZATREX is a safe and effective means to treat hypogonadal men,with a safety profile consistent with other TRT products and as an oral medication without the constraints of other routes of administration. Oral TU products are associated with blood pressure increases in some men, with a statistically significant mean increase reported for SBP. In this study, a very high percentage (96.1%) of the trial participants completing 90 days of treatment achieved average T-levels within the normal range. KYZATREX met all FDA safety guidance regarding the maximum T concentrations for all three threshold groups. The majority of the recorded TEAEs were of mild-to-moderate intensity, and no drug-related SAE were observed in this study. The type of diet (low-,normal-, or high-fat) did not significantly affect the percentage of men achieving T values in the normal range. The flexibility of obtaining a blood sample within a window of 3- to 5-h after the morning dose improves the convenience of titrating KYZATREX.
Background
Oral testosterone undecanoate (TU) formulations may provide effective, safe, and easily titratable testosterone replacement therapy.
Objective
Demonstrate efficacy and safety of a novel oral TU formulation.
Design
An open-label, single-arm, multi-center trial treated 155 hypogonadal men for 180 days. Treatment began at 200mg TU twice daily with meals; doses were titrated over two 28-day cycles to between 100 and 800 mg TU daily, measuring average testosterone (T Cavg) after 90 days. Ambulatory blood pressure monitoring (ABPM) occurred at baseline, 120, and 180 days.
Methods
Titrations used a randomized blood sample taken 3-, 4-, or 5-h post-morning dose. Outcomes used sodium fluoride/ethylenediaminetetraacetate plasma testosterone (T) values;serum results were also reported. Blood pressure (ABPM and in-clinic) was evaluated for change from baseline.
Results
After titration, 87.8% of KYZATREX™ treated participants (worse-case scenario) and 96.1% of 90-day completers achieved eugonadal mean plasma T values. Serum T Cavg was 452 ng/dL and maximum T concentrations (T Cmax) met all FDA criteria. Participant eugonada lpercentages were comparable across subgroups for age, weight, and body mass index. Diet had no effect on participant eugonadal percentages. KYZATREX was well tolerated, with no drug-related serious adverse events (SAE) and one adverse drug reaction (hypertension)observed in 2% or more of participants. Systolic ambulatory blood pressure increased 1.7mmHg (95% confidence interval: 0.3–3.1). At baseline, 36% of 155 participants were receiving anti-hypertensive medication and 22% were diabetic. No dose increases occurred in existing anti-hypertensive medication; five participants (3.2%) started anti-hypertensive medication.
Conclusion
KYZATREX provided safe and effective testosterone levels within the normal range in hypogonadal male study participants.
Several products have been approved for testosterone replacement therapy (TRT) in the United States of America (USA).1 They contain either T, a T prodrug (i.e. T ester), or an active derivative of T (i.e. methyl derivative). Testosterone and related substances are Schedule III non-narcotic controlled substances in the USA. Routes of administration include implantable pellets, intramuscular injections, transdermal, buccal, nasal,and oral formulations. T products are indicated for TRT in males with a deficiency or absence of endogenous T due to primary or secondary hypogonadism. Side effects common to all TRT products include increases in hematocrit and prostate-specific antigen (PSA), changes in lipid levels, sleep apnea, and increases in blood pressure. These side effects are well characterized in product labeling and scientific literature. Results of long-term cardiovascular safety of TRT in men 45–80years with hypogonadism and pre existing or a high risk of cardiovascular disease (TRAVERSE; NCT03518034) were recently published. Testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events(MACE).6
Five oral preparations are currently available in the USA. The two oldest, methyltestosterone and fluoxymesterone, are associated with liver toxicity.1,2 Three oral testosterone undecanoate (TU) preparations have recently received approval from the US FDA: JATENZO™ was approved in March2019, TLANDO™ was approved in March 2022, and KYZATREX™ was approved in July 2022.7–9
Drug product
KYZATREX (known as SOV2012-F1 during clinical evaluations) is a Self-Emulsifying Drug Delivery System containing propylene glycol monolaurate (Type II), polyoxyl 40 hydrogenated castor oil, phytosterol esters, DL-alpha-tocopheryl acetate, and TU enclosed in a soft gelatin capsule. The drug product was provided in strengths of 100, 150, and 200 mg TU per capsule.9
Study design and titration procedure
Participants were either newly recruited or participated in the previous 12-month study(MRS-TU-2019) of the same KYZATREX formulation which used different titration criteria and doses. All participants were completely washed out of any previously approved or investigational TRT for at least 2 weeks before the beginning of treatment (longer times for depot type TRT). Figure 1 outlines the disposition of participants for MRS-TU-2019EXT.
Prior to the beginning of treatment, all participants completed the National Institute of Health ASA24® dietary assessment tool to identify diet habits for meals to be consumed on trial days on which PK samples were obtained.14 Participants were classified into low-, moderate-, and high-fat categories for each of breakfast and dinner. Breakfast and dinner meals were designed t odeliver varying percentages of calories from fat: low-fat meals (⩽20% calories from fat), normal fat meals (>20–35%), and high-fat meals (>35%). All lunches were normal fat as no drug was administered with lunch. Meal consumption for breakfast and dinner was recorded for all PK collection visits. Participants were instructed to take KYZATREX capsules with water 30 (±5) min after the start of the morning and evening meals (breakfast only for the 100mg dose level).
Treatment was initiated with a starting dose of 400mg TU given as 200 mg twice daily with breakfast and the evening meal. After 14 days, a 6-h PK sampling period was used to collect plasma (and serum) samples from which a titration decision would be based on the T-concentration in either the 3-, 4-, or 5-h plasma sample according to a randomization schedule. The titration decision was implemented on the 28th day of dosing. A second titration cycle was conducted in the same manner on the 42nd and 56th days of treatment. All titration decisions were determined centrally and communicated through interactive web response technology.
The primary endpoint of percent of participants in the normal range was assessed by a 24-h PK measurement (T Cavg) using NaF/EDTA plasma samples after 90 days of treatment. Serum T was assessed in a sub-study group on Day 90 as well. After the two cycles of titration, participants could be at daily dose levels of 100 (morning only), 200, 400, 600, or 800 mg using capsule strengths of 100, 150, and 200mg. Participants continued at their Day 90 dose for the remainder of the study to 180 days.
The titration algorithm used is provided in Table 2, noting that all doses are taken with meals.
The day prior to treatment initiation, a 24-h ABPM and in-clinic assessment (SBP, DBP, HR, arterial pressure, and pulse pressure) was completed to establish the BP baseline. After 120 and 180days of treatment, the 24-h ABPM assessment was repeated. This design allowed assessment of whether treatment-related changes in BP and HR continued or plateaued between the Day120 and Day 180 treatment assessments. In-clinic BP and HR were collected at scheduled visits.
Pharmacokinetic and efficacy assessments
Efficacy assessment was based on the percent age of treated participants whose 24-h T Cavg was within the NaF/EDTA plasma normal range. The T Cavg was calculated using actual sample times,and the percentage of participants within the normal range calculated using a worse-case scenario(WCS) that treated study drop-outs as treatment failures. The percentage of participants achieving T Cavg within the normal range was also assessed as a function of the Day 42 sample time (3-, 4-, or 5-h post-dose) used for determination of the titration decision.
Sample times for PK assessment were chosen to maximize the density of sampling around the expected time of maximum T concentration. Samples for PK assessments were collected at 0, 1.5, 3, 4, 5, 6, 8, 12, 13.5, 15, 16, 17, 18, 20, and 24h after the Day 90 morning dose. On Days 14 and 42, samples (plasma and serum) were collected at 0, 1.5, 3, 4, 5, and 6h only; the 3-, 4-, or 5-h plasma sample was used for making the titration decision as described above. Free T concentrations were calculated according to Vermeulen.15
Serum sub-study
After initiation of the trial, a sub-study was added to the protocol for assessment of the Day 90 24-hPK of T and DHT by serum samples. Serum samples (in addition to NaF/EDTA plasma) were collected for 89 participants in the study and evaluated against the primary and secondary endpoints for T Cavg and C
Evaluation of food effects on efficacy
The effect of diet choice was explored in two ways: first, geometric least squares mean (GLSM) ratios were calculated for T Cavg and T Cmax across breakfast diet categories (low-, normal-,and high-fat); second, the percentage of participants achieving the normal range on Day 90 was evaluated for breakfast diet categories.
Hormonal parameters
The percentage of participants at Day 90 with DHT Cavg below the ULN was 41.3%. The percentage of Day 90 participants with DHT Cavg above 2× the ULN was 4.8%; one value was above 3× but less than 5× the ULN on Day 90. The DHT Cavg for 95% of participants was below 2× the ULN. The pre-dose values on Day 1 of plasma DHT and T were 14.2 and 231.5 ng/dL, respectively, for a pre-dose ratio (percent) of 6.1%. However, the limit of quantitation for DHT was 10ng/dL, and the standard deviation reported for pre-dose DHT was 10.4ng/dL; thus, the pre-dose ratio has significant uncertainty. At Day 90, the ratio of DHT to T increased to 21.0% (SD=7.7%).
Figure 5 shows mean SHBG (5a), FSH (5b) and LH (5c) decreased from baseline to Day 90 and to end of treatment (nominally Day 180). While TSH levels decreased slightly at Day 90, they returned to near-baseline levels by end of treatment. Estradiol increased from 2.3 ng/dL (single sample, pre-treatment) to a Cavg of 3.5ng/dL at Day 90. The estradiol/testosterone ratio at Day 90 remained unchanged from 1.00% at pre-treatment. The mean values of these hormones remained within the normal range.
Vermeulen postulated that the sum of free T plus T bound to albumin reflects the concentration available for androgenic activity more than total T. In place of direct measurement of free T, Vermeulen presented a simple method for calculation of free T using total T, SHBG, and albumin concentrations and showed good correlation of the calculated value versus measured free T.15 Using Vermeulen’s calculation, the mean free T (SD) in serum at baseline was 7.0 (3.1) ng/dL;after 90 days of treatment with KYZATREX, the calculated mean free T was 14.1 (4.5)ng/dL.
Adverse events
Table 12 categorizes TEAEs observed in MRSTU-2019EXT. The majority of TEAEs were of mild to moderate intensity. Treatment-related TEAEs occurring in more than 1 participant included (number of participants, percent of treated participants): Hgb increased (3, 1.9%), acne (2, 1.3%), and hypertension (2, 1.3%).There were six (3.9%) TEAE reports of hypertension or blood pressure increase; two were judged of moderate intensity and four of mild intensity. No cases of treatment-related SAE nor of treatment-related severe TEAE’s was reported for the MRS-TU-2019EXT trial. There were no deaths and no cases of MACE reported in this trial.
The two serious TEAE were atrial fibrillation and diverticular perforation, neither of which was judged to be treatment related. Three participants account for the four severe TEAE observed: atrial fibrillation (1, SAE), diverticulum (1, SAE), diverticular perforation (1, SAE), and tendon rupture (1). The TEAE leading to discontinuation was acne of moderate intensity.
Red blood cell mass
Mean Hgb was 14.7 g/dL at baseline, 15.1 g/dL at Day 90, and 15.2 g/dL at Day 180, for a mean increase of 0.5g/dL, appearing to plateau between 90 and 180 days of treatment. There were 21 (14.7%) study participants with Hgb values greater than the upper limit of the lab normal range (16.9 g/dL) at the final study visit. Three participants (1.9%) had a TEAE of increased Hgb, with maximum values of 18.7, 17.1, and 18.0g/dL. As noted earlier, Hgb was used as an index of red blood cell mass.
Results of liver enzymes and blood chemistry
There was no clinically significant change in mean values for LFTs throughout the study. There were also no trends over time in the percent of participants LFT values between 1–2×, 2–3×, or > 3× the ULN for alanine transaminase (ALT), aspartate trans-aminase (AST), alkaline phosphatase (ALP), or bilirubin. One participant had elevated LFT values prior to the start of dosing and withdrew at Day 120 because of persistent elevation (ALP, ALT, and AST).There were no clinically significant changes in blood urea nitrogen, creatinine, sodium, potassium, or calcium.
Results of lipid profiles
From baseline, total cholesterol decreased 11.1 mg/dL (−5.2%), low-density lipoprotein cholesterol decreased 4.0 mg/dL (−0.8%), high density lipoprotein (HDL) cholesterol decreased 6.9 mg/dL (−14.0%), and triglycerides decreased 18.6 mg/dL (−1.2%). The median decrease from baseline for triglycerides was 6.0 mg/dL (−6.1%).
PSA results, prostate, and physical examination
Mean PSA at baseline was 1.0 ng/mL. The mean change from baseline after 90 and after 180 days of treatment was an increase of 0.2 ng/mL. Two participants (1.5%) had an increase in PSA >1.4ng/mL, and the same two participants had a PSA ⩾4.0ng/mL. All participants had a normal digital rectal examination at baseline and end of treatment. No participants had clinically significant gynecomastia at any time point.
Discussion
Efficacy
This phase III study of KYZATREX demonstrated that a flexible titration window (samples taken 3- to 5-h after morning dose) approach coupled with a novel formulation met FDA standards for efficacy and Cmax. The KYZATREX dose range is wide enough to treat both super responders who require down-titration as well as poor responders requiring higher doses. Results show that for participants who completed two titration cycles and 90 days of treatment, the large majority (96.1%) achieved Cavg values within the normal range. The use of serum results (serum sub-study) gave very comparable results for the percent of participants within the normal range after 90 days of treatment (86.5% using WCS,lower bound of the 95% CI: 79.4%).
The trial participants were drawn from a geographically diverse population of men in the USA and included substantial sub-populations with respect to hypertension, diabetic status, weight, body mass index, ethnicity, and age. Representation from diverse racial groups was limited; about 16% of the participants identified as black, but significant participation from other racial groups was small.
Subgroup analyses showed that the percent of participants in the normal range was not affected by age, weight, and BMI subgroups (trends to lower Cavg were noted with weight >93kg and BMI >30 kg/m2). The logistic analysis showed a relationship of dose and baseline body mass: higher body mass was associated with higher KYZATREX doses. Similarly, dose and diabetic status were related: the presence of diabetes at baseline (HbA1c >6.5%) was associated with higher KYZATREX doses.
With respect to the time at which the blood sample is obtained for adjusting or maintaining the KYZATREX dose level, analysis of the percentage of participants achieving the normal range outcome after two titration cycles and 90 days of treatment showed that regardless of whether the 3, 4, or 5-h time point was used on Day 42, more than 84% of participants achieved Cavg in the normal range.
Diet choices in MRS-TU-2019EXT had little to no observable effect on the percent of participants in the normal range or on PK parameters of T. In contrast to single-dose food effect studies in which a food effect for the highly lipophilic TU is usually observed,18 the phase III results forKYZATREX show that patient diet choices have minimal or no effect on the percentage of participants achieving the normal range for T Cavg. This may be due to participants consuming enough lipids even in low-fat meals such that sufficient absorption of TU occurs. The Day 90 GLSM ratios have a narrow range, even when comparing the low-fat versus high-fat breakfast, indicating that patients can achieve Cavg within the normal range regardless of diet choices.
A direct approach was used in calculating titration thresholds for use of serum samples, rather than a model-based approach. The data set for this direct approach used serum and NaF/EDTA plasma samples collected simultaneously at both titration visits (0–6h collected, hours 3, 4, and 5 used in defining the relationship). A regression analysis using the 3-, 4-, and 5-h time points yields an empirical relationship between the serum and plasma values based on samples from 18 clinical sites and 139 participants. This empirical relationship incorporates the stability and bioanalytical factors that are modeled separately in other studies.12
Conclusion
The authors conclude that within the limits of the study reported here, KYZATREX is a safe and effective means to treat hypogonadal men,with a safety profile consistent with other TRT products and as an oral medication without the constraints of other routes of administration. Oral TU products are associated with blood pressure increases in some men, with a statistically significant mean increase reported for SBP. In this study, a very high percentage (96.1%) of the trial participants completing 90 days of treatment achieved average T-levels within the normal range. KYZATREX met all FDA safety guidance regarding the maximum T concentrations for all three threshold groups. The majority of the recorded TEAEs were of mild-to-moderate intensity, and no drug-related SAE were observed in this study. The type of diet (low-,normal-, or high-fat) did not significantly affect the percentage of men achieving T values in the normal range. The flexibility of obtaining a blood sample within a window of 3- to 5-h after the morning dose improves the convenience of titrating KYZATREX.
