madman
Super Moderator
New testosterone 2% gel using Ferring Advanced Skin Technology (FAST), for the treatment of testosterone deficiency in men, with a novel applicator
Michael Kirby, Atul Kalhan & Geoffrey Hackett
Abstract
Introduction: Testosterone deficiency (TD) is an increasing problem that can affect a man’s physical and psychological health and quality of life. Testosterone replacement therapy (TRT), combined with weight reduction, lifestyle advice, and the treatment of co-morbidities, is the treatment of choice in men who are not concerned about fertility. However, there remains an unmet need in this therapeutic area, relating to factors such as inconvenient or painful administration, fluctuations in testosterone levels, supra-physiologic testosterone levels, poor tolerability, and secondary safety issues, which may be associated with the current TRT options. Advances in transdermal delivery systems have resulted in the development of a new 2% transdermal testosterone gel, that may offer some additional features over the other currently available TRTs.
Areas covered: We performed a comprehensive review of the published and grey literature to identify randomized studies and non-randomized studies (NRS) involving adult men receiving treatment for low testosterone levels.
Expert opinion: Topical gels are often the most convenient first-line treatment for testosterone deficiency, but options are important as patient preference is more important than virtually any other clinical area of medicine. The chosen therapy must be convenient to use and reach reliable therapeutic levels to effectively and consistently relieve symptoms. Testavan a new 2% testosterone gel, goes some way to achieving these goals.
1. Introduction
Testosterone is the main androgen in men. It plays a crucial role in the development and maintenance of secondary male characteristics and influences body composition, sexual and cognitive function, erythropoiesis, and bone and muscle health 1.
When testosterone levels fall, men can suffer a variety of physical, sexual, and psychological effects, and a subsequent reduction in the quality of life2. TD has been shown, in multiple longitudinal studies, to be linked to earlier all-cause and cardiovascular disease (CVD)- related mortality, and incident type 2 diabetes 3.
The clinical burden of TD has increased notably over the last few years 4, paralleling the increasing rates of obesity, metabolic syndrome, type 2 diabetes and opiate use 5. In the European Male Ageing Study (EMAS), the prevalence of TD was 2.1% overall in men aged 40- 79 years and rates increased with age, from 0.1% in men in their 40’s to 0.6% in those in their 50’s, to 3.2 % in those in their 60’s, to 5.1% in those in their 70’s 6. Projected estimates suggest that TD will affect as many as 6.5 million American men aged between 30-79 years by 2025; a 38% increase from 2000 7.
While testosterone levels decrease naturally with advancing age 8, the EMAS study found that three-quarters of men maintained normal testosterone levels into old age, which suggests that TD is not solely a consequence of ageing 9. Furthermore, only a small percentage of older men with suppressed testosterone levels develop the genuine syndrome of TD, associated with diffuse physical (e.g. frailty and loss of vigour), sexual (e.g. erectile dysfunction) and psychological (e.g depression) symptoms 8.
The global prevalence of testosterone deficiency (TD) ranges from 10–40%. The actual diagnosis of TD is controversial, as Internationally, a wide range of total testosterone (TT) thresholds are used for diagnosis 200–400 ng/dL, (7-14 nmol/L), and physicians differ in their emphasis placed on clinical symptoms. There are also significant global differences in the prescription patterns of testosterone replacement therapy (TRT). In the United States, for example, prescription of TRT is significantly higher than the rest of the world, increasing 3- fold over the last 10 years and more so in eugonadal men which are concerning 10.
TD occurs as a result of testicular abnormalities (primary TD), defects in the pituitary or hypothalamus (secondary TD), or a combination of both (combined/mixed TD)11. TD is more likely to affect men of advanced age and those with obesity, metabolic syndrome (MetS) and poor general health3.
TD signs and symptoms vary depending on age at onset, duration and severity 1,12,13. Physical signs and symptoms include decreased body hair, gynecomastia, reduced muscle mass and strength, poor sleep, hot flushes/sweats, fatigue and osteoporosis. Cardio-metabolic signs and symptoms include increased Body Mass Index (BMI), visceral obesity, Metabolic Syndrome (MetS), insulin resistance and type 2 diabetes mellitus. Sexual signs and symptoms include small testicles, delayed puberty, infertility, decreased sexual desire/activity, reduced frequency of sexual thoughts, absent or fewer morning/night-time erections, ED, delayed ejaculation and decreased volume of ejaculate. Psychological signs and symptoms include mood changes, impaired cognitive function and decreased well-being or poor self-rated health 1,2,11-14.
A diagnosis of genuine TD requires both clinical and biochemical evidence of suppressed testosterone levels 12,14. In this regard, testosterone replacement therapy should only be prescribed when blood levels are unequivocally low, in the presence of clinical signs & symptoms & in the absence of any other potentially treatable causes.
3. Testavan®
Advances in transdermal testosterone delivery systems have resulted in the development of Testavan, a new 2% testosterone gel 15. Testavan provides enhanced absorption and higher bioavailability, meaning smaller doses, and therefore smaller volumes can be used15,19
Enhanced absorption results from Ferring’s Advanced Skin Technology (FAST), which uniquely combines volatile and non-volatile solvents with permeation enhancers to temporarily increase skin permeability, reducing both the volume of gel required and the residual volume. Testavan is also applied with an applicator, instead of the hand, which further reduces the risk of secondary exposure 4.
4. Pharmacokinetics, clinical efficacy and adverse events
4.1 Phase 1 studies
4.2 Phase II studies
4.3 Phase III studies
5. Regulatory affairs, dosing and administration
6. Conclusion
Low testosterone is a real concern for many men, and because three-quarters of men in the EMAS maintained normal testosterone levels into old age 9, we can assume that TD is not solely a consequence of ageing, but is often related to underlying co-morbidity.
Testavan’s optimal absorption and bioavailability mean that smaller volumes of gel can be used to achieve normalisation of serum testosterone levels, which reduces skin residue. Applicator-application also minimises hand contamination with testosterone, which further reduces the risk of transferring testosterone to a partner or child. Testavan, therefore, expands the treatment options for men with TD who are not concerned about fertility and may also aid compliance in those concerned about secondary transference.
7. Expert opinion
International expert guidelines now recognise TD and ED as independent risk factors for CVD. Multiple professional associations recommend screening for TD and ED in high-risk groups, such as type 2 diabetes, metabolic syndrome, obesity and regular opiate users 12,33,34. Currently, however, few diabetes specialists routinely include assessment of ED and TD as part of the routine case. Implementation of these guidelines will uncover many previously undiagnosed patients who require treatment because of bothersome symptoms. In early 2020, a large double-blind placebo-controlled study from Australia, the T4DM trial 35, will report on whether treatment with TRT, in obese men with pre-diabetes and TD, can prevent progression to type 2 diabetes. It is therefore likely that health care professionals will see increasing numbers of patients who are candidates for TRT and have complex treatment needs.
Men with TD, by definition, are symptomatic and require therapy that is usually life-long and effectively relieves those bothersome symptoms. This is particularly relevant for urologists, who receive referrals for patients requesting therapy sexual dysfunction. In contrast, endocrinologists rarely ask about sexual symptoms and patients seldom complain. Issues of convenience, tolerability and reliable efficacy are therefore of critical importance. The high rates of discontinuation seen with existing therapies clearly demonstrate that patients have important unmet needs.
Oral testosterone is not commonly used in the UK, mainly due to the need for frequent dosing, the need to be taken with a fatty meal and concerns about first-pass effects on the liver.
Self- administered short-acting injections are cheap but inconvenient as they require training to be safely and reliably administered. This can be a major life change that many men find unacceptable. A major risk is a rapid change in levels that can lead to a patient increasing doses of their own volition due to rebound symptoms leading to rises in haematocrit and possible increased CV risk.
Long-acting depot injections, such as Testosterone Undecanoate, usually require appointments with health care professionals with associated costs. Steady-state levels within the normal range can usually be achieved but raised haematocrit can still be a problem in around 6% of patients Injection site pain can be a problem for some men. Pellets of long-acting testosterone requiring specialist insertion are popular in the US, but not available in the UK and Europe.
Topical gels are often the most convenient first-line treatment, but options are important as patient preference is more important than virtually any other clinical area of medicine. The Accepted Manuscript chosen therapy must be convenient to use and reach reliable therapeutic levels to effectively and consistently relieve symptoms.
Studies suggest that Testavan may provide more effective in reaching therapeutic levels with a reduced volume of gel and testosterone dose due to improved skin absorption. A 2% gel requires less volume of product but may be associated with a greater risk of skin irritation. There may be an advantage for convenience, and especially in areas or occasions where access to soap and water is limited. Lifestyle issues such as frequent showering, swimming, sun exposure, shift work and frequent flying can be significant issues for some patients. A third-party transfer is an important issue for a significant number of men, especially those with small children, and the novel applicator seems to largely overcome the transfer problem.
There are still unmet needs with current regimes. Combination therapies with long-acting injections and top-up gels may be a way of reaching therapeutic levels in patients who do not respond to one agent alone, but this is off label use, and expensive. We now know that some men have insensitive androgen receptors with a high number of CAG repeats and require much higher doses for clinical benefits 36. It is likely that more men will be tested for androgen receptor polymorphism in future to detect these patients requiring higher doses for clinical effect.
Currently licensed preparations suppress LH/FSH production and therefore significantly reduce fertility. Many men might state that this is not an issue for them, but as most men present with sexual problems, the chance of marital breakup might lead to fertility becoming a problem in the future. Whilst there is evidence that, for most men, endogenous production might return after 9-12 months, this is unpredictable and cessation of therapy is usually associated with the return of bothersome sexual symptoms, such as loss of desire and ED, which will clearly affect fertility. Many men are therefore condemned to tolerate their symptoms, throwing further strain on their work and relationships.
In primary hypogonadism, there is little alternative to TRT, but for secondary cases, other strategies are possible. Clomiphine 37 or Tamoxifen can block the inhibitory effect of oestradiol on pituitary feedback and increase endogenous testosterone production. Both are off-label in men, a considerable problem for GP prescribing and response is less predictable in older men, especially over 50. HCG (Human Chorionic Gonadotrophin) at 5000 units by subcutaneous injection twice to 3 times weekly can be effective but is expensive for long term use 38. There are few published long term studies as to clinical benefits for HCG. Combination therapy with TRT and low dose HCG (500 units twice or 3 times weekly) or Clomiphene can effectively preserve fertility for many men but this is off-label use with little long- term data to support this approach. Unfortunately, such trials, involving these generic products are unlikely to be conducted, due to expense and the limited indications. Sperm storage may be a logical approach before commencing treatment but few patients or physicians consider this, often due to expense and logistic issues. As ED and TD are now widely accepted as independent risk factors for CVD, the next five years is likely to see many more patients presenting for treatment, as the screening recommendations for high-risk patients are implemented, according to evidence-based guidelines. The outcome of studies such as T4DM 35and TRAVERSE 39 is likely to have a considerable impact on future prescribing patterns. As more men with ED are screened and seek treatment and fail to respond to oral therapy in around 50% of cases, many will elect for correction of low/borderline testosterone levels to enhance response to cheaper generic PDE5 inhibitors rather than move to expensive and invasive second-line therapies such as intra-cavernosal injection 12. As the patents for testosterone gel preparations expire in the next 12-18 months, these savings will become even more relevant.
Novel products are in development to meet these unmet needs. A new oral testosterone formulation is under development 40. This is likely to prove more acceptable than current formulations, either alone or in combinations.
A testosterone nasal spray is currently licensed in North America and shortly likely to be licensed in Europe. This requires twice-daily administration and may be acceptable to many men either alone or in combination with other TRT. The major advantage is the prompt onset of action and the lack of LH/FSH suppression 41.
A long-acting oral Aromatase Inhibitor (AI) is under-development and could represent considerable advantages in blocking the conversion of testosterone to oestrogen, thus increasing endogenous levels. This has the potential to preserve fertility and reduce visceral adiposity, but monitoring will be required as a reduction of oestradiol might potentially increase the risk of osteopenia in the long term 42.
Enclomiphine (a mixture of 2 isomers of clomiphene) has been under development for several years, targeting the treatment of men with secondary hypogonadism wishing to preserve fertility. This might be useful for younger obese men wishing to preserve fertility, either alone or in combination with existing therapies 43.
Michael Kirby, Atul Kalhan & Geoffrey Hackett
Abstract
Introduction: Testosterone deficiency (TD) is an increasing problem that can affect a man’s physical and psychological health and quality of life. Testosterone replacement therapy (TRT), combined with weight reduction, lifestyle advice, and the treatment of co-morbidities, is the treatment of choice in men who are not concerned about fertility. However, there remains an unmet need in this therapeutic area, relating to factors such as inconvenient or painful administration, fluctuations in testosterone levels, supra-physiologic testosterone levels, poor tolerability, and secondary safety issues, which may be associated with the current TRT options. Advances in transdermal delivery systems have resulted in the development of a new 2% transdermal testosterone gel, that may offer some additional features over the other currently available TRTs.
Areas covered: We performed a comprehensive review of the published and grey literature to identify randomized studies and non-randomized studies (NRS) involving adult men receiving treatment for low testosterone levels.
Expert opinion: Topical gels are often the most convenient first-line treatment for testosterone deficiency, but options are important as patient preference is more important than virtually any other clinical area of medicine. The chosen therapy must be convenient to use and reach reliable therapeutic levels to effectively and consistently relieve symptoms. Testavan a new 2% testosterone gel, goes some way to achieving these goals.
1. Introduction
Testosterone is the main androgen in men. It plays a crucial role in the development and maintenance of secondary male characteristics and influences body composition, sexual and cognitive function, erythropoiesis, and bone and muscle health 1.
When testosterone levels fall, men can suffer a variety of physical, sexual, and psychological effects, and a subsequent reduction in the quality of life2. TD has been shown, in multiple longitudinal studies, to be linked to earlier all-cause and cardiovascular disease (CVD)- related mortality, and incident type 2 diabetes 3.
The clinical burden of TD has increased notably over the last few years 4, paralleling the increasing rates of obesity, metabolic syndrome, type 2 diabetes and opiate use 5. In the European Male Ageing Study (EMAS), the prevalence of TD was 2.1% overall in men aged 40- 79 years and rates increased with age, from 0.1% in men in their 40’s to 0.6% in those in their 50’s, to 3.2 % in those in their 60’s, to 5.1% in those in their 70’s 6. Projected estimates suggest that TD will affect as many as 6.5 million American men aged between 30-79 years by 2025; a 38% increase from 2000 7.
While testosterone levels decrease naturally with advancing age 8, the EMAS study found that three-quarters of men maintained normal testosterone levels into old age, which suggests that TD is not solely a consequence of ageing 9. Furthermore, only a small percentage of older men with suppressed testosterone levels develop the genuine syndrome of TD, associated with diffuse physical (e.g. frailty and loss of vigour), sexual (e.g. erectile dysfunction) and psychological (e.g depression) symptoms 8.
The global prevalence of testosterone deficiency (TD) ranges from 10–40%. The actual diagnosis of TD is controversial, as Internationally, a wide range of total testosterone (TT) thresholds are used for diagnosis 200–400 ng/dL, (7-14 nmol/L), and physicians differ in their emphasis placed on clinical symptoms. There are also significant global differences in the prescription patterns of testosterone replacement therapy (TRT). In the United States, for example, prescription of TRT is significantly higher than the rest of the world, increasing 3- fold over the last 10 years and more so in eugonadal men which are concerning 10.
TD occurs as a result of testicular abnormalities (primary TD), defects in the pituitary or hypothalamus (secondary TD), or a combination of both (combined/mixed TD)11. TD is more likely to affect men of advanced age and those with obesity, metabolic syndrome (MetS) and poor general health3.
TD signs and symptoms vary depending on age at onset, duration and severity 1,12,13. Physical signs and symptoms include decreased body hair, gynecomastia, reduced muscle mass and strength, poor sleep, hot flushes/sweats, fatigue and osteoporosis. Cardio-metabolic signs and symptoms include increased Body Mass Index (BMI), visceral obesity, Metabolic Syndrome (MetS), insulin resistance and type 2 diabetes mellitus. Sexual signs and symptoms include small testicles, delayed puberty, infertility, decreased sexual desire/activity, reduced frequency of sexual thoughts, absent or fewer morning/night-time erections, ED, delayed ejaculation and decreased volume of ejaculate. Psychological signs and symptoms include mood changes, impaired cognitive function and decreased well-being or poor self-rated health 1,2,11-14.
A diagnosis of genuine TD requires both clinical and biochemical evidence of suppressed testosterone levels 12,14. In this regard, testosterone replacement therapy should only be prescribed when blood levels are unequivocally low, in the presence of clinical signs & symptoms & in the absence of any other potentially treatable causes.
3. Testavan®
Advances in transdermal testosterone delivery systems have resulted in the development of Testavan, a new 2% testosterone gel 15. Testavan provides enhanced absorption and higher bioavailability, meaning smaller doses, and therefore smaller volumes can be used15,19
Enhanced absorption results from Ferring’s Advanced Skin Technology (FAST), which uniquely combines volatile and non-volatile solvents with permeation enhancers to temporarily increase skin permeability, reducing both the volume of gel required and the residual volume. Testavan is also applied with an applicator, instead of the hand, which further reduces the risk of secondary exposure 4.
4. Pharmacokinetics, clinical efficacy and adverse events
4.1 Phase 1 studies
4.2 Phase II studies
4.3 Phase III studies
5. Regulatory affairs, dosing and administration
6. Conclusion
Low testosterone is a real concern for many men, and because three-quarters of men in the EMAS maintained normal testosterone levels into old age 9, we can assume that TD is not solely a consequence of ageing, but is often related to underlying co-morbidity.
Testavan’s optimal absorption and bioavailability mean that smaller volumes of gel can be used to achieve normalisation of serum testosterone levels, which reduces skin residue. Applicator-application also minimises hand contamination with testosterone, which further reduces the risk of transferring testosterone to a partner or child. Testavan, therefore, expands the treatment options for men with TD who are not concerned about fertility and may also aid compliance in those concerned about secondary transference.
7. Expert opinion
International expert guidelines now recognise TD and ED as independent risk factors for CVD. Multiple professional associations recommend screening for TD and ED in high-risk groups, such as type 2 diabetes, metabolic syndrome, obesity and regular opiate users 12,33,34. Currently, however, few diabetes specialists routinely include assessment of ED and TD as part of the routine case. Implementation of these guidelines will uncover many previously undiagnosed patients who require treatment because of bothersome symptoms. In early 2020, a large double-blind placebo-controlled study from Australia, the T4DM trial 35, will report on whether treatment with TRT, in obese men with pre-diabetes and TD, can prevent progression to type 2 diabetes. It is therefore likely that health care professionals will see increasing numbers of patients who are candidates for TRT and have complex treatment needs.
Men with TD, by definition, are symptomatic and require therapy that is usually life-long and effectively relieves those bothersome symptoms. This is particularly relevant for urologists, who receive referrals for patients requesting therapy sexual dysfunction. In contrast, endocrinologists rarely ask about sexual symptoms and patients seldom complain. Issues of convenience, tolerability and reliable efficacy are therefore of critical importance. The high rates of discontinuation seen with existing therapies clearly demonstrate that patients have important unmet needs.
Oral testosterone is not commonly used in the UK, mainly due to the need for frequent dosing, the need to be taken with a fatty meal and concerns about first-pass effects on the liver.
Self- administered short-acting injections are cheap but inconvenient as they require training to be safely and reliably administered. This can be a major life change that many men find unacceptable. A major risk is a rapid change in levels that can lead to a patient increasing doses of their own volition due to rebound symptoms leading to rises in haematocrit and possible increased CV risk.
Long-acting depot injections, such as Testosterone Undecanoate, usually require appointments with health care professionals with associated costs. Steady-state levels within the normal range can usually be achieved but raised haematocrit can still be a problem in around 6% of patients Injection site pain can be a problem for some men. Pellets of long-acting testosterone requiring specialist insertion are popular in the US, but not available in the UK and Europe.
Topical gels are often the most convenient first-line treatment, but options are important as patient preference is more important than virtually any other clinical area of medicine. The Accepted Manuscript chosen therapy must be convenient to use and reach reliable therapeutic levels to effectively and consistently relieve symptoms.
Studies suggest that Testavan may provide more effective in reaching therapeutic levels with a reduced volume of gel and testosterone dose due to improved skin absorption. A 2% gel requires less volume of product but may be associated with a greater risk of skin irritation. There may be an advantage for convenience, and especially in areas or occasions where access to soap and water is limited. Lifestyle issues such as frequent showering, swimming, sun exposure, shift work and frequent flying can be significant issues for some patients. A third-party transfer is an important issue for a significant number of men, especially those with small children, and the novel applicator seems to largely overcome the transfer problem.
There are still unmet needs with current regimes. Combination therapies with long-acting injections and top-up gels may be a way of reaching therapeutic levels in patients who do not respond to one agent alone, but this is off label use, and expensive. We now know that some men have insensitive androgen receptors with a high number of CAG repeats and require much higher doses for clinical benefits 36. It is likely that more men will be tested for androgen receptor polymorphism in future to detect these patients requiring higher doses for clinical effect.
Currently licensed preparations suppress LH/FSH production and therefore significantly reduce fertility. Many men might state that this is not an issue for them, but as most men present with sexual problems, the chance of marital breakup might lead to fertility becoming a problem in the future. Whilst there is evidence that, for most men, endogenous production might return after 9-12 months, this is unpredictable and cessation of therapy is usually associated with the return of bothersome sexual symptoms, such as loss of desire and ED, which will clearly affect fertility. Many men are therefore condemned to tolerate their symptoms, throwing further strain on their work and relationships.
In primary hypogonadism, there is little alternative to TRT, but for secondary cases, other strategies are possible. Clomiphine 37 or Tamoxifen can block the inhibitory effect of oestradiol on pituitary feedback and increase endogenous testosterone production. Both are off-label in men, a considerable problem for GP prescribing and response is less predictable in older men, especially over 50. HCG (Human Chorionic Gonadotrophin) at 5000 units by subcutaneous injection twice to 3 times weekly can be effective but is expensive for long term use 38. There are few published long term studies as to clinical benefits for HCG. Combination therapy with TRT and low dose HCG (500 units twice or 3 times weekly) or Clomiphene can effectively preserve fertility for many men but this is off-label use with little long- term data to support this approach. Unfortunately, such trials, involving these generic products are unlikely to be conducted, due to expense and the limited indications. Sperm storage may be a logical approach before commencing treatment but few patients or physicians consider this, often due to expense and logistic issues. As ED and TD are now widely accepted as independent risk factors for CVD, the next five years is likely to see many more patients presenting for treatment, as the screening recommendations for high-risk patients are implemented, according to evidence-based guidelines. The outcome of studies such as T4DM 35and TRAVERSE 39 is likely to have a considerable impact on future prescribing patterns. As more men with ED are screened and seek treatment and fail to respond to oral therapy in around 50% of cases, many will elect for correction of low/borderline testosterone levels to enhance response to cheaper generic PDE5 inhibitors rather than move to expensive and invasive second-line therapies such as intra-cavernosal injection 12. As the patents for testosterone gel preparations expire in the next 12-18 months, these savings will become even more relevant.
Novel products are in development to meet these unmet needs. A new oral testosterone formulation is under development 40. This is likely to prove more acceptable than current formulations, either alone or in combinations.
A testosterone nasal spray is currently licensed in North America and shortly likely to be licensed in Europe. This requires twice-daily administration and may be acceptable to many men either alone or in combination with other TRT. The major advantage is the prompt onset of action and the lack of LH/FSH suppression 41.
A long-acting oral Aromatase Inhibitor (AI) is under-development and could represent considerable advantages in blocking the conversion of testosterone to oestrogen, thus increasing endogenous levels. This has the potential to preserve fertility and reduce visceral adiposity, but monitoring will be required as a reduction of oestradiol might potentially increase the risk of osteopenia in the long term 42.
Enclomiphine (a mixture of 2 isomers of clomiphene) has been under development for several years, targeting the treatment of men with secondary hypogonadism wishing to preserve fertility. This might be useful for younger obese men wishing to preserve fertility, either alone or in combination with existing therapies 43.
