WO2009101182A1 - Use of etonogestrel for benign prostate hyperplasia (bph). - Google Patents

Use of etonogestrel for benign prostate hyperplasia (bph). Download PDF

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Publication number
WO2009101182A1
WO2009101182A1 PCT/EP2009/051724 EP2009051724W WO2009101182A1 WO 2009101182 A1 WO2009101182 A1 WO 2009101182A1 EP 2009051724 W EP2009051724 W EP 2009051724W WO 2009101182 A1 WO2009101182 A1 WO 2009101182A1
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etonogestrel
treatment
bph
prostate
range
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PCT/EP2009/051724
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French (fr)
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Eduard Ruijter
Kees Van Der Voort Maarschalk
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N.V. Organon
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Publication of WO2009101182A1 publication Critical patent/WO2009101182A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams

Definitions

  • BPH benign prostate hyperplasia
  • the invention relates to a new use of a progestagenic drug for the treatment of benign prostate hyperplasia (BPH) and to a new use of said progestagenic drug in a treatment regime with a new route of administration for the progestagenic drug.
  • BPH benign prostate hyperplasia
  • Benign prostate hyperplasia being a non-cancerous enlargement of the prostate gland, is a common disorder in elderly men. The condition is characterized by a progressive enlargement of prostatic tissue, resulting in obstruction of the proximal urethra and causing urinary flow disturbances. BPH is associated with both obstructive and irritative voiding symptoms, with bladder outlet obstruction as the most prominent symptom. Obstructive symptoms include straining, hesitancy, decreased force and caliber of the urine stream, an intermittent stream, a sense of incomplete emptying, and terminal dribbling. Irritative symptoms include urinary frequency, urgency, and nocturia.
  • DHT dihydrotestosterone
  • the current standard treatment for BPH-related symptoms consists of 5 ⁇ -reductase inhibitors (ARI's; finasteride, dutasteride) and ⁇ -blockers.
  • ARI's prevent the conversion of testosterone into DHT, thereby lowering the androgenic activity in the prostate. This will eventually result in shrinking of the prostate, thereby preventing progression of the disease progression and avoiding progress to acute urinary retention (AUR) and avoiding more drastic medical intervention by surgery.
  • AUR acute urinary retention
  • ARI's have a slow onset of action (3A months).
  • Theceblockers e.g. tamsulosin
  • the ⁇ blockers do not shrink the prostate and do not prevent progress to acute urinary retention, requiring surgery.
  • Suppression of testosterone to the low normal range in order to decrease the androgenic effects on the prostate can be mediated by GnRH antagonists as well as by progestagens.
  • Suppression of testosterone to the low normal range by progestins has been shown in the broad male contraception experience (Matthiesson et al., 2006;, Grimes et al., 2005).
  • progestins are well tolerated in men (Matthiesson et al., 2006).
  • There are two progestagens known to be used (mainly in Japan) for the treatment of BPH-related symptoms: allylestrenol and chlormadinone acetate (CMA).
  • Allylestrenol is a selective progestin that has been approved for the indication BPH in Japan. Allylestrenol is administered in doses of 50 mg twice daily p.o. Efficacy has been shown in two clinical trials in 34 and 129 patients, respectively, suffering from BPH related symptoms (Noguchi et al., 2002: Noguchi et al., 1998). In both trials patients were treated for 16 weeks. Treatment with allylestrenol resulted in testosterone suppression to 40% of baseline levels which improved the BPH related symptoms, as measured on the International Prostate Symptom Score (IPSS), on average with five points. Moreover, a mean prostate volume reduction of 6 ml. and improvement of mean urinary flow rates of 3 mL/sec was reported.
  • IPS International Prostate Symptom Score
  • MFR maximum urinary flow rate
  • symptom scores Sixteen weeks after cessation of treatment, treatment effects on these parameters were still present, despite normal testosterone levels. Eight percent of subjects experienced loss of libido during the trial (Noguchi et al., 1998).
  • CMA chlormadinone acetate
  • GnRH Gonadotropin Releasing Hormone
  • the disadvantage of the GnRH antagonists at least is the need for the injection route of administration and the higher cost price of the acive ingredient.
  • the present invention provides for means for a method of treatment of benign prostate hyperplasia by administering an effective dose of etonogestrel to an individual having benign prostate hyperplasia.
  • the treatment is particularly advantageous by administering the dose of etonogestrel with a spray or solution into the oral cavity of the individual.
  • the spray enables adaptation of the dose in a more subtle manner than treatments initiated with tablets.
  • the number of possible subdivisions and accuracy of manner of administration by the spray or solution is an improvement over the use of tablets with different dose strengths.
  • adsorption from the mucous tissue is steady and protracted, enabling a more constant level of the progestagen and its effect.
  • Etonogestrel is the active metabolite of desogestrel.
  • Etonogestrel in the dose range of 0.07 mg to 0.3 mg provides for testosterone levels, which are low or slightly below normal but effective for alleviating BPH-related symptoms and at the same time are well above castrate levels, thereby avoiding hypogonadal side effects. More specifically in an orally administered dose of 150 and 300 ⁇ g etonogestrel provides for testosterone suppression to a level that has been proven to be effective and safe for intermittent treatment of LUTS/BPH. The long lasting and potent effect is particularly advantageous for intermittent dosing regimes.
  • the dose is administered sublingually by directing the spray or solution to the strongly vascularized region below the tongue.
  • Bio-availability and absorption profile is exceptionally good in this embodiment.
  • the treatment is a regime of intermittent administration, said regime comprises a period of a duration in the range of from 2 to 12 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg, preferably 0.1 mg to 0.2 mg is administered to the individual and said regime comprises a period without administering etonogestrel for a duration in the range of from 1 month to 6 months. It was found that a limited, relatively short treatment period with etonogestrel can be sufficient to have a long lasting therapeutic benefit. The result is minimized exposure to progestagenic drug.
  • the dose of etonogestrel can be increased or decreased during the treatment or per separate drug treatment period.
  • the regime comprises a period of a duration in the range of from 4 to 10 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg, preferably 0.1 mg to 0.2 mg is administered to the individual and said regime comprises a period without administering etonogestrel for a duration in the range of from 1 month to 6 months.
  • the regime comprises a period of a duration in the range of from 4 to 10 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg, preferably 0.1 mg to 0.2 mg is administered to the individual and said regime comprises a period without administering etonogestrel for a duration in the range of from 3 month to 6 months.
  • the invention provides for etonogestrel for a treatment of an individual having benign prostate hyperplasia.
  • the invention provides for etonogestrel for the treatment of benign prostate hyperplasia by administering an effective dose of etonogestrel with a spray or solution into the oral cavity of an individual in need of the treatment.
  • the invention provides for etonogestrel for the treatment of benign prostate hyperplasia whereby the treatment comprises a period of a duration in the range of from 2 to 12 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg, preferably 0.1 mg to 0.2 mg is administered to the individual and the treatment comprises a period without administering etonogestrel for a duration in the range of from 1 month to 6 months.
  • the invention provides for etonogestrel for the treatment of benign prostate hyperplasia whereby the dose of etonogestrel can be increased or decreased during the treatment or per separate drug treatment period.
  • the invention provides for administration of etonogestrel in accurately metered doses into an oral cavity of an individual.
  • LUTS lower urinary tract symptoms
  • BPH benign prostate hyperplasia
  • Benign prostate hyperplasia (BPH) is as described in the introduction.
  • the disorder can be diagnosed with a variety of methods. Examples of such methods are given in the section of examples, example 1.
  • An individual having benign prostate hyperplasia is usually a male human but a male animal can also have benefit from the treatment as specified here.
  • Etonogestrel is a known progestagenic compound and can be manufactured according to published methods. An effective dose of etonogestrel needs to be determined depending on assessment of the clinical condition.
  • the complex syndrome of lower urinary tract syndrome reflects the clinical manifestation of this physiological disorder. Efficacy of the dose can be determined by the clinically observable symptoms as reported by the patient having the disorder or by measurements of urinary flow, prostate size, frequency and volume of urine voiding etc.
  • the dose of etonogestrel can be administered orally or by parenteral depot formulation but it is preferred to use a formulation for spraying a vapor or solution into the mouth of an individual. Spray formulations are known in the pharmaceutical art. Oral cavity or buccal cavity is meant to be the mouth.
  • Buccal route of administration is meant to be drug administration by having the pharmaceutical formulation with active ingredient applied to the surface tissue lining the mouth, such as the tongue, the throat, below the tongue, the gingiva, the palate and the inner buccal surface proper.
  • Sublingual administration is obtained by applying the formulation more selectively on the mucous surface below the tongue and behind the lower teeth. When applied with a spray this requires upholding the tongue and spraying on the tissue with a more focused spray held at a short distance. This may be in contrast to spraying into the oral cavity, which can be done with a less focused spray.
  • a daily dose is the amount of etonogestrel administered on a day in one or cumulatively in a day with a plurality of doses, expressed in weight of the compound itself without water or other solvate content or co-crystallizing components of any physical form of etonogestrel.
  • Fujimoto, Kiohide et al. Prostate-specific antigen changes as a result of chlormadinone acetate administration to patients with benign prostatic hyperplasia A retrospective multi-institutional study. International Journal of Urology, Volume 13, Number 5, 2006, pp. 543-549.
  • Lepor H The role of gonadotropin-releasing hormone antagonists for the treatment of benign prostatic hyperplasia. Rev Urol 2006, 8: 183-189. Matthiesson KL, McLachlan Rl. Male hormonal contraception: concept proven, product in sight? Human Reproduction Update 2006, 12: 463-482.
  • This example describes the conduct of a clinical trial to demonstrate the effect of etonogestrel in men with Lower Urinary Tract Symptoms (LUTS) related to Benign Prostatic hyperplasia (BPH).
  • the trial is a placebo-controlled, multiple dose trial, measuring effects on prostate volume, International Prostate Symptom Score (IPSS) and peak urinary flow.
  • LUTS Lower Urinary Tract Symptoms
  • Etonogestrel is administered during eight weeks treatment with oral tablets in doses of 5 150 ⁇ g per two days, 150 ⁇ g or 300 ⁇ g per day or placebo.
  • subjects with LUTS/BPH are to be randomly assigned to one of the following regimens (60 subjects per treatment group): Group 1 : 150 ⁇ g etonogestrel per two days Group 2: 150 ⁇ g etonogestrel per day 0 Group 3: 300 ⁇ g etonogestrel per day Group 4: placebo
  • Etonogestrel treatment duration is eight weeks with a follow up period of 16 weeks. The effect is be evaluated on prostate volume, lower urinary tract symptoms, urinary flow, post-void residual volume, sexual function, well-being and LUTS-related Quality of5 Life.
  • Prostate volume (total and transition zone) is to be measured using trans-rectal ultrasound (TRUS).
  • TRUS trans-rectal ultrasound
  • PSA Prostate Specific Antigen
  • 0 The effect on LUTS is to be evaluated by using the seven questions of the International Prostate Symptom Score (IPSS).
  • Urinary flow (Q ma ⁇ and Q av ) is to be measured using an automatic uroflow meter.
  • Post- void residual volume is to be measured using transabdominal ultrasound.
  • Progression of LUTS is defined as occurrence of either 1 ) Acute Urinary Retention (AUR), 2) need for5 Transurethral Resection of Prostate (TURP) or other minimal invasive therapy or 3) worsening of symptoms defined as IPSS increase of ⁇ 4 points compared to baseline. The first two will be assessed by means of (serious) adverse event reporting.
  • BPH-QoL9 Benign Prostatic Hypertrophy-Related Quality of Life Questionnaire
  • MSHQ-EjD Short Form the0 Male Sexual Health Questionnaire to assess Ejaculatory Dysfunction
  • IPSS-Quality of Life question the IPSS-Quality of Life question.
  • each treatment group there are to be 48 subjects so that Dunnetfs correction for multiple testing can be used to show a difference in change from baseline of 10 mL of total prostate volume as measured by TRUS. Taking into account a 20% drop out rate,5 preferably 60 subjects per treatment group are to be recruited.
  • Inclusion criteria 1. Signed written informed consent, obtained before screening evaluations; 2. Men diagnosed with LUTS suggestive of BPH: 2.1. Baseline IPSS score of>12 (moderate to severe); 2.2. Prostate volume of>40 ml. and ⁇ 100 ml. (based on TRUS); 2.3. Peak urinary flow rate ⁇ 15 mL/s with a voided volume of ⁇ 125 ml_; 3. Age at least 50 but not older than 80 years at screening; 4.
  • PSA PSA ⁇ 10 ng/mL and exclusion of prostate cancer to the satisfaction of the investigator (e.g. by biopsy).
  • Exclusion criteria 1. A postvoid residual volume >250 ml_; 2. Use of anti-androgens, androgens, Gonadotropin Releasing Hormone (GnRH) antagonists, or 5 ⁇ -reductase inhibitors within six months prior to start trial medication; 3. Use ofceblockers, phytotherapy (for LUTS) or drugs interfering with bladder function within two weeks prior to start trial medication; 4. Presence of hypogonadism as judged by the (sub)investigator; 5. Acute urinary retention within the past 12 months; 6. History of surgery for BPH, including other minimally invasive procedures; 7.
  • Presence of urinary tract infection Presence or history of (subclinical) prostate cancer, bladder cancer, urethral stricture, or pelvic irradiation; 9. Presence or history (within the past 12 months) of depression or other psychiatric disease of moderate or severe intensity; 10. Cardiac or cerebrovascular event within the past six months; 11. Presence or history of any neurological disease associated with primary bladder dysfunction; 12. Presence or history of liver disease or disturbance of liver function that failed to return to normal; 13. Presence or history of renal disease or disturbance of renal function that failed to return to normal; 14.
  • Tablets contain 150 or 300 ⁇ g etonogestrel or placebo.
  • the tablets contain magnesium stearate, HPC, lactose and corn starch.
  • the coating contains: HPMC E15, Talc, Peg 400 and Titanium dioxide. Subjects will be instructed to take one tablet p.o. per day, in the morning, with water.
  • Group 1 One tablet of 150 ⁇ g etonogestrel or one placebo tablet per day, in an alternating fashion;
  • Group 2 One tablet of 150 ⁇ g etonogestrel per day
  • Group 3 One tablet of 300 ⁇ g etonogestrel per day; Group 4: One placebo tablet per day.
  • LUTS LUTS and drugs interfering with bladder function
  • hepatic microsomal enzyme-inducing medication which may affect the bioavailability of steroids: phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate, hydantoins, rifampicin, ritonavir, nelfinavir and griseofulvin.
  • the total duration of the trial will be approximately 28 weeks: up to four weeks screening, eight weeks treatment and 16 weeks follow up period.
  • SHBG routine lab parameters (only lipids), bone markers (CTX, osteocalcin) and etonogestrel, all before first medication intake. After sampling and during this visit, the subject should take the first trial medication. Again perform blood sampling for etonogestrel: one sample one hour after trial medication intake and one sample at least
  • This visit should be scheduled at Day 15 ⁇ 3 days.
  • This visit should be scheduled at Day 57 ⁇ 3 days or after early treatment discontinuation.
  • the subject should come to the clinic in a fasted state.
  • IPSS-QoL, BPH-QoL9 and MSHQ-EjD Short Form questionnaires Have subject complete the IPSS-QoL, BPH-QoL9 and MSHQ-EjD Short Form questionnaires; Perform TRUS to determine prostate volume; Perform uroflow measurement. Perform transabdominal ultrasound to determine postvoid residual volume; Week 12 visit
  • This visit should be scheduled 4 weeks ⁇ 5 days after end of treatment. In case of treatment completion, this will be at Day 85 ⁇ 5 days.
  • the subject should come to the clinic in a fasted state. Perform blood sampling for PSA (should be done prior to TRUS), hormones (T, DHT, LH, FSH, E2, SHBG) and routine lab parameters; Have subject complete the IPSS-QoL, BPH-QoL9 and MSHQ-EjD Short Form questionnaires; Perform TRUS to determine prostate volume; Perform uroflow measurement. Perform transabdominal ultrasound to determine postvoid residual volume. Week 16 visit
  • This visit should be scheduled 16 weeks after end of treatment or after early discontinuation from the trial. In case of treatment completion, this will be at Day 169 ⁇ 5 days.
  • the subject should come to the clinic in a fasted state. Perform blood sampling for PSA (should be done prior to TRUS), hormones (T, DHT, LH, FSH, E2, SHBG), bone markers (CTX, osteocalcin), routine lab parameters; Have subject complete the IPSS- QoL, BPH-QoL9 and MSHQ-EjD Short Form questionnaires; Perform TRUS to determine prostate volume; Perform uroflow measurement. Perform transabdominal ultrasound to determine postvoid residual volume.
  • Total prostate volume will be measured by TRUS using the ellipsoid calculation method (height x width x length x pi/6).
  • the same person in an investigational site measures all TRUS's. If this is not feasible, another person can perform the TRUS, but he should use the same technique and device.
  • the transition zone volume will only be measured by those investigational sites which perform this routinely or are experienced with it. This will be established before the first measurement.
  • PSA will be measured. Blood samples for PSA should be taken before TRUS (if applicable). The effect on LUTS will be evaluated by using the IPSS. This questionnaire will be filled in by the subject. It contains seven questions with a possible score from 0-5. The total scores can range from 0 to 35.
  • Peak and average urinary flow (CW and Qav) will be measured by using an automatic uroflow meter.
  • the urinary volume and Qav will be determined by the machine and the investigator will enter these data to the CRF.
  • a copy of the recording paper slip
  • a central assessor for manual standardized calculation of the 'smoothed' CW in order to correct for artefacts [23].
  • the central assessor will be assigned before the clinical trial start and should be experienced with calculation of the 'smoothed' CW.
  • the uroflow curve should be smoothed by eye into a continuous curve and a sliding average over two seconds should be used as CW to remove positive and negative spike artefacts.
  • Qmax can be calculated locally after which a copy of the paper slip should be sent to the central assessor anyway to obtain a standardized baseline value.
  • the subjects will be instructed to void in a 'relaxing manner 1 .
  • Postvoid residual volume will be measured using transabdominal ultrasound. Progression of LUTS is defined as occurrence of either 1) AUR, 2) need for TURP or other minimal invasive therapy or 3) worsening of symptoms defined as IPSS increase of >4 points compared to baseline. The first two will be assessed by means of (S)AE reporting.
  • An Adverse Event is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
  • Lack of efficacy i.e. preexisting complaints or symptoms related to LUTS/BPH which did not worsen but also did not improve during the trial, should not be reported as AE.
  • Pre-existing complaints or symptoms related to LUTS/BPH that did worsen during the trial should be reported as AE, except for worsening of IPSS, increase in prostate volume, worsening of uroflow parameters, and increased post-void residual volume as these are efficacy endpoints.
  • a Serious Adverse Event is defined as any untoward medical occurrence that at any dose: results in death, is life-threatening.
  • life-threatening refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.
  • Post-treatment evaluation Subjects will be followed up 16 weeks after treatment cessation in order to assess sustained efficacy.
  • IPSS-QoL uroflow
  • postvoid residual volume completion of the BPH-QoL and MSHQ-EjD Short Form questionnaires
  • TRUS and blood sampling for hormones, PSA and routine lab parameters will be done at Week 12 and Week 24 (End of Trial).
  • Blood sampling for bone markers and retrospective analysis will only be done at Week 24.
  • the progression of LUTS will be defined as the occurrence of one or more of the following events: - Acute Urinary Retention (AUR);
  • Etonogestrel or placebo was orally administered in the form of tablets once daily for 13 or 26 weeks. The dogs were dosed each morning after they had access to their food.
  • Dose group 1 0.000 (Placebo) 5 male dogs
  • Dose group 2 0.00625 (6.25 ⁇ g/kg) 5 male dogs
  • compositions as tablets for oral administration were made for each dose level containing a quantity of etonogestrel sufficient for 10 kg body weight and additional tablets for 1 kg body weight. From each dose group 2 animals were sacrificed after 13 weeks of dosing and 3 animals were sacrificed after 26 weeks of dosing. 2 animals of group 4 were kept for a further 9 weeks without drug treatment and sacrificed after a total of 35 weeks after initiation of the study.
  • Dogs in group 3 and 4 showed a slight increase in weight gain during the dosing period.
  • a very low prostate gland weight was seen in one dog each of groups 2 and 3 and 2 dogs from group 4 after 26 weeks of dosing. This was observed also in the males 9 weeks after termination for drug treatment. The result demonstrate a clear and long- lasting dose-related atrophy of the glandular structures.
  • a formulation for buccal mucosal administration of etonogestrel is depicted in table 1.
  • a bulk solution is made by mixing the ingredients as indicated in Table 1.
  • the oral spray is then prepared by addition of the active compound etonogestrel.
  • the solution can be used for direct application in the mouth as drops or as a vaporous spray.
  • a sufficient amount to administer is 0.1 mL of the solution so prepared was filled into a 0.2 mL glass vial.
  • the glass vial was placed in a device to enable spraying the solution in the mouth.

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Abstract

The invention provides for the use of tonogestrel for a treatment of an individual having benign prostate hyperplasia, preferably with a spray or solution into the oral cavity of the individual in need of the treatment. The treatment can be for a period of a duration in the range of from 2 to 12 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg is administered to the individual followed by a period without administering etonogestrel for a duration in the range of from 1 month to 6 months.

Description

Use of etonogestrel for benign prostate hyperplasia (BPH).
The invention relates to a new use of a progestagenic drug for the treatment of benign prostate hyperplasia (BPH) and to a new use of said progestagenic drug in a treatment regime with a new route of administration for the progestagenic drug.
Benign prostate hyperplasia (BPH), being a non-cancerous enlargement of the prostate gland, is a common disorder in elderly men. The condition is characterized by a progressive enlargement of prostatic tissue, resulting in obstruction of the proximal urethra and causing urinary flow disturbances. BPH is associated with both obstructive and irritative voiding symptoms, with bladder outlet obstruction as the most prominent symptom. Obstructive symptoms include straining, hesitancy, decreased force and caliber of the urine stream, an intermittent stream, a sense of incomplete emptying, and terminal dribbling. Irritative symptoms include urinary frequency, urgency, and nocturia. The occurrence of an enlargement of the prostate is thought to be related to many factors, but the presence of androgens in the prostate is a prerequisite. Castrated men do not develop BPH. In the prostate, testosterone, the main natural androgen, is converted into dihydrotestosterone (DHT) by 5κeductase, giving rise to an approximately 5 times more potent androgen than testosterone. Testosterone and DHT are active on the same androgen receptor.
The current standard treatment for BPH-related symptoms consists of 5α-reductase inhibitors (ARI's; finasteride, dutasteride) andα-blockers. ARI's prevent the conversion of testosterone into DHT, thereby lowering the androgenic activity in the prostate. This will eventually result in shrinking of the prostate, thereby preventing progression of the disease progression and avoiding progress to acute urinary retention (AUR) and avoiding more drastic medical intervention by surgery. However, ARI's have a slow onset of action (3A months). Theceblockers (e.g. tamsulosin) relax muscles in the bladder neck and prostate and relieve pressure, resulting in an improvement of BPH symptoms with a fast onset of action. However, theαblockers do not shrink the prostate and do not prevent progress to acute urinary retention, requiring surgery.
Suppression of testosterone to the low normal range in order to decrease the androgenic effects on the prostate can be mediated by GnRH antagonists as well as by progestagens. Suppression of testosterone to the low normal range by progestins has been shown in the broad male contraception experience (Matthiesson et al., 2006;, Grimes et al., 2005). In addition, progestins are well tolerated in men (Matthiesson et al., 2006). There are two progestagens known to be used (mainly in Japan) for the treatment of BPH-related symptoms: allylestrenol and chlormadinone acetate (CMA). Allylestrenol is a selective progestin that has been approved for the indication BPH in Japan. Allylestrenol is administered in doses of 50 mg twice daily p.o. Efficacy has been shown in two clinical trials in 34 and 129 patients, respectively, suffering from BPH related symptoms (Noguchi et al., 2002: Noguchi et al., 1998). In both trials patients were treated for 16 weeks. Treatment with allylestrenol resulted in testosterone suppression to 40% of baseline levels which improved the BPH related symptoms, as measured on the International Prostate Symptom Score (IPSS), on average with five points. Moreover, a mean prostate volume reduction of 6 ml. and improvement of mean urinary flow rates of 3 mL/sec was reported. Improvement was also seen on maximum urinary flow rate (MFR) and/or residual urine volume and symptom scores. Sixteen weeks after cessation of treatment, treatment effects on these parameters were still present, despite normal testosterone levels. Eight percent of subjects experienced loss of libido during the trial (Noguchi et al., 1998).
Another progestagen approved for treatment of BPH is chlormadinone acetate (CMA), which is administered in doses of 50 mg once daily. Analyses of 192 patients treated with CMA showed that also effects on PSA (Prostate Specific Antigen) occur and values reached a nadir, which was approximately-50% of the baseline, after 16 weeks (Fujimoto et al., 2006).
Intermittent therapy with Gonadotropin Releasing Hormone (GnRH) antagonists might provide fast onset of action and prevention of clinical progression. At least two GnRH antagonists are currently in development for BPH, cetrorelix (Phase III) and teverelix (Phase II) (Tiwari et al., 2005; Lepor, 2006). Both compounds are administered by injection and aim for short term treatment of 1-2 months with a long lasting effect up to four months after treatment cessation. Initial short term castrate levels of testosterone (90% suppression) and 64-75% suppression in the maintenance phase up to two months result in a fast reduction of IPSS score with 38% (9 points) at four weeks and 53% (12 points) at eight weeks (cetrorelix) and 34% (6 points) at 16 weeks (teverelix) (Comaru-Schally et al., 1998; NN Medscape 2007). Interestingly, although testosterone recovered to normal levels, IPSS further reduced after treatment cessation, ranging from 67-72% at weeks 20 to 85 (cetrorelix) (Comaru-Schally et al., 1998). Teverelix also induced improvement in peak urinary flow rate (CW) of 3.3 mL/sec and reduction of prostate volume of 11.5% (NN Presentation 2007). Both compounds are well tolerated with few side effects including effects on libido (Tiwari et al., 2005; Comaru-Schally et al 1998). The disadvantage of the GnRH antagonists at least is the need for the injection route of administration and the higher cost price of the acive ingredient. There remains a need for a single compound that can be administered orally and has both a fast onset of action (faster than 5α-reductase inhibitors) and is preventing clinical progression (reduction of prostate volume, prevention of acute urinary retention and surgery). It is a further aim of the invention to obtain a more constant low testosterone level during treatment and an equally constant blood plasma level of the active compound administered to suppress the testosterone level. The present invention provides for means for a method of treatment of benign prostate hyperplasia by administering an effective dose of etonogestrel to an individual having benign prostate hyperplasia. As a more specific embodiment the treatment is particularly advantageous by administering the dose of etonogestrel with a spray or solution into the oral cavity of the individual. The spray enables adaptation of the dose in a more subtle manner than treatments initiated with tablets. The number of possible subdivisions and accuracy of manner of administration by the spray or solution is an improvement over the use of tablets with different dose strengths. Also adsorption from the mucous tissue is steady and protracted, enabling a more constant level of the progestagen and its effect. Etonogestrel is the active metabolite of desogestrel. Both etonogestrel and desogestrel in combination with testosterone pellets or injections have been studied in males as a potential male hormonal contraceptive (Brady et al., 2006; Anderson et al 2002; Hay et al., 2005). Also some data are available on desogestrel and etonogestrel alone in males. In a male contraception trial, men were treated with 150 or 300μg desogestrel alone during the first 3 weeks, in which testosterone decreased to approximately 42% (8.8 nMol/L or 2.5 ng/mL) and 33% (6.4 nMol/L or 1.8 ng/mL) of baseline levels in the groups treated with 150μg or 300μg desogestrel, respectively (Wu et al., 1999). A trial of BeIMs et al. also showed the suppressive effect of 300μg desogestrel whereas 450μg did not provide additional testosterone suppression as compared to 300μg (Bellis et al 1996).
Etonogestrel in the dose range of 0.07 mg to 0.3 mg, for example when administered intrabuccally, provides for testosterone levels, which are low or slightly below normal but effective for alleviating BPH-related symptoms and at the same time are well above castrate levels, thereby avoiding hypogonadal side effects. More specifically in an orally administered dose of 150 and 300μg etonogestrel provides for testosterone suppression to a level that has been proven to be effective and safe for intermittent treatment of LUTS/BPH. The long lasting and potent effect is particularly advantageous for intermittent dosing regimes.
In an embodiment of the invention the dose is administered sublingually by directing the spray or solution to the strongly vascularized region below the tongue. Bio-availability and absorption profile is exceptionally good in this embodiment.
In another more specific embodiment of the invention the treatment is a regime of intermittent administration, said regime comprises a period of a duration in the range of from 2 to 12 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg, preferably 0.1 mg to 0.2 mg is administered to the individual and said regime comprises a period without administering etonogestrel for a duration in the range of from 1 month to 6 months. It was found that a limited, relatively short treatment period with etonogestrel can be sufficient to have a long lasting therapeutic benefit. The result is minimized exposure to progestagenic drug. In order to adapt the dose to the needs of the individual and to minimize exposure to the drug, the dose of etonogestrel can be increased or decreased during the treatment or per separate drug treatment period. In another embodiment the regime comprises a period of a duration in the range of from 4 to 10 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg, preferably 0.1 mg to 0.2 mg is administered to the individual and said regime comprises a period without administering etonogestrel for a duration in the range of from 1 month to 6 months. In another embodiment the regime comprises a period of a duration in the range of from 4 to 10 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg, preferably 0.1 mg to 0.2 mg is administered to the individual and said regime comprises a period without administering etonogestrel for a duration in the range of from 3 month to 6 months.
The potency of etonogestrel and good bioavailability via the buccal route make this progestagenic drug such a suitable choice for the spray and treatment regimes provided by this invention.
In general the invention provides for etonogestrel for a treatment of an individual having benign prostate hyperplasia. In another embodiment the invention provides for etonogestrel for the treatment of benign prostate hyperplasia by administering an effective dose of etonogestrel with a spray or solution into the oral cavity of an individual in need of the treatment. In another embodiment the invention provides for etonogestrel for the treatment of benign prostate hyperplasia whereby the treatment comprises a period of a duration in the range of from 2 to 12 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg, preferably 0.1 mg to 0.2 mg is administered to the individual and the treatment comprises a period without administering etonogestrel for a duration in the range of from 1 month to 6 months. In yet another embodiment the invention provides for etonogestrel for the treatment of benign prostate hyperplasia whereby the dose of etonogestrel can be increased or decreased during the treatment or per separate drug treatment period. In a further embodiment the invention provides for administration of etonogestrel in accurately metered doses into an oral cavity of an individual.
This term lower urinary tract symptoms (LUTS) is used to describe the subjects' urinary complaints without implying a cause. The term benign prostate hyperplasia (BPH) refers to the condition characterized by the histopathological pattern known for this condition. When in this specification the term LUTS/BPH is used it refers to LUTS suggestive of BPH.
Benign prostate hyperplasia (BPH) is as described in the introduction. The disorder can be diagnosed with a variety of methods. Examples of such methods are given in the section of examples, example 1. An individual having benign prostate hyperplasia is usually a male human but a male animal can also have benefit from the treatment as specified here. Etonogestrel is a known progestagenic compound and can be manufactured according to published methods. An effective dose of etonogestrel needs to be determined depending on assessment of the clinical condition.
The complex syndrome of lower urinary tract syndrome (LUTS) reflects the clinical manifestation of this physiological disorder. Efficacy of the dose can be determined by the clinically observable symptoms as reported by the patient having the disorder or by measurements of urinary flow, prostate size, frequency and volume of urine voiding etc. The dose of etonogestrel can be administered orally or by parenteral depot formulation but it is preferred to use a formulation for spraying a vapor or solution into the mouth of an individual. Spray formulations are known in the pharmaceutical art. Oral cavity or buccal cavity is meant to be the mouth. Buccal route of administration is meant to be drug administration by having the pharmaceutical formulation with active ingredient applied to the surface tissue lining the mouth, such as the tongue, the throat, below the tongue, the gingiva, the palate and the inner buccal surface proper. Sublingual administration is obtained by applying the formulation more selectively on the mucous surface below the tongue and behind the lower teeth. When applied with a spray this requires upholding the tongue and spraying on the tissue with a more focused spray held at a short distance. This may be in contrast to spraying into the oral cavity, which can be done with a less focused spray.
A daily dose is the amount of etonogestrel administered on a day in one or cumulatively in a day with a plurality of doses, expressed in weight of the compound itself without water or other solvate content or co-crystallizing components of any physical form of etonogestrel.
References
Anderson RA, Kinniburgh D, Baird DT. Suppression of spermatogenesis by etonogestrel implants with depot testosterone: potential for long-acting male contraception. J Clin Endocrinol Metab 2002, 87: 3640-3649
BeIMs AJ, Mitchell R, Mackness Ml, Durrington P, Coelingh-Bennink H, Wu F. Effects of oral progestogen (desogestrel) on pituitary-testicular function and lipid metabolism in normal men (Abstract P2-597). Proc of the 19th lnt Congr of Endocrinol 1996: 554. Brady BM, Amory JK, Perheentupa A et al. A multicentre study investigating subcutaneous etonogestrel implants with injectable testosterone decanoate as a potential long-acting male contraceptive. Human Reproduction 2006, 21 : 285-294.. Comaru-Schally AM, Brannan W, Schally AV, Colcolough M, Monga M. Efficacy and safety of luteinizing hormone-releasing hormone antagonist cetrorelix in the treatment of symptomatic benign prostatic hyperplasia. J Clin Endocrinol Metab 1998, 83: 3826- 3831.
Fujimoto, Kiohide et al. Prostate-specific antigen changes as a result of chlormadinone acetate administration to patients with benign prostatic hyperplasia: A retrospective multi-institutional study. International Journal of Urology, Volume 13, Number 5, 2006, pp. 543-549. Grimes DA, GaIIo MF, Grigorieva V, Nanda K, Schulz KF. Steroid hormones for contraception in men: systematic review of randomized controlled trials. Contraception 2005, 71 : 89-94.
Hay CJ, Brady BM, Zitzmann M et al. A multicenter Phase Nb study of a novel combination of intramuscular androgen (testosterone decanoate) and oral progestogen (etonogestrel) for male hormonal contraception. J Clin Endocrinol Metab
2005, 90: 2042-2049. Lepor H. The role of gonadotropin-releasing hormone antagonists for the treatment of benign prostatic hyperplasia. Rev Urol 2006, 8: 183-189. Matthiesson KL, McLachlan Rl. Male hormonal contraception: concept proven, product in sight? Human Reproduction Update 2006, 12: 463-482.
NN, Presentation on European Association of Urology 22nd Annual Congress, Berlin, March 2007: Teverelix effective in treating benign prostatic hyperplasia. http.www.medscape.com/viewarticle/554194. Noguchi K, Takeda M, Hosaka M, Kubota Y. Clinical effects of allylestrenol on patients with benign prostate hyperplasia (BPH) evaluated with criteria for treatment efficacy in
BPH. Hinyokika Kiyo 2002, 48: 269-273 (Reference to English abstract) Noguchi K, Harada M, Masuda M, Takeda M, Kinoshita Y, Fukushima S, Miyai K,
Fukuoka H, Hosaka M. Clinical significance of Interruption therapy with allylestrenol in patients with benign prostatic hypertrophy, lnt J Urology 1998;5:466-470. Tiwari A, Krshna NS, Nanda K, Chugh A. Benign prostatic hyperplasia: an insight into current investigational medical therapies. Expert Opin Investig Drugs 2005, 14: 1359- 1372.
Wu FCW, Balasubramanian RAM, Mulders TMT, Coelingh-Bennink HJT. Oral progestogen combined with testosterone as a potential male contraceptive: additive effects between desogestrel and testosterone enanthate in suppression of spermatogenesis, pituitary-testicular axis, and lipid metabolism. J Clin Endocrinol Metab 1999, 84: 112-122.
Example 1
This example describes the conduct of a clinical trial to demonstrate the effect of etonogestrel in men with Lower Urinary Tract Symptoms (LUTS) related to Benign Prostatic hyperplasia (BPH). The trial is a placebo-controlled, multiple dose trial, measuring effects on prostate volume, International Prostate Symptom Score (IPSS) and peak urinary flow.
Etonogestrel is administered during eight weeks treatment with oral tablets in doses of 5 150μg per two days, 150μg or 300μg per day or placebo.
240 subjects with LUTS/BPH are to be randomly assigned to one of the following regimens (60 subjects per treatment group): Group 1 : 150μg etonogestrel per two days Group 2: 150μg etonogestrel per day 0 Group 3: 300μg etonogestrel per day Group 4: placebo
Etonogestrel treatment duration is eight weeks with a follow up period of 16 weeks. The effect is be evaluated on prostate volume, lower urinary tract symptoms, urinary flow, post-void residual volume, sexual function, well-being and LUTS-related Quality of5 Life.
Methods of evaluation
Prostate volume (total and transition zone) is to be measured using trans-rectal ultrasound (TRUS). In addition, as a biomarker for prostate volume, PSA (Prostate Specific Antigen) is to be measured. 0 The effect on LUTS is to be evaluated by using the seven questions of the International Prostate Symptom Score (IPSS).
Urinary flow (Qmaχ and Qav) is to be measured using an automatic uroflow meter. Post- void residual volume is to be measured using transabdominal ultrasound. Progression of LUTS is defined as occurrence of either 1 ) Acute Urinary Retention (AUR), 2) need for5 Transurethral Resection of Prostate (TURP) or other minimal invasive therapy or 3) worsening of symptoms defined as IPSS increase of≥4 points compared to baseline. The first two will be assessed by means of (serious) adverse event reporting. Sexual function, well-being and LUTS-related quality of life is to be assessed by the Benign Prostatic Hypertrophy-Related Quality of Life Questionnaire (BPH-QoL9), the0 Male Sexual Health Questionnaire to assess Ejaculatory Dysfunction (MSHQ-EjD Short Form), and the IPSS-Quality of Life question.
In each treatment group there are to be 48 subjects so that Dunnetfs correction for multiple testing can be used to show a difference in change from baseline of 10 mL of total prostate volume as measured by TRUS. Taking into account a 20% drop out rate,5 preferably 60 subjects per treatment group are to be recruited. Inclusion criteria: 1. Signed written informed consent, obtained before screening evaluations; 2. Men diagnosed with LUTS suggestive of BPH: 2.1. Baseline IPSS score of>12 (moderate to severe); 2.2. Prostate volume of>40 ml. and < 100 ml. (based on TRUS); 2.3. Peak urinary flow rate≤15 mL/s with a voided volume of≥125 ml_; 3. Age at least 50 but not older than 80 years at screening; 4. PSA < 10 ng/mL and exclusion of prostate cancer to the satisfaction of the investigator (e.g. by biopsy). Exclusion criteria: 1. A postvoid residual volume >250 ml_; 2. Use of anti-androgens, androgens, Gonadotropin Releasing Hormone (GnRH) antagonists, or 5α-reductase inhibitors within six months prior to start trial medication; 3. Use ofceblockers, phytotherapy (for LUTS) or drugs interfering with bladder function within two weeks prior to start trial medication; 4. Presence of hypogonadism as judged by the (sub)investigator; 5. Acute urinary retention within the past 12 months; 6. History of surgery for BPH, including other minimally invasive procedures; 7. Presence of urinary tract infection; 8. Presence or history of (subclinical) prostate cancer, bladder cancer, urethral stricture, or pelvic irradiation; 9. Presence or history (within the past 12 months) of depression or other psychiatric disease of moderate or severe intensity; 10. Cardiac or cerebrovascular event within the past six months; 11. Presence or history of any neurological disease associated with primary bladder dysfunction; 12. Presence or history of liver disease or disturbance of liver function that failed to return to normal; 13. Presence or history of renal disease or disturbance of renal function that failed to return to normal; 14. Present use or use within two months prior to screening of the following drugs: phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate, hydantoins, rifampicin, ritonavir, nelfinavir, and griseofulvin; 15. Presence or history (within the past 12 months) of alcohol or drug abuse as judged by the (sub)investigator; 16. Clinically relevant abnormal laboratory result at screening as judged by the (sub)investigator; 17. Known hypersensitivity to any of the components of trial medication; 18. Administration of investigational drugs and/or participation in another clinical trial within two months prior to screening.
Formulation and dose
Tablets contain 150 or 300μg etonogestrel or placebo.
In addition to the active compound, the tablets contain magnesium stearate, HPC, lactose and corn starch. The coating contains: HPMC E15, Talc, Peg 400 and Titanium dioxide. Subjects will be instructed to take one tablet p.o. per day, in the morning, with water. Group 1 : One tablet of 150μg etonogestrel or one placebo tablet per day, in an alternating fashion;
Group 2: One tablet of 150μg etonogestrel per day;
Group 3: One tablet of 300μg etonogestrel per day; Group 4: One placebo tablet per day.
The following medication should not be used during the trial:
Anti-androgens, androgens, and 5>reductase inhibitors;ceblockers, phytotherapy (for
LUTS) and drugs interfering with bladder function; hepatic microsomal enzyme-inducing medication which may affect the bioavailability of steroids: phenytoin, barbiturates, primidone, carbamazepine, oxcarbazepine, topiramate, felbamate, hydantoins, rifampicin, ritonavir, nelfinavir and griseofulvin.
Schedule of testing and assessments
For all participating subjects, the total duration of the trial will be approximately 28 weeks: up to four weeks screening, eight weeks treatment and 16 weeks follow up period.
At each visit of the patients in the trial to the clinic the following is to be performed:
Record vital signs: Body weight, heart rate and blood pressure.
Check the use of any concomitant medication and the occurrence of (serious) adverse events since the previous visit. Screening visit
Inform the subject, orally and in writing, about the purpose, procedures, and general risks of participating in the trial; Obtain written informed consent; Assign subject number;
Record general medical history and perform general physical examination; Perform blood sampling for PSA (should be done prior to TRUS), and routine lab parameters; Perform the following procedures for the in- and exclusion criteria: a. TRUS to determine prostate volume; b. Uroflow measurement to determine Qmax and voided volume, c.
Transabdominal ultrasound to determine postvoid residual volume; d. Urinalysis to determine urinary tract infection (according to local practice); Check the other in- and exclusion criteria; Have subject complete the IPSS-QoL questionnaire; Record pre- treatment medication used within the last 60 days; Have subject complete the BPH-
QoL9 and MSHQ-EjD Short Form questionnaires before tablet intake at Day 1 visit (can be completed at home); Instruct the subject to come in a fasted state for the randomization visit.
Randomization visit. Day 1. This visit should preferably be scheduled within 30 days of the screening visit. On day 1 the subject should come to the clinic in a fasted state. Randomization and treatment assignment will be done on this day 1. Check in- and exclusion criteria where needed, e.g. for those criteria for which a lab assessment was done. Trial medication will be supplied to the subject and instructions regarding tablet intake will be given (first drug intake at the clinic). Perform blood sampling for hormones (T, DHT, LH, FSH, E2,
SHBG), routine lab parameters (only lipids), bone markers (CTX, osteocalcin) and etonogestrel, all before first medication intake. After sampling and during this visit, the subject should take the first trial medication. Again perform blood sampling for etonogestrel: one sample one hour after trial medication intake and one sample at least
2 hours after trial medication intake (could also be at the end of the same day).
Week 2 visit
This visit should be scheduled at Day 15 ± 3 days.
Check the use of any concomitant medication and the occurrence of (serious) adverse events since the previous visit;
Record vital signs (body weight, heart rate and blood pressure);
Perform blood sampling for hormones (T, DHT, LH, FSH, E2, SHBG) and etonogestrel
(one sample at the beginning of the visit and one sample at least two hours later (could also be at the end of the same day)); Have subject complete the IPSS-QoL;
Perform uroflow measurement.
Perform transabdominal ultrasound to determine postvoid res
Week 4 visit:
This visit should be scheduled at Day 29 ± 3 days. Perform blood sampling for PSA (should be done prior to TRUS), routine lab parameters
(only Hb and Ht), etonogestrel and hormones (T, DHT, LH, FSH, E2, SHBG).
Have subject complete the IPSS-QoL, BPH-QoL9 and MSHQ-EjD Short Form questionaires
Perform uroflow measurement. Perform transabdominal ultrasound to determine postvoid residual volume.
Week 8 / End of Treatment visit
This visit should be scheduled at Day 57 ± 3 days or after early treatment discontinuation. The subject should come to the clinic in a fasted state.
Perform blood sampling for PSA (should be done prior to TRUS), etonogestrel, hormones (T, DHT, LH, FSH, E2, SHBG), bone markers (CTX, osteocalcin), routine lab parameters
Have subject complete the IPSS-QoL, BPH-QoL9 and MSHQ-EjD Short Form questionnaires; Perform TRUS to determine prostate volume; Perform uroflow measurement. Perform transabdominal ultrasound to determine postvoid residual volume; Week 12 visit
This visit should be scheduled 4 weeks ± 5 days after end of treatment. In case of treatment completion, this will be at Day 85 ± 5 days. The subject should come to the clinic in a fasted state. Perform blood sampling for PSA (should be done prior to TRUS), hormones (T, DHT, LH, FSH, E2, SHBG) and routine lab parameters; Have subject complete the IPSS-QoL, BPH-QoL9 and MSHQ-EjD Short Form questionnaires; Perform TRUS to determine prostate volume; Perform uroflow measurement. Perform transabdominal ultrasound to determine postvoid residual volume. Week 16 visit
This visit should be scheduled 8 weeks ± 5 days after end of treatment. In case of treatment completion, this will be at Day 113 ± 5 days. Have subject complete the IPSS- QoL, BPH-QoL9 and MSHQ-EjD Short Form questionnaires; Perform uroflow measurement; Perform transabdominal ultrasound to determine postvoid residual volume.
Week 20 visit
This visit should be scheduled 12 weeks ± 5 days after end of treatment. In case of treatment completion, this will be at Day 141 ± 5 days. Have subject complete the IPSS- QoL, BPH-QoL9 and MSHQ-EjD Short Form questionnaires; Perform uroflow measurement.; Perform transabdominal ultrasound to determine postvoid residual volume;
Week 24 / End of Trial visit
This visit should be scheduled 16 weeks after end of treatment or after early discontinuation from the trial. In case of treatment completion, this will be at Day 169 ± 5 days. The subject should come to the clinic in a fasted state. Perform blood sampling for PSA (should be done prior to TRUS), hormones (T, DHT, LH, FSH, E2, SHBG), bone markers (CTX, osteocalcin), routine lab parameters; Have subject complete the IPSS- QoL, BPH-QoL9 and MSHQ-EjD Short Form questionnaires; Perform TRUS to determine prostate volume; Perform uroflow measurement. Perform transabdominal ultrasound to determine postvoid residual volume. Methods
Total prostate volume will be measured by TRUS using the ellipsoid calculation method (height x width x length x pi/6). Preferably the same person in an investigational site measures all TRUS's. If this is not feasible, another person can perform the TRUS, but he should use the same technique and device. The transition zone volume will only be measured by those investigational sites which perform this routinely or are experienced with it. This will be established before the first measurement.
In addition, as a biomarker for prostate volume, PSA will be measured. Blood samples for PSA should be taken before TRUS (if applicable). The effect on LUTS will be evaluated by using the IPSS. This questionnaire will be filled in by the subject. It contains seven questions with a possible score from 0-5. The total scores can range from 0 to 35.
Peak and average urinary flow (CW and Qav) will be measured by using an automatic uroflow meter. The urinary volume and Qav will be determined by the machine and the investigator will enter these data to the CRF. A copy of the recording paper slip
(including subject number, date and visit) should then be sent to a central assessor for manual standardized calculation of the 'smoothed' CW in order to correct for artefacts [23]. The central assessor will be assigned before the clinical trial start and should be experienced with calculation of the 'smoothed' CW. To calculate the 'smoothed' CW, the uroflow curve should be smoothed by eye into a continuous curve and a sliding average over two seconds should be used as CW to remove positive and negative spike artefacts. For inclusion criterion 2 at screening, Qmaxcan be calculated locally after which a copy of the paper slip should be sent to the central assessor anyway to obtain a standardized baseline value. The subjects will be instructed to void in a 'relaxing manner1.
Postvoid residual volume will be measured using transabdominal ultrasound. Progression of LUTS is defined as occurrence of either 1) AUR, 2) need for TURP or other minimal invasive therapy or 3) worsening of symptoms defined as IPSS increase of >4 points compared to baseline. The first two will be assessed by means of (S)AE reporting.
Sexual function, well-being and LUTS-related QoL will be assessed by two validated questionnaires, the Benign Prostatic Hypertrophy-Related Quality of Life Questionnaire (UROLI FETM/ BPHQOL9) and the Male Sexual Health Questionnaire to assess Ejaculatory Dysfunction (MSHQ-EjD Short Form) [24,25]. In addition, the Quality of Life question from the IPSS-QoL questionnaire will be used for this [26]. Blood samples for assessment of serum testosterone, dihydrotestosterone, follicle stimulating hormone luteinizing hormone, estradiol and sex hormone binding globuline will be taken on Day 1 (before tablet intake), Week 2, Week 4, Week 8 and post- treatment on Week 12 and Week 24. An Adverse Event (AE) is defined as any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. Lack of efficacy, i.e. preexisting complaints or symptoms related to LUTS/BPH which did not worsen but also did not improve during the trial, should not be reported as AE. Pre-existing complaints or symptoms related to LUTS/BPH that did worsen during the trial should be reported as AE, except for worsening of IPSS, increase in prostate volume, worsening of uroflow parameters, and increased post-void residual volume as these are efficacy endpoints. In addition, symptoms related to LUTS/BPH that did not exist prior to the trial, but occur during the trial should be reported as AE. A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose: results in death, is life-threatening. The term "life-threatening" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. Post-treatment evaluation Subjects will be followed up 16 weeks after treatment cessation in order to assess sustained efficacy. During the post-treatment period, IPSS-QoL, uroflow, postvoid residual volume and completion of the BPH-QoL and MSHQ-EjD Short Form questionnaires will be done every four weeks. TRUS and blood sampling for hormones, PSA and routine lab parameters will be done at Week 12 and Week 24 (End of Trial). Blood sampling for bone markers and retrospective analysis (see Section 4.5.4) will only be done at Week 24. Efficacy variables
Efficacy is to be observed with the following assessments. Prostate volume Prostate volume measurement
For each subject, the following variables will be calculated per assessment:
- Change from baseline in total prostate volume;
- Percentage change from baseline in total prostate volume;
- Change from baseline in prostate transition zone volume; - Percentage change from baseline in prostate transition zone volume. Effect on Lower Urinary Tract Symptoms (LUTS)
Urinary flow rate
For each subject, the following variables will be calculated per assessment:
- Change from baseline in peak urinary flow rate (CW) - Percentage change from baseline in peak urinary flow rate (Qmax)
- Change from baseline in average urinary flow rate (Qav)
- Percentage change from baseline in average urinary flow rate (Qav) Postvoid residual volume
For each subject, the following variables will be calculated per assessment: - Change from baseline in postvoid residual volume
- Percentage change from baseline in postvoid residual volume Progression of LUTS
The progression of LUTS will be defined as the occurrence of one or more of the following events: - Acute Urinary Retention (AUR);
- Transurethral Restriction of Prostate (TURP) or other minimal invasive therapy;
- IPSS increase of≥4 points compared to baseline.
Sexual functioning, well-being and LUTS-related Quality of life Pharmacokinetic-pharmacodynamic evaluation
Example 2
Effect of etonogestrel on prostate weight of beagle dogs.
This test was performed with 22 pure bred male young beagle dogs. Initial body weight ranged from 8-12 kg and ages ranged from 8-26 months.
Etonogestrel or placebo was orally administered in the form of tablets once daily for 13 or 26 weeks. The dogs were dosed each morning after they had access to their food.
Three dosages, expressed in mg/kg per day were tested:
Dose group 1 : 0.000 (Placebo) 5 male dogs Dose group 2: 0.00625 (6.25 μg/kg) 5 male dogs
Dose group 3: 0.0625 (62.5 μg/kg) 5 male dogs
Dose group 4: 0.625 (625 μg/kg) 7 male dogs
Pharmaceutical formulations as tablets for oral administration were made for each dose level containing a quantity of etonogestrel sufficient for 10 kg body weight and additional tablets for 1 kg body weight. From each dose group 2 animals were sacrificed after 13 weeks of dosing and 3 animals were sacrificed after 26 weeks of dosing. 2 animals of group 4 were kept for a further 9 weeks without drug treatment and sacrificed after a total of 35 weeks after initiation of the study.
Results
No changes in behavior were observed. Dogs in group 3 and 4 showed a slight increase in weight gain during the dosing period.
The following table shows mean values of prostate weights per group in grams with measurements for individual do s in arentheses
Figure imgf000017_0001
Conclusion:
A very low prostate gland weight was seen in one dog each of groups 2 and 3 and 2 dogs from group 4 after 26 weeks of dosing. This was observed also in the males 9 weeks after termination for drug treatment. The result demonstrate a clear and long- lasting dose-related atrophy of the glandular structures.
Example 3
A formulation for buccal mucosal administration of etonogestrel is depicted in table 1.
Table 1 :
Figure imgf000017_0002
Figure imgf000018_0001
Note: 1 ) Contribution to total volume is negligible due to its small amount
Preparation:
A bulk solution is made by mixing the ingredients as indicated in Table 1. The oral spray is then prepared by addition of the active compound etonogestrel. The solution can be used for direct application in the mouth as drops or as a vaporous spray.
A sufficient amount to administer is 0.1 mL of the solution so prepared was filled into a 0.2 mL glass vial. The glass vial was placed in a device to enable spraying the solution in the mouth.

Claims

Claims
1. A method of treatment of benign prostate hyperplasia by administering an effective dose of etonogestrel to an individual having benign prostate hyperplasia.
2. The method according to claim 1 , characterized in that administering the dose of etonogestrel is with a spray or solution into the oral cavity of the individual.
3. The method according to claim 2, characterized in that the administering of the spray or solution is sublingually.
4. The method according to any one of claims 1-3, characterized in that the treatment comprises a period of a duration in the range of from 2 to 12 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg is administered to the individual and the treatment comprises a period without administering etonogestrel for a duration in the range of from 1 month to 6 months.
5. The method according to claim 4, characterized in that the amount is in the range of from 0.1 mg to 0.2 mg.
6. Etonogestrel for a treatment of an individual having benign prostate hyperplasia.
7. Etonogestrel for the treatment according to claim 6, characterized in that the treatment is by administering an effective dose of etonogestrel with a spray or solution into the oral cavity of the individual in need of the treatment.
8. Etonogestrel for the treatment according to claim 6 or 7, characterized in that the treatment comprises a period of a duration in the range of from 2 to 12 weeks in which a daily dose of etonogestrel in an amount per dose in the range of from 0.07 mg to 0.3 mg is administered to the individual and the treatment comprises a period without administering etonogestrel for a duration in the range of from 1 month to 6 months.
9. Etonogestrel for the treatment according to claim 8, characterized in that said amount of etonogestrel is in the range of from 0.1 mg to 0.2 mg.
10. A drug delivery system for administration metered doses of a drug into an oral cavity of an individual, characterized in that the system comprises etonogestrel for delivery.
PCT/EP2009/051724 2008-02-15 2009-02-13 Use of etonogestrel for benign prostate hyperplasia (bph). WO2009101182A1 (en)

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EP08151525.6 2008-02-15

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WO2011073995A3 (en) * 2009-12-14 2011-08-11 Lincoln Pharmaceuticals Limited Liquid vaginal spray of progesterone
WO2017000081A1 (en) * 2015-06-30 2017-01-05 上海交通大学 Applications of etonogestrel in preparation of products for resisting against prostate cancer
US10441591B2 (en) 2015-06-30 2019-10-15 Shanghai Jiao Tong University Applications for etonogestrel in preparing anti-prostate cancer products

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