Abstract
Leuprolide acetate is the first GnRH agonist that entered clinical development after the discovery of the native GnRH. Several long-acting depot formulations of leuprolide acetate (ranging from 1-month to 6-month intramuscular injections) have been successively developed for various suppressive treatments in men, women, and children, which are available in the United States and globally. This mini review aims to summarize the key clinical studies that led to regulatory approval of leuprolide acetate depot suspension for injection.
After the isolation and chemical characterization of the gonadotropin-releasing hormone (GnRH) in 1971, drug discovery programs aimed at more potent synthetic GnRH agonists have been initiated in several pharmaceutical companies and scientific research centers, including the Salk Institute (1). Shortly thereafter, leuprolide (known as leuprorelin outside the United States) acetate was discovered by Takeda Pharmaceutical Company Ltd. (Takeda, Japan) around 1973 and subsequently developed in collaboration with Abbott Laboratories (United States). It became the first GnRH agonist that entered clinical development for various clinical indications. Leuprolide acetate (5-oxo-L-prolyl-L-histidyl-L-tryptophyl- L-seryl-L-tyrosyl-D-leucyl-L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate) is a synthetic peptide analog of GnRH with increased potency and longer half-life compared with GnRH (1). Subsequently, several long-acting delivery formulations using microsphere delivery system have been developed by Abbott Laboratories and Takeda (Table 1) (2, 3, 4). The microspheres are fine microcapsules with polycores containing the peptide at a high concentration and are easily injectable through a conventional fine needle. The biodegradable polymers poly(lactic/glycolic acid) and poly(lactic acid) were used as wall materials in the preparation of microspheres containing leuprolide acetate (7). Drug release from poly(lactic/glycolic acid) and poly(lactic acid) particles occurs by diffusion of the drug through the polymer and by material degradation (8). The degradation rate is adjustable by copolymer composition and molecular weight. Different comonomer ratios allow for 1-month to 6-month depot formulations, which maintain a steady concentration of drug in the circulation, providing prolonged suppression of hormone levels (7). The depot formulations of leuprolide acetate were evaluated clinically by TAP (Takeda-Abbott Partnership) Pharmaceuticals in the United States. Based on these studies, Lupron Depot(R) has been approved in the United States by the Food and Drug Administration (FDA) and globally (under different tradenames) for different suppressive therapies in men and women, including the palliative treatment of advanced prostate cancer, management of endometriosis alone and in combination with the progestin norethindrone acetate (NETA), preoperative hematologic improvement of women with anemia caused by uterine fibroids, and for the treatment of children with central precocious puberty (CPP) (Table 1).
TABLE 1.
Lupron Depot formulations approved in the United States.
| Dosage | Administration | Maximum Treatment Duration | Indications | References |
|---|---|---|---|---|
| Lupron Depot(R)for Gynecological Indications | ||||
| 3.75 mg | 1 IM injection every 1 mo | Endometriosis: Initial Treatment: 6 mo Retreatment: 6 mo Total: 12 mo |
|
(2) |
| 3 mo |
|
(3) | ||
| 11.25 mg | 1 IM injection every 3 mo for 1 to 2 doses | Initial Treatment: 6 mo Retreatment: 6 mo Total: 12 mo |
|
(4) |
| 3 mo |
|
(3) | ||
| Lupron Depot(R)for Prostate Cancer | ||||
| 7.5 mg | 1 IM injection every 1 month | No restrictions |
|
(5) |
| 22.5 mg | 1 IM injection every 3 mo | |||
| 30 mg | 1 IM injection every 4 mo | |||
| 45 mg | 1 IM injection every 6 mo | |||
| Lupron Depot Ped(R)for Pediatric Patients | ||||
| 7.5 mg | 1 IM injection every 1 month based on the child’s weight | No restrictions |
|
(6) |
| 11.25 mg | ||||
| 15 mg | ||||
| 11.25 mg | 1 IM injection every 3 mo based on the child’s weight |
|||
| 30 mg | ||||
The objective of this mini review is to discuss clinical studies which led to the approval of leuprolide acetate depot (Lupron Depot(R), Lupron Depot-Ped(R)) in the United States. In the meantime, several generic depot formulations of leuprolide acetate and other GnRH agonists are available (1). There is a plethora of studies with generic formulations of leuprolide acetate, as well as indications that have not been formally approved. These studies are not included in this review.
Materials and methods
This review is based on a PubMed search for human studies with leuprolide acetate conducted between 1985 and 2022, focusing on registration phase II and phase III studies and gynecological indications.
Mechanism of action of GnRH agonists
One of the key discoveries in GnRH research was the observation that native GnRH is secreted from the hypothalamus in a pulsatile manner and the frequency of its pulses determines whether follicle-stimulating hormone or luteinizing hormone is secreted from the pituitary gland (9). Depot formulations of GnRH agonists provide continuous stimulation of the GnRH receptors that, after an initial stimulatory phase, consequently leads to their desensitization resulting in profound suppression of gonadotropins and ovarian steroids (Fig. 1) (10). This unexpected effect provided the rationale for suppressive therapies in various clinical indications.
FIGURE 1.
Mechanism of action of GnRH, depot GnRH agonists and GnRH antagonists.
The figures in the upper level present the interaction of native GnRH (A), depot GnRH agonists (B) and GnRH antagonists (C) with the GnRH-R in the pituitary gland. The corresponding figures in the lower level present relative estradiol suppression. (A) Native GnRH is released in a pulsatile manner from the hypothalamus. The frequency of GnRH pulses regulates cyclic changes in gonadotropins (LH, FSH) and estradiol concentrations during the cycle. (B) Depot GnRH agonists initially stimulate the HPO axis, which results in a transient hormonal flare. Continued stimulation of GnRH-R consequently leads to their desensitization and profound estradiol suppression. (C) GnRH antagonists competitively bind to GnRH-R and produce rapid and dose-dependent suppression of the HPO axis, which results in a partial estradiol suppression at lower doses to nearly full suppression at higher doses.
FSH = Follicle-stimulating hormone; GnRH = Gonadotropin-releasing hormone; GnRH-R = GnRH receptor; HPO = Hypothalamo–pituitary–ovarian; LH = Luteinizing hormone.
(From Taylor et al. [10]. Reprinted by permission of the publisher.)
Clinical development of lupron depot for gynecological indications
Management of Endometriosis
Endometriosis is an estrogen-dependent disease, and GnRH agonists have been shown to be effective in reducing pelvic pain associated with endometriosis (11). However, treatment with GnRH agonists is associated with severe hypoestrogenic side effects, including progressive bone loss and vasomotor symptoms, such as hot flashes and vaginal dryness. Therefore, the use of Depot Lupron(R) as a monotherapy (ie, without hormonal add-back therapy) is limited to a single 6-month course of therapy in the United States. In the early 1990s, several hormonal add-back therapy regimens, including different estrogen-progestin combinations, estrogen monotherapy, and tibolone (in Europe), were shown to ameliorate hypoestrogenic symptoms during GnRH agonist therapy in women with endometriosis without major effects on therapeutic efficacy (12, 13).
To evaluate the efficacy and safety of leuprolide acetate depot, alone and in combination with 3 hormonal add-back regimens, a 12-month study (n = 201) was conducted in women with endometriosis-associated pelvic pain (14). Patients were assigned to 1 of 4 treatment groups: Group A received placebos for progestin and estrogen, group B received NETA 5 mg daily and placebo for conjugated equine estrogens (CEE) 0.625 mg, daily, group C received NETA 5 mg and CEE 0.625 mg, and group D received NETA 5 mg and CEE 1.25 mg daily. At each visit, dysmenorrhea and nonmenstrual pelvic pain (NMPP) were evaluated, and a pelvic examination (for pelvic tenderness) was performed by the investigator. These symptoms were graded according to a modification of the 4-point Biberoglu and Behrman grading scale. By week 8, all 4 groups showed significant improvement in pelvic pain scores compared with baseline levels. There were no statistically significant differences between treatment groups. The study concluded that the use of leuprolide acetate depot in combination with NETA 5 mg alone or with NETA and CEE 0.625 mg provides effective suppression of pelvic pain associated with endometriosis while protecting against bone loss. Based on this study, leuprolide acetate (3.75 mg depo suspension for monthly injections) in combination with NETA 5 mg as add-back therapy was approved by the FDA for the management of endometriosis pain as an initial 6-month therapy with an option of additional 6-month therapy (maximum up to 12 months) as needed for the recurrence of symptoms.
It is somewhat surprising that NETA 5 mg was as effective as NETA 5 mg plus medium (CEE 0.625 mg) or high dose estrogen (CEE 1.25 mg) in preventing bone loss. Furthermore, other studies showed that progesterone and different progestins failed to prevent bone mineral density loss during combined treatment with a GnRH agonist in women with endometriosis. These inconsistencies have prompted the ESHRE Guideline for Diagnosis and Treatment of Endometriosis to issue a statement against the use of progestin-only add-back therapies in combination with GnRH agonists (15). However, NETA is a unique progestin that has both estrogenic (as a prodrug to the potent estrogen ethinyl estradiol) and androgenic properties that explain its effectiveness as an add-back therapy. Mostly through its estrogenic activity, NETA exerts beneficial effects on bone mineral density and vasomotor symptoms in women treated with leuprolide acetate, which explains its efficacy as add-back therapy (Fig. 2) (15).
FIGURE 2.
Potential mechanism of action of NETA as an add-back therapy to GnRH agonists in women with endometriosis.
NETA, after oral administration, is metabolized by the liver to various metabolites, including NET and EE. EE seems to be responsible for the alleviation of hypoestrogenic side effects of GnRH agonists, such as hot flashes and bone resorption. NET may exert antiproliferative effects on the endometrium via PR-mediated mechanisms, as well as AR-mediated anabolic effects on bones, although these effects have not yet been studied in women with endometriosis.
AR = androgen receptor; EE = ethinyl estradiol; NET = norethindrone; NETA = norethindrone acetate; PR = progesterone receptor.
(From Chwalisz et al. [15]. Reprinted by permission of the publisher.)
Preoperative Treatment of Women With Uterine Fibroids and Anemia
Leuprolide acetate depot plus iron compared with iron alone was studied as a preoperative treatment (hysterectomy, myomectomy, endometrial ablation) in women with anemia due to prolonged or excessive bleeding associated with uterine fibroids (3). This was a phase III, stratified, randomized, double-blind, placebo-controlled, parallel-group, 12-week multicenter study (n = 309). Enrolled women had hemoglobin levels of ≤10.2 g/dL and/or hematocrit values of ≤30%. Women were entered into 1 or 2 strata based on their baseline hematocrit level: Stratum A, hematocrit ≤ 28%; Stratum B, hematocrit ≥28%. Women within each stratum were randomized to 1 of 3 treatment arms: leuprolide acetate depot 7.5 mg, leuprolide acetate depot 3.75 mg, or placebo. All patients received iron orally. A clinically relevant hematologic response (primary endpoint) was defined as a hemoglobin level of ≥12 g/dL and a hematocrit value of ≥36%. Secondary endpoints included changes in uterine and fibroid volumes and other fibroid symptoms.
A significantly greater proportion of women in both leuprolide acetate groups (combined strata) responded to therapy than did those in the placebo group (iron alone): 74% in each leuprolide acetate group versus 46% in the placebo group (P<.001). Women treated with leuprolide acetate depot also showed a significant reduction in uterine and fibroid volumes versus the placebo group (P<.01) (3). Hot flashes and vaginitis were the major adverse events in the leuprolide acetate groups. This study concluded that both depo formulations of leuprolide acetate plus iron were more effective than iron alone in treating the anemia of patients with uterine fibroids, in reducing uterine fibroid volume, and in alleviating bleeding and other fibroid-related symptoms (bloating, pelvic pain and pelvic pressure). Ameliorating the anemia makes women with heavy uterine bleeding and fibroids better surgical candidates by potentially eliminating the need for preoperative blood transfusion and allowing them to be autologous blood donors. Similarly, fibroid volume reduction may potentially influence the type of surgery (eg, myomectomy vs. hysterectomy). Based on this study, both doses of leuprolide acetate depot (Lupron Depot(R) 3.75 mg, 7.5 mg) in combination with iron were approved by the FDA for the preoperative hematologic improvement of women with anemia caused by fibroids for whom 3 months of hormonal suppression is deemed necessary (Table 1).
Clinical development of lupron depot for the treatment of prostate cancer
Androgen deprivation therapy (ADT) with GnRH agonists is an established first-line treatment for advanced/metastatic prostate cancer (PCa). It is recommended for use before, during, or after definitive radiotherapy for intermediate- and high-risk localized prostate cancer (16). The ADT decreases serum testosterone (T) levels, a promoter of prostate cancer growth, and increases overall survival and palliative alleviation of symptoms in patients with PCa. However, GnRH agonist-induced ADT is associated with an increased rate of hypoandrogenic adverse events and an increased risk of metabolic and cardiovascular diseases. In 2010, the FDA highlighted an increased risk of diabetes, heart attack, stroke, and sudden death with GnRH agonists, based on a review of published studies, and requested additional warnings of such risks in GnRH agonist labels (17).
Leuprolide acetate was first approved for ADT by the FDA in 1985 as a daily subcutaneous injection (18). Subsequently, several leuprolide acetate depot formulations have been developed for these indications. Lupron Depot(R) for ADT is available in the US at doses of 7.5 mg (1 month), 22.5 mg (3 months), 30 mg (4 months), and 45 mg (6 months) and is injected intramuscularly (Table 1). In the meantime, several generic leuprolide acetate long-term formulations using different formulation technologies are also available for ADT (18, 19).
The most recent open-label study with Lupron Depot(R) for ADT evaluated the efficacy and safety of leuprolide acetate 45 mg 6-month depot formulation in 151 men with locally advanced and advanced prostate cancer who received 2 injections intramuscularly administered 24 weeks apart (20). The primary efficacy measurement was the proportion of patients achieving suppression of serum testosterone to ≤ 50 ng/ dL from week 4 through week 48. The primary efficacy endpoint was achieved in 93.4% of subjects. There were nine escapes from testosterone suppression during the study, none of which were accompanied by a rise in prostate-specific antigen levels. This study demonstrated the efficacy and safety of the leuprolide acetate 6-month depot formulation for sustained reduction of serum testosterone to castrate levels in men with advanced prostate cancer (Fig. 3). Based on this study, this formulation was approved by the FDA and is available in the United States as Lupron Depot(R) 45 mg for 6-month administration. The availability of a 6-month depot formulation of leuprolide acetate limits the number of injections needed per year to 2, which may improve patient compliance and outcomes.
FIGURE 3.
Mean testosterone levels (A) and mean luteinizing hormone (LH) concentrations (B) during the treatment period.
The dashed line in (A) represents castrate levels for serum testosterone (50 ng/dL). Time points for administration of leuprolide acetate 6-month depot injections are indicated in both panels. (From Spitz et al. [20]. Reprinted by permission of the publisher.)
Clinical development of lupron depot-ped for the treatment of cpp in children
The CPP results from premature pubertal activation of the hypothalamic-pituitary-gonadal axis resulting in the pulsatile release of GnRH and premature secretion of gonadal steroids in both girls and boys. Treatment with GnRH agonists has been the standard of care for CPP for more than 30 years (21). Treatment results in hormonal suppression, cessation of pubertal development, and normalization of growth and skeletal maturation rates. Leuprolide acetate was the first GnRH agonist used for the treatment of CPP (22, 23). It was initially developed as monthly intramuscular injections (7.5, 11.25, and 15 mg) and later as 3-month intramuscular injections (11.25 and 30 mg). It is available in the United States under the brand name Lupron Depot-Ped(R) (Table 1). The dose selection is based on child weight for both 1-month and 3-month formulations (6). It was established during clinical phase III studies performed in the United States. Biochemical (peak-stimulated luteinizing hormone, estradiol in girls, and testosterone in boys) and anthropometric (growth rate, bone age acceleration, pubertal progression) parameters and safety were assessed in these studies.
The safety and efficacy of leuprolide acetate 1-month depot formulations have been established in children with CPP (6, 23). Subsequently, the 3-month depot formulations were evaluated in phase III, a randomized, open-label study in children (n = 84) with CPP (24, 25). This study concluded that treatment with leuprolide acetate 3-month depot formulations effectively suppressed the GnRH axis and may positively affect patient convenience and compliance. Both 1- and 3-month depot formulations were well-tolerated, with injection site pain being the most frequent treatment-emergent adverse event.
Conclusions
Leuprolide acetate was the first GnRH agonist that entered clinical development as daily subcutaneous injections in men with advanced prostate cancer and was approved by the FDA in 1985. Successively, several long-acting depot formulations of leuprolide acetate (ranging from 1-month to 6-month, depending on indication) have been developed for various indications in men, women, and children, including palliative treatment of prostate cancer, management of endometriosis, preoperative treatment of women with anemia and fibroids, and CPP. These formulations are available in the United States under the tradenames of Lupron Depot and Lupron Depot-Ped.
Footnotes
As a former employee of TAP Pharmaceuticals, Abbott Laboratories, and AbbVie inc., K.C. was involved in the clinical development of leuprolide acetate. K.C. owns AbbVie stock.
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