Summary Basis of Decision for Luveris ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Luveris®
Lutropin alpha, 75 IU/vial, Powder for solution, Subcutaneous injection
Serono Canada Inc.
Submission control no: 065790
Date issued: 2007-01-19
Health Products and Food Branch
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Health Canada
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrLUVERISMD, lutropine alpha, 75 IU/flacon, poudre pour solution, Serono Canada Inc., N° de contrôle de la présentation 065790
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02269066
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On June 24, 2005, Health Canada issued a Notice of Compliance to Serono Canada Inc. for the drug product Luveris.
Luveris contains the medicinal ingredient lutropin alpha which is a gonadotrophin, specifically, a recombinant human luteinizing hormone (LH).
Luveris, administered concomitantly with Gonal-F (follitropin alpha), is indicated for stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH <1.2 IU/L). During the ovarian follicular phase, LH stimulates theca cells to secrete androgens which become the substrate that granulosa cell aromatase enzymes use to produce estradiol, thereby supporting FSH-induced follicular development. In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect of lutropin alpha is an increase in estradiol secretion by the follicles, the growth of which is stimulated by follitropin alpha.
The market authorization was based on quality (chemistry and manufacturing), preclinical, and clinical data. The safety and efficacy of Luveris was examined in six clinical trials that treated 170 infertile women with hypogonadotropic hypogonadism, of whom 152 received Luveris and Gonal-F in 283 treatment cycles. Patients treated with Luveris exhibited adequate evidence of efficacy for the authorized indication. The data submitted demonstrate that Luveris can be administered safely when used under the conditions stated in the Product Monograph.
Luveris (75 IU lutropin alpha) is presented as a powder for injection. Luveris should be administered as a course of daily injections simultaneously with Gonal-F until adequate follicular development is indicated by ovary ultrasonography and serum estradiol measurement. Treatment duration should not normally exceed 14 days unless signs of follicular development are present. The recommended regimen is 75 IU of Luveris daily associated with 75-150 IU Gonal-F. Dosing guidelines are available in the Product Monograph.
Luveris is contraindicated in the presence of hypersensitivity to gonadotrophins or to any of the excipients, ovarian failure, uncontrolled thyroid or adrenal failure, active untreated tumours of the hypothalamus and pituitary gland, abnormal uterine bleeding of unknown origin, sex hormone-dependent tumours of the reproductive tract and accessory organs, and pregnancy and lactation. Detailed conditions for the use of Luveris are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Luveris, when administered concomitantly with Gonal-F (follitropin alpha), is favourable for stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH <1.2 IU/L).
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Description
Lutropin alpha (a recombinant human luteinizing hormone), the medicinal ingredient of Luveris, is a human glycoprotein which consists of two non-covalently linked, non-identical protein components, designated α- and β-subunits. Lutropin alpha binds on the ovarian theca (and granulosa) cells and testicular Leydig cells.
Manufacturing Process and Process Controls
Lutropin alpha is produced by recombinant DNA technology in mammalian cells. The manufacture of lutropin alpha is based on a master and working cell bank system, where the master and working cell banks were thoroughly characterized and tested for adventitious contaminants and endogenous viruses in accordance with ICH guidelines. Results of these tests confirmed cell line identity and absence of adventitious agents/viral contaminants. Genetic characterization (restriction endonuclease mapping and copy number analysis) also demonstrated the stability of the master cell bank ranging from storage to production at the limit of in vitro cell age.
The manufacture of lutropin alpha comprises a series of steps which include cell culture, harvest and purification. The purification is performed via a combination of chromatographic and viral reduction steps. The manufacturing process consistency is ensured through defined production procedures, critical quality tests, in-process limits and lutropin alpha certificate of analysis specifications. Microbial control is maintained throughout the manufacturing process by testing for bioburden as well as for bacterial endotoxins. In-process controls performed during manufacture were reviewed and considered acceptable. The specifications for the raw materials used in manufacturing the drug substance were also considered satisfactory.
Characterization
The structure of lutropin alpha has been adequately explained and the representative spectra have been provided. Physical and chemical properties have been described and found to be satisfactory. Detailed characterization studies were performed to provide assurance that lutropin alpha consistently exhibits the desired structure. A table of all batches employed for characterization tests was provided and found satisfactory.
Control of Drug Substance
Validation reports were satisfactorily submitted for all analytical procedures used for in-process and release testing of the drug substance. Results from process validation studies indicate that the methods used during purification adequately controlled the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits. The drug substance specifications and the analytical methods used for quality control of lutropin alpha are considered acceptable.
Stability
Based upon the real-time stability data submitted, the proposed shelf-life and storage conditions for the drug substance were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Luveris is presented as a single 75 IU dose, with no preservative added. It should be used immediately after reconstitution and any remaining drug should be discarded. The container/closure system used for Luveris is a 3 mL colourless type I glass vial with a lyophilized rubber stopper, an aluminum seal ring and flip-off cap. Luveris is available as single unit and 3-unit packs and each vial of Luveris is accompanied by 1 mL of water for injection. Luveris is also available as a combination pack with 150 IU Gonal-F with water for injection, and a 2.5 mL syringe diluent container. The diluent is packaged in 2 mL glass ampoules or vials, with rubber stoppers and an aluminum overseal.
All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of lutropin alpha with the excipients and the container closure system is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, were considered acceptable. Data provided in this section includes composition of the lutropin alpha dosage form, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of lutropin alpha. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and considered to be acceptable.
Manufacturing Process and Process Controls
All manufacturing equipment, in-process manufacturing steps, and detailed operating parameters are adequately described in the submitted documentation and considered to be acceptable. Luveris is filled into vials and freeze dried using proper aseptic process techniques, and conventional pharmaceutical equipment and facilities.
Analytical testing results from final batch analyses were reviewed and considered to be acceptable according to the proposed drug product specifications.
Control of Drug Product
Luveris is tested to verify its appearance, clarity, composition, pH, potency, sterility, uniformity, and presence of particulates and degradation products. The justification provided to support the release tests and their specifications was acceptable.
Satisfactory validation reports were submitted for all analytical methods used for in-process and release testing of the drug product. Data from final batch analyses were reviewed and considered to be acceptable according to the proposed drug product specifications.
Stability
The real-time and accelerated stability results provided for the Luveris drug product support a shelf-life of 24 months when stored between 2°C and 25°C.
3.1.3 Facilities and Equipment
An On-Site Evaluation (OSE) of facilities involved in the manufacture and testing of lutropin alpha and Luveris was conducted by the Biologics and Genetic Therapies Directorate, Health Canada. The design, operations, and controls of the facilities and the equipment involved in production of Luveris are considered suitable for the activities and products manufactured. All facilities are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Luveris has demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Pre-clinical pharmacology studies and development feasibility studies were conducted in vitro, as well as in vivo in several different animal species including rodents, rabbit, dog, and primates.
Binding of recombinant human luteinizing hormone (r-hLH) to the LH/CG (luteinizing hormone/chorionic gonadotrophin) receptor occurs with an affinity that is slightly greater than that of pituitary hLH, but still within the same order of magnitude. This is a good indication that r-hLH will evoke similar physiological actions as natural hLH, and that lower doses of r-hLH may achieve the same pharmacodynamic effect as higher doses of natural hLH.
Binding to the specific antibody was strikingly similar to endogenous hLH, confirming antigenic affinity. The study established that the immunoactive and bioactive serum clearance half-lives of r-hLH are approximately 48 and 123 minutes, respectively. These values are comparable to those of pituitary LH and human menopausal gonadotrophin (hMG), which suggests that the carbohydrate and sialic acid moieties present in the r-hLH preparation may be similar to those of pituitary LH. These findings confirm that appropriate binding of the r-hLH hormone occurs, and also that such binding has activity at the receptor and post-receptor levels quantitatively indistinguishable from the other naturally occurring hormones.
Bioactivity of the r-hLH preparation was also found to be similar to hLH and hMG. Mid-luteal phase administration of the various hLH preparations to monkeys resulted, uniformly, in increases in peripheral serum progesterone after IV treatment. Administration of r-hLH manifested induction of ovulation, completion of oocyte meiosis and adequate preparation for fertilization, and corpus luteum formation and its tonic support.
In a study examining the efficacy of recombinant human folliscle stimulating hormone (r-hFSH) vs. r-hFSH + r-hLH, follicular growth and maturation during the pre-ovulatory interval in LH-deficient rhesus monkeys occurred in response to r-hFSH alone. Thus, LH was not required for folliculogenesis in primates. Oocyte maturation and progesterone receptor expression were greater in granulosa cells derived from r-hFSH-treated animals, and higher fertilization rates occurred with oocytes from the r-hFSH treatment group. The presence of r-hLH with r-hFSH (at a ratio of 1:1) during the pre-ovulatory interval may impair granulosa cell and oocyte functions during the subsequent peri-ovulatory period.
Intramuscular administration of r-hLH at a dose of 2500 IU/monkey is an effective stimulus for peri-ovulatory events. Two injections of r-hLH, 2500 IU each, 18 hours apart, is a better approximation of the duration of the endogenous midcycle LH surge and results in oocyte maturation and fertilization rates similar to those associated with use of hCG as an ovulatory stimulus. Luteal phases following an ovulatory dose of r-hLH are of shorter duration than those following hCG, however this may be clinically insignificant given routine use of exogenous progesterone or hCG as luteal phase support. The results of this study appear to indicate that r-hLH is comparable to hCG in most of the efficacy endpoints evaluated, however, at a dose of r-hLH 2.5 to 5 fold higher than the dose of hCG. Therefore these results do not appear to provide strong evidence for r-hLH as an efficacious alternative ovulatory stimulus as compared to hCG.
A further study was conducted to compare embryo quality after administration of r-LH to that obtained with the use of hCG and to study the implantation process until 14 days of pregnancy in rabbits in the absence of the endogenous LH discharge that takes place during mating. Study of the ovaries showed that the same percentage of does ovulated in both groups; the number of luteinized follicles was significantly higher in the hCG group, and the number of pre-ovulatory follicles remained, in this group, significantly lower compared to the r-LH group. At 72 hours post-ovulation induction, since there were no differences between groups in terms of ovulatory potential, nor in terms of numbers of hemorrhagic follicles, the effect of hCG was much more potent/efficient in terms of producing ovulation, as a consequence of its longer half-life. Approximately eight luteinized follicles occur naturally in the doe in a spontaneous cycle, similar to those obtained in the r-LH group, and much lower than those occurring in the hCG group. This fact may indicate a more physiological ovulatory mechanism with the administration of r-LH. In the r-LH group, the majority of the blastocytes were located in the uterus 72 hours after ovulation induction and insemination, whereas in the hCG group the majority of them were still in the oviducts. These results point out that r-LH produces faster oviductal transit of the blastocytes. The total number of embryos however, was significantly higher in the hCG group. On the other hand, the percentage of good quality embryos (Grade 1 and 2) was significantly higher in the r-LH group, while the percentage of degenerated embryos (Grade 5) was significantly higher in the hCG group.
By 14 days post-ovulation induction, the significant differences in total number of embryos at 72 hours had disappeared. The implantation rate was significantly better in the r-LH group than in the hCG group. This may be a result of the higher embryo quality produced by r-LH, in spite of the lower number of embryos.
In regards to other physiological systems, with the exception of a slight reduction of the force of uterine contractions at the highest dose assayed, r-hLH dose not induce significant effects on the central and autonomic nervous systems, nor does it affect the digestive and renal functions in experimental animals up to a dose of 20, 000 IU/kg body weight.
3.2.2 Pharmacokinetics
The animal pharmacokinetic and biodistribution (absorption, distribution, metabolism, excretion [ADME]) results were influenced by the following:
- formation of significant levels of neutralizing antibodies, which potentially affected the accuracy of the pharmacokinetic results based on the immunoassay;
- inadequate serum r-hLH concentration profiles with low doses of r-hLH (e.g. 10 IU/kg) as determined by the immunoassay;
- dissociation of the I-125 radioisotope from the r-hLH molecule, which potentially affected the accuracy of the pharmacokinetic and biodistribution (ADME) results based on radioactivity measurements since radioactivity in body fluids and tissues did not necessarily represent only the 125I-r-hLH molecule, but also I-125 bound to proteins (e.g. thyroxine-binding-globulin) and free I-125 iodide.
Despite the difficulties encountered due to neutralizing antibodies in some animals, low serum concentrations, or dissociation of the I-125 radioisotope from the r-hLH molecule, the pharmacokinetic (PK) studies provided useful results in the characterization of the PK profile of r-hLH. This was supported by consistency in the PK parameters calculated in different studies. r-hLH exhibited a linear PK profile following IV administration of 3 escalating doses in monkeys (10, 63, and 400 IU/kg), with a total clearance of 0.03-0.05 L/h/kg, and an elimination half-life of 10.7-12.6 hours. The bioavailability of an r-hLH dose of 400 IU/kg was also studied following a single intramuscular (IM) or subcutaneous (SC) administration. The results demonstrated that the bioavailability of r-hLH was 0.61±0.14 and 0.48±0.14 for IM and SC administration, respectively. The results of the animal PK studies are acceptable in support of this marketing application for r-hLH.
After IV administration of 125I-r-hLH to the rat at a dose of 63 IU/kg, total radioactivity in plasma was detected up to the last sampling time (72h). An almost complete recovery of the administered radioactivity was found in the excreta within 168 h of the treatment; most of the administered dose was excreted in urine (about 84%) and only about 10% in feces. In accordance with the low fecal excretion, biliary excretion of radioactivity was also very low (about 5%). A strong affinity of 125 I-r-hLH to the ovaries was confirmed by whole-body autoradiography. Concerning placental transfer of the radioactivity, the concentrations in fetuses and in the amniotic fluid were found to be 10-50% of the plasma concentrations at all sampling times. This low fetal penetration of radioactivity was confirmed by a whole-body autoradiography study. In lactating females the radioactivity concentrations in milk exceeded up to 7 times the plasma concentration.
There were no statistically significant changes in blood pressure, heart rate, cardiac function, respiration, or blood flow when r-hLH was administered intravenously at doses of 20, 200, 2000, and 20000 IU/kg. Minor changes in blood pressure and heart rate were not considered to be drug-related. Changes in heart rate tended to be associated with changes in depth of anaesthesia. Similarly, minimal changes in cardiac function and respiration were also considered to be due to fluctuating anaesthesia levels.
3.2.3 Toxicology
Two acute toxicity studies and nine long-term toxicity studies were performed. The long-term toxicity studies included dose-range finding studies of 2 weeks duration, one-month toxicity studies followed by 2 weeks recovery, and 13-week toxicity studies followed by 6 weeks recovery, each performed in rats and in monkeys. The observations were generally similar after both SC or IV administration. As concluded in each study, these changes were related to exaggerated pharmacological effects of r-hLH in a species which largely differs from humans (i.e. changes to testes and accessory organs were related to effects on gonadotropin; estrus cycle, increase in body weight of females due to water retention induced by steroids; atrophy of thymus and hepatocellular hypertrophy due to prolonged exposure to high steroid levels). Liver enzyme changes were noted in almost all of the studies, however there is no consistent evaluation of this change. Some studies conclude only that "slight involvement of the liver function cannot be excluded", one report did not address the issue, and others attribute it to "hepatocellular hypertrophy due to prolonged exposure to high steroid levels" thus causing "changes in hepatic metabolism", or "decrease of liver enzyme activity due to hemodilution" (based on water retention). None of the changes were considered to be detrimental to the general health status of the treated animals.
An appropriate combination of tests were performed both in vivo and in vitro to look for chromosome aberrations and gene mutations. The four studies all produced negative results which suggest that the test article, r-hLH, has low mutagenic potential.
Six studies were performed to assess fertility, general toxicity in dams and offspring, and teratology of the test article in rats and rabbits, at doses ranging from 5 IU/kg/day to 500 IU/kg/day. The preliminary reproductive toxicity studies in rats and rabbits indicated that the dose of 5 IU/kg/day r-hLH, which is close to the clinical dose, did not appear to cause effects on reproduction when given in different periods of the reproductive cycle. However, doses of 50 and 500 IU/kg/day in rats induced impairment of the reproductive capacity such as inhibition of mating when given in the pre-mating period, resorptions when given in the pre-implantation period, and difficult and prolonged parturition with early death of pups when given in late pregnancy and lactation. Also, r-hLH given subcutaneously to pregnant rabbits from day 6 to day 18 of gestation induced effects on reproduction (increase in resorptions) at 50 and 500 IU/kg/day.
In the peri- and postnatal study in rats, r-hLH given to pregnant rats from day 17 of gestation to day 21 of lactation induced some slight toxic effects at the 10 and 20 IU/kg/day levels. Dams treated with 20 IU/kg/day of r-hLH had lower body weight and food consumption. Also at this dose, a shorter gestation period was observed. In the 10 and 20 IU/kg/day groups, the pre- and postnatal mortality of pups was increased and the F1 generation had a lower body weight, a lower testes and ovaries weight, and a delay in the testes descent and in the vaginal opening. Moreover, an effect on the reproductive performance of the F1 generation at 20 IU/kg/day could not be excluded.
In the fertility and reproduction study in female rats, r-hLH given subcutaneously at
20 IU/kg/day for 14 days before mating and until day 7 of gestation, induced a lower fertility index, with an increase of pre- and post- implantation losses (early resorptions) and a lower mean fetal weight. An increase of pre- and post-implantation losses was also found at 10 IU/kg/day.
The teratogenesis study in rats showed that r-hLH given subcutaneously to pregnant female rats from day 7 to day 17 of pregnancy induced some slight toxic effects at 10 IU/kg/day and to a greater extent at 20 IU/kg/day, but did not affect the morphological, physical, and behavioural development of the offspring or the F1 reproductive performance.
The teratogenesis study in rabbits showed that r-hLH administered during the organogenesis period to pregnant rabbits induced slightly lower body weight gain at 20 IU/kg/day and a dose-related increase of resorptions. Although one incidental plurimalformed fetus was found in the 20 IU/kg/day group, the report concludes that no teratogenic effect was observed.
Overall, the no observed adverse effect level (NOAEL) is considered to be 5 IU/kg/day both for dams and fetuses.
Additional studies examining r-hLH for local irritation and tolerability, sensitization, and immune reactions found it to be well tolerated, a moderate sensitizer by intradermal injection, and of limited capability to induce allergic reactions.
3.2.4 Summary and Conclusion
Binding of r-hLH to the specific antibody was strikingly similar to endogenous hLH, confirming antigenic affinity. This is a good indication that r-hLH will evoke similar physiological actions as natural hLH. Despite the difficulties encountered due to neutralizing antibodies in some animals, low serum concentrations, or dissociation of the I-125 radioisotope from the r-hLH molecule, the PK studies provided useful results in the characterization of the PK profile of r-hLH.
The preclinical studies for this drug submission are considered acceptable. The non-clinical pharmacology and toxicology program for Luveris demonstrated its appropriateness for use in human trials. Adequate statements are present in the Product Monograph to address any safety concerns.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The pharmacodynamic results showed that a one week daily subcutaneous administration of 150 IU of r-hFSH combined with 150 IU of r-hLH induces a significant follicle growth in 2/3 of the pituitary down-regulated female volunteers. Inhibin as well as estradiol serum levels are early markers and good predictors of follicle development, which is defined by the sponsor to be the clinical response to the treatment. However, analysis of these and other pharmacodynamic markers (maximal progesterone and maximal follicular volume) showed a marked inter-individual variability in responses, with no correlation between maximal serum concentration of r-hLH or r-hFSH and any of the four pharmacodynamic markers. These findings were reported by the sponsor to be in complete agreement with a previous study where r-hFSH was given alone. This indicates that, when administered concomitantly at the dose of 150 IU per day, r-hLH does not markedly affect the response to r-hFSH (i.e. significant follicle growth). Therefore, there does not appear to be any therapeutic benefit of adding the r-hLH treatment to r-hFSH with this dosage regimen based on the chosen pharmacodynamic endpoints. These results agree with those shown in animals, where addition of r-hLH to the r-hFSH regimen did not appear to yield a significant benefit over r-hFSH alone for most of the therapeutic endpoints studied.
Over a dose range of 15000 to 30000 IU, the exposure variables could be of predictive use to maximize the ovarian/follicular (O/F) ratio and minimize the risk of ovarian hyperstimulation syndrome (OHSS) (or associated symptoms). However, no relation was found between pregnancy and the exposure variables, and no relation was reported between the O/F ratio and pregnancy. Therefore, the clinical value of using the LH Cmax to maximize the O/F ratio with respect to the final outcome of pregnancy is questionable. On the other hand, with the exception of ovarian diameter, the remaining safety variables (moderate OHSS, ascites, and serum renin) were found to be significantly related to exposure variables. Therefore, while the data suggest that it may not be possible to estimate the potential efficacy endpoint of pregnancy based on the exposure variables (the outcome variable of O/F ratio is not considered clinically relevant if it is not related to the ultimate desired outcome of pregnancy and delivery of healthy offspring), the potential risks associated with r-hLH doses as used in this study could be estimated from the exposure variables AUC and dose.
3.3.2 Pharmacokinetics
The pharmacokinetic studies were conducted in normal, healthy volunteers, down-regulated with a GnRH agonist. One study investigated the PK profile of r-hLH following various intravenous doses. The lower dose of 75 IU of r-hLH did not yield an adequate serum r-hLH concentration profile in order to reliably determine the PK parameters. The PK parameters from the 300, 10000, and 40000 IU doses could be reliably determined, and this dose range suggested a linear PK profile for r-hLH, with a terminal elimination half-life of approximately 10 hours. These results support those obtained in the monkey PK studies above.
The PK profile of r-hLH following IM and SC administration compared to that following IV administration was also examined. The mean bioavailability estimates for IM and SC administration were 0.54±0.30 and 0.56±0.23, respectively; there were no statistically significant differences between these two routes of administration for Cmax, Tmax or F (absolute bioavailability).
A further study investigated the PK of a single SC injection of both r-hLH (150 IU) and r-hFSH (150 IU) alone, or a single SC injection of r-hLH (150 IU) in combination with r-hFSH (150 IU), or r-hLH (150 IU) in combination with r-hFSH (150 IU) SC once a day for 7 days. The results of r-hLH or r-hFSH single administration alone were found to compare well with those obtained when r-hLH and r-hFSH were administered in combination, with no statistical significance in the PK parameters Cmax, Tmax, and AUC0-24h. The AUC0-24h achieved after the final dose of the multiple dose regimen was higher than that following single dosing, with a mean accumulation ratio of 1.6 for r-hLH and 2.9 for r-hFSH. The sponsor indicated in the sectional report that the data was analyzed following subtraction of the concentration measured at t=0 from the remaining data points for each subject. It was found that the concentration of LH and FSH appeared to rise in later samples of a number of volunteers following the single SC injection of the test drugs. This was taken to be due to fluctuations in endogenous levels of the two hormones. Even though the down-regulation of endogenous secretion of LH/FSH was satisfactory, these fluctuations were significant because the doses of r-hLH and r-hFSH injected were small, achieving low serum levels as measured by the immunoassay. Thus, the quality of the data used to assess the PK parameters is considered poor, especially for LH: 4/12 subjects could not be analyzed for LH following administration alone or in combination with FSH; in comparison, 1/12 could not be analyzed for FSH following FSH administration alone, and 4/12 could not be analyzed for FSH when in combination with LH. The method of data selection used to reduce 'pollution' of the PK by baseline fluctuations was to discard data beyond 24 h (for LH) or 72 h (for FSH), if they increased above the previous sample's level. The impact of baseline fluctuations on LH and FSH PK following multiple dosing was less, especially for the final (7th) dose. This was because the accumulation of drug (especially FSH) led to increased serum concentrations, therefore concentrations were relatively less affected by fluctuations in baseline concentrations. One subject in 12 (1/12) could not be analyzed for LH, and 2/12 could not be analyzed for FSH following the repeated SC administrations. Given the difficulty with estimating the PK of the test drugs in normal volunteers (i.e. women with normal endogenous cycling LH and FSH), the sponsor could have conducted the PK analyses in the intended treatment population (women severely deficient in LH and FSH), thus potentially reducing the problem with interfering endogenous levels of LH/FSH in the normal female. If patients were used and endogenous levels of the hormones were detected during the PK analysis, this would not be considered as problematic and the PK profile could be described in the true clinical situation without any manipulation of the data, rather than trying to isolate the PK profile of the test drug r-hLH in healthy females.
Notably, no study was conducted to investigate the effect of co-administration of r-hFSH and r-hLH on the pharmacokinetics of the two drugs following intramuscular injection, and therefore it is unknown whether any pharmacokinetic interaction could occur following intramuscular injection of these drugs.
A population PK analysis was also performed to quantify inter-subject variability, and explore the effect of co-variates (i.e. age, weight, height, body mass index, smoking habit, nature of infertility [primary, secondary], and creatinine) on the absorption and/or distribution of r-hLH. Of these co-variates investigated, body weight was found to explain 2% and 4% of the inter-individual variability for the apparent volume of distribution and the absorption rate constant, respectively. The mean (% coefficient of variation [CV]) for the absorption rate constant and volume of distribution ranged 0.041/h to 0.043/h (%CV 9.8 to 14.6) and 20.2L to 27.8L (%CV 26.5 to 29.4) in the final population co-variate model.
A bioequivalence study was conducted but the results could not be verified since the sectional report could not be found within the submission volumes. If the results are eventually verified to be as described, the to-be-marketed (test) formulation of r-hLH does not meet one of the standards for bioequivalence with the formulation used in the clinical trials (reference formulation). Additionally, a bioequivalence study of the intramuscular route does not appear to have been conducted, therefore, the bioavailability of the to-be-marketed formulation as compared to the clinical trials formulation following intramuscular administration is unknown.
In conclusion, the PK studies are considered sufficient to support the dosage regimen and the subcutaneous route as proposed in this marketing application. However, the PK parameters of r-hLH in combination with r-hFSH have not been studied with the intramuscular route and the to-be-marketed formulation of r-hLH is not considered to be bioequivalent to the clinical trial formulation following subcutaneous or intramuscular administration. Notwithstanding the above, the data were considered sufficient to gauge whether the dosage used in the pivotal clinical trials is appropriate to the indication sought.
3.3.3 Clinical Efficacy
Two pivotal studies were conducted in women with hypogonadotrophic hypogonadism (WHO group I anovulation), who were deficient in both FSH and LH, where LH level is <1.2 IU/L.
The first pivotal study was an open, dose-finding study where all thirty-eight (38) patients were randomized in four groups receiving either 0, 25, 75, or 225 IU of r-hLH together with a fixed dose of 150 IU of r-hFSH daily. The specific dose of LH was given in the first cycle, called cycle A, which was used for efficacy analysis. Some patients were treated in additional cycles B and C where the dose of LH was increased if there was no response to the LH dose given in the prior treatment cycle and decreased if there had been a response in the prior cycle. The efficacy results are manifested as a trend in this type of study.
The second pivotal study, which was initially considered as a non-pivotal study, was a double-blind study to confirm the efficacy of the 75 IU (3.4 mcg) dose of r-hLH for co-administration with 150 IU r-hFSH for induction of follicular development in women with hypogonadotropic hypogonadism and profound LH deficiency (LH <1.2 IU/L) desiring pregnancy. This study had only one cycle with a duration of 21 days.
The primary efficacy endpoint in these studies was defined in the protocol as follicular development, comprising 3 parameters: at least one follicle ≥ 17 mm, pre-ovulatory E2 serum level ≥109 pg/ml (400 pmol/L), and mid-luteal phase P4 level ≥7.9 ng/mL (25nmol/L), all of which had to be fulfilled. Any patient cancelled for risk of OHSS and any patient achieving pregnancy was counted as achieving follicular development.
The secondary endpoints included estradiol level per follicle ≥15 mm at mid-cycle, number of follicles on DhCG (day of hCG administration), endometrial thickness on days 5, 10, and DhCG, and pregnancy.
Both studies included 77 patients but only 68 were evaluable.
Although the sponsor showed, in Cycle A, a statistically significant difference in the percentage of treated and control patients achieving the primary endpoint of follicular development (p=0.0002) in the Intent-to-Treat (ITT) analysis from both pivotal studies, two of the three criteria which define the primary efficacy endpoint were not statistically significant (at least one follicle ≥17mm, and mid-luteal phase P4 level ≥7.9 ng/mL).
Twenty-four (64.9%) of the thirty-seven (37) patients treated with 75 IU r-hLH and 150 IU r-hFSH responded to treatment as compared to 3 (13.6%) of 22 in the placebo/0 IU r-hLH and 150 IU r-hFSH group. The follicular development rates for both the 75 IU r-hLH and placebo/0 IU groups were consistent across studies with 65.4% and 63.6% response rates in the 75 IU r-hLH group, and 15.4% and 11.1% response rates in the placebo/0 IU r-hLH group from the second and first studies, respectively.
There were 4 clinical pregnancies among the 23 patients willing to conceive (enrolled in the pivotal studies) who had received hCG (55 total patients willing to conceive); three clinical pregnancies were in the 75 IU r-hLH group and one clinical pregnancy was in the placebo/0 IU r-hLH group.
The first study identified a positive trend between dose of r-hLH and follicular development, with 75 IU r-hLH identified as the effective starting dose. Although the sponsor had originally claimed that in some patients optimal follicular development may require up to 225 IU/day of r-hLH, there is no evidence that 225 IU/day is better than 75 IU/day in terms of efficacy.
Under "Statistical Considerations", an expectation of 20% efficacy was claimed for the active control group (150 IU FSH/ 0 IU r-hLH group) and 90% efficacy for the 225 IU r-hLh group. The power to detect this difference was based on the first cycle 85%. The final efficacy results show 0% success in the 0 IU r-hLH group and 50% success in the 225 IU r-hLH group when OHSS was not included, or 75% success in the 225 IU r-hLH when OHSS was included. The achieved results are not the same as the expected results and the active control does not meet the minimal efficacy as stated by sponsor.
Both pivotal studies enrolled women with hypogonadotrophic hypogonadism (WHO group I anovulation), deficient in both FSH and LH where LH level is <1.2 IU/L and revealed that in these patients it is necessary to administer r-hLH together with r-hFSH in order to obtain follicular maturation. Effects of LH substitution by lutropin alpha in women with hypogonadotrophic hypogonadism with levels higher than 1.2 IU/L have not been shown. Therefore, the use of Luveris is restricted to patients with severe LH and FSH deficiency as defined by levels of LH <1.2 IU/L.
3.3.4 Clinical Safety
All patients (N=77) in the two pivotal trials were included in the safety analysis, reporting the incidence and severity of adverse events (AEs), including local tolerance at the injection site and occurrence of antibodies.
In the two pivotal trials the most frequently reported events were gastrointestinal system disorders (5 events in 3 patients in the placebo/0 IU r-hLH group and 13 events in 7 patients in the 75 IU r-hLH group), central and peripheral nervous system disorders (2 events in 2 patients in the placebo/0 IU r-hLH group and 9 events in 6 patients in the 75 IU r-hLH group), body as a whole general disorders (3 events in 1 patient in the placebo/0 IU r-hLH group and 7 events in 5 patients in the 75 IU r-hLH group) and reproductive disorders in females (3 events in 2 patients in the placebo/0 IU r-hLH group and 4 events in 4 patients in the 75 IU r-hLH group).
There were 12 patients with risk of OHSS (3 in 225 IU group, 8 in 75 IU group, 1 in 0 IU group), mild to moderate in intensity. Although the sponsor claimed there was no difference in the incidence or type of adverse events between the patients in the treatment group and the patients in the control group, 11 of these 12 cases were in the treatment group. From these data we can conclude that the risk of getting OHSS with the combination treatment is greater (20%) than the risk with Gonal-F alone (6%).
Two serious adverse events (SAEs) were reported in two patients in one study (one patient had a road accident two weeks after completing cycle C and another patient had a miscarriage two months after completing her treatment). No SAEs were reported during the first pivotal study. No deaths were reported. There was one drop-out (moderate, delayed hypersensitivity reaction) in the first study, and three drop-outs in the second study (OHSS).
There were statistically significant hematological changes from baseline to post-treatment observed in mean hemoglobin (p=0.001) and mean hematocrit (p=0.021) during the second study. This was explained by the sponsor as being attributable to the repeated blood sampling during treatment for ovarian response monitoring and possibly also to hemodilution resulting from elevated E2 levels. However, the blood sampling was repeated every five days and the quantity of blood drawn cannot, by itself, explain the decrease in hemoglobin.
A statistically significant increase in neutrophils was observed in all groups after treatment (p=0.021). According to the sponsor, this reflects the well-known impact of repeated parenteral injections as well as a possible mild inflammatory syndrome usually observed in patients with stimulated ovaries.
No hematological toxicity or immune reaction related haematological changes were recorded. Subcutaneous injections of up to 225 IU/day r-hLH in combination with Gonal-F were safe and well tolerated. Few adverse events were reported during the studies. Local tolerance at the injection site was good with 90% or more of the r-hLH injections having no or only mild itching, redness, swelling, bruising, or pain.
Serum samples for the detection of antibodies to LH and FSH were collected on day 1 before the first dose of study drug and at the post-study visit within time frame indicated in the protocol. No antibodies were detected for any of the samples tested.
In the non-pivotal trials the most commonly reported events included ovarian cyst, abdominal pain, breast pain, dysmenorrhea, headache, dizziness, and nausea. All were mild to moderate in severity. Occasionally, there were reported cases of influenza and anxiety. There were six serious adverse events, OHSS, of mild to moderate intensity, but resolved with hospitalization.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/risk Assessment
Hypogonadotrophic hypogonadal females are not able to conceive without stimulation of follicular development and ovulation. Often, follicular development can be achieved with FSH alone, but inadequate follicular estradiol production may lead to impaired endometrial growth and failure to form a functional corpus luteum when exposed to hCG. Clinical studies have demonstrated the efficacy of lutropin alpha in association with FSH in stimulating follicular development in women with severe LH and FSH deficiency (hypogonadotrophic hypogonadism).
In Canada, the treatment currently available to hypogonadotropic hypogonadal women consist of hMG and/or gonadotrophin-releasing hormone (GnRH) agonist. The urine derived menopausal gonadotrophins (hMG) contain both FSH and LH in a fixed ratio 1:1. The other approved treatment for severe hypogonadotropic hypogonadism consists of GnRH agonist that stimulates endogenous FSH and LH secretion when administered every 60 to 120 minutes over a week via a portable pump, which is inconvenient.
Luveris is the first preparation that consists of LH alone. It has not been compared to the medication available currently on the market such as urine derived menopausal gonadotrophins and GnRH agonist. In addition, several shortcomings limit the usefulness of LH including marginal efficacy over women given FSH or Gonal F, as well as the increased risk of hyperstimulation due to possible excessive estrogen response and multiple follicular development, and the increased risk of multiple pregnancy due to possible multiple follicular development. From the data presented, we can conclude that the risk of getting OHSS with the combination treatment is greater (20%) than the risk with Gonal-F alone (6%, as it is stated in the Product Monograph).
Overall, the clinical data only support the use of Luveris in the treatment of a selected subset of patients with LH and FSH deficiency. This product should only be used under specific conditions as noted under Section 3.4.2 below, in those circumstances when r-FSH alone has failed to induce follicle development and most likely in cases of severe hypogonadotropic hypogonadism in which the serum LH is <1.2 IU/L. A dose of 75 IU/day of lutropin alpha is the only recommended dose as the clinical data did not support other doses in either efficacy or safety.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Luveris, when administered concomitantly with Gonal-F (follitropin alpha), is favourable for stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (LH <1.2 IU/L). The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Luveris®
| Submission Milestone | Date |
|---|---|
| Request for priority status | |
| Filed | 2000-01-25 |
| Rejection | 2000-02-22 |
| Submission filed | 2000-03-13 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2000-04-27 |
| Update Notice issued | 2001-02-21 |
| Response filed | 2001-05-22 |
| Review 1 | |
| On-Site Evaluation | 2002-10-07 |
| Quality Evaluation complete | 2003-03-25 |
| Clinical Evaluation complete | 2003-01-16 |
| Radiation Dosimetry Evaluation complete | 1999-03-26 |
| NON issued by Director General | 2003-04-02 |
| Response filed | 2003-06-24 |
| Screening 2 | |
| Screening Acceptance Letter issued | 2003-07-23 |
| Review 2 | |
| Quality Evaluation complete | 2003-12-12 |
| Clinical Evaluation complete | 2005-06-06 |
| Label review complete | 2005-02-22 |
| NOC issued by Director General | 2005-06-24 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| LUVERIS | 02269066 | EMD SERONO, A DIVISION OF EMD INC., CANADA | LUTROPIN ALFA 75 UNIT / VIAL |