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`European Medicines Agency
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`London, 25 August 2009
`Doc. Ref: EMEA/595129/2009
`
`
`ASSESSMENT REPORT
`FOR
`Torisel
`
`International non-proprietary name/Common name:
`temsirolimus
`
`Procedure No. EMEA/H/C/000799/II/0001
`
`Variation Assessment Report as adopted by the CHMP with
`all information of a commercially confidential nature deleted
`
`7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
`Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 68
`E-mail: mail@emea.europa.eu http://www.emea.europa.eu
`
`(cid:164) European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged.
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`Exhibit 2004 Page 001
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`Pharmacyclics LLC - Ex. 2004
`Coalition for Affordable Drugs IV LLC v. Pharmacyclics LLC
`Case IPR2015-01076
`
`

`

`SCIENTIFIC DISCUSSION
`
`Introduction
`
`Torisel (temsirolimus) was first granted a marketing authorisation in the EU on 19 Nov 2007 for first-
`line treatment of patients with advanced Renal Cell Carcinoma (RCC) who have at least 3 of 6
`prognostic risk factors.
`
`This type II variation concerns an extension of the indication for Torisel to add the new therapeutic
`indication: “treatment of adult patients with relapsed and/or refractory mantle cell lymphoma
`(MCL)”.
`
`Torisel (temsirolimus) is a selective inhibitor of mTOR (mammalian target of rapamycin), a
`serine/threonine kinase involved in controlling many cellular functions, such as cell proliferation, cell
`survival, protein synthesis and transcription. Temsirolimus binds to an intracellular protein (FKBP-
`12), and the protein-temsirolimus complex inhibits the activity of mTOR that controls cell division. In
`treated tumour cells, inhibition of mTOR activity results in a G1 growth arrest caused by the
`disruption of translation of regulatory cell cycle proteins (D-type cyclins, c-myc, and ornithine
`decarboxylase). When mTOR is bound to the temsirolimus-FKBP-12 complex, its ability to
`phosphorylate and control the activity of protein translation factors that regulate cell division (4E-BP1
`and S6K), is blocked. These protein translation factors are both downstream of mTOR in the P13
`kinase/AKT pathway.
`
`In addition to regulating cell cycle proteins, mTOR can regulate translation of the hypoxia-inducible
`factors, HIF-1 and HIF-2 alpha. These transcription factors regulate the ability of tumours to adapt to
`hypoxic microenvironments and to produce the angiogenic factor VEGF. Even though cyclin D1
`mRNA is constitutively expressed in mantle cell lymphoma (MCL), it is potentially subject to
`translational regulation by a pathway involving the mammalian target of rapamycin (mTOR). In
`mantle cell lymphoma, mTOR kinase regulates mRNA translation by phosphorylation of two critical
`substrates—eukaryotic initiation factor 4E binding protein and p70S6 kinase. These phosphorylation
`events enhance translation of cyclin-D1 mRNA into cyclin-D1 protein.
`
`Scope of the variation
`
`This type II variation concerns an extension of indication to add treatment of adult patients with
`relapsed and/or refractory mantle cell lymphoma (MCL). Based on the results of the clinical
`development program for MCL, the recommended dosing regimen is different from that in advanced
`renal cell carcinoma. In this context, sections 4.1, 4.2, 4.3, 4.4, 4.5, 4.8, 4.9, 5.1, 5.2 and 6.6 of the
`SPC have been amended and the Package Leaflet has been updated accordingly. In addition, the MAH
`has taken the opportunity to make some minor editorial changes to the annexes and to update the
`contact details of the UK local representative in the Package Leaflet. The MAH has also updated
`annex IIB to include the version number of the latest Risk Management Plan (version 2.4) agreed with
`the CHMP.
`
`This application is based on the final clinical study report for a phase 3 study in patients with relapsed
`and/or refractory MCL (study 3066K1-305-WW). In addition the following reports were included as
`part of the application:
`- Population PK Analysis (CSR-70829): This is a summary of studies 3066K1-305-WW, 3066K1-
`124-US, -145-US, -200-US, and -203-EU;
`- Study 3066K1-147-US (final clinical study report): a biomarker study in head and neck cancer that
`was ongoing at the time of the MAA for RCC;
`- Study 3066K1-402-WW (final clinical study report): A completed phase 1/2 study of temsirolimus in
`combination with sunitinib;
`- Study 3066K1-139-US (updated progress report): An ongoing study in paediatric patients, previously
`reported in the RCC MAA.
`
`
`Mantle cell lymphoma
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`
`Non-Hodgkin Lymphomas can be seen as two major prognostic groups: the indolent lymphomas and
`the aggressive lymphomas. Mantle cell lymphoma (MCL) is a specific entity of B-cell lymphoma
`defined by the REAL classification (1994) and by the WHO classification (2001). The entity
`corresponds to the centrocytic lymphomas as defined previously by the Kiel classification (1988).
`Although MCL belongs to the group of indolent lymphomas the clinical course is rather more
`aggressive than in other entities of indolent lymphomas.
`
`MCL accounts for approximately 8% of all lymphoma diagnoses. Patients with MCL are typically
`older adults with a male predominance and usually present with stage IV disease. The cells are
`characterized as CD20+ CD5+ CD23– with a t(11;14)(q13;q32) and cyclin D1 overexpression on
`immunohistochemistry. Response to chemotherapy usually results in a tumour response but
`unmaintained remissions are short and the median survival is 3 to 4 years. The treatment approach to
`newly diagnosed patients with MCL depends on the patient's eligibility for stem cell transplantation
`(SCT). Those who are eligible are usually treated with either rituximab-CHOP (cyclophosphamide,
`doxorubicin, vincristine, and prednisone) followed by SCT or high dose cytarabine or other regimens
`such as HyperCVAD (cyclophosphamide, vincristine, doxorubicin, decadron, cytarabine, and
`methotrexate). The purine nucleoside analogues also have activity as single agents and with rituximab.
`Unfortunately none of these approaches can definitively cure patients with MCL, and new agents are
`needed.
`
`In 2006, Velcade (bortezomib) was approved in the United States for use in patients with MCL who
`have had at least 1 prior treatment. Bortezomib was approved on the basis of data from 155 patients in
`1 single-group phase 2 study because it demonstrated objective response benefits. The ORR was 33%
`and patients with response had a median duration of response of 9.2 months, and updated results report
`a median OS of 23.5 months for this single arm study.
`
`In the EU there are no approved treatments for relapsed MCL. However, there are a number of
`cytotoxic medicinal agents that are approved for Non-Hodgkin Lymphoma in general or for indolent
`Non-Hodgkin Lymphoma, including anthracycline, alkylating agents, vinca alkaloids, antimetabolites
`etc. Many different single-agent treatments are in use for patients who have received prior treatment
`with an alkylating agent, an anthracycline, and rituximab, individually or in combination. Currently no
`single-agent treatment is consistently used or considered superior for the treatment of relapsed MCL.
`
`Non-Clinical aspects
`
`N/A
`
`Clinical aspects
`
`GCP compliance
`
`According to the MAH all studies were conducted in accordance with the ethical requirements of
`Directive 2001/20/EC and with the ICH E6 guideline on Good Clinical Practice and the principles set
`forth in the Declaration of Helsinki.
`
`
`Pharmacokinetics
`
`Introduction
`
`In support of this application for the use of temsirolimus IV in patients with MCL, an integrated
`population PK analysis of temsirolimus was provided in CSR-70829. The analysis combined PK data
`obtained from studies 3066K1-124-US, -145-US, -200-US, -203-EU (all previously submitted for the
`RCC marketing authorisation application (MAA)) and the pivotal MCL study -305-WW, and included
`concentration measurements from 1342 whole blood or plasma samples from 150 subjects for
`
` Clinical Pharmacology
`
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`temsirolimus and from 1648 samples from 279 subjects for sirolimus. The MCL population
`represented 40% and 24.2% of the total subjects in the population PK datasets for temsirolimus and
`sirolimus, respectively, and the blood sampling typically spanned study weeks 3 to 6.
`Furthermore, an additional completed phase 1/2 dose-escalation study of temsirolimus in combination
`with sunitinib (study 3066K1-402-WW), and an updated progress report on safety in 1 ongoing study
`in paediatric patients (study 3066K1-139-US) was provided (see Table 8). A progress report for 1
`additional ongoing study in subjects with cancer who had hepatic impairment (NCI protocol 6813,
`Wyeth study 3066K1-152-US) was previously provided in support of the RCC MAA.
`
`In vitro studies have demonstrated that single-agent temsirolimus exhibits important antitumour
`activity. Sirolimus, which is a major metabolite of temsirolimus following IV treatment, was also
`shown to have antitumour activity. The appearance of appreciable levels of sirolimus in the circulation
`of subjects with cancer therefore provided a rationale to derive a composite metric of drug exposure
`that described the algebraic sum of the areas under the concentration-time curve (AUCsum) for both
`entities. Although temsirolimus and sirolimus share some common biological properties, substantial
`differences in the profile of activity and side effects can be obtained with differences in dose level,
`dose schedule, or route of administration.
`
`The proposed treatment regimen for patients with MCL is 175 mg IV weekly for 3 weeks followed by
`weekly 75-mg IV doses. The comparative PK parameters described below were determined using the
`typical values and variance terms for clearance and volume of distribution terms from the integrated
`population PK analysis. Since blood sampling in the subjects with MCL was sparse in nature, data
`pooling of PK values was not performed.
`
`Methods
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`Analytical methods
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` (cid:120)
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`Temsirolimus and its major metabolite sirolimus were assayed in blood and plasma using a combined
`HPLC/MS/MS assay in which both temsirolimus and sirolimus were simultaneously measured. This
`assay was split into 2 methods to quantify 2 differing concentration ranges (i.e., low range 0.25-25
`ng/ml, and high range 2.5-2500 ng/ml). A cross-validation of this combined method with the previous
`separate temsirolimus and sirolimus assays, which were used for earlier PK studies, was conducted.
`The methods were sufficiently validated. Accuracy (% bias) and precision (% coefficient of variation)
`were reported at low, mid and high QC levels, and were within generally accepted ranges.
`
`Pharmacokinetic data analysis
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` (cid:120)
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`Population PK analysis
`Pharmacokinetic data from the final models of the previous mechanistic integrated analysis (CSR-
`64107) were merged with data from subjects with MCL (Study 3066K1-305-WW) in Study CSR-
`70829. Studies included in the population PK analysis CSR-70829 are presented in Table 1.
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`Table 1: Studies included in population PK analysis CSR-70829
`Study Number
`Study Description
`
`Number
`Enrolled
`
`IV Dose
`Range
`
`30
`
`1 to 25 mg
`
`3066K1-200-USa
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`3066K1-203-EUa
`
`3066K1-305-WW
`
`111
`
`25, 75, 250 mg
`
`109
`
`75, 250 mg
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`162
`
`175 and 75 mg,
`175 and 25 mg
`
`Clinical Pharmacology Studies in Healthy Subjects
`3066K1-145-USa
`the
`to quantify
`Phase 1, open-label study
`temsirolimus
`exposure/response
`relationship
`using S6 ribosomal protein in blood.
`Clinical Studies with a Clinical Pharmacology Component in Subjects with Cancer
`3066K1-124-USa
`Phase
`1,
`open-label,
`dose-escalation
`71
`5 to 25 mg
`combination study with IFN to determine MTD
`in subjects with advanced RCC.
`Phase 2, randomized, blinded, parallel-group,
`dose-ranging study for efficacy, safety, and
`population PK in subjects with advanced RCC.
`Phase 2, randomized, open-label, parallel-group,
`dose-ranging study to evaluate efficacy, safety,
`and population PK in subjects with advanced or
`metastatic breast cancer.
`Phase 3, randomized, open-label, parallel-group,
`pivotal study to evaluate efficacy and safety in
`subjects with relapsed or refractory MCL.
`a Final data were presented in the previous MAA for RCC. Data from these studies are included in population
`PK analyses in this MAA.
`
` A
`
` summary of the comparison of the previous CSR-64107 and current population CSR-70829 PK data
`set is provided in Table 2.
`Table 2: Comparison of the number of subjects and observations included in integrated
`population PK analyses CSR-64107 and CSR-70829
`
`
`N
`
`
`
`Integrated analysis
`CSR-70829, with data
`from Study 305
`150
`1342
`279
`1648
`
`Change (%)
`+67%
`+16%
`+32%
`+25%
`
`Analyte
`Temsirolimus
`
`Sirolimus
`
`
`For the temsirolimus model, a nonlinear structure to describe both plasma and whole blood
`disposition, based on Study 3066K1-145-US of temsirolimus with healthy subjects, was applied. This
`model utilized 4 compartments in which specific, saturable distribution of temsirolimus to 2 of 3
`peripheral compartments (blood cells and peripheral tissue) was described. The linear, 2-compartment
`model with first-order formation was applied to characterize sirolimus concentrations in blood. The
`same mechanistic model was used in current CSR-70829 as in the previous CSR-64107 (Figure 1).
`The final model for temsirolimus was based a data set of 1342 observations for 150 subjects.
`
`
`Subgroup
`Subjects
`Observations
`Subjects
`Observations
`
`Integrated analysis
`from CSR-64107
`90
`1153
`211
`1312
`
`
`
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`

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`Figure 1: PK model of temsirolimus (Study CSR-70829)
`
`
`
` A
`
` linear, 2-compartment model with first-order formation was applied to characterize sirolimus
`concentrations in blood. The final model for sirolimus was based a data set of 1648 observations for
`279 subjects.
`
`The temsirolimus model was validated using goodness of fit and residual plots. Simulation yielded
`good predictability in plasma and blood. The sirolimus model was validated using diagnostic plots and
`a bootstrap approach.
`
`Results
`
`The results of the Final population PK model indicate that patients with MCL from study 3066K1-
`305-WW and patients with breast cancer from study 3066K1-203-EU yielded different temsirolimus
`CL values as compared to the other studies of the analysis.
`
`The expanded relationship of temsirolimus CL for the typical patient was:
`
`TVCL (L/h) = 112 * [1 + FLG1*(-0.178) + FLG2*(- 0.443)]
`
`in which TVCL denotes typical value for CL; FLG1 = 1 for subjects with breast cancer in study
`3066K1-203-EU and FLG1 = 0 for other; and FLG2 = 1 for subjects with MCL in study 3066K1-305-
`WW and FLG2 = 0 for other. Thus, for subjects without MCL (and without breast cancer), CL for the
`typical patient was 112 L/h, and for subjects with MCL (and without breast cancer), CL was 62.4 L/h.
`Other parameters were unaffected by covariate effects.
`
`The effect of this reduced clearance in MCL patients was visualized using a Monte Carlo simulation of
`the final model. Based on this simulation, an increase of temsirolimus in blood was apparent in MCL
`patients, as compared to a typical patient without MCL (see Table 3).
`
`The expression for sirolimus apparent clearance from whole blood was:
`
`TVCL (L/h) = 15.5 · (DOSE/25000)0.172 · (1 – 0.0082 · DNUM) · (WT/75.5)-0.354 [3]
`
`in which TV denotes typical value for CL; DOSE = temsirolimus dose in micrograms; DNUM = flag
`variable for dose (0 = single, 1 = multiple); and WT = body weight in kg. Other factors for sirolimus
`were also reported that included effect of study protocol (study 145 or study 124) on central volume of
`distribution.
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`Absorption
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`Based on data obtained by the population PK model, after treatment of MCL patients with 175/75 mg
`IV doses, the temsirolimus model-predicted peak concentration (Cmax) in whole blood were 2457
`ng/ml and 2574 ng/ml at week 1 and week 3. These values are 28.3% higher at week 1 and 43.7%
`higher at week 3, compared with predicted Cmax values for the typical subject without MCL (see Table
`3). This increase in MCL patients as compared to patients without MCL was caused by the decreased
`clearance in MCL patients (see section ’excretion’). In MCL patients receiving the 175/75 mg IV
`doses, model-predicted median (minimum, maximum) AUC for temsirolimus was 885 (327, 2752)
`ng.h/mL and for sirolimus was 2602 (976, 5929) ng.h/ml.
`Table 3. Comparative PK exposure of temsirolimus in the typical subject with and without
`MCL(CSR-70829)
`
`
`Data represented as median (10th, 90th percentile) concentrations in units of ng/ml. Treatment was temsirolimus
`175 mg IV once weekly for 3 weeks, following by weekly doses of 75 mg.
`
`The disposition of sirolimus was not affected by the presence or absence of MCL.
`
`Distribution
`
`Information on distribution of IV temsirolimus was previously described in the RCC MAA. No
`additional information on the distribution of temsirolimus is available at this time.
`
`Elimination
`
` (cid:120)
`
` (cid:120)
`
` Excretion
`Information on the elimination of IV temsirolimus was previously described in the RCC MAA,
`indicating a clearance from blood of 11.4 ± 2.4 l/h. Based on data from the population PK CSR-70829,
`for the typical subject (75.5 kg), mean values for clearance from plasma were 62.4 L/h in subjects with
`MCL versus 112 L/h in subjects without MCL. Due to this lower clearance in patients with MCL,
`temsirolimus Ctrough in whole blood at end of week 6 was 1.19 ng/mL in subjects with MCL versus
`0.148 ng/mL in subjects without MCL (see Table 3).
`For sirolimus, clearance in MCL patients was not significantly different from that in patients without
`MCL. A moderate effect of body weight on sirolimus clearance was noted (See section ‘Special
`population – weight’).
`Since sirolimus clearance is not different for patients with and without MCL, sirolimus trough levels
`were comparable in these two subgroups of patients. Sirolimus trough levels at week 6 were estimated
`as 10.7 ng/ml.
`
` Metabolism
`(cid:120)
`Inter-conversion
`(cid:120) Pharmacokinetics of metabolites
`(cid:120) Consequences of possible genetic polymorphism
`
`Information on metabolism, interconversion, PK of metabolites, and consequences of genetic
`polymorphism of IV temsirolimus was previously described in the RCC MAA. No additional
`information on the distribution of temsirolimus is available at this time.
`
`
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`Dose proportionality and time dependency
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` (cid:120)
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` Dose proportionality
`As indicated in the RCC MAA, temsirolimus Cmax and AUC increase with increasing dose in a less
`than proportional manner. This non-linear PK is believed to be due to saturable binding of
`temsirolimus to FKBP-12 in blood cells and peripheral tissues, leaving relatively more temsirolimus
`available for clearance at higher doses.
`
`Pharmacokinetics in target population
`
`The additional data included in this Application are obtained from MCL patients.
`
`Special populations
`
`Intrinsic factors of PK variability were tested as part of the integrated population PK analysis in CSR-
`70829.
`
`
`Impaired renal function
`No effect of renal impairment was previously indicated in the RCC MAA. Additional data obtained in
`this MCL application from covariate assessment in the population PK report CSR-70829 confirm no
`significant differential effects for creatinine clearance.
`
` (cid:120)
`
` (cid:120)
`
`
`Impaired hepatic function
`Initial safety and PK data on subjects with varying degrees of hepatic impairment were provided in the
`RCC MAA. In an ongoing NCI/CTEP study (NCI protocol 6813, Wyeth study 3066K1-152-US),
`dose-limiting toxicity events of grade 3 or higher thrombocytopenia were identified. However, current
`data are insufficient to draw any definitive conclusions related to the PK association to toxicity in
`patients with hepatic impairment. This lack of definitive data notwithstanding, to mitigate the risk for
`toxicity in patients with MCL, section 4.4 of the SPC has been updated with a warning in order to
`recommend that temsirolimus be used with caution in patients with hepatic impairment. The SPC
`further states that the use of temsirolimus in patients with severe hepatic impairment is not
`recommended. In addition, section 4.2 of the SPC has been updated to highlight that use of
`temsirolimus in patients with moderate (total bilirubin greater than 1.5-3 times upper limit of normal
`[ULN] and any AST greater than ULN) or severe (total bilirubin greater than 3 times ULN and any
`AST greater than ULN) hepatic impairment is not recommended.
`
`Further, the MAH has committed to provide additional PK data from patients with hepatic impairment
`as a post-authorisation follow-up measure for review by CHMP.
`
` (cid:120)
`
` Gender
`(cid:120) Race
`No effect of gender and race was previously indicated in the RCC MAA. Additional data obtained in
`this MCL application from covariate assessment in the population PK CSR-70829 indicated no
`significant differential effects for gender or race.
`
` (cid:120)
`
` Weight
`The disposition of temsirolimus was not affected by weight. However, for sirolimus, clearance was
`reduced at increased weight, and the extremes of body weight from the population PK dataset were
`shown to alter Ctrough values, as shown in Table 4.
`
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`Table 4. Comparative exposure of sirolimus in the typical subject with varying body weight
`(CSR-70829)
`
`
`Data represented as median (10th, 90th percentile) concentrations in units of ng/ml. Treatment was 175 mg IV
`once weekly for 3 weeks followed by weekly doses of 75 mg.
`
` (cid:120)
`
` (cid:120)
`
` Elderly
`The results from covariate assessment in the population PK Study CSR-70829 indicated no significant
`differential effects for age. In the previous RCC MAA, the effect of age on temsirolimus PK has been
`investigated up to an age of 79 years. Age did not appear to affect temsirolimus and sirolimus PK
`significantly.
`
` Children
`A phase 1/2 study in paediatric patients with cancer (3066K1-139-US) is currently being conducted,
`and an updated interim report was provided by the applicant.
`This is an open-label, 2-part study. Part 1 was a dose-escalation study designed to establish the MTD
`or a biologically effective dose of temsirolimus. The starting dose was 10 mg/m2, and the dose was
`increased to 25, 75, and 150 mg/m2. Sequential cohorts of subjects (paediatric and adolescent subjects
`aged 1 to 21 years) were enrolled at each dose level.
`Based on the interim analysis for this study, clearance of temsirolimus from blood appears lower and
`AUC is higher in the paediatric population as compared to adults. However, exposure to sirolimus is
`reduced in paediatric patients, and the resulting total temsirolimus + sirolimus exposure, as measured
`by AUCsum is comparable to that in adults. These findings collectively suggest that the paediatric
`population is not at risk for excessive exposure to temsirolimus-related active moieties.
`Still, the MTD in the paediatric population of 150 mg/m2, and the further investigated dose appear
`lower than in the adult population, where in Study 3066K1-101-EU the 220 mg/m2 dose was
`considered the MTD.
`This study will be assessed in detail when the final study report is provided. At this stage, based on the
`interim study report, it is concluded that the paediatric population is not at risk of excessive exposure
`to temsirolimus and sirolimus. Final recommendations on the use of temsirolimus in the paediatric
`population will be considered for inclusion in the SPC upon completion of part 2 of this study.
`
`Interactions
`
`Information on drug interactions of temsirolimus was previously provided in the RCC MAA for
`subjects receiving the 25-mg IV weekly dosage regimen. The proposed treatment regimen for patients
`with MCL uses higher doses than that for patients with RCC.
`
`Inhibition of CYP3A4
`Information was provided in the RCC MAA, demonstrating that sirolimus exposures (AUC) increased
`approximately 3.1-fold after concomitant administration of 25 mg IV temsirolimus with ketoconazole,
`a cytochrome P450 (CYP)3A4 inhibitor, compared with temsirolimus treatment alone. Considering
`that the dose proposed for patients with MCL (175 mg once weekly for 3 weeks followed by weekly
`doses of 75 mg) is higher and the regimen is different from that defined for patients with RCC (25 mg
`once weekly), it is recommended that coadministration of strong CYP3A4 inhibitors with
`temsirolimus to patients with MCL be avoided. This warning is included in the SPC, section 4.4,
`Special warnings and precautions for use.
`
`Induction of CYP3A4
`Information was provided in the RCC MAA demonstrating that sirolimus exposures (AUC) decreased
`by 56% when given concomitantly with rifampicin, a CYP3A inducer, compared with temsirolimus
`treatment alone. Considering that the dose proposed for patients with MCL (175 mg once weekly for 3
`weeks followed by weekly doses of 75 mg) is higher and the regimen somewhat different from that
`defined for patients with RCC (25 mg once weekly), it is recommended that coadministration of
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`CYP3A4/5 inducers with temsirolimus to patients with MCL be avoided. This warning is included in
`the SPC, section 4.4, Special warnings and precautions.
`
`Inhibition of CYPs by temsirolimus and sirolimus
`Data were also provided in the RCC MAA, demonstrating that temsirolimus 25 mg IV did not alter the
`disposition of desipramine, a CYP2D6 substrate. No additional data on the potential for drug
`interaction applying the higher temsirolimus dose are available at this time.
`
`For information purpose, the in vitro Ki of temsirolimus, as obtained in Study RPT-45792 are
`provided in Table 5.
`
`Table 5: Ki values of temsirolimus for CYP isoforms (RPT-45792)
`Temsirolimus Cmax/Ki ratioa
`Temsirolimus Ki
`Isoform tested
`((cid:541)M)
`0.80
`3.1
`CYP3A4/5
`1.65
`1.5
`CYP2D6
`0.18
`14
`CYP2C9
`0.09
`27
`CYP2C8
`a Cmax following 175-mg IV temsirolimus dose. Ki values assume Cmax of 2574 ng/ml (2.47 µM) (Study CSR-
`70829).
`
`Inhibition of CYP2D6 and 3A4 by temsirolimus is not yet considered sufficiently investigated. With
`the current treatment, applying the 175/75 mg dose, the Cmax after 3 weeks of treatment, as estimated
`based on the population PK model in CSR-70829, is 2574 ng/ml. By applying this Cmax level, it is
`clear that the potential for clinically relevant inhibition of CYP3A4 and 2D6 at this dose in vivo is
`much higher (Cmax/Ki is 0.80 and 1.65 for CYP3A4 and CYP2D6, respectively, see Table 5) than that
`for the 25 mg dose, where temsirolimus Cmax/Ki of 0.19 and 0.38 were found for CTYP3A4 and 2D6,
`respectively. Only a CYP2D6 in vivo DDI study, applying a temsirolimus dose of 25 mg, was
`conducted so far. Although based on that study, it was concluded that no clinically relevant inhibition
`of either CYP2D6 or 3A4 occurs at a temsirolimus dose of 25 mg for RCC, this can not be concluded
`yet for the higher dose of 175/75 mg for MCL.
`
`The MAH has committed to conduct an in vivo interaction study with desipramine and to provide the
`final clinical study report for review by CHMP following the completion of the study. This study is
`planned to be conducted in MCL patients, and in case a relevant interaction is observed, an additional
`DDI study with CYP3A4 substrates will be initiated.
`
`Exposure relevant for safety evaluation
`
`Based on simulations by the population PK model in CSR-70829, the estimated temsirolimus Cmax is
`2575 ng/ml. Estimated AUC for temsirolimus was 885 ng.h/mL and for sirolimus 2602 ng.h/ml.
`
`Discussion on Pharmacokinetics
`
`The pharmacokinetics of temsirolimus and sirolimus in MCL patients after IV treatment with 175/75
`mg temsirolimus was investigated using a population PK model. The model provided data related to
`nonlinear exposure, covariate effects, and comparative measures of exposure to be compared with
`other non-MCL patients. Simulations conducted using this model indicated that subjects with MCL
`exhibited a 44% lower clearance of temsirolimus from plasma compared to subjects without MCL.
`The difference in temsirolimus clearance resulted in increases in temsirolimus Cmax and Ctrough
`compared with subjects without MCL. No changes in sirolimus apparent clearance in MCL patients as
`compared with other patients were found. The contribution of temsirolimus to the concentrations of
`active moieties at the end of the dosage interval is considered to be modest.
`Body weight increasing from 38.7 kg to 158.9 kg was shown to exert a modest reduction of sirolimus
`apparent clearance that translated to an almost 2-fold range in Ctrough values of sirolimus.
`
`
`Page 10 of 41
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`Exhibit 2004 Page 010
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`Treatment differences in the temsirolimus-containing regimens for MCL were associated with
`differences in drug exposure. For subjects receiving the 175/75 mg doses, mean AUC of temsirolimus
`and sirolimus were 3-fold and 2.5 fold higher, respectively, than these values after the 175/25 mg
`regimen.
`
` study investigating the effect of hepatic impairment is ongoing, and only an interim report is
`available yet. This lack of definitive data notwithstanding, to mitigate the risk for toxicity in patients
`with MCL, section 4.3 of the SPC has been updated to include a contraindication in MCL patients
`with moderate or severe hepatic impairment and section 4.4 of the SPC with a corresponding warning.
`In addition, section 4.2 of the SPC has been updated to highlight that use of temsirolimus in patients
`with moderate (total bilirubin greater than 1.5-3 times upper limit of normal [ULN] and any AST
`greater than ULN) or severe (total bilirubin greater than 3 times ULN and any AST greater than ULN)
`hepatic impairment is not recommended.
`
`The lack of data in hepatically impaired patients was previously considered acceptable for the RCC 25
`mg dose. However, considering the increased dose of 175/75 mg in MCL patients, with more profound
`AEs, in addition to the increased exposure indicated in the interim report of the hepatic impairment
`study in hepatically impaired patients, it is considered not enough to only warn for the use in patients
`with hepatic impairment. In this regard, the MAH has committed to provide the final results of the
`completed hepatic impairment study and to provide concomitant dose advice for patients with various
`stages of hepatic impairment as a follow-up measure for review by CHMP.
`
`The proposed warnings on inhibitors and inducers of CYP3A4 are agreed. However, inhibition of
`CYP2D6 and 3A4 by temsirolimus is not yet considered sufficiently investigated. With the current
`treatment, applying the 175/75 mg dose, the Cmax after 3 weeks of treatment, as estimated based on the
`population PK model in CSR-70829, is 2574 ng/ml. By applying this Cmax level, it is clear that the
`potential for clinically relevant inhibition of CYP3A4 and 2D6 at this dose in vivo is much higher
`(Cmax/Ki is 0.80 and 1.65 for CYP3A4 and CYP2D6, respectively) than that for the 25 mg dose, where
`temsirolimus Cmax/Ki of 0.19 and 0.38 were found for CTYP3A4 and 2D6, respectively. Only a
`CYP2D6 in vivo DDI study, applying a temsirolimus dose of 25 mg, was conducted so far. Although
`based on that study, it was concluded that no clinically relevant inhibition of either CYP2D6 or 3A4
`occurs at a temsirolimus dose of 25 mg for RCC, this can not be concluded yet for the higher dose of
`175/75 mg for MCL.
`
`The MAH has committed to conduct an in vivo drug interaction study with desipramine and to provide
`the final clinical study report for review by CHMP following the completion of the study. This study is
`planned to be conducted in MCL patients, and in case a relevant interaction is observed, an additional
`DDI study with CYP3A4 substrates will be initiated.
`
`Overall, by applying population PK modelling, the applicant has demonstrated that the temsirolimus
`exposure in MCL patients is increased as compared to non-MCL patients. Two FUMs have been
`agreed; one related to hepatically impaired patients and one related to the possible inhibition of
`CYP2D6 and 3A4 by temsirolimus. The MAH has committed to provide the requested data within
`agreed tim