Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, Monoclonal antibodies, ATC code: L04AG06.

Mechanism of action

Alemtuzumab, is a recombinant DNA-derived humanised monoclonal antibody directed against the 21-28 kD cell surface glycoprotein CD52. Alemtuzumab is an IgG1 kappa antibody with human variable framework and constant regions, and complementary-determining regions from a murine (rat) monoclonal antibody. The antibody has an approximate molecular weight of 150 kD.

Alemtuzumab binds to CD52, a cell surface antigen present at high levels on T (CD3+) and B (CD19+) lymphocytes, and at lower levels on natural killer cells, monocytes, and macrophages. There is little or no CD52 detected on neutrophils, plasma cells, or bone marrow stem cells. Alemtuzumab acts through antibody-dependent cellular cytolysis and complement-mediated lysis following cell surface binding to T and B lymphocytes.

The mechanism by which LEMTRADA exerts its therapeutic effects in MS is not fully elucidated. However, research suggests immunomodulatory effects through the depletion and repopulation of lymphocytes, including:

- Alterations in the number, proportions, and properties of some lymphocyte subsets post-treatment - Increased representation of regulatory T cell subsets
- Increased representation of memory T- and B-lymphocytes
- Transient effects on components of innate immunity (i.e., neutrophils, macrophages, NK cells) 
The reduction in the level of circulating B and T cells by LEMTRADA and subsequent repopulation, may reduce the potential for relapse, which ultimately delays disease progression.

Pharmacodynamic effects

LEMTRADA depletes circulating T and B lymphocytes after each treatment course with the lowest observed values occurring 1 month after a course of treatment (the earliest post-treatment time point in phase 3 studies). Lymphocytes repopulate over time with B-cell recovery usually completed within 6 months. CD3+ and CD4+ lymphocyte counts rise more slowly towards normal, but generally do not return to baseline by 12- months post-treatment. Approximately 40% of patients had total lymphocyte counts reaching the lower limit of normal (LLN) by 6 months after each treatment course, and approximately 80% of patients had total lymphocyte counts reaching the LLN by 12 months after each course.

Neutrophils, monocytes, eosinophils, basophils, and natural killer cells are only transiently affected by LEMTRADA.

Clinical efficacy and safety

The safety and efficacy of alemtuzumab in MS were evaluated in 3 randomised, rater-blinded, active- comparator clinical trials and 1 uncontrolled, rater-blinded extension study in patients with RRMS.

Study design/demographics for Studies 1, 2, 3 and 4 are shown in Table 2 
Table 2: Study Design and Baseline Characteristics for Studies 1, 2, 3 and 4 Study 1                       Study 2                    Study 3
CAMMS323                    CAMMS32400507
Study name                                                                                  CAMMS223 (CARE-MS I)                    (CARE-MS II)
Controlled,
Controlled, randomised, Controlled, randomised, rater and
Study design                                                                             randomised, rater- rater-blinded                  dose-blinded blinded
Patients with active
MS, defined as at least
Disease history                Patients with active MS, defined as at least 2 relapses  2 relapses within the within the prior 2 years.                prior 2 years and 1 or more contrast- enhancing lesions
Duration                                               2 years                                 3 years‡ Patients with inadequate response   Treatment-naïve
Study population                 Treatment-naïve patients to prior therapy*              patients
Baseline characteristics
Mean Age (years)                         33                              35                          32 Mean/Median Disease
2.0/1.6 years                   4.5/3.8 years               1.5/1.3 years duration
Mean duration of prior MS
None                         36 months                     None therapy (≥1 drug used)
% receiving ≥2 prior MS
Not applicable                       28%                    Not applicable therapies
Mean EDSS score at
2.0                            2.7                          1.9 baseline
Study 4
Study name                                                        CAMMS03409 Study design                                     Uncontrolled, rater-blinded extension study Study population              Patients who participated in CAMMS223, CAMMS323, or CAMMS32400507 (see baseline characteristics above)
Duration of extension                                             4 years * Defined as patients having experienced at least 1 relapse during treatment with beta interferon or glatiramer acetate after having been on therapy with medicinal product for at least 6 months.
‡
Study primary endpoint was scored at 3 years. Additional follow-up provided data through a median of 4.8 years (maximum 6.7).


Results for Studies 1 and 2 are shown in Table 3
Table 3: Key Clinical and MRI Endpoints from Studies 1 and 2
Study 1                       Study 2
CAMMS323                   CAMMS32400507
Study name
(CARE-MS I)                   (CARE-MS II)
LEMTRADA SC IFNB-1a LEMTRADA SC IFNB-1a
Clinical endpoints                               12 mg             (N=187)       12 mg           (N=202) (N=376)                         (N=426)
Relapse Rate1
Annualised Relapse rate (ARR)                  0.18               0.39         0.26             0.52 (95% CI)                                   (0.13, 0.23)       (0.29, 0.53) (0.21, 0.33) (0.41, 0.66) Rate ratio (95% CI)                               0.45 (0.32, 0.63)             0.51 (0.39, 0.65) Risk reduction                                           54.9                          49.4 (p<0.0001)                    (p<0.0001)
Disability1
Confirmed Disability Worsening [CDW]2
Patients with 6-month CDW                      8.0%              11.1%        12.7%            21.1% (95% CI)                                    (5.7, 11.2)        (7.3, 16.7)  (9.9, 16.3)     (15.9, 27.7) Hazard ratio (95% CI)                             0.70 (0.40, 1.23)             0.58 (0.38, 0.87) (p=0.22)                     (p=0.0084)
Patients who are relapse free at Year 2          77.6%              58.7%        65.4%             46.7 (95% CI)                                   (72.9, 81.6)       (51.1, 65.5) (60.6, 69.7) (39.5, 53.5) (p<0.0001)                      (p<0.0001)

Change from Baseline in EDSS at Year 23
(95% CI)                                   -0.14 (-0.25, -   -0.14 (-0.29,     -0.17 (-0.29, -   0.24 (0.07, 0.02)            0.01)             0.05)            0.41)
(p=0.42)                          (p<0.0001)
MRI Endpoints (0-2 years)
Median % change in MRI-T2 lesion volume       -9.3 (-19.6, - -6.5 (-20.7, 2.5)       -1.3             -1.2 0.2)                            (p=0.14)
(p=0.31)
Patients with new or enlarging T2 lesions        48.5%            57.6%             46.2%            67.9% through Year 2                                 (p=0.035)                          (p<0.0001) 
Patients with Gadolinium enhancing lesions       15.4%            27.0%             18.5%            34.2% through Year 2                                 (p=0.001)                          (p<0.0001) 
Patients with new T1 hypointense lesions         24.0%            31.4%             19.9%            38.0% through Year 2                                 (p=0.055)                          (p<0.0001) 
Median % Change in Brain Parenchymal             -0.867           -1.488             -0.615          -0.810 Fraction                                       (p<0.0001)                          (p=0.012) 
1 Co-primary endpoints: ARR & CDW. The study was declared successful if at least one of the two co- primary endpoints was met.
2 CDW was defined as an increase of at least 1 point on the expanded disability status scale (EDSS) from a baseline EDSS score ≥1.0 (1.5 point increase for patients with baseline EDSS of 0) that was sustained for 6 months.
3 Estimated using a mixed model for repeated measures.



Figure 1: Time to 6 Month Confirmed Disability Worsening in Study 2

30
HR: 0.58
Percentage of Patients with CDW

 p‐value: 0.0084
25
Alemtuzumab
20                 SC IFNB‐1a

15

10


5

0

0         3           6     9        12        15     18       21         24 

Follow‐up month
Relapse severity
In alignment with the effect on relapse rate, supportive analyses from Study 1 (CAMMS323) showed that LEMTRADA 12 mg/day led to significantly fewer LEMTRADA-treated patients experiencing severe relapses (61% reduction, p=0.0056) and signficantly fewer relapses that led to steroid treatment (58% reduction, p<0.0001) compared to IFNB-1a.
Supportive analyses from Study 2 (CAMMS32400507) showed that LEMTRADA 12 mg/day led to significantly fewer LEMTRADA-treated patients experiencing severe relapses (48% reduction, p=0.0121), and significantly fewer relapses that led to steroid treatment (56% reduction, p<0.0001) or to hospitalization (55% reduction, p=0.0045) compared to IFNB-1a.

Confirmed disability improvement (CDI)
Time to onset of CDI was defined as a decrease of at least one point on the EDSS from a baseline EDSS score ≥2 that was sustained for at least 6 months. CDI is a measure for sustained disability improvement.
29% of patients treated with LEMTRADA reached CDI in Study 2, while only 13% of subcutaneous IFNB-
1a treated patients reached this endpoint. The difference was statistically significant (p=0.0002).

Study 3 (phase 2 study CAMMS223) evaluated the safety and efficacy of LEMTRADA in patients with RRMS over the course of 3 years. Patients had an EDSS from 0-3.0, at least 2 clinical episodes of MS in the prior 2 years, and ≥1 gadolinium-enhancing lesion at study entry. Patients had not received prior therapy for MS. Patients were treated with LEMTRADA 12 mg/day (N=108) or 24 mg/day (N=108) administered once per day for 5 days at month 0 and for 3 days at month 12 or subcutaneous IFNB-1a 44 µg (N=107) administered 3 times per week for 3 years. Forty-six patients received a third course of LEMTRADA treatment at 12 mg/day or 24 mg/day for 3 days at month 24.

At 3 years, LEMTRADA reduced the risk of 6-month CDW by 76% (hazard ratio 0.24 [95% CI: 0.110, 0.545], p<0.0006) and reduced the ARR by 67% (rate ratio 0.33 [95% CI: 0.196, 0.552], p<0.0001) as compared to subcutaneous IFNB-1a. LEMTRADA 12 mg/day led to significantly lower EDSS scores (improved compared to baseline) through 2 years of follow up, compared with IFNB-1a (p<0.0001).

In the subgroup of RRMS patients with 2 or more relapses in the prior year and at least 1 Gd-enhanced T1 lesion at baseline, the annualised relapse rate was 0.26 (95% CI: 0.20, 0.34) in the Lemtrada treated group (n=205) and 0.51 (95% CI: 0.40, 0.64) in the IFNB-1a group (n=102) (p<0.0001). This analysis includes data from Phase 3 studies only (CAMMS324 and CAMMS323) due to differences in the MRI acquisition 

algorithms between the Phase 2 and Phase 3 studies. These results were obtained from a post hoc analysis and should be interpreted cautiously.

Long-term efficacy data
Study 4, was a Phase 3, multicenter, open-label, rater-blinded, efficacy and safety extension study for patients with RRMS who participated in Study 1, 2, or 3 (prior phase 3 and 2 studies) to assess long-term efficacy and safety of LEMTRADA. The study provides efficacy and safety through a median of 6 years from entry into Studies 1 and 2. Patients in the extension study (Study 4) were eligible to receive additional as-needed LEMTRADA treatment course(s) upon documentation of resumed disease activity, defined as the occurrence of ≥1 MS relapse and/or ≥2 new or enlarging brain or spinal lesions on magnetic resonance imaging (MRI). Additional course(s) of LEMTRADA were administered at 12 mg/day for 3 consecutive days (36 mg total dose) at least 12 months after the prior treatment course.

91.8% of the patients treated with LEMTRADA 12 mg in Studies 1 and 2 entered Study 4. 82.7% of these patients completed the study. Approximately half (51.2%) of patients initially treated with LEMTRADA 12 mg/day in Study 1 or 2 who enrolled in Study 4, received only the initial 2 courses of LEMTRADA and no other disease modifying treatment throughout 6 years of follow-up.

46.6% of the patients initially treated with LEMTRADA 12 mg/day in Study 1 or 2 received additional courses upon documented evidence of MS disease activity (relapse and/or MRI) and the treating physician’s decision to retreat. No characteristics at study entry identified patients who would later receive one or more additional courses.

Through 6 years from initial LEMTRADA treatment, patients continuing in follow-up showed rates of MS relapse, brain lesion formation on MRI, and brain volume loss consistent with LEMTRADA’s treatment effects during Studies 1 and 2 as well as predominantly stable or improved disability scores. Including follow-up in Study 4, patients originally treated with LEMTRADA in Studies 1 and 2, respectively, had ARRs 0.17 and 0.23, CDW was seen in 22.3% and 29.7%, while 32.7% and 42.5% achieved CDI. In each year of Study 4, patients from both studies continued to show a low risk of forming new T2 (27.4% to 33.2%) or gadolinium-enhancing lesions (9.4% to 13.5%), and the median annual percent change in brain parenchymal fraction ranged from 0.19% to -0.09%.

Among patients who received one or two additional LEMTRADA treatment courses, improvements were seen in relapse rate, MRI activity and mean disability scores following a first or second LEMTRADA retreatment (Courses 3 and 4) when compared with outcomes in the preceding year. For these patients, the ARR declined from 0.79 in the year prior to Course 3 to 0.18 one year after, and the mean EDSS score from 2.89 to 2.69. The percentage of patients with new or enlarging T2 lesions declined from 50.8% the year prior to Course 3 to 35.9% one year after, and new gadolinium-enhancing lesions from 32.2% to 11.9%. Similar improvements in ARR, mean EDSS score, and T2 and gadolinium-enhancing lesions were seen after Course 4 when compared with the prior year. These improvements were subsequently maintained, but no firm conclusions can be made with regards to the longer-term efficacy (e.g. 3 and 4 years after additional treatment courses) because many patients completed the study before reaching these time points.

The benefits and risks of 5 or more treatment courses have not been established.

Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Data reflect the percentage of patients whose test results were considered positive for antibodies to alemtuzumab using an enzyme-linked immunosorbent assay (ELISA) and confirmed by a competitive binding assay. Positive samples were further evaluated for evidence of in vitro inhibition using a flow cytometry assay. Patients in clinical trials in MS had serum samples collected 1, 3, and 12 months after each treatment course for determination of anti- alemtuzumab antibodies. Approximately 85% of patients receiving LEMTRADA tested positive for anti- alemtuzumab antibodies during the study, with ≥90% of these patients testing positive also for antibodies that inhibited alemtuzumab binding in vitro. Patients who developed anti-alemtuzumab antibodies did so by 15 months from initial exposure. Through 2 treatment courses, there was no association of the presence of anti-alemtuzumab or inhibitory anti-alemtuzumab antibodies with a reduction in efficacy, change in pharmacodynamics, or the occurrence of adverse reactions, including infusion-associated reactions. High titer anti-alemtuzumab antibodies observed in some patients were associated with incomplete lymphocyte depletion following a third or fourth treatment course, but there was no clear impact of anti-alemtuzumab antibodies on the clinical efficacy or safety profile of LEMTRADA.
The incidence of antibodies is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including inhibitory antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medicines, and underlying disease. For these reasons, comparison of the incidence of antibodies to LEMTRADA with the incidence of antibodies to other products may be misleading.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of alemtuzumab were evaluated in a total of 216 patients with RRMS who received intravenous infusions of either 12 mg/day or 24 mg/day on 5 consecutive days, followed by 3 consecutive days 12 months following the initial treatment course. Serum concentrations increased with each consecutive dose within a treatment course, with the highest observed concentrations occurring following the last infusion of a treatment course. Administration of 12 mg/day resulted in a mean Cmax of 3014 ng/ml on day 5 of the initial treatment course, and 2276 ng/ml on day 3 of the second treatment course. The alpha half-life approximated 4-5 days and was comparable between courses leading to low or undetectable serum concentrations within approximately 30 days following each treatment course.

Alemtuzumab is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by widely distributed proteolytic enzymes. Classical biotransformation studies have not been conducted.

Conclusions cannot be made with available data on the effect of race and gender on the pharmacokinetics of alemtuzumab. The pharmacokinetics of alemtuzumab in RRMS has not been studied in patients aged 55 years and older.