Summary Basis of Decision for Arzerra ™

3.3.1 Pharmacodynamics

Peripheral B-cell counts decreased after the first Arzerra infusion in patients with haematologic malignancies. In patients with refractory CLL, the median decrease in B-cell counts was 23% after the first infusion and 92% after the eighth infusion. Peripheral B-cell counts remained low in most patients throughout the remainder of Arzerra therapy administration and then gradually recovered (median decrease in B-cell counts was 68% below baseline three months after the end of Arzerra therapy). Significant B-cell depletion may continue for up to three to twelve months after the last Arzerra infusion.

There is also a potential for immunogenicity with therapeutic proteins such as Arzerra; however the formation of anti-Arzerra antibodies may be decreased because Arzerra is a human antibody that depletes B-cells.

In the pivotal clinical study (discussed in detail in section 3.3.3 Clinical Efficacy), no anti- Arzerra antibodies were detected in the 46 patients who had received at least eight infusions (33 of whom received all 12 infusions) and had sufficiently low circulating Arzerra concentrations to allow detection.

3.3.2 Pharmacokinetics

The population pharmacokinetic (PPK) analysis for Arzerra combined the data from the two studies specific for CLL (Hx-CD20-402, Hx-CD20-406) along with two other indications (Rheumatoid Arthritis, Follicular Lymphoma).

As is characteristic of most IgG monoclonal antibodies, the pharmacokinetic profile of Arzerra could be described by a two compartment model with a long half-life. However, the large mass of CD20+B-cells, typical of the CLL indication, created a relatively large target-mediated clearance (TMC), which could not be ignored. Although the authors managed to capture this TMC through mathematical constructions, they emphasized that the modelled total body B-cell mass and the corresponding TMC effect were only indirectly related to measurable peripheral B-cell counts. While CD5+CD19+B-cell counts showed a time course similar to the pharmacokinetic-derived target mass during the treatment period in CLL, the modelled total B-cell mass and TMC cannot be directly validated with the available clinical data. Like most pharmacokinetic analyses, the model parameters could not be equated with particular biological processes. Furthermore, it is the opinion of the authors of the final population pharmacokinetic/pharmacodynamics report (page 76):

While the pharmacokinetic-derived target B-cell mass seemed to be a useful mathematical component in this modelling, it would be an unreasonable extrapolation to suggest that this quantity was in any way correlated with effect of ofatumumab on disease.

While the model described above was the most complete in terms of describing the TMC, this model was not available for use to generate the estimated pharmacokinetic parameters presented in the submission. A simpler pharmacokinetic model was used to estimate pharmacokinetic parameters from the pivotal study (Hx-CD20-406). However, this model did not take into account the TMC and depended on data from pharmacokinetic profiles obtained in a previous study (Hx-CD20-402). This simpler model was considered to be a 'reduced' model in comparison to the first. Its two main assumptions 1) ofatumumab pharmacokinetic behaviour was similar for the populations studied in the two trials (i.e., the pharmacokinetic profiles were of similar shape with comparable interindividual differences) and 2) the expected change in the elimination rate with repeated dosing associated with B-cell depletion was assumed to be comparable after four weekly infusions and after eight weekly or eight weekly followed by four monthly infusions were considered to be too speculative for a valid assessment.

The only measured pharmacokinetic parameters available from the pivotal study (Hx-CD20-406) were maximum plasma concentration (C_max), minimum plasma concentration (C_min), and time to maximum plasma concentration (T_max). Maximum plasma concentration values were 63, 1,482, and 881 mg/L after the first, eighth and twelfth infusions, respectively. Minimum plasma concentration values were 579, and 47 mg/L prior to the eighth and twelfth infusion, respectively. Time to C_max (T_max) was 7.4 h at the first infusion and 4.5 h at both the eighth and twelfth infusions.

The Phase I dose-escalation study (Hx-CD20-402) in CLL patients employed a dense sampling method allowing for the measurement and calculation of relevant pharmacokinetic parameters at the first and fourth infusions. Patients in the highest dose group in this study [number (n) = 27] received an initial infusion of 500 mg followed weekly by 3 infusions of 2,000 mg. The observed pharmacokinetic values at the first and fourth infusions respectively were 136 and 1,061 µg/mL for C_max and 7,848 and 420,840 µg.h/mL, for area under the curve AUC_0-∞. Clearance decreased from 63.7 mL/h at the first infusion to 8.5 mL/h at the fourth as did the volume of distribution (Vss), which was 3.24 L at the first infusion and 1.73 L at the eighth. The half-life increased from 1.3 days after the first infusion to 11.5 days after the fourth and final infusions.

These parameters are consistent with a relatively large proportion of the clearance process being directed through the specific binding with a large initial mass of CD20+B-cells. Once the source of this target-mediated clearance is depleted after several infusions the removal of ofatumumab shifts to non-specific clearance mechanisms which are not as rapid and are associated with a longer half-life.

3.3.3 Clinical Efficacy

The efficacy of Arzerra was evaluated primarily in one Phase II, single-arm, multicentre study conducted in 154 patients with relapsed or refractory CLL. Within this study, efficacy was assessed based on an interim analysis that included data from 59 patients with CLL, refractory to fludarabine and alemtuzumab.

The study population comprised of three CLL groups which were classified by an independent review committee (IRC). Patients who were refractory to both fludarabine and alemtuzumab were classified as the double refractory (DR) group. Patients who were fludarabine-refractory and considered inappropriate for alemtuzumab due to bulky lymphadenopathy were classified as the bulky fludarabine refractory (BFR) group. Patients, who did not meet either the DR or BFR classification criteria, were grouped in the 'Other' category. Patients who met the criteria for both double refractory and bulky fludarabine refractory were assigned to the DR group.

Patients enrolled in the study received a maximum of 12 infusions of Arzerra over a period of 24 weeks. Dosing consisted of 8 weekly infusions of Arzerra from week 0 to week 7, followed by 1 infusion of Arzerra every 4 weeks from week 12 through week 24. The first infusion was 300 mg Arzerra. All subsequent infusions were 2,000 mg Arzerra.

Patients who completed the treatment period entered a subsequent follow-up period where disease status was evaluated every 3 months. Hereafter, end-of-study procedures were completed and the extended follow-up period was initiated. In the extended follow-up period, patients were monitored every 3 months for survival and malignant B-cell values. Monitoring continued until the B-cell values reached baseline level or above, alternative CLL therapy was initiated, or until Month 48. Patients were also allowed to enter the extended follow-up period following withdrawal from treatment- or follow-up period.

The primary efficacy endpoint was objective response rate (ORR). The objective response was measured over a 24-week period beginning with the first administration of Arzerra. All clinical assessments were conducted by site investigators, while response evaluations and classification of patients were conducted centrally by an IRC that followed NCI-WG 1996-guidelines. Patients were classified as either responders or non-responders as follows: patients achieving complete remission (CR) or partial remission (PR) were classified as responders, while patients whose best response was stable disease (SD) or progressive disease (PD) were classified as non-responders. Responses were required to be maintained for a minimum of two months, in accordance to NCI-WG 1996 guidelines.

Secondary efficacy endpoints also assessed were as follows:

• Duration of objective response - time from initial response (first visit where response was observed) to disease progression or death as assessed by the IRC.
• Progression free survival (PFS) - time from treatment allocation (Week 0) until disease progression or death.
• Time to next CLL therapy - time from treatment allocation (Week 0) until the time of first administration of CLL treatment other than Arzerra.
• Overall Survival (OS) - time from treatment allocation (Week 0) until death.

It was determined by Health Canada that to a large extent these secondary endpoints could not be adequately characterized through a single-arm non-randomized study. Therefore, other than that of 'duration of objective response', these secondary endpoints were considered as adding little to the overall evaluation of the efficacy and safety of Arzerra.

Other secondary endpoints evaluated included: malignant B-cells in peripheral blood, reduction in tumour size; resolution of lymphadenopathy; resolution of constitutional symptoms; resolution of splenomegaly and hepatomegaly (organomegaly); improvement in performance status [assessed through Eastern Cooperative Oncology Group (ECOG) scale]; improvement in haemoglobin; improvement in thrombocytopaenia; improvement in neutropaenia; and blood product transfusions. The composite endpoint of ORR which takes into account of each of the other endpoints listed above was determined to be appropriate.

Based on advice obtained from clinical experts, it was estimated that the ORR for best supportive care in this patient populations was 15% and that an ORR of 30% for Arzerra therapy would be a clinically important improvement. Knowing, based on previous scientific literature, that ORR with salvage chemotherapy was established between 20-25%, and 0% with monoclonal antibodies, it was suggested by the sponsor that observing a 30% overall response rate which excludes a 15% overall response rate at the 1% significance level would indicate meaningful efficacy in this refractory population.

When discussing efficacy results below, highlights of results should be viewed in context of the following important observations made by Health Canada. The primary efficacy endpoint of the pivotal study was ORR, which was measured over a 24 week period. Thereafter, each patient's data was assessed by the IRC. The IRC conducted their assessment based on the review of each patient's case report form (CRF), which had been completed by each respective clinical investigator. Review of radiographical images in assisting the IRC's assessment was not performed in the majority of cases. Therefore, the IRC's review was based solely on investigator's measurements and observations. Based on these observations, it could be considered that the IRC assessment was a confirmation of the results obtained by the algorithm applied to the clinical investigator assessments.

Also during the review, the IRC was instructed to following NCI-WG 1996 guidelines; however, it appears the IRC did not strictly adhere to these guidelines given the IRC indicated they "may have determined that transient changes were clinically insignificant and compatible with continued response instead of progressive disease". Furthermore, the IRC considered a response to begin on the date at which it was first evaluated and to end on the date on which an assessment of progressive disease was first recorded. This approach in methodology overestimates the length of time a patient is considered a responder, given that progression does not begin on the day it is evaluated, but rather at an earlier point in time.

Additionally, an examination of the responses assigned to each visit by IRC members suggests that differences existed in the way that IRC members applied the NCI-WG 1996 guidelines. Because different IRC readers were assigned to determine the responses of each patient, it is not possible to determine what the inter-reader variability may be, and whether it is considered acceptable or not.

Finally, some patients were assigned an overall assessment of response, when clear evidence of non-response was recorded on the submitted CRF. This oversight persisted after the sponsor requested two rounds of re-consensus readings due to a number of patients having responses of less than the required two months. Therefore, given investigator bias was not reduced through the IRC's independent review, and because the investigator calculated ORR in accordance with NCI-WG 1996 guidelines (i.e. requiring response to be present for a minimum of two months), Health Canada chose to focus on the investigators' assessment of the ORR for evaluation purposes.

The sensitivity analyses applied in determining the ORR were carried out using two methods. First, the investigator based responses were used to calculate the ORR. Second, an algorithm developed by the sponsor was used to determine an ORR value. The investigators' response rate for the DR group was 42% (compared to the IRC response rate of 58%). The concordance rate (71 %) between these two assessments was considered to be low. In more detail, the IRC and investigator assessments agreed on 21 responders and 21 non-responders. Yet, there was disagreement on the status of 17 patients. If the IRC had relied on independent measurements made from radiographic images, a discordance rate of this size may have been expected; however, the IRC assessment was based entirely on measurements performed by the investigators. In this case, it would be expected that the two assessments should have a higher concordance given the response is defined in the NCI-WG 1996 guidelines. As previously discussed above, one of the major differences in the investigator versus the IRC assessment is that the IRC panel could, based on expert judgement, classify a patient as a responder if they met the guidelines for a response in only one evaluation, which goes against the NCI-WG 1996 guidelines, which specify that a response must be observed for at least 2 months (a period that covers two evaluations). On the other hand, the investigator assessment would not consider a patient as a responder unless the guidelines were met for at least two consecutive evaluations spanning over an 8 week period. It is Health Canada's opinion that 56 days (8 weeks) is the minimum number of days which could reasonably fulfill the criteria of a response, as per NCI-WG 1996 guidelines.

In addition to the investigator sensitivity analysis, the sponsor also carried out an algorithmic assessment of response. The sponsor's sensitivity analysis calculated that the proportion of responders in the DR group was 37% with a concordance to the IRC assessment of 80%. There was disagreement between these two assessments on the response of 12 patients, all of whom were classified as responders by the IRC assessment but as non-responders by the sponsor's algorithmic approach.

Significant variation in ORR was observed by the three different assessment approaches. However, the minimum ORR calculated, per the sponsor's algorithm, was 37% for the DR group. This level of response exceeded the pre-selected target of 30% with a 99% confidence bound that excludes an ORR of 15%. Therefore, the sponsor did meet the primary endpoint, ORR. The IRC assessment was the protocol specified assessment. However this assessment was blinded only to investigators' assessments and could not be considered a true independent assessment as it relied on physical measurements made by investigators' (e.g., lymph node, spleen, and liver measurements), which were not confirmed by radiographic imaging. Therefore, for the reasons discussed above, the investigator assessment of response was considered as the more appropriate measure of ORR as it managed to adhere to the guidelines specified in the study protocol, but still allowed for expert judgement to be applied to the by visit assessments of response.

The analyses of secondary endpoints, 'time to response' and 'duration of response' indicated that response onset was achieved quickly with a median time to onset of 1.8 months in responders. Time to onset was 2.1 months in the DR group. The duration of response for DR responders was 7.1 months by IRC assessment but 5.1 months by sensitivity analysis. The duration of response analysis indicates that the response to Arzerra is not maintained for a long period of time once treatment is complete; however, this is to be expected as Arzerra is a targeted therapy that cannot be expected to continue to reduce or maintain the number of malignant B-cells once treatment is withdrawn and circulating Arzerra is cleared.

In the pivotal study, no endpoint was specified to measure the patient's quality of life. However, an analysis of the individual components of the NCI-WG 1996 criteria for ORR in patients with B-cell CLL indicates that a large proportion of patients experienced resolution of constitutional symptoms that were present at baseline. Those who did not have symptoms at baseline remained symptom free for the duration of study. Furthermore, many patients experienced improvement or resolution in one or more of the following parameters: lymphadenopathy; splenomegaly; hepatomegaly; and haematological parameters.

3.3.4 Clinical Safety

The safety of Arzerra in relapsed/refractory CLL population was evaluated in one pivotal study previously described in section 3.3.3 Clinical Efficacy and in addition one Phase I/II dose-escalation study. For the pivotal study, while efficacy data was based on an interim analysis of 59 patients; the analysis of safety data was based on the fully enrolled population of 223 patients.

The assessment of the safety of Arzerra monotherapy was difficult due to the uncontrolled, unblinded design of the pivotal study. Given the single-arm design, it was impossible to discern whether causal relationships existed between observed adverse events (AEs) and exposure to Arzerra. It is possible that many AEs could be manifestations of the underlying illness that given these patients were heavily pre-treated and in many cases immunocompromised. Furthermore, the number of patients treated within the pivotal study was small, making the detection of rarer events difficult.

In the pivotal study, reporting of AEs occurred following the first dose administration (visit 2) until the final clinic visit at Month 24 (end of follow-up period). Only Serious Adverse Events (SAEs) were reported once a patient entered the extended follow-up period (Month 24-48); therefore, AEs are likely to have been under-reported during this period. Also, the study protocol allowed for patients who withdrew from the study during treatment to complete the Visit 21 (end of follow-up) assessments and immediately enter into the extended follow-up period. This permitted a number of patients to continue directly into the extended-follow up period after only a short period of time had passed since their final Arzerra administration. This design may have contributed to under-reporting of AEs that would have otherwise been reported had these patients continued in the treatment or follow-up period.

The most common adverse reactions (≥10%) during therapy with Arzerra were cough, pyrexia, anaemia, neutropaenia, diarrhoea, fatigue, dyspnoea, pneumonia, chills, nausea, bronchitis, peripheral oedema, back pain, and upper respiratory tract infection. The majority of patients (62%) had at least one adverse event (AE) ≥Grade 3 in severity, with the DR group showing a higher proportion of Grade 3 AEs than the BFR group (72% versus 52%). The 'Other' group had the highest number of ≥Grade 3 AEs at 76%, but this was based on a small sample size [number (n) = 17]. A total of 67% of patients had an AE considered to be related to Arzerra treatment; however, the AE frequency and patterns appeared to be typical for a monoclonal antibody treatment in a refractory CLL population.

Overall, 59% of patients experienced SAEs. A total of 17% of patients had SAEs that were considered to be drug-related. The most common drug-related SAEs were neutropaenia, pneumonia, and sepsis.

Of the 223 patients enrolled in the pivotal study, 138 died as of the safety analysis cut-off date. The most common cause of death was disease progression (27 patients) followed by septic complications (20 patients). All patients who experienced septic complications died (sepsis n = 10; neutropenic sepsis n = 5; escherichia sepsis n = 1; bacterial urosepsis n = 1; septic shock n = 3). Pneumonia was responsible for 15 (7%) deaths. One case of progressive multifocal leukoencephalopathy (PML), which was considered drug-related by the investigator, resulted in death. Cases of PML have been documented in CLL patients receiving either fludarabine or chlorambucil, and are most commonly observed in immunocompromised individuals such as human immunodeficiency virus (HIV) infected individuals. Therefore, it is unclear whether the manifestation of PML is due in this case to Arzerra exposure or due to the underlying disease. Progressive multifocal leukoencephalopathy has also been observed in patients receiving other anti-CD20 treatment. As such, a cautionary approach should be taken for any patient that exhibits neurological symptoms. Patients should be monitored for signs of PML and appropriate action should be taken if neurological symptoms manifest. The use of Arzerra is contraindicated in patients who have PML or have had PML. This is specified in the serious warnings and precautions section of the Product Monograph.

Development of infections was a common occurrence during treatment with Arzerra and subsequent follow-up; however, it must also be noted that the rate of infections in persons with advanced CLL is also high. Of the 223 patients enrolled, 163 (73%) patients reported 392 infections which were either bacterial, viral, or fungal in nature. A total of 43 (19%) patients experienced Grade 3 infections and 16 (7%) patients experienced Grade 4 infections. Of 223 patients, [22 (10%)] had fatal infections. The most frequent types of infections reported were of the respiratory tract, with lower respiratory tract infections being more common than upper. Respiratory tract infections (all pneumonia) were the most common cause of death by infection. Due to the large number of infections observed in the pivotal study and the number of cases of neutropaenia (discussed below) considered to be related to study drug exposures, it should be assumed that Arzerra may contribute to the acquisition of infections in the CLL population. Infection was the most common reason for drug discontinuation.

Infusion reactions were notably observed in both the pivotal and supportive study. These reactions included anaphylactic reactions, bronchospasm, cardiac events, chills/rigors, cough, cytokine release syndrome, diarrhoea, dyspnoea, fatigue, flushing, hypertension, hypotension, nausea, pain, pyrexia, rash, and urticaria. In the majority of cases, infusion reactions were generally mild in nature and did not require study withdrawal. Furthermore, none of the infusion reactions resulted in death. Pre-medication may help to attenuate infusion reactions, but reactions may still occur especially during the first two infusions.

Hematologic AEs were also commonly noted during Arzerra treatment. Neutropaenia occurred in 17% of patients and was considered by investigators to be related to treatment in 13% of patients. Three of the neutropaenia events were fatal. These included one neutropaenic sepsis, one Grade 5 neutropaenia, and one grade 5 febrile neutropaenia. Neutropaenia has been associated with other anti-CD20 monoclonal antibody therapies; however, it is unlikely that Arzerra is directly toxic to neutrophils since these cells do not express CD20. Nevertheless, Arzerra may act as a trigger for neutropaenia via other mechanisms. Overall, patients with baseline neutropaenia did not have a decrease in the median neutrophil counts; however, they also did not show any improvement in the median neutrophil count. Neutropaenia is common in heavily treated CLL patients. Therefore, it may be important to manage this complication in patients that present with baseline neutropaenia and those that develop neutropaenia to prevent serious infections from occurring.

Serious and fatal cardiovascular events were reported following administration of Arzerra. These events included, myocardial infarction, myocardial ischaemia, atrial fibrillation, perimyocarditis, ventricular systolic dysfunction with cardiac failure, hypotension leading to heart failure, tachyarrhythmia, and tachycardia. Fatal cardiac events (myocardial infarction, cardiac arrest, and cardiac failure) occurred in four patients during the treatment or follow-up periods of the pivotal study. One fatal case of myocardial infarction occurred within one day of the fourth infusion of Arzerra. Given these events and the proximity with which several occurred to study drug administration, patients with a history of cardiac disease should be monitored closely during and after infusions and resuscitative measures should be readily available. Arzerra should be discontinued in patients who experience serious or life-threatening cardiac arrhythmias.

Tumour lysis syndrome was observed in one patient within the pivotal study during administration of the first Arzerra infusion. The infusion was stopped and restarted later after the patient had recovered. Therefore, tumour lysis syndrome may occur in patients with high tumour burden when they are treated with a tumour lysing agent, such as Arzerra.

3.3.5 Additional Issues

Under the Notice of Compliance with Conditions (NOC/c) policy, additional data is required to confirm the clinical benefit and safety of Arzerra. The sponsor has agreed to submit the following:

• Data from the completed pivotal study Hx-CD20-406, a single-arm international, multicentre study of HuMax-CD20, a fully human monoclonal anti-CD20 antibody, in patients with B-cell chronic lymphocytic leukaemia who have failed fludarabine and alemtuzumab.
• Data from the completed study OMB11091, Phase III open-label, randomized, multicentre study of ofatumumab added to chlorambucil versus chlorambucil monotherapy in previously untreated patients with chronic lymphocytic leukaemia.
• Data from the completed study OMB112855, a study of QTc intervals in patients who have been administered ofatumumab.
• Conduct an assessment of QTc intervals as a sub-study in the clinical study OMB110911.
• Conduct an assessment of anti-drug antibody (ADA) response to ofatumumab with a validated assay capable of sensitively detecting ADA responses in the presence of ofatumumab levels that are expected to be present at the time of patient sampling.
• Submit to Health Canada any other analyses that have been designated as post-marketing commitments to other international authorization granting agencies.
• Provide information in relation to communications and consultations with other agencies, when available.
• Provide safety updates for all on-going Arzerra studies.
• Provide reports of all serious adverse reactions that occur in Canada and all serious unexpected adverse reactions that occur outside of Canada within fifteen days to Health Canada.
• Submit Periodic Safety Reports for Arzerra (ofatumumab) on a semi-annual basis until such time as conditions associated with the market authorization are removed.
• Implement the Risk Management Plan (RMP) in Canada and provide any updates to the RMP when available. The Risk Management Plan is currently under review by Health Canada's Marketed Health Products Directorate (MHPD). The sponsor should comply with the recommendations of the MHPD in regards to the RMP.
• Comply with the notification and reporting of specific issues of concern as outlined in Section 6.2.4 of the Guidance for Industry: Notice of Compliance with Conditions (NOC/c) and section 6Eiii of the NOC/c policy.
• Provide a complete listing of ongoing additional clinical studies related to Arzerra, appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance for Industry: Notice of Compliance with Conditions (NOC/c).
• Provide copies of any marketing authorisations or other regulatory actions for Arzerra from any other drug regulatory authority as per Section 4.6 of the Guidance for Industry: Notice of Compliance with Conditions (NOC/c).