Auspar attachment 3: Extract from the Supplementary Clinical Evaluation Report for Daclizumab
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- 9.Supplementary safety data
- 9.3.Safety issues flagged in the US product information
- 9.3.1.Summary on first page
- 9.3.2.Complete boxed warning
- 9.4.Patient exposure Patient exposure was not evaluated in the SCER. Please also see the extract of the CER (Attachment 2). 9.5.Post-marketing experience
- 9.6.Safety issues the potential for major regulatory impact
- 9.6.2.Hypersensitivity reactions
- 9.6.4.1.Reductions in white cells, including CD4+ and CD8+ cell counts
- 9.6.4.2.Changes in mean counts
- 9.6.4.3.Shifts in counts and values of potential clinical concern
- 9.6.5.Progressive Multifocal Leukoencephalopathy
- 9.7.Evaluator’s overall conclusions on clinical safety
8.Clinical safety8.1.Summary of clinical safety from the CERThe First Round Clinical Evaluation Report (CER) summarised the safety of DAC HYP as follows: AEs were common in subjects treated with DAC HYP. Treatment-related adverse events (TRAE) occurred in about 22% of subjects treated with DAC HYP, the most common being injection site pain, influenza-like illness, headache, alanine transaminase (ALT) increased, aspartate transaminase (AST) increased, liver function tests (LFT) abnormal, gamma-glutamyl transaminase (GGT) increased, nasopharyngitis, pyrexia, injection site erythema, injection site bruising, upper respiratory tract infection, pharyngitis, MS relapse, fatigue, rash, eczema, nausea, lymphadenopathy, and lymphopaenia. The majority were mild to moderate and were manageable with standard treatment or interruption or discontinuation of DAC HYP. There were two deaths attributed to DAC HYP. One was a case of autoimmune hepatitis following planned washout and re-initiation of DAC HYP. The second was a case of bacteraemia, following an exfoliative rash leading to the development of a psoas abscess, emboli and bowel ischaemia. The case of hepatitis lead to more intensive monitoring in the clinical study programs. Though derangements in LFTs remained common in the DAC HYP studies, these cases were managed by interruption or discontinuation of treatment. No further ‘Hy’s Law’ cases were seen, and there were no further episodes of hepatitis. It is considered that the risk can be adequately managed in the post-market environment with a program that frequently monitors LFTs and the provision of adequate advice with regard to managing derangements. The second death was related to DAC HYP but appears to have been as a secondary consequence of the adverse event of skin rash. It is unclear whether this case was true Steven’s-Johnson syndrome (SJS) but, at the very least, it was a case of a severe skin hypersensitivity reaction. Skin reactions were common treatment emergent adverse events (TRAE) and occurred in about 37% of subjects in the active control study; 2% of cutaneous adverse events met the criteria for serious. Typically, the cutaneous adverse events were mild to moderate in nature and resolved with treatment. The serious cases were treated with systemic corticosteroids; this should be reflected in the PI. A low incidence of colitis was seen in patients treated with DAC HYP. The colitis largely resolved after DAC HYP was discontinued. The mechanism, optimal treatment and long-term management remain unknown. An excess of mild to moderate depression in subjects treated with DAC HYP was seen in the placebo-controlled study. The incidence of depression appears to be no worse than that for IFN β-1a which is a standard treatment for MS. DAC HYP should be contraindicated in patients with a recent history of severe depression. 9.Supplementary safety dataAs noted in Section 7.2.2, EMA Question 94 (p60) the sponsor reanalysed Treatment Emergent Adverse Events (TEAEs) according to their new, post hoc definition of high disease activity. In this analysis, the number of subjects with an AE was broadly similar in subjects with high disease activity and low disease activity, as shown in the tables below. In Study MS201, there was a slight excess of AEs in subjects with high disease activity, but there was no consistent difference across treatment groups. For subjects with serious AEs, the placebo group had a higher incidence than either of the active dose groups (32% and 25% in high activity and low activity subgroups, respectively). There was no consistent pattern amongst active groups, with the 150 mg dose group showing more SAEs in the high activity subgroup (19% and 14%), and the 300 mg dose group showing a slight excess of SAEs in the low/unknown activity subgroup (15% and 18%). In Study MS301, the proportion of subjects with a TEAE was similar across both treatment arms and in both high and low activity subgroups. For SAEs, there was a similar incidence in each treatment arm, with the exactly the same incidence in the high activity subgroups (28% for IFN β-1a and for DAC HYP), but a slightly lower incidence in the low activity subgroups (16% for IFN β-1a and 22% for DAC HYP). For hepatic events and for abnormal LFTs, there was no overall pattern in relation to disease activity (as shown in the tables below). Although there is evidence of some hepatic risk with DAC HYP treatment, discussed in more detail in later sections, this risk does not appear to be particularly prominent in subgroups defined on the basis of disease activity. Similarly, for cutaneous events, there was a clear excess in recipients of DAC HYP, relative to placebo or IFN β-1a, but the problem was not prominent in the high or low disease activity subgroups. 9.1.Study MS201Table 30. Summary of TEAEs by Disease Activity Subgroup, Study MS201 
9.2.Study MS301Table 31. Summary of TEAEs by Disease Activity Subgroup, Study MS301 
Table 32. Maximum Liver Function Test Values by Disease Activity Subgroup, Study MS301 
9.3.Safety issues flagged in the US product informationZinbryta was approved in the US during preparation of this report. Because of concerns about hepatic injury and immune-mediated disorders, the US Product Information carries a black box warning, as shown below. The safety issues were considered sufficiently serious that the drug is currently only available in the US through a restricted distribution program. (Section numbers within the boxes refer to the US PI.) 9.3.1.Summary on first page
9.3.2.Complete boxed warning
9.4.Patient exposurePatient exposure was not evaluated in the SCER. Please also see the extract of the CER (Attachment 2). 9.5.Post-marketing experienceThe sponsor’s comments on post-marketing data for DAC HYP begin with the following observation: ‘DAC HYP is an investigational product and has not been approved or marketed in any countries.’ The sponsor then discusses the fact that similar agents have been marketed previously, including two products containing alternative preparations of daclizumab.: ‘In addition to DAC HYP, there are several other drugs that target CD25, including 2 other forms of daclizumab (Zenapax, also referred as DAC Nutley; and DAC Penzberg) and basiliximab (Simulect). Simulect and Zenapax are approved products and are indicated for prophylaxis of acute organ rejection in patients receiving renal transplant. DAC Penzberg was used only as an investigational product and has not been approved or marketed’. Simulect has been assessed in 4 randomised, double-blind, placebo-controlled clinical studies for the prevention of renal allograft rejection.10,11, 12, 13, 14 It is difficult to draw any firm conclusions about the safety of DAC HYP from this indirect evidence, partly because the patient population had substantial comorbidities and they were often treated with other immunosuppressive agents. The sponsor notes that Simulect was associated with hypersensitivity reactions: ‘Severe acute hypersensitivity reactions (onset within 24 hours), including anaphylaxis, have been observed on initial exposure to Simulect and/or following re-exposure after several months. Capillary leak syndrome and cytokine release syndrome have been reported during the post-marketing experience with Simulect. Simulect should be administered only in facilities equipped and staffed with adequate laboratory and supportive medical resources.’ In the absence of clear evidence that DAC HYP is less likely to cause hypersensitivity reactions, similar caution should be used with DAC HYP. The proposed Australian PI only contains one reference to hypersensitivity: ‘Zinbryta is contraindicated in patients with a history of severe hypersensitivity (for example anaphylaxis or anaphylactoid reactions) to daclizumab, or any of the excipients.’ In view of the experience with Simulect, this issue should be given greater prominence. The US PI includes several references to hypersensitivity, along with the following comment: ‘Zinbryta can cause anaphylaxis, angioedema, and urticaria after the first dose or at any time during treatment. Discontinue and do not re-start Zinbryta if anaphylaxis or other allergic reactions occur.’ The other forms of daclizumab for which there is trial experience include DAC Penzberg and DAC Nutley. Several studies have been performed for each of these agents, as summarised by the sponsor in their SCS. Daclizumab was associated with a greater incidence of infections and hepatobiliary dsorders than placebo, when used in the renal transplant setting and in subjects with MS. A full evaluation of this material is beyond the scope of this report, but no substantial new issues appear to arise from a review of the sponsor’s brief summary. As the sponsor notes, these older daclizumab products differ from DAC HYP in terms of the cell line used to produce the antibodies, the manufacturing process and the degree of glycosolation. DAC HYP also differs from these other daclizumab agents in that it has less antibody-dependent cellular-cytotoxicity activity in functional assays.
9.6.1.Liver toxicityThe pivotal studies suggested that DAC HYP may be associated with liver injury in a small proportion of subjects and occasionally this may be severe. Two deaths in the study program were considered potentially attributable to DAC HYP, and one of these was caused by autoimmune hepatitis (the other was caused by sepsis and ischaemic colitis occurring as a complication of skin lesions). The sponsor provided a narrative for the hepatic death, which occurred in a woman who was exposed to DAC HYP 300 mg in two different studies (Study 205MS201 and the extension, Study 205MS202). DAC HYP 300 mg/washout/300 mg Subject [information redacted] (Autoimmune hepatitis; Study 205MS202): The subject was a [information redacted] female with a medical history of MS, chronic pyelonephritis, and photoallergy and no other risk factors for liver disease, who died of autoimmune hepatitis, liver failure and multiple organ failure on Day 692 (Day 315 of the extension). The subject received 13 doses of DAC HYP in Study 205MS201 and 5 doses of placebo and 4 doses of DAC HYP in Study 205MS202 with the last dose on Day 602, approximately 3 months prior to her death. The investigator assessed the death as unrelated to study treatment. The sponsor assessed the death as related because a contributory role for DAC HYP could not be excluded. This narrative is too brief to allow a complete assessment of the likelihood that DAC HYP contributed to the death. The fact that the subject had nearly two years of exposure before dying of hepatitis and the delay between the last dose and the death, argues against a direct toxic effect of DAC HYP on the liver, but is nonetheless consistent with a potential autoimmune mechanism triggered by DAC HYP exposure. Minor shifts in LFTs did not appear to be more common in recipients of DAC HYP. In the placebo-controlled pivotal study, Study 205MS201, shifts from normal to high in LFTs occurred in similar percentages in the placebo and DAC HYP treatment groups for ALT (29% placebo versus 28% DAC HYP), total bilirubin (8% placebo versus 7% DAC HYP), GGT (10% for both groups), and alkaline phosphatase (ALP) (4% placebo, 5% DAC HYP). There were more shifts from normal to high for AST in the DAC HYP group (19%) than in the placebo group (11%). In the active-controlled study, 205MS301, shifts in LFTs from normal to high were also similar between the IFN β-1a and DAC HYP treatment groups, including ALT (45% and 38%), AST (33% and 31%), total bilirubin (5% and 8%), GGT (16% and 17%), and ALP (4% and 9%), respectively. In Study 205MS201, severe shifts were slightly more common in recipients of DAC HYP, but only when levels > 5 x the upper limit of normal (ULN) were considered. Although the number of patients involved was small, and the excess in the DAC HYP group was partially disguised by the presentation of the incidence data in separate bins for different levels of elevation, abnormalities were clearly more common in the DAC HYP group. The total number of subjects with worst AST or ALT > 3 x ULN was 7 out of 204 subjects (3.4%) for placebo and 30 out of 414 subjects (7.2%) for DAC HYP. This difference in distribution of outcomes approaches (p = 0.07) or achieves (p = 0.04) statistical significance by Fisher’s exact test, depending on whether a two- or one-tailed test is used (without considering issues of multiplicity). Table 33. Incidence of maximum post-baseline LFT abnormalities, Study 205MS201
In Study 205MS301, an excess in moderately and severely elevated LFTs was also observed, as shown in Table 35 below. For ALT or AST ≥ 3 x ULN, the difference in incidence between IFN β 1a and DAC HYP was minimal (9% with IFN β-1a versus 10% with DAC HYP). For ALT or AST > 5 x ULN, there was a two-fold excess in the DAC HYP group (3% versus 6%), but this was based on very low patient numbers. Table 34. Incidence of maximum post-baseline LFT abnormalities, Study 205MS301
These results should be interpreted in the context of a study that involved close monitoring of LFTs, as explained by the sponsor: ‘Following the occurrence of fatal autoimmune hepatitis during Study 205MS202 approximately 3 months after discontinuation of DAC HYP, all ongoing study protocols were updated to include LFT monitoring every 4 weeks during treatment if not already required, and guidelines were added for temporarily suspending dosing for ALT or AST elevations > 3 x ULN and permanently discontinuing study treatment for confirmed elevations of ALT or AST > 5 x ULN, or for elevations of ALT or AST > 3 x ULN that lasted longer than 1 week.’ Close monitoring of this nature would be expected to increase the sensitivity for detecting abnormal LFTs while they were still mild, and hopefully reduce the incidence of progressive hepatic injury. More severe cases of liver injury might be expected if DAC HYP were used in a clinical setting with less stringent monitoring. Subjects satisfying Hy’s law (concurrent elevation of ALT/AST ≥ 3 x ULN and bilirubin ≥ 2 x ULN) were infrequent in both pivotal studies. In Study 205MS201, three subjects (1 in the placebo group and 2 in the DAC HYP-treated groups) had elevations in liver transaminases ≥ 3 x ULN in association with bilirubin > 2 x ULN. In Study 205MS301, substantially more subjects in the DAC HYP group (7 subjects) had had elevations in liver transaminases ≥ 3 x ULN and concurrent elevation in total bilirubin > 2 x ULN than in the IFN β-1a group (1 subject). A review of the cases found only two subjects (one in each treatment group) that were felt to represent cases of Hy’s Law, which requires a lack of alternative explanations in addition to the observed abnormalities in LFTs. Nonetheless, the excess in the DAC HYP group, as well as the overall excess of moderately elevated transaminases in both studies, is of concern, particularly in view of the fact that IFN β-1a has also been associated with an excess of abnormal LFTs. On balance, reviewing all of this evidence, it appears likely that DAC HYP carries a small but significant risk of inducing hepatic injury, which can occasionally be severe, and it may have contributed to one death by this mechanism.
Across the full spectrum of hypersensitivity reactions, there was an excess of events in the DAC HYP treatment groups in both pivotal studies. In Study 205MS201, the incidence of hypersensitivty-related AEs was 8%, 12%, and 12% for the placebo, DAC HYP 150 mg, and DAC HYP 300 mg groups, respectively. Most of these were skin and subcutaneous disorders (6%, 11%, and 11% in the placebo, DAC HYP 150 mg, and DAC HYP 300 mg groups, respectively), including rash (3%, 6%, and 5%, respectively) and allergic dermatitis (< 1%, 2%, and 2%, respectively). Other hypersensitivity-related AEs had an incidence of ≤ 1% for each group. In Study 205MS301, there was also a higher incidence of AEs in the DAC HYP group (25%) than in the IFN β-1a group (12%) and many of these were skin and subcutaneous tissue disorders (11% for IFN β-1a and 23% for DAC HYP). The most common hypersensitivity-related AEs in the DAC HYP group were rash, eczema, dermatitis, allergic dermatitis, urticaria, maculo-papular rash, contact dermatitis and atopic dermatitis. All other hypersensitivity-related AEs had an incidence of ≤ 1%. Lymphadenopathy was also more common in DAC HYP recipients and is mentioned in the US black box warning. In Study 205MS201, the incidence of lymphadenopathy was broadly similar across treatment groups (1% placebo, 2% DAC HYP 150 mg, < 1% DAC HYP 300 mg). By contrast, in Study 205MS301, the incidence of lymphadenopathy events was clearly higher in the DAC HYP group (5%) than in the IFN β-1a group (< 1%). There was also an excess of DAC HYP recipients who had AEs of lymphadenitis (1 subject (< 1%) for IFN β-1a, 13 subjects (1%) for DAC HYP). 8 subjects in the DAC HYP group but no subjects in the IFN β-1a group had lymphadenopathy-related events rated as serious (lymphadenopathy, 5 subjects; lymphadenitis, 3 subjects). One of the two deaths classified as potentially attributable to DAC HYP was related to a skin reaction to DAC HYP, although the mechanism of death was somewhat unrelated. A rash became infected, led to sepsis, and the patient subsequently developed bowel ischaemia.
9.6.3.InfectionsThe pivotal studies showed a small excess of infections that is likely to represent a mildly immunosuppressive effect of DAC HYP. The excess was observed in both pivotal studies, and included both mild and severe infections. In Study 205MS201, infections were reported in 44%, 50%, and 54% of subjects in the placebo, DAC HYP 150 mg, and DAC HYP 300 mg groups, respectively. The most common infections were upper respiratory tract infections (26% placebo versus 31% DAC HYP) and viral infections (6% placebo versus 10% DAC HYP). The incidence of infections rated as ‘severe’ was 0% in the placebo group, compared to 1% in the DAC HYP 150 mg group, and < 1% in the DAC HYP 300 mg group. The incidence of serious infections was 0% in the placebo group and 2% (9 subjects) in the combined DAC HYP groups. The incidences of herpes viral infections (6% placebo versus 6% DAC HYP) and candida infections (0% placebo versus < 1% DAC HYP) were not substantially different across treatment groups, but infections characterised as ‘opportunistic’ were only seen in in the DAC HYP group as no subjects in the placebo group versus 4 subjects (< 1%) in the combined DAC HYP treatment groups experienced potential opportunistic infections; these included oral candidiasis (3 subjects) and cytomegalovirus infection (1 subject). In Study 205MS301, there was also an excess of infections in the DAC HYP group, but there was no clear pattern and no clear excess of potentially opportunistic infections. The overall incidence of infections was 57% and 65% in the IFN β-1a and DAC HYP groups, respectively. The most common infections were upper respiratory tract infections (39% IFN β-1a versus 44% DAC HYP) and urinary tract infections (12% in both groups). The incidence of herpes viral infections (7% IFN β-1a versus 8% DAC HYP) and candida infections (2% IFN β-1a versus 2% DAC HYP) was similar in both treatment groups. Most infections were rated as ‘mild’ or ‘moderate’ in severity, but infections rated as ‘severe’ were more common with DAC HYP (1% IFN β-1a and 3% DAC HYP). 3 subjects (< 1%) in the IFN β-1a group and 5 subjects (< 1%) in the DAC HYP group discontinued treatment due to infections. The incidence of serious infections was also increased with DAC HYP (2% IFN β-1a versus 4% DAC HYP). Most of the serious infections were typical of the infections that can occur in a general population of MS subjects: serious infections that occurred in more than 3 subjects in the IFN β 1a or DAC HYP group included urinary tract infection (2 subjects IFN β-1a, 8 subjects DAC HYP), and pneumonia (2 subjects IFN β-1a, 5 subjects DAC HYP). Unlike the placebo-controlled study, the incidence of potential opportunistic infections was similar between the 2 groups (2% in both groups). The most common potential opportunistic infections were candida infections, which were similar in incidence across the IFN β-1a (2%) and DAC HYP (2%) groups. None of the candidial infections were characterised as invasive. Of the potential opportunistic infections reported, there were 2 serious infections in the IFN β-1a group (strongyloidiasis and viral myocarditis) and 1 serious infection in the DAC HYP group (pulmonary tuberculosis). Overall, this data suggests that DAC HYP might increase the risk of infection, but there is no clear signal for opportunistic infections compared to IFN β-1a. The potential risk of progressive multifocal leukoencephalopathy (PML) due to opportunistic reactivation of the JC virus is considered separately, below.
9.6.4.Haematology9.6.4.1.Reductions in white cells, including CD4+ and CD8+ cell countsPhase 1 studies of DAC HYP suggested that it caused lymphopaenia, and the pivotal studies confirmed this, but changes in mean total lymphocyte counts were small. The main lymphocyte class showing a decrease in mean counts was the CD8+ subtype. 9.6.4.2.Changes in mean countsIn Study 205MS201, total white blood cell (WBC) counts were similar between the groups, but mean total lymphocyte counts were lower at Week 52 in the DAC HYP groups than the placebo group. For the combined DAC HYP groups (150 mg and 300 mg), mean WBC counts decreased 0.03% and mean lymphocyte counts decreased 5.12% from baseline to Week 52. An assessment of lymphocyte subtypes suggested an unequal effect on different cell types. Mean B-cell, CD4+ T cell, and CD8+ T-cell counts were all lower in the DAC HYP groups, but the fall was greatest in CD8+ cells: mean B-cell counts decreased 7.70%, mean CD4+ T-cell counts decreased 7.93% and CD8+ T-cell counts decreased 47.78% from baseline to Week 52. Differences between active treatment and placebo were highly statistically significant for both CD4+ and CD9+ cells, as shown in the tables below. In contrast to the fall in CD4+ and CD8+ cells, mean NK cell counts were higher in the DAC HYP groups than in the placebo group at Week 52, with the mean NK cell counts increasing by 49.30% from baseline to Week 52 in the combined DAC HYP groups, and no substantial difference across the two different active doses (48.14% increase in the DAC HYP 150 mg group, 50.50% in the DAC HYP 300 mg group); by contrast, there was only a 2.77% increase from baseline in the placebo group. The difference between the placebo and DAC HYP groups was highly statistically significant. The increase in NK cells with DAC HYP treatment was primarily due to an increase in the CD56bright NK subtype. In Study 205MS301, mean WBC counts remained within normal limits and were similar between groups. There were small decreases over time in both treatment groups, with the percentage change being greater in the IFN β-1a group (< 10%) than in the DAC HYP group (≤ 5%). Mean lymphocyte counts also remained within normal limits, but showed small decreases in both treatment groups. The largest mean percentage decreases in lymphocyte count from baseline at any time point were -2.4% in the IFN β-1a group at Week 120 and -8.7% in the DAC HYP treatment group at Week 144. Changes in the mean counts of individual lymphocyte subtypes were not clearly reported in the Summary of Clinical Safety, particularly for Study MS301. In some places, the study report mentioned CD4+ cells, and in other places it concentrated on the T-cell marker FoxP3+, which appears to identify a regulatory subset of CD4+ cells. The table excerpt below shows that FoxP3+ cells fell during treatment with DAC HYP. The patient numbers are low, indicating that lymphocyte subtypes were only assessed in a minority of subjects, as part of a pharmacodynamic assessment rather than as a major feature of safety monitoring. Summary statistics are given in Table 32, below. Table 35. Summary statistics FoxP3+ regulatory T-cells (cells/mm3) at Week 96, Study 205MS301 
In keeping with these results, the clinical study report included the following summary: The PD response to DAC HYP seen in previous DAC HYP clinical studies was confirmed in this study and included sustained CD25 saturation, an increase in CD56bright NK cells, and a decrease in CD4+ CD127 lowFoxP3+ regulatory T-cells. CD25 saturation was apparent by Week 4, the first timepoint examined, and sustained through Week 24, the last timepoint examined. While the changes in CD4+ CD127 lowFoxP3+ regulatory T-cells plateaued by Week 12, the expansion of CD56bright NK cells appeared to plateau by Week 96. The changes in these markers were consistent with the hypothesized effect of DAC HYP on the modulation of IL-2 signalling, including decreased signalling at the high-affinity IL-2 receptor and increased signalling at the intermediate-affinity IL-2 receptor.5 This summary does not mention changes to CD8+ cell counts, and a suitable summary table showing changes in CD8+ cell counts could not be located. The clinical study report mentions that CD8+ counts were similar in subjects with and without infection, but it is not clear how CD8+ counts differed across treatment groups. The sponsor should be asked to clarify the effect of DAC HYP on lymphocyte subtypes in Study 205MS301. To some extent, the lack of clear reporting of the effect of DAC HYP on CD4+ and CD8+ cells in Study MS301 is understandable, given that the effects were already well documented in the placebo-controlled study, 205MS201. On the other hand, 205MS301 represents the only Phase 3 pivotal study in the DAC HYP study program and its duration (up to 144 weeks) potentially provided a better opportunity to study this issue than the shorter study, MS201 (52 weeks), so it would have been appropriate to provide a more detailed assessment of this issue. 9.6.4.3.Shifts in counts and values of potential clinical concernIn Study 205MS201, an analysis of shifts in counts, including values of potential clinical concern, showed a dose-dependent increase in the number of subjects with low CD4+ counts, as summarised in Table 33, below. A similar table for CD8+ cells was not provided, and the sponsor should be asked to clarify how many subjects had significant or concerning falls in CD8+ counts in Study 205MS201. This is particularly important because CD8+ cells may play a role in preventing PML. Falls in CD8+ cells have been implicated in the mechanism by which the oral MS therapy, dimethyl fumarate, has caused PML in some subjects. Table 36. Percentage of subjects with low post-baseline CD4 counts 
In Study 205MS301, potentially clinically significant changes in haematology parameters were slightly more common in the IFN β-1a group, which had a higher incidence of lymphopaenia. It was unclear how often there were significant falls in CD4+ or CD8+ cells, and this should be further clarified by the sponsor. SAEs involving low WBC cell parameters included one of agranulocytosis and one of lymphopenia, both in the DAC HYP group. Table 37. Potentially clinically significant haematology laboratory abnormalities 
9.6.5.Progressive Multifocal LeukoencephalopathyPML is a rare but serious inflammatory condition affecting the white matter of the central nervous system, often causing death or disability. It is caused by the JC virus, which is carried asymptomatically in a significant proportion of the population. PML is known to be a complication of JC viral activation in CNS, usually in subjects with immune compromise, such as acquired immune deficiency syndrome (AIDS) or immunosuppressive drugs. Although the original injectable agents for MS (beta interferon and glatiramer acetate) have not been associated with an elevated risk of PML, several new MS agents do appear to cause a low incidence of PML, particularly when associated with lymphopaenia or with reduced lymphocyte access to the CNS. In general, this risk cannot be inferred from the pivotal study data. For natalizumab, where there is a well-characterised risk of PML, the original pivotal studies did not detect the risk. Similarly, for dimethylfumarate, PML has developed in a few subjects with prolonged lymphoaenia, but this was not a feature of the original pivotal studies and only occurred during postmarketing use of the drug. PML has also been reported in subjects using fingolimod. The risk with different agents has usually been estimated at less than 1 in 1000 subjects, but varies with JC positivity and duration of exposure. PML was not reported in subjects exposed to DAC HYP, but the studies were too brief and too small to detect a low risk of PML. In general, all agents with efficacy against MS should be considered to pose a PML risk until proven otherwise, because lymphocyte function in the CNS is important for normal immune surveillance, including protection against the JC virus, as well playing a strong role in the pathogenesis of MS. This concern is particularly relevant in view of the results of haematological monitoring, which showed that DAC HYP reduces CD4+ and CD8+ lymphocytes. The PI should make it clear that exposure to DAC HYP has not yet been extensive enough to characterise the PML risk, and this issue should be the focus of ongoing post-marketing surveillance. 9.7.Evaluator’s overall conclusions on clinical safetyOverall, the safety profile of DAC HYP has been reasonably well characterised in terms of tolerability and common side effects, but the extent to which it may cause serious idiosyncratic reactions is still unclear. Although it might be expected to pose a risk of PML, it has not yet been used in a large JC virus-positive population for long enough to characterise this risk accurately. In terms of tolerability and common AEs, DAC HYP has an acceptable profile. In the placebo controlled study, 205MS201, the incidence of AEs was 74% in DAC HYP recipients (73% for 150 mg, 76% for 300 mg), compared to 79% in placebo recipients, as summarised in Table 35 below. Although these percentages appear to favour DAC HYP over placebo, a direct comparison of AE incidence is unreliable because of the inclusion of MS relapses. ‘MS relapse’ was the most commonly reported AE, but clearly reflected efficacy rather than safety. It would have been appropriate to report total AEs excluding MS-relapse. ‘Treatment-related’ AEs were thought to have occurred in about 22% of subjects treated with DAC HYP. The most common AEs with an apparent causal relation to DAC HYP consisted of: injection-site pain, influenza-like illness, headache, abnormal LFTs (ALT increased, AST increased, LFT abnormal, or GGT increased), injection-site erythema or bruising, rash, eczema, nausea, lymphadenopathy, and lymphopenia. Many other common AEs seem less likely to have been causally related to treatment: nasopharyngitis, pyrexia, upper respiratory tract infection, pharyngitis, MS relapse, and fatigue. The majority of AEs were mild to moderate and responded to standard treatment or interruption or discontinuation of DAC HYP. Skin reactions were common TEAEs and occurred in about 37% of subjects in the active-control study, 205MS301. Most of the cutaneous adverse events were mild to moderate and resolved with topical treatment or interruption of DAC HYP. About 2% of cutaneous adverse events were rated as serious. The serious cases were usually treated with systemic corticosteroids, and this should be mentioned in the PI. One severe skin hypersensitivity reaction to DAC HYP led to a patient death, albeit indirectly: the patient developed bacteraemia in the setting of an exfoliative rash, leading to the development of a psoas abscess, emboli and bowel ischaemia. It remains unclear whether this was a case of SJS. Another death attributed to DAC HYP was a case of autoimmune hepatitis, which occurred during re-initiation of DAC HYP in a patient involved in two DAC HYP studies. This case led to more intensive monitoring in the clinical study programs. Abnormal LFTs were common in the DAC HYP studies, and were managed by interruption or discontinuation of treatment. There were no further episodes of autoimmune hepatitis, but the increased vigilance could have led to a lower incidence of severe hepatic abnormalities in this closely monitored environment than might be expected in routine clinical use. At least one DAC HYP recipient in Study MS301 satisfied Hy’s Law. Other subjects had abnormal LFTs sufficient to be characterised as Hy’s Law cases, but were not classified as satisfying Hy’s law because alternative explanations of abnormal LFTs were considered possible. The risk of severe hepatic abnormalities has led US authorities to place a boxed warning in the US PI. It appears likely that the risk could be adequately managed in the post-marketing environment with a program of monitoring LFTs and ceasing treatment when these become sufficiently abnormal. The precise level of LFT derangement that should trigger a cessation of treatment is unclear. Colitis was observed in some patients treated with DAC HYP. This largely resolved after DAC HYP was discontinued. The mechanism and optimal management of colitis in this setting remain unknown. Table 38. Adverse events, DAC HYP versus placebo, Study 205MS201 
An excess of mild to moderate depression was observed in subjects treated with DAC HYP, compared to placebo, in Study MS201. The incidence of depression appeared to be similar to that observed with IFN β-1a in Study MS301. DAC HYP should be contraindicated in patients with a recent history of severe depression. The use of DAC HYP was associated with a significant reduction in CD4+ and CD8+ T-cells, which might be expected to increase the risk of PML. Experience with other disease-modifying agents in MS suggests that this risk will not be fully characterised until the drug has been used in a large population of at-risk, JC-positive subjects. The pivotal studies showed a mild excess of infections in DAC HYP recipients, but a substantially increased risk of opportunistic infections, was not observed. The risk of infections should remain a focus of post marketing surveillance. In conclusion, the tolerability of DAC HYP is broadly acceptable. In terms of serious but rare safety issues, DAC HYP appears to be associated with a risk of severe reactions in a small proportion of subjects. These include: hepatic reactions, including autoimmune hepatitis hypersensitivity reactions, incuding skin reactions and anaphylaxis lymphopaenia, especially affecting CD4+ and CD8+ lymphocytes a theoretical risk of progressive multifocal leukoencephalopathy.
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