Auspar attachment 3: Extract from the Supplementary Clinical Evaluation Report for Daclizumab

11.First round recommendation regarding authorisation

The sponsor’s application to register DAC HYP for all subjects with relapsing forms of MS should be rejected.

Authorisation should be reconsidered after the sponsor has:

provided adequate answers to the clinical questions raised by the evaluator

addressed concerns raised about the proposed PI

provided a satisfactory mechanism to ensure DAC HYP is only prescribed by clinicians aware of its safety issues, with appropriate monitoring of LFTs

modified the wording of the indication so that it matches the study population in the two pivotal studies.

11.1.Issues raised in the first round clinical evaluation report

The First Round clinical evaluator expressed many concerns about the proposed PI that are shared by the supplementary evaluator. These are addressed below.

11.1.1.Efficacy

11.1.1.1.First round concerns

‘In the narrative under Table 2 reference is made to the MSIS-29 endpoint for Study 205MS201 under this heading and efficacy results and a p-value are given. However the difference for DAC HYP 150 mg versus placebo was not considered statistically significant per the sequential closed testing procedure because the procedure required that the 300 mg dose group be tested first and achieve statistical significance before the 150 mg dose group could be tested. The result should be amended to reflect this or removed.’

Supplementary evaluator’s response

The supplementary evaluator fully agreed with this criticism.

11.1.2.Indications

11.1.2.1.First round concerns

‘The indication, treatment of relapsing forms of MS, is considered too broad and should be amended to reflect the target patient population and the primary endpoint investigated in the clinical studies. For example:

‘DAC HYP is indicated in patients aged 18-years or over who have RRMS who have had two or more clinical relapses within the previous 3 years with at least 1 clinical relapse in the 12 months prior to treatment’; or

‘One or more clinical relapses and 1 or more new MRI lesions (Gd-enhancing and/or T2 hyper-intense lesion) within the previous 2 years, with at least one of these events in the 12 months prior to treatment.’

Supplementary evaluator’s response

The supplementary evaluator agrees with the statement that the proposed indication is too broad. A strict interpretation of the pivotal studies suggests that efficacy for DAC HYP has only been demonstrated in subjects with RRMS and evidence of recent disease activity, as evidenced by at least 1 relapse in the previous year or 2 relapses in the previous 3 years (or a radiological substitute for clinical relapses). The supplementary evaluator does not fully agree that this highly restricted definition of the target population should be used in the PI.

Firstly, there is a spectrum of disease patterns in MS ranging from those with mild disease to those with more severe disease, and another spectrum from those primarily affected by relapses to those primarily affected by progression. Efficacy is likely to extend along both spectra to provide some benefit in subjects who are slightly outside the strict entry criteria applied to the pivotal studies.

Secondly, and more importantly, there is a large section of the MS population who have already been on disease-modifying treatment, prior to considering a switch to an agent like DAC HYP, and who are likely to have experienced a reduction in relapse rate because of this treatment, relative to what they would have experienced if they had not been treated. This reduction in relapse rate could mean that they have not experienced two relapses in the previous 3 years solely because they respond well to immunomodulatory treatment. If such subjects are switching disease-modifying agents because of poor tolerability with an existing agent, it would be unfair to exclude them on the basis of their good response to the previous agent – subjects showing a good response may be the most appropriate subjects to continue a disease-modifying agent. Conversely, if they are switching because of poor efficacy of the previous agent, as evidenced by clinical and radiological evidence of ongoing relapses, then they are likely to satisfy the entry criteria for the pivotal studies anyway, or at least be broadly similar to the study population.

Treatment-naïve RRMS subjects without recent relapses were not eligible the pivotal studies, and cannot be considered to have a low relapse rate that is attributable to treatment, so it would be reasonable to exclude this category from the proposed indication. One problem is that the indication could become unwieldy if it attempted to cover every clinical possibility. For instance, the indication could be expressed as follows:

‘DAC HYP is indicated in patients with Relapsing and Remitting MS (RRMS) aged ≥ 18 years who have had ≥ 2 clinical relapses within the previous 3 years OR ≥ 1 clinical relapse and ≥ 1 new MRI lesion within the previous 2 years; or are switching from a different disease-modifying treatment. DAC HYP is not indicated in subjects with Secondary Progressive MS or Primary Progressive MS’

This wording is somewhat simplified compared to the entry criteria for the pivotal studies (it does not require that subjects have had a relapse in the previous 12 months, for instance), but it allows for the possibility of subjects switching treatments.

Given the safety profile of DAC HYP, it would also be reasonable to restrict treatment to subjects who have failed on other disease-modifying agents. The US PI recommends this, without formally insisting on it:

‘Zinbryta is an interleukin-2 receptor blocking antibody indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (MS). Because of its safety profile, the use of Zinbryta should generally be reserved for patients who have had an inadequate response to two or more drugs indicated for the treatment of MS.’

To some extent, clinicians may be best placed to balance the risk and benefits of switching agents, and it is probably sufficient to restrict the indication to subjects with RRMS, while warning clinicians not to prescribe DAC HYP unless they feel the benefits outweigh the risks. This would lead to a simpler indication, as follows:

‘DAC HYP is indicated in patients with Relapsing and Remitting MS (RRMS) aged ≥ 18-years who have ongoing relapses; or are switching from a different disease-modifying treatment. DAC HYP is not indicated in subjects with Secondary Progressive MS or Primary Progressive MS.’

On balance, this is the preferred wording for the supplementary Evaluator, but the earlier wording requiring evidence of a sufficient number of relapses would also be acceptable.

These comments in favour of simplification should not be taken as supportive of a further relaxation of the definition of the target population, to include subjects who do not even have RRMS, because these subjects were not the focus of the pivotal studies and there has been ample evidence over decades that efficacy in RRMS does not translate well to subjects with SPMS.

11.1.3.Contraindications

11.1.3.1.First round concerns on hepatic impairment

‘Consideration should be given to adding a contraindication for patients with hepatic impairment as these patients were excluded from the clinical studies. Since the safety profile for DAC HYP includes elevations in LFTs and it is not known how patients with pre-existing hepatic impairment will be affected.’

Supplementary evaluator’s response

The supplementary evaluator supports listing hepatic impairment as a contraindication to use of DAC HYP. Currently, hepatic impairment is only listed as a precaution, and only if the pre-existing impairment is severe:

‘Zinbryta is not recommended for use in patients with pre-existing severe hepatic impairment.’

Hepatic abnormalities (and one liver-related fatality) were observed in the pivotal studies despite the exclusion of subjects with pre-existing hepatic impairment. As noted by the First Round clinical evaluator, hepatic complications might be more frequent if the drug was used in such subjects.

11.1.3.2.First round concerns on concomitant use of immunosuppressant therapy

‘Since this product is an immunomodulator, a contraindication for use in patients with increased risk for opportunistic infections [should be added to the PI], including those immunocompromised due to current or recent immunosuppressive therapies or systemic medical conditions resulting in significantly compromised immune system function (for example human immunodeficiency virus, organ transplant, active malignancy); subjects such as these were also excluded from the clinical studies.’

Supplementary evaluator’s response

The supplementary evaluator agrees that clinicians should avoid combining DAC HYP with other immunosuppressive treatments or conditions.

11.1.3.3.First round concerns on use in patients with a history of depression

‘A contraindication for patients with a recent history of severe depression should be added.’

Supplementary evaluator’s comment

This seems appropriate.

11.1.4.Precautions

11.1.4.1.First round concerns restricting prescribing to neurologists only

‘Although it is unlikely that any physician other than a neurologist will start treatment with DAC HYP, wording should be added to state that: DAC HYP should only be initiated by neurologists experienced at treating and monitoring patients who have MS.’

Supplementary evaluator’s response

Arguably, this statement should be even more strongly worded. The US PI restricts use of DAC HYP to treatment within the context of a strict ‘Risk Evaluation and Mitigation Strategy (REMS) called the Zinbryta REMS Program’. In Australia, a similar program should be considered. There is a clear precedent. When the monoclonal antibody natalizumab was registered for treatment of MS in Australia, it was initially restricted to neurologists who had undergone training about the particular risks associated with natalizumab, including PML. Balancing the benefits and risks of DAC HYP will not be straightforward, given that other agents offer similar efficacy, and it would be reasonable to restrict DAC HYP to neurologists with experience in MS who have undergone specific training about the risks of DAC HYP.

11.1.4.2.First round concerns regarding PML risk

‘The patient population in the clinical studies was not large enough to detect cases of progressive multifocal leukoencephalopathy. The possibility of development [of PML] cannot be excluded and this should be reflected in this section. For example: ‘Although not seen in the clinical development program for DAC HYP, due to the immunomodulatory action, the development of PML remains a rare possibility. Patients should be screened for JC virus prior to initiation of treatment to minimise the risk.’

Supplementary evaluator’s response

The proposed addition to the PI is appropriate, and the supplementary evaluator agrees that JC serological status should be monitored in subjects on DAC HYP. There is currently insufficient evidence to justify a policy of restricting DAC HYP to JC-negative subjects, but knowledge of JC status could allow a heightened index of suspicion for PML, more frequent MRI monitoring, and more appropriate action if PML cases are reported internationally. The following wording is proposed:

‘Although progressive multifocal leukoencephalopathy (PML) was not seen in the clinical development program for DAC HYP, the development of PML remains a possibility, because of the immunomodulatory action of DAC HYP. Patients should be screened for JC virus prior to initiation of treatment, and JC-positive subjects should be monitored closely, to minimise the risk.’

11.1.4.3.First round concerns regarding depression risk

‘Since an excess of depression was seen in subjects who received DAC HYP in the placebo controlled study appropriate warnings should be placed in this section. For example: In a placebo controlled study depression was seen more commonly in subjects who received daclizumab. Patients should be warned of the possibility of experiencing depression and should seek medical advice if they have alterations in mood.’

Supplementary evaluator’s response

The proposed addition to the PI is broadly appropriate. For consistency with the rest of the PI, the placebo-controlled study should be named.

12.Clinical questions

12.1.Additional expert input

The risks of serious hepatic injury with DAC HYP may be worse in subjects with pre-existing hepatic disorders. The opinion of a hepatologist should be sought about the degree to which pre-existing abnormalities of liver function should be considered a contraindication to DAC HYP.

Consideration should be given to obtaining expert advice about the PML risks likely to be associated with DAC HYP. Alternatively, it could be assumed that the risks are significant, on the basis of the observed effects of DAC HYP on lymphocytes and the experience with other disease-modifying agents in MS.

12.2.Efficacy

Q1. If the question had not already been raised by the EMA, it would be important to ask the sponsor to justify the proposed indication for ‘relapsing forms of MS’ given that the pivotal studies of DAC HYP were specifically conducted in subjects with RRMS. The sponsor’s response to this issue has already been discussed in detail in Section: Supplementary material submitted to the EMA in relation to pivotal efficacy data and largely rejected. The sponsor is invited to read this section and suggest a more appropriate indication that matches the entry criteria of the pivotal studies.

Q2. What evidence is available to establish the minimum effective dose of DAC HYP? Given that Study 205MS201 showed no substantial difference between 150 mg and 300 mg, it appears possible that lower doses, such as 100 mg SC 4-weekly, would also have acceptable efficacy, and these lower doses might have improved safety. Please comment on the proposed dose in light of these observations.

Q3. In the efficacy results for Study 205MS201, the precise meaning of the p-values cited next to footnote ‘(b)’ in the sponsor’s table was not clear (please see Table 6 of this document). The sponsor should be asked to clarify what test has been used and what the p-values indicate.

Q4. Please provide clear summary tables of the number and nature of protocol deviations in the two pivotal studies. In Study 205MS201, a clear tale grouping protocol deviations by type and severity was not provided. In Study 205MS301, major protocol deviations were summarised by the sponsor as follows:

‘Overall, the incidence and category of major protocol deviations were similar between the two treatment groups. The most common major deviations (≥ 20%) were ‘Informed Consent’ (32% IFN β-1a versus 33% DAC HYP), ‘Key Study Procedures’ (28% IFN β-1a versus 27% DAC HYP), and ‘Other’ (27% each group).’

The sponsor’s text provided a link to a table of protocol deviations, reproduced below, but this table lacked detail and it is not possible to determine whether the deviations related to ‘Key Study Procedures’ or ‘Other’ substantially compromised the study. The sponsor should clarify the nature of the deviations and consider the extent to which these deviations could have compromised the study.

Table 39. Summary of Major Protocol Deviations, Study 205MS301

Q5. Did the sponsor attempt to identify the extent of inadvertent unblinding in the pivotal studies, because of tell-tale side effects? If not, why not? Please estimate the extent of unblinding by considering the incidence of side effects in the pivotal studies.

12.3.Safety

Q6. (A) For lymphocyte subtypes, such as CD4+ and CD8+ T-cells, changes in mean counts and the incidence of clinically significant shifts were not always clearly reported, particularly for the active-controlled study, Study 205MS301. The sponsor should be asked to clarify the effect of DAC HYP on lymphocyte subtypes in Study 205MS301, providing brief summary tables for changes in mean counts and the incidence of potentially clinically significant shifts in counts.

Q6. (B) In 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, but a similar table for CD8+ cells was not provided. The sponsor should clarify how many subjects had significant or concerning falls in CD8+ counts in Study 205MS201.

Q7. The sponsor should provide estimates of the risk of DAC HYP causing PML in JC positive subjects, and comment on the extent to which baseline lymphopaenia could modify this risk.

13.Second round evaluation of clinical data submitted in response to questions

The secondary clinical evaluation and the questions posed in Section 12 above were taken into consideration by the Delegate when writing the Delegate’s Overview (see Overall conclusion and risk/benefit assessment in AusPAR).

14.References

Durelli L et al; Independent Comparison of Interferon (INCOMIN) Trial Study Group. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002 Apr 27;359(9316):1453-60.

Gold R et al; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1098-107.

Schwid S et al; Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clin Ther. 2007;29(9):2031-2048.

Davies H et al; When can odds ratios mislead? BMJ. 1998;316:989–991.

Deeks, J; When can odds ratios mislead? Odds ratios should be used only in case-control studies and logistic regression analyses BMJ. 1998 Oct 24; 317(7166): 1155. PMCID: PMC1114127

Therapeutic Goods Administration

PO Box 100 Woden ACT 2606 Australia Email: [e-mail] Phone: [phone] Fax: [phone] https://www.tga.gov.au

1^ Adapted from: Lublin F et al. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996; 46:907–911.

2^ McDonald criteria Numbers 1 to 4 were defined as: Criterion 1 = 2 or more relapses, 2 or more objective lesions. Criterion 2: 2 or more relapses, 1 objective lesion, and dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with MS or further clinical attack involving different site. Criterion 3: 1 relapse, 2 or more objective lesions, and dissemination in time by MRI or second clinical attack. Criterion 4: 1 (mono-symptomatic) relapse, 1 objective lesion, dissemination in space by MRI or positive CSF and 2 or more MRI lesions consistent with MS, and dissemination in time by MRI or second clinical attack. Poleman (2005)

3^ According to the study report (Study 205MS201): “For inclusion purposes, a relapse was defined as neurologic signs and/or symptoms documented by a neurologist in the medical record and of at least 24 hours duration to be determined by the Investigator or the Treating Neurologist.”

4^ T1 and T2 are MRI images are produced by dual spin echo frequency. Echo represents the signal received from the slice of interest in the body. T1 imaging is produced using short repetition and short echo times. T2 imaging is produced using long repletion and long echo times.

5^ Gold R et al; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1098-107.

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7^ Schwid S et al. Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clin Ther. 2007; 29(9):2031-2048.

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