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

1.Introduction

This submission proposes to register the new active substance daclizumab.

The submission proposes registration of the following dosage forms and strengths:

Zinbryta (daclizumab) 150 mg/ml solution for injection Pre-filled Pen

Zinbryta (daclizumab) 150 mg/ml solution for injection Pre-filled Syringe (PFS)

Daclizumab is a humanised immunoglobulin G (IgG) antibody (Ab), or more explicitly, a IgG1 monoclonal antibody (MAb) that binds specifically to the alpha subunit of the interleukin-2 receptor (IL-2Rα, also known as CD25) producing immunomodulatory effects by selectively blocking signalling through high affinity IL-2 receptors while leaving interleukin2 (IL2) signalling by intermediate affinity IL-2 receptors intact.

The sponsor’s preferred indication, according to the proposed Product Information (PI), is as follows:

‘Zinbryta is indicated for the treatment of relapsing forms of multiple sclerosis (MS).’

As will be discussed, the clinical evaluator believes that this indication is too broad, because it does not match the entry criteria for the pivotal studies. The indication should be reworded so that it explicitly applies to relapsing and remitting multiple sclerosis (RRMS), and not to primary or secondary progressive multiple sclerosis.

2.Clinical rationale

Figure 1. Different clinical courses of multiple sclerosis¹

also occurs, in which the disease is progressive from the onset. some patients appear to have a progressive course from the onset, but also have superimposed relapses, a combination known as progressive-relapsing multiple sclerosis (prms). " align=bottom width=454 height=272 border=0>

Multiple sclerosis (MS) is a complex neurological condition characterised by inflammation and demyelination in the central nervous system (CNS). Several subtypes are recognised, based on the temporal pattern of disability, as illustrated in Figure 1, above. The most common form is RRMS, characterised by acute episodes of focal inflammation, usually followed by recovery. This often transforms into secondary progressive multiple sclerosis (SPMS), in which progression of disability occurs between relapses, or in the absence of identifiable relapses. Primary progressive multiple sclerosis (PPMS) also occurs, in which the disease is progressive from the onset. Some patients appear to have a progressive course from the onset, but also have superimposed relapses, a combination known as progressive-relapsing multiple sclerosis (PRMS).

MS is thought to be primarily an autoimmune disease, although there are also some neurodegenerative elements. Most approved therapies for MS are thought to reduce the incidence of relapses by modifying the immune system, and in some cases this has been shown to reduce the accumulation of disability.

Daclizumab High Yield Process (DAC HYP) is also thought to produce its benefits in MS by modifying the immune response and reducing CNS inflammation. Specifically, by blocking highaffinity IL-2 receptors, it produces the following immunomodulatory effects:

• 
  Selective antagonism of activated T-cell responses.
  
• 
  Expansion of immunoregulatory CD56^bright natural killer (NK) cells which have been shown to selectively decrease activated T cells.
  
• 
  Reduction in lymphoid tissue inducer (LTi) cells which are associated with cortical inflammation and demyelination.
  

3.Contents of the clinical dossier

3.1.Scope of the clinical dossier

This document (Attachment 3) is based upon the Supplementary Clinical Evaluation Report (SCER) written in response to the provision of new information by the sponsor. Accordingly, this extract from the SCER should not be considered a comprehensive assessment of all submitted clinical data. It should be read in conjunction with Attachment 2, the extract from the Clinical Evaluation Report (CER).

The primary material being evaluated in this SCER consists of the pivotal efficacy study reports, the sponsor’s response to key Clinical Questions from the European Medicines Agency (EMA), and parts of the Summary of Clinical Safety (SCS) relevant to safety issues of particular interest.

The SCS has already been evaluated, as discussed in the First Round CER, and the main safety conclusions of that CER are summarised at the beginning of Section: Safety in this document.

One problem the current evaluator had with the SCS was that it did not directly include the tables and figures being discussed, so it was difficult to confirm claims made in the text of the SCS as they were being made. To a limited extent, this deficiency was offset by including hyperlinks to the relevant tables and figures, but this format increases the risk that discrepancies could be missed. The current clinical evaluator has not reassessed all aspects of the SCS to find such potential discrepancies.

In summary, the clinical material being evaluated is as follow:

2 pivotal efficacy and safety studies, Study 205MS201 and Study 205MS301

Summary of Clinical Efficacy (SCE)

Summary of Clinical Safety (SCS)

Sponsor’s responses to EMA questions (questions 70, 94 and 95).

3.2.Paediatric data

Please see Attachment 2, Extract of the CER.

3.3.Good clinical practice

Please see Attachment 2, Extract of the CER.