Siponimod (Mayzent) for multiple sclerosis

• On 1 November 2020, siponimod (Mayzent) was listed on the PBS General Schedule as an Authority Required (Streamlined) listing for patients with multiple sclerosis (MS)
  The intent of the listing is to enable use by patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS).
• The PBAC noted a high clinical need for patients with secondary progressive MS (SPMS) who are ambulant but require support
  Before the listing of siponimod, there was no PBS-listed therapy specifically for patients with SPMS.
• The PBAC considered it may be appropriate to include siponimod within the existing treatment algorithm for relapsing-remitting MS (RRMS) disease-modifying treatments (DMTs)
  This listing provides flexibility for clinicians to choose the most appropriate therapy for individual patients based on their clinical judgement.
• The new listings include a continuation criterion that the patient must not show continuing progression of disability while receiving siponimod treatment
  If a patient’s expanded disability status scale (EDSS) score increases to > 6.5, they must cease subsidised siponimod treatment.

On 1 November 2020, siponimod (Mayzent) 250 microgram and 2 mg tablets were listed on the PBS General Schedule (Section 85) as Authority Required (Streamlined) listings for the treatment of MS for patients who have a current or previous diagnosis of relapsing-remitting MS (RRMS).¹

The diagnosis of RRMS must be clinically definite as determined by:²

• magnetic resonance imaging (MRI) of at least one of the brain or spinal cord,
  OR
• supported by written certification from a radiologist, which is documented in the patient’s medical records, that an MRI scan is contraindicated because of the risk of physical (not psychological) injury to the patient.

The intent of the listing is to enable use by patients:

• who are ambulant (with or with support, including walking aids)
  AND
• who have RRMS (and at minimum, mild disability in at least 3 functional systems or moderate disability in at least one functional system^a)
  OR
• who have secondary progressive MS (SPMS).² SPMS is the phenotype of MS that follows on from RRMS as progressive neurodegeneration occurs.³

^aFunctional systems referred to in this listing include: visual, brain stem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral/cognitive systems.

See the PBS website for complete details for each item.

High clinical need

At the July 2020 PBAC meeting, siponimod was recommended for people with SPMS. The PBAC noted the high clinical need for effective treatments for patients with SPMS who are ambulant but require support, consistent with an EDSS score of 6.0–6.5.^b,3

The wording of the listing (ie, patients requiring a previous diagnosis of RRMS) reflects observations from the 2013 International Advisory Committee on Clinical Trials of MS which stated ‘in most clinical contexts, SPMS is diagnosed retrospectively by a history of gradual worsening after an initial relapsing disease course, with or without acute exacerbations during the progressive course.’³

Based on the results from the EXPAND trial, which included patients with SPMS and EDSS scores of 3 to 6 at baseline as part of the trial population, showed that siponimod is superior to placebo in terms of confirmed disability progression (CDP) and annualised relapse rate (ARR) outcomes.

The PBAC also considered the results of a matching adjusted indirect comparison, that showed siponimod was associated with a statistically significant improvement in time to CDP at 6 months, compared to interferon-beta therapies (interferon beta-1a HR 0.43, 95% CI 0.20 to 0.93; interferon beta-1b HR 0.55, 95% CI 0.33 to 0.91). It was satisfied that siponimod can provide a significant improvement in effectiveness and safety over interferon-beta, for some patients.

Fingolimod was nominated as the main comparator, as a point of reference for PBS-listed DMTs. Additionally, fingolimod is a pharmacological analogue of siponimod.³

An indirect comparison of adverse events between siponimod and fingolimod found that siponimod was associated with statistically significant fewer hypertensive events and had a non-inferior safety profile compared to fingolimod.³

The Australian and New Zealand Association of Neurologists supported the listing of siponimod and also noted that the titrated starting dose of siponimod avoids the bradycardia (and first dose monitoring) that occurs with fingolimod.³

Cost-effectiveness

The PBAC considered that the cost-effectiveness of siponimod could be determined by a comparison with the DMTs among people with RRMS and also that other PBS-listed treatments were listed on the basis of similar efficacy and safety compared to fingolimod.

It also noted that based on the pricing approach in this resubmission and pre-PBAC response, the cost of siponimod would be less than fingolimod and treatments that have been listed on a cost-minimisation basis versus fingolimod.³

^b EDSS 6.0 applies to patients who require intermittent or unilateral constant assistance to walk 100 metres with or without resting and EDSS 6.5 applies to those requiring constant bilateral assistance (using canes, crutches, braces) to walk 20 metres without resting.³

Before this listing, there was no PBS-listed therapy specifically for SPMS.³

The PBAC noted at its November 2019 meeting that while the key evidence for siponimod is for patients with SPMS, it may not be appropriate to exclude patients with RRMS as it can be clinically difficult to determine when patients transition from RRMS to SPMS.⁴ The International Advisory Committee on Clinical Trials of MS (mentioned above) noted ‘to date, there are no clear clinical, imaging, immunologic or pathologic criteria to determine the transition point when RRMS coverts to SPMS; this transition is usually gradual’.³

The Pre-Sub-Committee Response stated there is ‘legitimate and appropriate use of and switching between current DMTs, and in the future with siponimod’ (which may be due to adverse events or inadequate response) based on the difficulty of determining whether patients have RRMS or SPMS.⁴

Additionally, the pre-PBAC response also suggested it was reasonable to allow patients to switch back to an alternative DMT for RMMS, following treatment with siponimod, if they meet the RRMS criteria, as patients who cannot tolerate siponimod, or for whom it is ineffective may continue to realise a benefit in terms of relapse and lesion development. As a result, the PBAC considered it may be appropriate to include siponimod within the existing treatment algorithm for RRMS disease-modifying treatments (DMTs). As siponimod shows evidence for reducing CDP, the PBAC considered that this listing provides flexibility for clinicians to choose the most appropriate therapy for individual patients based on clinical judgement, which could be siponimod when deemed clinically appropriate. This approach would also allow patients to transition back to RRMS DMTs following treatment with siponimod.⁴

International guidelines have started to include siponimod as one of the recommended treatment options for multiple sclerosis.⁵ The US Food and Drug Administration approved siponimod for relapsing forms of MS, including active SPMS in 2019.⁶ However, Therapeutic Guidelines have not updated their guidance for multiple sclerosis to include siponimod.⁷

The new listings include a continuation criterion: ‘the patient must not show continuing progression of disability while on treatment with this drug.’² This means that if the patient’s condition progresses so that they are no longer ambulant, or their EDSS score rises above 6.5, subsidised treatment with siponimod must cease.³

Patients should be tested for CYP2C9 genotype before initiation of siponimod treatment. Patients with the rarer CYP2C9*3*3 genotype (which is less than 0.4%–0.5% of the population) should not receive treatment with siponimod.^9,10 Note that there is no specific Medical Benefits Schedule (MBS) item for CYP2C9 metabolising enzyme status testing.²

Patients should not receive live attenuated vaccines during treatment and for 4 weeks after completing treatment with siponimod, due to the risk of infection. Vaccinations may be less effective if administered during treatment with siponimod.⁹

Patients should be aware that their doctor may test their antibody status against varicella zoster virus and decide to vaccinate them in the absence of antibodies to the virus. Treatment with siponimod must wait one month after the full course of the varicella zoster vaccination.⁹

Before starting treatment, a blood test may be required to check white blood cells and liver function.⁹

Patients should inform their doctors if they believe they may have an infection, as it may worsen. This is particularly important for patients with a lowered immune response, as siponimod lowers white blood cell count.⁹

Other adverse effects that patients should consider include headache, increased infection risk, macular oedema (vision changes) and transient decreases in heart rate.¹¹