7. 06 Perampanel, Film-coated tablets, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg, Fycompa®



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Public Summary Document – July 2017 PBAC Meeting


7.06 PERAMPANEL,
Film-coated tablets, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg, Fycompa
®, Eisai Australia Pty Ltd



  1. Purpose of application




    1. The re-submission proposed an Authority Required (STREAMLINED) listing for perampanel for the treatment of Idiopathic Generalised Epilepsy (IGE) with primary generalised tonic-clonic (PGTC) seizures. The first submission was considered by the PBAC in July 2016.

Table 1: Key components of the clinical issues addressed by the re-submission

Component

Description

Population

Idiopathic Generalised Epilepsy (IGE) patients with Primary Generalised Tonic-Clonic (PGTC) seizures

Intervention

Perampanel tablets taken orally once daily before bedtime. Initial dose of 2mg/day, increased to a maintenance dose of up to 8mg/day. The dose may be increased up to a maximum of 12mg/day depending upon clinical response and tolerability.

Comparator

Mixed comparators – (i) placebo for use as a last option add-on treatment and (ii) other antiepileptic drugs (AEDs) (individually) when used as an additional option to the currently used AEDs

Outcomes

The percent change from baseline in PGTC or GTC seizure frequency, the 50% PGTC or GTC seizure responder rate, defined as the percentage of subjects experiencing a 50% or greater reduction in PGTC or GTC seizure frequency relative to baseline, and treatment-emergent adverse events (TEAEs).

Clinical claim

Perampanel versus placebo: perampanel (plus standard care, i.e. background AEDs) is superior to placebo (plus standard care) in terms of efficacy and inferior to placebo (plus standard care) in terms of safety.

Perampanel versus lamotrigine or levetiracetam: perampanel (plus standard care) is non-inferior, in terms of both comparative effectiveness and comparative safety, to either lamotrigine (plus standard care) or levetiracetam (plus standard care).



Source: Compiled during the evaluation



  1. Requested listing

Suggestions and additions proposed by the Secretariat to the requested listing are added in italics and suggested deletions are crossed out with strikethrough.




Name, Restriction,

Manner of administration and form



Max.

Qty


№.of

Rpts


Dispensed Price for Max. Qty

Proprietary Name and Manufacturer

PERAMPENAL

2 mg tablet, 7


2

1

$'''''''''''''''


Fycompa®


Eisai Australia Pty Ltd






Category /

Program

GENERAL – General Schedule (Code GE)


Prescriber type:


Dental Medical Practitioners Nurse practitioners Optometrists

Midwives

Severity:

Primary generalised tonic-clonic seizures

Condition:

Idiopathic generalised epilepsy with Primary Generalised Tonic-Clonic seizures

PBS Indication:

Idiopathic generalised epilepsy with primary generalised tonic-clonic seizures

Treatment phase:

Initial therapy

Restriction Level / Method:


Restricted benefit

Authority Required - In Writing

Authority Required - Telephone

Authority Required - Emergency

Authority Required - Electronic

Streamlined

Treatment criteria:

Must be treated by a neurologist

Clinical criteria:



The condition must have failed to be controlled satisfactorily by at least two anti-epileptic drugs,
AND
The treatment mMust be in combination with at least one PBS subsidised anti-epileptic drug,
AND
The treatment must be for dose titration purposes (2mg, 7 packs sizes only).

Population criteria:


Patient must be aged 12 years or older.


Administrative Advice

No applications for increased to the maximum quantities will be authorised.




Name, Restriction,

Manner of administration and form



Max.

Qty


№.of

Rpts


Dispensed Price for Max. Qty

Proprietary Name and Manufacturer

PERAMPENAL

4 mg tablet, 28

6 mg tablet, 28

8 mg tablet, 28

10 mg tablet, 28

12 mg tablet, 28


1

1



1

1

1


2

2



5

5

5


$''''''''''''''''''

$'''''''''''''''

$''''''''''''''''

$'''''''''''''''

$'''''''''''''''


Fycompa®


Eisai Australia Pty Ltd






Category /

Program

GENERAL – General Schedule (Code GE)


Prescriber type:


Dental Medical Practitioners Nurse practitioners Optometrists

Midwives

Severity:

Primary generalised tonic-clonic seizures

Condition:

Idiopathic Generalised epilepsy with Primary Generalised Tonic-Clonic seizures

PBS Indication:
PBS Indication is the combination of the Episodicity, Severity and Condition.

Idiopathic generalised epilepsy with primary generalised tonic-clonic seizures

Treatment phase:

Continuing therapy

Restriction Level / Method:



Restricted benefit

Authority Required - In Writing

Authority Required - Telephone

Authority Required - Emergency

Authority Required - Electronic

Streamlined



Treatment criteria:


For prescribing by nurse practitioners as continuing therapy only, where the treatment of, and prescribing of medicine for, a patient has been initiated by a medical practitioner. Further information can be found in the Explanatory Notes for Nurse Practitioners.

Clinical criteria:


Patient must have previously been treated with PBS-subsidised perampanel.

issued with an authority prescription for this drug

Population criteria:

Patient must be aged 12 years or older.

Administrative Advice


No applications for increased to the maximum quantities will be authorised.

For prescribing by nurse practitioners as continuing therapy only, where the treatment of, and prescribing of medicine for, a patient has been initiated by a medical practitioner. Further information can be found in the Explanatory Notes for Nurse Practitioners.



    1. The re-submission was based on:

  • A cost-minimisation analysis of perampanel plus standard care compared with other anti-epileptic drugs (AEDs) (represented by lamotrigine or levetiracetam) plus standard care; and

  • A cost-utility analysis of perampanel plus standard care compared with placebo plus standard care. Standard care refers to AEDs that patients currently receive.

    1. The recommended dose regimen for perampanel for the treatment of PGTC seizures in patients ≥ 12 years old with IGE is an initial dose of 2mg/day, which may be increased based on clinical response and tolerability, by increments of 2mg/day, weekly or fortnightly, to a maintenance dose of up to 8mg/day. Depending upon clinical response and tolerability at a dose of 8mg/day, the dose may be increased up to a maximum of 12mg/day. Perampanel tablets are to be taken once daily before bedtime.

    2. The re-submission proposed a special pricing arrangement with a confidential price for perampanel for this indication. Based on the weighted pricing analysis across ‘substituted use’ and ‘last line use’ of perampanel, the Sponsor proposed a confidential dispensed price of $''''''''''''' for the 8mg, 10mg, and 12mg packs (i.e. flat pricing as per the current PBS listing). No special pricing arrangement was proposed for the 2mg, 4mg and 6mg packs, which are sub-therapeutic doses intended only for titration in the PGTC seizure indication.

    3. Compared to the original submission, the listing for the initial treatment phase proposed in the re-submission has been revised to reduce the number of AEDs that a patient is required to have failed before being eligible for perampanel from at least three to at least two, and reduce the minimum number of AEDs that perampanel must be used in combination with from two to one.

    4. The PSCR to the original submission proposed that patients must have failed to be controlled satisfactorily by all available and reimbursed AEDs unless those AEDs are contraindicated, could exacerbate other seizure types, or could worsen tolerability. The revised restriction allows perampanel to be used as an earlier line of treatment. The PBAC noted that this is consistent with its earlier consideration that “the most appropriate place in therapy for perampanel was for it to be an additional option to those currently available for the treatment of refractory patients” (Paragraph 4.4, Item 6.05, Perampanel PSD, July 2016).

    5. The ESC noted the requirement in the proposed restriction that the condition must have failed to be controlled satisfactorily by at least two AEDs was not well justified given 33.7% of Trial 332 participants were treated with only one AED at baseline.

    6. The pre-PBAC Response stated that trial 332 included a heavily pre-treated and refractory population, with 20% of patients taking three or more AEDs and 46% of patients taking two AEDs at study baseline. It argued that while the number of AEDs ever tried by patients was not collected, given the median length of time since diagnosis (14 years) and the inclusion criteria for the trial (a minimum of 3 seizures in the 8 week period prior), it was not unreasonable to infer that most, if not all, suitable treatments had previously been tried by patients.

For more detail on PBAC’s view, see section 7 “PBAC outcome.”


  1. Background




    1. TGA status: Perampanel received approval by the TGA in May 2014 for the indication of:

"adjunctive treatment of partial-onset seizures with or without secondary generalised seizures in patients with epilepsy aged 12 years and older".

    1. In May 2016, the TGA indication for perampanel was extended to include:

“PGTC seizures in adult and adolescent patients from 12 years of age with idiopathic generalised epilepsy.”

    1. This was the second submission of perampanel to the PBAC for the treatment of PGTC seizures in patients with IGE. Perampanel is listed on the PBS for the treatment of partial onset seizures.

    2. The major outstanding matters of concern from the previous submission are summarised in Table 2 below.

Table 2: Summary of outstanding matters of concern

Matters of concern

How the resubmission addressed it

The submission's analysis of perampanel as a last-line therapy (i.e. against placebo) was not an appropriate reflection of its likely place in therapy (as an additional option for refractory patients). The Committee considered that a comparison with other treatments currently available for treatment of refractory patients would be more appropriate. These treatments would include valproate, lamotrigine, levetiracetam, and topiramate (Paragraphs 7.1 and 7.3, Item 6.05, Perampanel PSD, July 2016).

The re-submission proposed two distinct clinical places of therapy

(1) Perampanel (plus standard care) as a last option add-on to the current regimen for patients who are refractory to or have exhausted all currently available treatments (e.g. last-line use – the same as the July 2016 submission). Supported by a cost-utility analysis, and

(2) Perampanel (plus standard care) as an additional option to those currently available for the treatment of refractory patients. This was supported by indirect comparisons of perampanel with lamotrigine or levetiracetam, and a cost-minimisation analysis of perampanel versus levetiracetam, lamotrigine, topiramate and valproate.

The results of these analyses were then used to calculate a weighted ex-manufacturer price of 8mg of perampanel. The proportion of expected use of perampanel as a substituted drug (perampanel vs. other AEDs), and as a last-line therapy (perampanel vs. placebo) were obtained from a survey of epileptologists conducted by the re-submission, and used to weight the proposed price of perampanel.



The PBAC reflected that the clinical trials provided in the major submission did not match the requested PBS population and that patients in these trials were unlikely to be ‘refractory’. (Paragraph 7.1 & 7.4, Item 6.05 perampanel PSD, July 2016 Meeting).

The listing for the initial treatment phase has been revised to:

  • Reduce the number of AEDs that a patient is required to have failed before being eligible for perampanel from at least three to at least two; and

  • Reduce the minimum number of AEDs that perampanel must be used in combination with from two to one.

However, the re-submission maintained its request for last line treatment of perampanel, using the same Trial 332 as the key clinical evidence in comparison with placebo, in addition to requesting perampanel as an earlier line of therapy, again using the same evidence of Trial 332 in the indirect comparison with other AEDs.

The PBAC considered, although the claim of superior comparative effectiveness was supported in the trial population in terms of number of seizures, it was not adequately supported in the requested PBS population and it was not supported in terms of improvement in quality of life. (Paragraph 7.5, Item 6.05, perampanel PSD, July 2016).

This issue remains for the comparison of perampanel with placebo.

Notwithstanding the issues with the appropriateness of the presentation of a cost-utility analysis against placebo, the PBAC noted a number of issues raised with the economic analysis presented. These included issues with:

  • The structure of the model

  • The treatment effect of perampanel applied in the model

  • The extrapolation of the treatment effect observed in the study

  • The mortality risk applied in the model

  • The validity of the health state utilities applied in the model

(Paragraph 7.8, Item 6.05 perampanel PSD, July 2016 Meeting).

Although the re-submission updated a few input variables and corrected the error identified with the previous submission, the key concerns relating to the economic model remain outstanding and have not been addressed in the re-submission.

AED = anti-epileptic drug; QoL = quality of life; PGTC = primary generalised tonic-clonic
For more detail on PBAC’s view, see section 7 “PBAC outcome.”



  1. Population and disease




    1. PGTC seizures are clinically characterised by a sudden onset with an initial tonic phase, in which patients experience generalised muscle contraction and body stiffening, followed by a clonic phase of rhythmic clonic jerking of the face and limbs.

    2. Treatment of PGTC seizures is primarily through therapy with AEDs. The management of epilepsy with multiple AEDs is a complex algorithm, with no clearly demarcated lines of therapy. Following stabilisation on new adjunctive therapy, gradual withdrawal of marginally ineffective drugs from multiple AED regimens may occur over time.


For more detail on PBAC’s view, see section 7 “PBAC outcome.”

  1. Comparator




    1. Although the re-submission revised its requested restriction to allow perampanel to be used as an early line of therapy, the re-submission proposed two distinct clinical places of therapy, and hence two different comparators, for perampanel:

  1. Perampanel (plus standard care, i.e. including background AEDs) as a last option add-on to the current regimen for patients who are refractory to or have exhausted all currently available treatments, where the nominated comparator is placebo (plus standard care), and

  2. Perampanel (plus standard care) as an additional option to those currently available for the treatment of refractory patients, where the nominated comparator is another adjunctive AED treatment, represented by either lamotrigine (plus standard care) or levetiracetam (plus standard care), that may be substituted by perampanel.

    1. The ESC noted that in its previous consideration of perampanel (July 2016) the PBAC stated that the submission’s nomination of placebo plus standard care as the comparator was not appropriate. At that time, the PBAC considered that the most appropriate place in clinical therapy for perampanel was as an additional therapeutic option in refractory patients, and that the appropriate comparison was therefore against other therapies currently available for treating this population, including valproate, lamotrigine, levetiracetam, and topiramate (paragraph 5.4, Item 6.05, perampanel PSD, July 2016).

    2. The ESC considered that the choice of comparators for the cost-minimisation analysis was not well justified; however, it noted the July 2016 PBAC advice that valproate, lamotrigine, levetiracetam and topiramate may be relevant comparators.

    3. The ESC recommended the PBAC should consider whether a cost-minimisation against a mixed basket of comparators with different PBS prices is a relevant approach.

    4. The Pre-Sub-Committee Response (PSCR) stated the sponsor is willing to work with the Department to reach an agreement on an appropriate split between the comparators of placebo and other PBS listed AEDs

    5. Overall, the PBAC maintained the view that a comparison wholly against placebo was not appropriate. However, on balance – noting the clinical need for another therapeutic option in refractory patients – it considered that the approach of a mixed comparison against placebo for patients who have failed to respond adequately to existing treatment options and against other currently available AEDs (valproate, lamotrigine, levetiracetam and topiramate) for patients in whom perampanel will substitute for another AED could be acceptable - subject to changes to the proportion of patients in each comparator group presented in the submission.

For more detail on PBAC’s view, see section 7 “PBAC outcome.”


  1. Consideration of the evidence


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