Lanreotide Acetate, pre-filled syringe, 60 mg in 0.3mL (base), 90 mg in 0.3 mL (base) and 120 mg in 0.5 mL (base), Somatuline Autogel®, July 2005

Public Summary Document for Lanreotide Acetate, pre-filled syringe, 60 mg in 0.3mL (base), 90 mg in 0.3 mL (base) and 120 mg in 0.5 mL (base), Somatuline Autogel®, July 2005.

Page last updated: 24 October 2005

Public Summary Document
Product: Lanreotide Acetate, pre-filled syringe, 60 mg in 0.3mL (base), 90 mg in 0.3 mL (base) and 120 mg in 0.5 mL (base), Somatuline Autogel®
Sponsor: Ipsen Pty Ltd
Date of PBAC Consideration: July 2005

1. Purpose of Application

This application sought an extension to the current Section 100 listing of Lanreotide Acetate to include the treatment of carcinoid syndrome. (Highly Specialised Drugs (HSDs) are medicines for the treatment of chronic conditions, which, because of their clinical use or other special features, are restricted to prescribing through public and private hospitals which have appropriate specialist facilities.)

2. Background

Lanreotide Acetate prolonged release depot suspension (Somatuline LA® 30 mg) was recommended for Section 100 listing for the treatment of active acromegaly at the
September 2001 PBAC meeting on a cost-minimisation basis compared with octreotide acetate (modified release) injection.

At the September 2003 meeting, the PBAC recommended Section 100 listing of Lanreotide Acetate (Somatuline Autogel) ready to inject pre-filled syringe, 60 mg, 90 mg and 120 mg, for the treatment of acromegaly on a cost-minimisation basis against octreotide long acting formulation and Lanreotide Acetate prolonged release suspension (Somatuline LA).

3. Registration Status

Lanreotide Acetate is registered by the Therapeutic Goods Administration (TGA) for the treatment of acromegaly when the circulating levels of growth hormone and IGF-1 remain abnormal after surgery and/or radiotherapy and in patients who are dopamine agonist treatment refractory.

TGA registration was extended on 17 December 2004 to include the treatment of symptoms of carcinoid syndrome associated with carcinoid tumours.

4. Listing Requested and PBAC’s View

The sponsor requested the following listing:

Section 100 (Highly Specialised Drug) Private hospital authority required
For the treatment of the clinical symptoms of carcinoid syndrome associated with carcinoid tumours.
Following advice from the PBAC’s Restrictions Working Group and response by the sponsor, the listing requested was amended to read:

Section 100 (Highly Specialised Drug) Private hospital authority required
Patients with a histologically-confirmed diagnosis of a functional carcinoid tumour, experiencing on average over 1 week, 3 or more episodes per day of diarrhoea and/or flushing, which persists despite the use of anti-histamines, anti-serotonin agents and anti-diarrhoea agents, and for whom surgery or antineoplastic therapy has failed or is inappropriate.
Treatment must cease if there is failure to produce a clinically significant reduction in the frequency and severity of symptoms after 3 months’ therapy at a dose of 120 mg every 28 days. Dosage and tolerance to the drug should be assessed regularly and the dosage should be titrated slowly downwards to determine the minimum effective dose.

5. Clinical Place for the Proposed Therapy

Somatuline Autogel is to be used for the treatment of symptoms of carcinoid syndrome, which include episodic cutaneous flushing, cyanosis, abdominal cramps and diarrhoea. The Autogel formulation is claimed to have advantages over the standard injectable formulation in terms of ease of preparation and administration.

6. Comparator

The submission nominated octreotide acetate (Sandostatin LAR) as the comparator.

This was accepted by the PBAC.

7. Clinical Trials

The submission presented the results of one non-randomised single-arm study to confirm activity of lanreotide Autogel treatment in patients with carcinoid syndrome (Ipsen Study 718, Ruszniewski et al, 2004).

To demonstrate clinical equivalence between lanreotide Autogel and octreotide LAR, indirect comparisons were made via lanreotide LA and octreotide SC as follows.
(1) To show lanreotide Autogel was equivalent to lanreotide LA, a pharmacokinetic study in acromegalic patients was used (Ipsen Study 051).
(2) To show equivalence in carcinoid syndrome between lanreotide LA versus octreotide SC, a randomised, cross-over trial was used (O’Toole et al 2000).
(3) To show equivalence in carcinoid syndrome between octreotide SC versus octreotide LAR, a randomised, unblinded, parallel-group trial was included (Rubin et al 1999).

Three studies of the four studies had been published at the time of submission, as follows:

Trial/first author	Protocol title	Publication citation
718/ Ruszniewski P	Rapid and sustained relief from the symptoms of carcinoid syndrome: results from an open 6-month study of the 28 day prolonged release formulation of lanreotide.	Neuroendocrinology 2004 80: 244-251
O’Toole D	Treatment of carcinoid syndrome. A prospective crossover evaluation of lanreotide versus octreotide in terms of efficacy, patient acceptability and tolerance.	Cancer 2000 88:770-776
Rubin J,	Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome.	J Clin Oncol 1999 17(2) 600-606

8. Results of Trials

In the key lanreotide LA study (Ipsen 718) in carcinoid syndrome 18% of patients responded when diarrhoea was the target syndrome, and 65% when flushing was the target symptom. Response was pre-defined as improvements of 50% or more in the target symptom.

The pharmacokinetic study (Ipsen Study 051) indicated that in acromegaly, similar trough plasma levels of lanreotide are achieved following the administration of lanreotide Autogel and lanreotide LA.

In the randomised trials in carcinoid syndrome (O’Toole et al 2000 and Rubin et al 1999), lanreotide LA had similar efficacy to octreotide SC and octreotide SC had similar efficacy to octreotide LAR.

Given the nature of the evidence spanning this series of indirect comparisons, the differences between the included trials, and the possibility of bias, the PBAC considered that the evidence to support the claim that lanreotide Autogel is no worse than octreotide LAR in terms of effectiveness was weak.

The data on comparative toxicity are sparse and arose from indirect comparisons, based on the same trials. The PBAC considered that the submission’s claim that the overall safety profile of lanreotide Autogel was no worse than octreotide LAR was probably defensible, but the evidence was weak.

9. Clinical Claim

The submission claimed that Lanreotide Acetate (Somatuline Autogel) is no worse than octreotide acetate (Sandostatin LAR) in terms of effectiveness and toxicity.

The PBAC accepted that, in view of the orphan status of the requested listing, the evidence presented across a series of indirect comparisons was sufficient to accept listing on a cost-minimisation basis.

10. Economic Analysis

The submission presented a preliminary economic evaluation. The resources included were drug costs.

11. Estimated PBS Usage and Financial Implications

The submission estimated the likely number of patients to be up to <10,000 in Year 3.

The PBAC considered this to be a reasonable estimate.

12. Recommendation and Reasons

The PBAC recommended listing for the treatment of carcinoid tumour on a cost-minimisation basis compared with octreotide acetate modified release injection (Sandostatin LAR®). A dose relativity of 4.67:1 for lanreotide Autogel versus octreotide LAR was considered appropriate and is consistent with the ratio between these products established for the acromegaly PBS listing.

Recommendation:
Extend the section 100 (Highly Specialised Drug) Program listing to include:

Restriction:

Private hospital authority required Patients with a histologically-confirmed diagnosis of a functional carcinoid tumour, experiencing on average over 1 week, 3 or more episodes per day of diarrhoea and/or flushing, which persists despite the use of anti-histamines, anti-serotonin agents and anti-diarrhoea agents, and for whom surgery or antineoplastic therapy has failed or is inappropriate. Treatment must cease if there is failure to produce a clinically significant reduction in the frequency and severity of symptoms after 3 months’ therapy at a dose of 120 mg every 28 days. Dosage and tolerance to the drug should be assessed regularly and the dosage should be titrated slowly downwards to determine the minimum effective dose.

Pack Size

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13. Context for Decision

The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.

14. Sponsor’s comment

The PBAC suggestion that the clinical evidence in the orphan indication of carcinoid syndrome was weak was addressed in the sponsor’s pre-PBAC response. The sponsor agreed that the dose-relativity ratio established using the more robust clinical data in the non-orphan indication of acromegaly, should also be applied to the carcinoid syndrome. The PBAC subsequently recommended listing, agreeing that the evidence was sufficient to accept listing on a cost-minimisation basis in view of the orphan status of the requested listing.