August 2015 Australian Public Assessment Report for Insulin glargine

I. Introduction to product submission

Submission details

Type of submission:	Biosimilar (Insulin analogue)
Decision:	Approved
Date of decision:	10 November 2014
Active ingredient(s):		Insulin glargine
Product name(s):		Abasria, Abasria KwikPen^1
Sponsor’s name and address:		Eli Lilly Australia Pty Ltd 112 Wharf Road, West Ryde, NSW 2114
Dose form(s):		Solution for injection
Strength(s):		100 U/mL
Container(s):		Cartridge and prefilled pen
Pack size(s):		1, 2, 5 and 10
Approved therapeutic use:		Insulin glargine an insulin analogue indicated for once-daily subcutaneous administration in the treatment of Type 1 diabetes mellitus, in adults and children and Type 2 diabetes mellitus in adults who require insulin for the control of hyperglycaemia.
Route(s) of administration:		Subcutaneous (SC) injection
Dosage:		Adjusted to the individual patient.
ARTG number (s):		215551 and 215552

Product background

This AusPAR describes the application by the sponsor Eli Lilly Australia Pty Ltd to register Abasria, containing insulin glargine as the active ingredient, as a biosimilar. The proposed indications

Once-daily subcutaneous treatment of Type 1 diabetes in adults and children and Type 2 diabetes mellitus in adults who require insulin for the control of hyperglycaemia

match those of the reference product, Lantus^®. The strength of the active ingredient (100 IU/mL) is the same and the excipient profile is similar to that of Lantus^®, except that zinc oxide is used in this product instead of zinc chloride; the resultant concentration of zinc ion (Zn²⁺) is however identical.

Insulin glargine is an insulin analogue indicated for once daily subcutaneous administration in the treatment of Type 1 diabetes mellitus in adults and children and Type 2 diabetes mellitus in adults who require insulin for the control of hyperglycaemia.

The approval sought is for adults, adolescents, and children 2 years and above.

Abasria is proposed for marketing in 2 presentations:

a 3 mL cartridge, for delivery by a compatible CE-marked reusable pen injector, and

the same 3 mL cartridge sealed in a prefilled pen injector (KwikPen).

The pack sizes and pen injectors differ from those available to administer Lantus (Sanofi-Aventis) cartridges but are appropriate for use with Eli Lilly insulin cartridges.

Long-acting insulin analogues, such as insulin glargine, provide smooth, peakless basal insulin profiles. The putative benefits over agents such as neutral protamine Hagedorn (NPH) include reduced frequency of hypoglycaemia and better fasting blood glucose control.

Under the EU guidelines (see below), the primary role of Phase III clinical studies is to assess immunogenicity.

The Committee for Medicinal Products for Human Use (CHMP) of the EMA produced the first overarching biosimilar guideline, ‘Guideline on similar biological medicinal products. CHMP/437/04’, in 2005.

The Biosimilar Medicinal Products Working Group (BMWG) produced a concept paper for revision of the guideline in 2011; and a revised guideline was produced², with a deadline for comments set as 31 July 2014. The TGA evaluated biosimilarity using this adopted guideline which states ‘acceptance of claim of biosimilarity means the product can be marketed and prescribed by medical practitioners. ‘ Substitution by the pharmacist without consulting the treating medical practitioner is not addressed in the relevant adopted EMA Guidelines.

The TGA also followed the guideline ’Evaluation of biosimilars, Version 1.0, TGA July 2013’ when evaluating this submission. This guideline stated at the time of the evaluation that:

‘As biosimilars are not generic versions of their reference products, to inform the prescriber the text of the PI should include words to the effect of:

‘The comparability of [biosimilar product name] with [Reference product name (AustR nnnnnn)] has been demonstrated, with regard to particular physicochemical characteristics and efficacy and safety outcomes [see PHARMACOLOGY and CLINICAL TRIALS]. The level of comparability that has been shown supports the use of [biosimilar product name] for the listed indication[s]. The level of comparability that has been shown is not sufficient to designate this product as a generic version of [Reference product name]. Replacement of [Reference product name] with [biosimilar product name], or vice versa, should take place only under the supervision of the prescribing medical practitioner.’

as the first paragraph under Precautions’.

This TGA guideline is currently under review.

CHMP released an insulin-specific guideline in 2006.³ Two particular issues that the insulin guidelines⁴ seek to address are:

Hypoglycaemia (possibly caused by differences in activity of different brands). PK and PD (euglycaemic clamp) studies are required to show that the efficacy of the biosimilar insulin is predictable and consistent.

Immunogenicity. The draft guidance states that ‘the issue of immunogenicity can only be settled through clinical trials of sufficient duration, that is, at least 12 months using subcutaneous administration, with a 6-month comparative phase to be completed pre-approval while data at the end of 12 months could be presented as part of the post-marketing commitment.’ The sponsor should also design a pharmacovigilance program that will rapidly detect any clinically significant immunogenicity that may emerge over extended time periods.

The following three EU guidelines which have been adopted by the TGA are also relevant to this application:

Guideline On Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins As Active Substance: Non-Clinical And Clinical Issues (EMEA/CHMP/BMWP/42832/2005)

Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ 2010)

Guideline On Immunogenicity Assessment Of Biotechnology-Derived Therapeutic Proteins (EMEA/CHMP/BMWP/14327/2006).

Regulatory status

The product has not been registered in Australia.

Abasria is the first biosimilar version of the long-acting insulin analogue, insulin glargine (Lantus; Sanofi-Aventis), which was first registered in Australia in 2001.

Although insulin-specific guidelines have been in place in Europe since 2006, no biosimilar insulin has been registered in Europe or Australia. Three products were submitted (biosimilars of Humalog) to the European medicines Agency (EMA) in 2007 (from the MJ Group, Mumbai, India) but all were withdrawn in 2008 prior to opinion. Concerns included, inter alia, the lack of euglycaemic clamp studies, differential loss to follow-up in the Phase III study and inadequacies in the assessment of immunogenicity in the Phase III study.⁴

At the time the TGA considered this application (in 2014), a similar application had been approved in the European Union (EU) and was under consideration in the USA.

Table 1: International regulatory status (as at September 2014)

Country	Decision	Approved indication
USA	Under consideration.	Not applicable.
European Union (EU)	Approved 9 September 2014.	Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.

Product information

The approved Product Information (PI) current at the time this AusPAR was prepared can be found as Attachment 1. For the most recent Product Information please refer to the TGA website at .