August 2015 Australian Public Assessment Report for Insulin glargine

II. Quality findings

Drug substance (active ingredient)

Insulin glargine is a 2-chain peptide containing 53 amino acids. The A-chain is composed of 21 amino acids and the B-chain is composed of 32 amino acids. As in human insulin, insulin glargine contains 2 interchain disulfide bonds and one intrachain disulfide bond. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and 2 arginines are added to the C-terminus of the B-chain. The drug substance has the following structure:

Figure 1: Structure

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A1 GIVEQCCTSI CSLYQLENYC G A21

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B1 FVNQHLCGSH LVEALYLVCG ERGFFYTPKT RR B32
The amino acid sequence of this product is the same as that of Lantus.

Synthesis of the gene and vector, development and characterisation of the cell line were satisfactorily described and validated. Cell banking processes are satisfactory.

The fermentation processes are at large scale but are relatively simple. The monitoring and acceptance criteria satisfactorily control the quality and consistency of the harvest. Purification is relatively intensive and complex. The acceptance criteria for the various steps and the drug substance specifications adequately control the quality and consistency of the drug substance.

All characteristics of the product of the product were investigated with multiple orthogonal techniques. These confirmed the expected primary, secondary and tertiary structure. Bioactivity was demonstrated by multiple in vitro and in vivo methodologies. Impurities were low and adequately controlled.

Appropriate validation data have been submitted in support of the test procedures; that is, the proposed specifications, which control identity, content, potency, purity and other biological and physical properties of the drug substance relevant to the dose form and its intended clinical use.

Drug product

The drug product, Abasria 100 U/mL solution for injection is a clear and colourless solution supplied in a 3 mL glass cartridge with elastomeric disc seal and plunger for administration via subcutaneous injection. It is supplied as a cartridge or as a Kwikpen in packs of 1, 2, 5 or 10. The formulation includes glycerine, metacresol and zinc oxide.

The proposed specifications, which control identity, potency, purity, dose delivery and other physical, chemical and microbiological properties relevant to the clinical use of the product were submitted.

Stability data have been generated under stressed and real time conditions to characterise the stability profile of the product. Photostability data indicate the product is not photostable.

The proposed shelf life is 12 months when stored at 2 to 8C.

In-use stability data have also been submitted. The proposed shelf life and storage conditions after first use are 28 days when stored at less than 30C.

The stability data also allow excursions from storage conditions of up to 25°C for 21 days during shipping.

Biopharmaceutics

Pharmacokinetic data following a single subcutaneous injection have been submitted and all issues resolved.

Quality summary and conclusions

The administrative, product usage, chemical, pharmaceutical, microbiological data submitted in support of this application have been evaluated in accordance with the Australian legislation, pharmacopoeial standards and relevant technical guidelines adopted by the TGA.

The quality evaluator recommends that Abasria (insulin glargine (rbe)) solution for injection in cartridge and prefilled pen 100 U/mL should be approved with the following conditions of registration:

1. 
   Batch release testing by the TGA
   

It is a condition of registration that, as a minimum, the first five independent batches of Abasria (insulin glargine (rbe)) solution for injection in cartridge and prefilled pen 100U/mL) imported into Australia are not released for sale until samples and/or the manufacturer’s release data have been assessed and endorsed for release by the TGA. This batch release condition will be reviewed and may be modified on the basis of actual batch quality and consistency.

Certified Product Details

An electronic draft of the Certified Product Details (CPD), as described in Guidance 7: Certified Product Details of the Australian Regulatory Guidelines for Prescription Medicines (ARGPM), should be provided upon registration of these therapeutic goods. In addition, an updated CPD should be provided when changes to finished product specifications and test methods are approved in a Category 3 application or notified through a self-assessable change.

III. Nonclinical findings

Introduction

The nonclinical submission contained comparative studies on primary pharmacology and repeat-dose toxicity. The scope of the nonclinical program was in accordance with the relevant TGA adopted EU guideline.⁵

EU and USA sourced batches of Lantus^® were used as the comparator (reference) product in separate experiments/studies.

Pharmacology

No statistically significant differences were identified between the form of insulin glargine in Abasria (‘LY2963016’) and that in Lantus^® in in vitro assays examining:

binding affinity for recombinant human insulin receptors and the human IGF-1 receptor;

metabolic activity (assessed as stimulation of lipogenesis in mouse adipocytes); and

mitogenic potency (assessed in rat and human cell lines with varying relative IGF1 receptor : insulin receptor expression levels).

A statistically significant difference was observed between Abasria and Lantus^® forms of insulin glargine by pairwise analysis in assays examining stimulation of human insulin receptor auto-phosphorylation. The magnitude of the difference, with the Abasria form being approximately 22% more potent, is not so large as to indicate a difference that is likely to be biologically significant. Furthermore, the finding was not confirmed in a second similar study or evident in the other assays. The sponsor also raised the absence of statistical significance after allowing for multiple comparison adjustment, reflecting that native human insulin and another analogue (AspB10) were also employed in the assays. This is not a compelling argument given that these additional comparisons are not necessary to establish the comparability of the sponsor’s form of the drug and the reference product and they only act to diminish the sensitivity of the assays to reliably detect small differences in activity between the two. The studies are considered to have established pharmacological comparability.

No specialised in vivo pharmacology assay was conducted (consistent with the applicable guideline) but relevant information was obtained as part of the toxicity studies conducted in rats, with the Abasria and Lantus^® forms of insulin glargine shown to display comparable glucodynamic profiles following SC administration.

Pharmacokinetics

Toxicokinetic data in rats showed comparable systemic exposure following SC administration of the Abasria and Lantus^® forms of insulin glargine. Bioequivalence in humans was claimed.

Toxicology

Repeat-dose toxicity studies of 4 weeks duration were conducted in rats. These were performed according to Good Laboratory practice (GLP), involved once daily injection by the clinical (SC) route, and featured comprehensive histopathological examination. Group sizes were appropriate. Dose selection was generally appropriate; the high dose level selected in the first study (comparing Abasria to US-sourced Lantus^®; 3 mg/kg/day) required lowering during the course of the study (to 2 mg/kg/day) due to excessive mortality. Systemic exposure in groups of animals treated with the Abasria form of insulin glargine ranged from 44 to 404 times (in terms of serum peak concentration (C_max)) and 8 to 171 times (in terms of serum area under the serum concentration versus time curve (AUC_{0–24 h})) that obtained in humans following administration of a 0.6 IU/kg dose.

Notable findings in the studies comprised:

mortality, occurring secondary to hypoglycaemia;

increased body weight gain, which was accompanied by increased food consumption

(to compensate for reduced glucose levels); and

histopathological changes in the

sciatic nerve (axonal degeneration)

skin and SC injection sites (increased adipose tissue), and

pancreas (decreased cytoplasm/ vacuolation of islet cells, consistent with atrophy).

These findings are consistent with the pharmacological activity of insulin⁶ and were minimal or absent at the low-dose level (0.3 mg/kg/day), which yielded a high multiple of the clinical exposure.

The nature, incidence and severity of findings with Abasria^® were comparable to those observed with both EU and US sourced Lantus^®.

Pregnancy classification

The sponsor has proposed Pregnancy Category B3.⁷ This matches the existing category for Lantus^® and is considered appropriate.

Nonclinical summary and conclusions

The nonclinical dossier contained comparative studies on primary pharmacology and repeat-dose toxicity. The scope of the nonclinical program complies with the relevant EU guideline.

Comparability between the form of insulin glargine in Abasria^® and the form of the drug in EU and US sourced batches of Lantus^® was shown in terms of pharmacological activity (receptor binding affinity and functional activity in cell-based assays; glucodynamic profile in vivo in rats) and toxicity profile (assessed in 4 week, GLP-compliant studies in rats).

The ability of the nonclinical studies to support comparability to Australian Lantus^® depends on the conclusion of the quality evaluator regarding the identity of Lantus^® products across jurisdictions. Provided that EU and/or US sourced Lantus^® is considered to be identical or highly comparable to the Australian product, there are no nonclinical objections to the registration of Abasria for the proposed indications.

The nonclinical evaluator also recommended amendments to the draft PI document but the details of these are beyond the scope of this AusPAR.