Articles

Newsletter Summer 2018 - Lutz on Biosimilar Insulin - Current Status

Biosimilar Insulins – Current Status

Lutz Heinemann, PhD, Science Consulting in Diabetes GmbH, Neuss Germany

Introduction

In view of the high number of patients with diabetes who regularly need subcutaneous insulin injections, it is obvious that the market for the different insulin formulations is huge, well above $5 billion on a worldwide basis. Until recently, three pharmaceutical companies (Eli Lilly, Novo Nordisk, and Sanofi) dominated this market. Because patent protection for human insulin and some insulin analogs that have been developed by these companies in the past has expired, “copies” of such insulins can be brought to the market. As it is not possible to manufacture truly identical copies of complex proteins by biotechnological processes (“the process is the product”), a much more thorough evaluation of insulins manufactured by new companies has to be performed in comparison to generics (= small molecules manufactured by means of chemical synthesis). Therefore, the guidelines provided by regulatory agencies for market approval of such “biosimilar” products are quite detailed, with a strong focus on manufacturing details. From a clinical point of view, the main requirements are to demonstrate similarity of the pharmacodynamic and pharmacokinetic properties of the “biosimilar” insulin formulation in comparison to the originator insulin. This can be shown in well-performed euglycemic glucose clamp studies. Such studies must be performed in patients with diabetes. However, no large Phase II and Phase III clinical trials with large numbers of patients are needed. It also must be shown that these insulins do not induce formation of insulin antibodies above the level of the originator insulin.  Reasons for immunological concerns are impurities in the formulations and/or e.g. glycosylations of the insulins that are induced by the manufacturing process.

Once such insulins are approved as biosimilar insulins (also referred to as BioIns) and can be launched (see below), they enter a market with well-established players who are fighting for market share.  Gaining market share will be driven by factors such as cost advantages and political pressure. Currently >20 companies have biosimilar insulins in clinical development. It will remain to be seen how many will ultimately come to the market; however, most probably a plethora of e.g. insulin glargines might be on the market within some years, which could generate some confusion both among patients and among healthcare professionals.

Approved biosimilar insulins: Basaglar

The first approved biosimilar insulin – an insulin glargine developed by Eli Lilly and Boehringer Ingelheim (Abasaglar® in the EU and Basaglar in the US®) – has been on the market now for 1-2 years in the EU and the US.  However, there has not yet been a general landslide in favour of this more affordable insulin.  Nevertheless, it has gained significant market share in some countries in the EU. The decrease in prices observed varies among such countries, with a maximum price drop of up to 30%.

Approved biosimilar insulins: Admelog

More recently, the first biosimilar insulin (Admelog®) of a rapid-acting insulin analog (insulin lispro) - developed by Sanofi - was approved in the US and the EU. Studies with patients with type 1 or type 2 diabetes were published and it is on the market on both continents now  ADDIN EN.CITE  ADDIN EN.CITE.DATA 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. Also, data about the risk of developing insulin antibodies  ADDIN EN.CITE <EndNote><Cite><Author>Home</Author><Year>2018</Year><RecNum>10724</RecNum><DisplayText>[3]</DisplayText><record><rec-number>10724</rec-number><foreign-keys><key app="EN" db-id="0dfd0tf0jpt9adesadv5rpw1xexv0efpa20x" timestamp="1527980459">10724</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Home, P.</author><author>Derwahl, K. M.</author><author>Ziemen, M.</author><author>Wernicke-Panten, K.</author><author>Pierre, S.</author><author>Kirchhein, Y.</author><author>Garg, S. K.</author></authors></contributors><auth-address>1 Institute for Cellular Medicine, Newcastle University , Newcastle upon Tyne, United Kingdom .&#xD;2 Institut fur Klinische Forschung und Entwicklung (IKFE) , Berlin, Germany .&#xD;3 Sanofi-Aventis Deutschland, Frankfurt, Germany .&#xD;4 Sanofi, Paris, France .&#xD;5 Barbara Davis Center for Diabetes, University of Colorado Denver , Aurora, Colorado.</auth-address><titles><title>Anti-Insulin Antibodies and Adverse Events with Biosimilar Insulin Lispro Compared with Humalog Insulin Lispro in People with Diabetes</title><secondary-title>Diabetes Technol Ther</secondary-title></titles><periodical><full-title>Diabetes Technol Ther</full-title></periodical><pages>160-170</pages><volume>20</volume><number>2</number><keywords><keyword>Anti-insulin antibodies</keyword><keyword>Biosimilar</keyword><keyword>Immunogenicity</keyword><keyword>Insulin lispro</keyword><keyword>Sar342434</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1557-8593 (Electronic)&#xD;1520-9156 (Linking)</isbn><accession-num>29355435</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29355435</url></related-urls></urls><custom2>PMC5771536</custom2><electronic-resource-num>10.1089/dia.2017.0373</electronic-resource-num></record></Cite></EndNote>[3] and when this biosimilar insulin is used in insulin pumps  ADDIN EN.CITE <EndNote><Cite><Author>Thrasher</Author><Year>2018</Year><RecNum>10723</RecNum><DisplayText>[4]</DisplayText><record><rec-number>10723</rec-number><foreign-keys><key app="EN" db-id="0dfd0tf0jpt9adesadv5rpw1xexv0efpa20x" timestamp="1527980253">10723</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thrasher, J.</author><author>Surks, H.</author><author>Nowotny, I.</author><author>Pierre, S.</author><author>Rotthaeuser, B.</author><author>Wernicke-Panten, K.</author><author>Garg, S.</author></authors></contributors><auth-address>1 Medical Investigations, Inc, Little Rock, AR, USA.&#xD;2 Sanofi, Bridgewater, NJ, USA.&#xD;3 Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.&#xD;4 Sanofi, Paris, France.&#xD;5 Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO, USA.</auth-address><titles><title>Safety of Insulin Lispro and a Biosimilar Insulin Lispro When Administered Through an Insulin Pump</title><secondary-title>J Diabetes Sci Technol</secondary-title></titles><periodical><full-title>J Diabetes Sci Technol</full-title></periodical><pages>680-686</pages><volume>12</volume><number>3</number><keywords><keyword>*Sar342434</keyword><keyword>*biosimilar</keyword><keyword>*continuous subcutaneous insulin infusion</keyword><keyword>*infusion set occlusion</keyword><keyword>*insulin lispro</keyword><keyword>*type 1 diabetes mellitus</keyword></keywords><dates><year>2018</year><pub-dates><date>May</date></pub-dates></dates><isbn>1932-2968 (Electronic)&#xD;1932-2968 (Linking)</isbn><accession-num>29359575</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29359575</url></related-urls></urls><electronic-resource-num>10.1177/1932296817753644</electronic-resource-num></record></Cite></EndNote>[4] were published, showing no difference in the properties of this biosimilar insulin, compared to the originator insulin.

Approved biosimilar insulins: Lusduna

The next biosimilar insulin that most probably will come to the market in the EU and the US is another insulin glargine developed by Merck-US (Lusduna®). Merck has secured approval by the FDA for their version of insulin glargine; however, they refrained from launching it as they are blocked by a law suit against them by Sanofi. In the past, Eli Lilly was able to get a settlement deal with Sanofi for their biosimilar insulin Basaglar. However, Merck recently published the results of clinical trials in patients with type 1 diabetes or type 2 diabetes with their insulin glargine  ADDIN EN.CITE  ADDIN EN.CITE.DATA 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.

Non-approved biosimilar insulin by Mylan / Biocon

A biosimilar insulin that most probably will come to the market is the insulin glargine being developed by US-based generics giant Mylan in cooperation with the huge Indian pharmaceutical company, BioCon. However, both EU and FDA inspectors independently raised concerns about the production facility in India. Nevertheless, both companies are confident that they can solve the issues and that they are progressing according to their plans for the launch of this biosimilar insulin.  Mylan had filed an application to the FDA for their insulin glargine in pre-filled pen and vial forms under the 505(b)(2) regulatory pathway, which enables a faster than usual regulatory approval process, partly relying on the data already generated by a previous drug maker. This approval process was created by the Hatch-Waxman Amendments of 1984 as part of the Federal Food, Drugs and Cosmetics Act.  The aim was to allow entry of differentiated drugs that offer alternatives at an accelerated pace and avoid duplication of existing safety and efficacy data.  Again, Sanofi is not willing to give up rights on its originator insulin glargine, which is a billion dollar drug for them. Thus, Sanofi filed a lawsuit against Mylan in the US alleging infringement of its patents.

Prices

As stated, until now market introduction of biosimilar insulins has not resulted in drastic changes in the insulin market; however, as more biosimilar insulins enter the market, the increase in competition will most probably change this rapidly  ADDIN EN.CITE <EndNote><Cite><Author>Heinemann</Author><Year>2017</Year><RecNum>10738</RecNum><DisplayText>[7]</DisplayText><record><rec-number>10738</rec-number><foreign-keys><key app="EN" db-id="0dfd0tf0jpt9adesadv5rpw1xexv0efpa20x" timestamp="1528144826">10738</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heinemann, L.</author><author>Carter, A. W.</author></authors></contributors><auth-address>1 Science &amp; Co , Dusseldorf, Germany .&#xD;2 MRIGlobal , Kansas City, Missouri.&#xD;3 University of Missouri-Kansas City , Kansas City, Missouri.</auth-address><titles><title>Will Biosimilar Insulins Be Cheaper?</title><secondary-title>Diabetes Technol Ther</secondary-title></titles><periodical><full-title>Diabetes Technol Ther</full-title></periodical><pages>513-515</pages><volume>19</volume><number>9</number><dates><year>2017</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1557-8593 (Electronic)&#xD;1520-9156 (Linking)</isbn><accession-num>28885037</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/28885037</url></related-urls></urls><electronic-resource-num>10.1089/dia.2017.0294</electronic-resource-num></record></Cite></EndNote>[7]. We will have to see if the prices start a race to the bottom as in the case of test strips for blood glucose measurement systems, which took place in recent years. This will also depend on the pressure to lower insulin prices by insurance companies and/or government healthcare systems. It is of interest to note that prices for originator insulins – which have substantially gone up especially in the US in recent years – have not be solely driven up by the manufacturers, but also by pharmacy benefit managers  ADDIN EN.CITE  ADDIN EN.CITE.DATA 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[8, 9] 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.  Another question is whether one or more biosimilar insulins will get approval by the FDA for interchangeability, and qualify for automatic substitution at the pharmacy level of a lower priced biosimilar insulin with comparable properties (see below).

Immunological aspects

A matter of concern is the question if biosimilar insulins might differ in their immunogenic properties from the originator insulin. The approval requirement of a clinical study with a limited number of subjects (300) over a limited period of time (6/12 months) might not be able to clarify if such reactions do show up in certain patient groups over a prolonged period of usage. A major concern is that – at least in the case of some patients – formation of (neutralizing) insulin antibodies is stimulated. Differences in immunological responses might be induced by certain differences between the biosimilar insulins and the originator insulin  ADDIN EN.CITE  ADDIN EN.CITE.DATA 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[3, 10] 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.

Quality

Another important question is the quality of different batches of originator and biosimilar insulins over time.  Insulin is manufactured in batches, which could differ considerably from each other as a reflection of the complexity of the manufacturing process.  The amount of information that companies are reporting about this topic is quite limited  ADDIN EN.CITE  ADDIN EN.CITE.DATA 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.

Interchangeability

Switching from one insulin to another for a given patient is a decision made by the treating physician  ADDIN EN.CITE <EndNote><Cite><Author>Dowlat</Author><Year>2016</Year><RecNum>10244</RecNum><DisplayText>[13]</DisplayText><record><rec-number>10244</rec-number><foreign-keys><key app="EN" db-id="0dfd0tf0jpt9adesadv5rpw1xexv0efpa20x" timestamp="1524336804">10244</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dowlat, H.A.</author><author>Kuhlmann, M.K.</author><author>Khatami, H.</author><author>Ampudia-Blasco, F.J.</author></authors></contributors><auth-address>PharmaBio Consulting, Freiburg, Germany&#xD;Department of internal Medicine-Nephrology, Vivantes Klinikum im Friedrichshain, Berlin, Germany&#xD;Fortress Biotech, New York, NY, USA&#xD;Department of Endocrinology and Nutrition, Clinic University Hospital of Valencia, Valencia, Spain</auth-address><titles><title>Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications</title><secondary-title>Diabetes Obes. Metab</secondary-title></titles><periodical><full-title>Diabetes Obes. Metab</full-title></periodical><reprint-edition>Not in File</reprint-edition><keywords><keyword>a</keyword><keyword>Article</keyword><keyword>Berlin</keyword><keyword>Clinical</keyword><keyword>Clinical Practice</keyword><keyword>Efficacy</keyword><keyword>Endocrinology</keyword><keyword>Experience</keyword><keyword>Germany</keyword><keyword>Hospital</keyword><keyword>insulin</keyword><keyword>Medicine</keyword><keyword>Patient</keyword><keyword>Patients</keyword><keyword>Practice</keyword><keyword>review</keyword><keyword>Safety</keyword><keyword>Spain</keyword><keyword>Universities</keyword><keyword>University</keyword><keyword>University Hospital</keyword></keywords><dates><year>2016</year><pub-dates><date>4/21/2016</date></pub-dates></dates><label>10509</label><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/27097592</url></related-urls></urls><electronic-resource-num>10.1111/dom.12676 [doi]</electronic-resource-num></record></Cite></EndNote>[13].  Interchangeability means the practice of changing one insulin for another that is expected to achieve the same blood glucose lowering effect in any patient with diabetes on the initiative or with the agreement of the physician. This requires that the insulin can be regarded as interchangeable, i.e. as a property of a given insulin. The FDA has relatively lately characterized what their expectations are for such a label; however, until now no biosimilar insulin has received such a label. In contrast, substitution is a process at the pharmacy level without (!) consulting the prescribing physician whereby a biosimilar insulin is dispensed instead of the prescribed insulin.  Currently, there is no “substitutability determination” in the EU, i.e., there is no automatic substitution in practice in the EU whereby a pharmacist is obliged to dispense a biosimilar insulin instead of a prescribed insulin.  Interesting differences exist between states in the US when it comes to guidelines for market allowance of biosimilar insulins.

Devices

In daily practice for patients, diabetologists and nurses, the devices (most often insulin pens) used for application of insulin are of high relevance.  Each manufacturer of biosimliar insulins comes to the market with a combination of e.g. their insulin glargine with an insulin pen, which – as indicated – is associated with a certain risk of confusion.  The switch from the pen(s) of the originator insulin to another one is associated with an additional teaching and training burden for the diabetes team. Such aspects are of high relevance from a practical point of view.

Summary

These are early days for biosimilar insulins.  They will without doubt gain more attention and momentum in coming years, mainly driven by lower cost.  Lower insulin prices in turn mean more patients can afford and gain access to some form(s) of safe and effective insulin  ADDIN EN.CITE <EndNote><Cite><Author>Perrin</Author><Year>2017</Year><RecNum>10614</RecNum><DisplayText>[14]</DisplayText><record><rec-number>10614</rec-number><foreign-keys><key app="EN" db-id="0dfd0tf0jpt9adesadv5rpw1xexv0efpa20x" timestamp="1524336806">10614</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Perrin, C.</author><author>Ewen, M.</author><author>Beran, D.</author></authors></contributors><auth-address>Independent consultant, Paris, France&#xD;Health Action International, Amsterdam, Netherlands&#xD;University of Geneva and Geneva University Hospitals, 1211 Geneva, Switzerland. Electronic address: This email address is being protected from spambots. You need JavaScript enabled to view it. </auth-address><titles><title>The role of biosimilar manufacturers in improving access to insulin globally</title><secondary-title>Lancet Diabetes Endocrinol</secondary-title></titles><periodical><full-title>Lancet Diabetes Endocrinol</full-title></periodical><reprint-edition>Not in File</reprint-edition><keywords><keyword>France</keyword><keyword>Health</keyword><keyword>Hospital</keyword><keyword>Hospitals</keyword><keyword>insulin</keyword><keyword>Netherlands</keyword><keyword>Switzerland</keyword><keyword>Universities</keyword><keyword>University</keyword><keyword>University Hospital</keyword></keywords><dates><year>2017</year><pub-dates><date>6/16/2017</date></pub-dates></dates><label>10879</label><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/28629907</url></related-urls></urls><electronic-resource-num>S2213-8587(17)30218-8 [pii];10.1016/S2213-8587(17)30218-8 [doi]</electronic-resource-num></record></Cite></EndNote>[14].

 

References

 ADDIN EN.REFLIST 1.             Garg, S.K., et al., Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 1 Diabetes Also Using Insulin Glargine-SORELLA 1 Study. Diabetes Technol Ther, 2017. 19(9): p. 516-526.

2.             Derwahl, K.M., et al., Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also Using Insulin Glargine: SORELLA 2 Study. Diabetes Technol Ther, 2018. 20(1): p. 49-58.

3.             Home, P., et al., Anti-Insulin Antibodies and Adverse Events with Biosimilar Insulin Lispro Compared with Humalog Insulin Lispro in People with Diabetes. Diabetes Technol Ther, 2018. 20(2): p. 160-170.

4.             Thrasher, J., et al., Safety of Insulin Lispro and a Biosimilar Insulin Lispro When Administered Through an Insulin Pump. J Diabetes Sci Technol, 2018. 12(3): p. 680-686.

5.             Home, P.D., et al., Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: a randomized, open-label clinical trial. Diabetes Obes Metab, 2018.

6.             Hollander, P.A., et al., Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: a randomized, open-label clinical trial. Diabetes Obes Metab, 2018.

7.             Heinemann, L. and A.W. Carter, Will Biosimilar Insulins Be Cheaper? Diabetes Technol Ther, 2017. 19(9): p. 513-515.

8.             Carter, A.W. and L. Heinemann, If PBMs Guard Access to Drugs, Then Quis Custodiet Ipsos Custodies? (Who Will Guard the Guardians?). J Diabetes Sci Technol, 2016.

9.             Carter, A.W., In the Biosimilar Marketplace Will There Be 50 Ways to Leave Your Insulin? J Diabetes Sci Technol, 2016.

10.          Owens, D.R., et al., The emergence of biosimilar insulin preparations--a cause for concern? Diabetes Technol. Ther, 2012. 14(11): p. 989-996.

11.          Carter, A.W., L. Heinemann, and D.C. Klonoff, Quality Control of Insulins and Biosimilar Insulins: What Do We Know? J Diabetes Sci Technol, 2016. 10(4): p. 811-815.

12.          Carter, A.W. and L. Heinemann, Insulin Concentration in Vials Randomly Purchased in Pharmacies in the United States: Considerable Loss in the Cold Supply Chain. J Diabetes Sci Technol, 2017: p. 1932296817747292.

13.          Dowlat, H.A., et al., Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications. Diabetes Obes. Metab, 2016.

 

14.          Perrin, C., M. Ewen, and D. Beran, The role of biosimilar manufacturers in improving access to insulin globally. Lancet Diabetes Endocrinol, 2017.