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The biosimilars are coming

Lilly on navigating the regulatory pathway for its insulin glargine
FDA headquarters

There has been a huge amount of interest across the industry about biosimilars - and, with biologic products like insulin among pharma's biggest-sellers, it's no surprise that diabetes is one of the key therapy areas being targeted.

At those companies not pursing developing biosimilar versions of diabetes treatments there is fear that biologics' traditional bulwark against competition, the inherent difficulty of manufacturing versions of a biologic that work in a similar enough way, is crumbling.

As one senior industry executive recently put it: “God help us if anybody actually goes out and makes the studies to make sure that they are actually as safe and effective as the mother compound.”

In diabetes that is already happening, with biosimilar versions of Sanofi's blockbuster Lantus (insulin glargine) being developed. Leading the charge are Lilly and Boehringer Ingelheim, whose insulin glargine won European approval in September - one month after gaining 'tentative approval' from US regulator the FDA.

For the partners to get their product to this stage, though it could still be many months away from launching it, has been quite a maze. 

Biosimilar barriers

In terms of the clinical programme that regulators would require, the companies found there was no guidance for what this should look like in the US, while in Europe there was at least some direction.

Gwen Krivi, VP, Lilly diabetes development, told PME: “From a regulatory perspective, no-one had ever done this before, so we were not clear, when we made the submissions, exactly what was going to happen along this process in terms of the kinds of questions we were going to get or how the regulators were going to react and look at this. So there was a lot of uncertainty in the regulatory path.“

So the company and its partner negotiated with European and US regulators about what that clinical submission package would need to look like, and how it would includes pharmacokinetic (PK) and pharmacodynamic (PD) studies.

“We had to demonstrate PK and PD similarity in five studies. It was a much bigger package of studies than you would traditionally do with a small molecule generic,” says Krivi.

“One of the biggest barriers [for a biosimilar] is being able to make it and analyse it and do it reliably and at very high quality, that's one of the biggest barriers certainly in the insulin space,” said Krivi. “Insulin is not the easiest drug to use or study. It has a relatively narrow margin of safety - because if you have too much you can become hypoglycaemic and have problems and if you have too little nothing happens.”

Speaking to Krivi it's clearly important for the company to be able to ground its forthcoming biosimilar insulin glargine in terms of its historical activity in the insulin market.

“Lilly was the first to product a viable pharmaceutical insulin back in the 1920s, the first to introduce a biotechnology-based human insulin - that was in partnership with Genentech - and then the first technology-based analogue insulin, the lispro molecule [marketed as Humalog],” she said. “So Lilly has been in this field almost 100 years, in the manufacture of commercial insulin.”

The reason of stating this - beyond, of course, the brand story - is that for any biosimilar, or innovative biologic, one of the first things that manufacturers are required to do is to be prove their manufacturing capabilities are up to the task. So it's on the back of its previous work developing insulin that Lilly and Boehringer will now want to stand.

“One of the biggest sections of the submissions for Boehringer-Lilly insulin glargine is not the clinical section, it's the section around what we call chemistry, manufacturing and control, so it's the basics of how you make it, purify it, formulate it, deliver it and then all of the analytical technology that goes around that,” says Krivi.

Questions on the company's approach to quality and manufacturing were one of the biggest topics of interest from regulatory authorities across the globe – and they wanted answers “in excruciating detail”, Krivi adds.

Biosimilar branding

How to brand the biosimilar is a question that Lilly and Boehringer have yet to fully answer. It was called Basaglar on receiving tentative FDA approval in August - when the US regulator was satisfied that the insulin is suitable for use in the treatment of people with diabetes. Final approval could not be granted because Sanofi filed a lawsuit against Boehringer and Lilly claiming patent infringement, hence the potential delay until mid-way through 2016.

“Lilly clearly will not infringe on valid patents and Sanofi has composition of matter patents and some other things - so at this point in time we're pretty much waiting for the valid patent claims to expire.”

Meanwhile, in Europe the biosimilar is approved and currently branded as Abasria, though the company wants to have a global brand name for the product.

The company currently hopes it will be able to launch its insulin glargine biosimliar in Europe next year, though having gone the distance with the regulators to get the product approved, it's clear there are still some miles left to run.

Article by
Dominic Tyer

is editorial director at PMGroup

28th November 2014

From: Sales, Marketing, Regulatory



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