US Biosimilars Pathway – A Step Closer to Reality

Today Sandoz announced that their Biologics License Application for filgrastim was accepted by the FDA. This news is significant in part because Zarzio (the brand name for this new product) is the first product to use the 351(k) pathway for biosimilars in the US (rather than the traditional 351(a) BLA). In contrast, there are a variety of biosimilars approved in Europe (including Zarzio). One of the key questions becomes: how similar does a biosimilars have to be?

As part of the Affordable Care Act, the FDA has been developing this biosimilars pathway and providing guidance documents. Alex Gaffney at Regulatory Affairs Professionals Society (RAPS) has a helpful write up of the FDA’s May 2014 guidance Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. In this particular guidance, FDA includes a four categories of “similarity”: not similar, similar, highly similar and highly similar with a fingerprint-like similarity.

At Quintessence, we are developing a protein as a cancer therapeutic, so at times I find myself talking to non-scientists about the challenges of consistency and characterization in manufacturing protein drugs. For example, therapeutic proteins are made in cells that we convince to act as factories, churning out the desired protein in larger quantities than any other proteins. In order to keep production going, the cells have to be kept happy, providing enough food, oxygen and other nutrients. Even with the same recipe and ingredients, growing the cells is not the same every time and companies have to do many tests on the products of different batches to see how similar they are. Once you collect historical information on the differences and how the protein acts in biological systems, you can start to discern which differences are most critical in answering the question: how similar are two proteins?

A real world examples of the complexity involves Genzyme’s Myozyme (an enzyme called aglucosidase alfa), which was first approved by FDA for Pompe disease in 2006. I think this example is important because there is a relatively large amount of public data on how manufacturing with the same recipe and ingredients can lead to products with different physical and biological/clinical properties.

Genzyme had more demand for Myozyme than they could meet growing their cells in a 160 liter tanks so the company embarked on scale up to 2000 and 4000 liter tanks. The same protein (aglucosidase alfa) produced by the same company that presumably had access to the recipe and ingredients ended up requiring a separate Biologics License Application in the US (of the 351(a) variety – there was no biosimilars pathway then). Importantly, the FDA also changes were enough to have two different names for the product: Myozyme when produced at small scale and Lumizyme from large scale batches.  If you are interested in more details of the Myozyme/Lumizyme story, you can read trough the briefing documents for an FDA Advisory Committee Meeting in 2008 (Open Session, Clinical Background, Questions, Statistical).

 

PS Another wrinkle in the story comes if you read the prescribing information for Myozyme and Lumizyme. Although both are approved for patients with Pompe diseae but Myozyme is for infantile onset (young children) while Lumizyme is for children 8 and older. Here is an excerpt from the FDA’s approval announcement for Lumizyme:

Lumizyme is being approved with a risk evaluation and mitigation strategy (REMS). It will only be available through a restricted distribution system called the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program to ensure that it is used by the correct patient group.

Currently, the only other treatment for Pompe disease available in the United States is Myozyme, which is also manufactured by Genzyme at its manufacturing facilities in Framingham and Allston Landing, Mass. Myozyme has been in short supply due to limited manufacturing capacity. The manufacturer reserved Myozyme to treat infants and children with Pompe disease because younger patients generally have a much more aggressive form of the disease.

Some adult patients in the U.S. received Lumizyme under a temporary access program. The approval of Lumizyme will ensure that treatment is available for all U.S. adult Pompe patients in need of treatment. Lumizyme is manufactured at Genzyme facilities in Ireland and Belgium.

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