Roche’s Gazyva (obinutuzumab) was approved for the treatment of chronic lymphocytic leukemia (CLL) in 2013, and according to Saurabh Aggarwal, founder of pharmaceutical consultancy Novel Health Strategies it is being touted as the “son of Rituxan,” a reference to Biogen Idec’s original monoclonal antibody for the treatment of several diseases.
“Gazyva is an anti-CD20 – CD20 is the antigen that Rituxan targets,” he told BioPharma-Reporter.com. “The way this product was designed, it was basically engineered with some slight modifications.
“The manufacturer was able to come up with a product that has potentially better efficacy than Rituxan, one of the biggest products on the market.” The biobetter will make “a very interesting case study for the industry” as it looks set to replace Rituxan for some indications, he said.
'Biosimilar manufacturers need to understand challenges
At the moment, Gazyva has been approved for only one of Rituxan’s indications: CLL. Gazyva has a glyco-engineered Fc (fragment crystallisable) region, allowing greater antibody-dependent cell-mediated cytotoxicity (ADCC) than Rituxan. Because of its greater efficacy in this area, Gazyva is considered a “biobetter”.
Biobetters vs Biosimilars
Biobetters are drugs in the same class as existing, approved biologics (they have the same epitope), but are not identical to the original – they are engineered with improvements. Often they will have the same therapeutic target as the first biologic, but their effect will last longer.
Unlike biosimilars, whose approval pathway has not been finalised in the US, biobetters are considered completely new drugs, and so they benefit from a patent and market protection (12 years in the US).
Example:
First-generation mAb: Rituxan (rituximab), developed by Biogen Idec, is a monoclonal antibody developed against the protein CD20 to treat lymphomas, leukaemia, and autoimmune diseases. Its US patent is due to expire next year.
Biosimilar: Reditux is a biosimilar of rituximab, launched in India in 2007 by Dr Reddy.
Biobetter: “Rituximab” biobetters have mutated amino acids in the Fc (fragment crystallisable) region, extending the drug’s pharmacokinetics. Amgen, Biogen Idec, Eli Lilly, GSK, Novo Nordisk, Merck & Co, Roche and Sanofi are among the companies said to be developing biobetters.
Second and third generations: Obinutuzumab (Roche’s Gazyva) has a different epitope from the original Rituximab, so although some people call it a biobetter, others define it as a third generation mAb.
For now, Gazyva is set to replace Rituxan for CLL treatment, but Rituxan has bigger, more lucrative markets, such as for non-hodgkin’s lymphoma. Gazyva is being trialled in seventeen other studies, and it remains to be seen whether it will be deemed a “biobetter” for other indications.
Because of Rituxan’s giant success ($7.9bn in sales in 2013), several small companies are developing biosimilars, said Aggarwal – a plan which could be fruitless if Gazyva replaces Rituxan.
“My view is they [biosimilar makers] need to better understand how this could replace Rituxan because that could pose challenges for biosimilar manufacturers if this drug is significantly better than Rituxan in some of the big indications.”
To biosimilar or not to biosimilar
“So that poses the question,” said Aggarwal, “is the good strategy to go forward with a biobetter or should you develop biosimilars?”
The example of Gazyva suggests it could be easier to develop biobetters, he continued, “because then you can come on to the market with an improved product which can get branded product pricing and it can potentially replace the previous product and get a large market share.”
However judging whether a new biologic is in fact better can be a “subjective” task, he added, depending on whether the medical profession and payers view sometimes slight increases in efficacy as worth a higher price. “That’s something we’ll have to watch.”
A bio-better financial model?
A plus to the biobetter strategy would be avoiding the red tape involved with biosimilars, Aggarwal told us, especially in the US where complicated state rules are delaying their route to market.
However developing a biobetter requires much larger trials than for a biosimilar. “So a company like Roche-Genentech can fund those trials but smaller companies which make off-patent products, for them to fund these multi-center global trials is a challenge which can cost easily a few billion dollars.”
It is possible therefore, but too early to tell, that the future could see large biopharmaceutical companies pushing smaller ones out of the biosimilar market.
Gazyva “could be potentially a game-changer,” Aggawarl told us, but the industry will have to wait a little longer to tell. If Gazyva is approved for broader indications, “how it’s received and how it replaces Rituxan will provide important lessons as to whether a biobetter strategy is a more profitable way to get drugs into this market,” he concluded.