bluebird tech to jump-start Novo in gene editing for hemophilia

A deal with bluebird bio is the latest move in Novo Nordisk’s push to remake its R&D, this time by partnering to develop a gene therapy for hemophilia A. The deal comes as sales for the company’s hemophilia franchise are slipping and a gene therapy from BioMarin is poised for registration.

Under the three-year deal, financial terms of which are undisclosed, the companies will use mRNA-based megaTAL gene editing technology from bluebird bio Inc. (NASDAQ:BLUE) to correct Factor VIII.

The deal follows a series of moves that Novo Nordisk A/S (CSE:NOVO B; NYSE:NVO) has made over the past few years to bolster its R&D. As it has faced growing downward pricing pressures on its diabetes franchise, the pharma has culled its pipeline of molecules that only provide an incremental benefit to focus on programs that substantially improve outcomes for patients and payers in a range of therapeutic areas beyond its historical remit of diabetes (see “Mountain Climbing”).

Marcus Schindler, Novo’s SVP and head of global drug discovery, told BioCentury in December that the upsurge in clinical gene therapies, including competitors on the horizon to Novo’s factor replacement therapies for hemophilia, made it clear the company “can no longer sit on the sidelines” of the technology. He had said the pharma will actively pursue the technology through its semi- translational research units (TRUs) and external collaborations (see “Novo Gets Serious about AI-Guided Drug Design”).

Novo has a TRU based in Denmark focused on gene therapy technologies and treatments for orphan diseases such as hemophilia. But Wednesday’s deal is its biggest step yet to catch up to companies with hemophilia gene therapies such as BioMarin Pharmaceutical Inc. (NASDAQ:BMRN), Sangamo Therapeutics Inc. (NASDAQ:SGMO), Pfizer Inc. (NYSE:PFE) and Spark Therapeutics Inc. (NASDAQ:ONCE).

BioMarin plans to seek approval this quarter of valoctocogene roxaparvovec in the U.S. and Europe to treat severe hemophilia A. SB-525 from Sangamo and Pfizer, and Spark’s SPK-8011 are in Phase I/II testing.

Novo Nordisk has at least three marketed factor replacement hemophilia A therapies, and has concizumab, a mAb against Tissue Factor Pathway Inhibitor (TFPI) in Phase II testing for hemophilia A and B. Overall hemophilia drug sales fell from DKK10.1 billion ($1.6 billion) in 2017 to DKK9.6 billion in 2018.

While Novo would not elaborate as to why it selected bluebird’s technology beyond saying megaTAL “holds key advantages over other gene therapy approaches,” bluebird CSO Philip Gregory said the tech is set apart by its higher binding specificity and simplicity.

A megaTAL is composed of two components: a TALE domain that binds DNA in the same fashion as transcription activator-like effector nucleases (TALENs), fused with a meganuclease, which makes site-specific DNA cuts. To make a cut, each half must recognize as a whole a sequence of about 36 adjacent base pairs, which is longer than the typical 20 base pairs for most zinc finger nucleases (ZFNs), TALENs and CRISPR proteins.

MegaTALs are also monomeric, whereas TALENs and ZFNs are dimers, making them smaller and easier to package within a vector. While CRISPR is monomeric, the system requires a guide RNA, which is a fairly large portion of the payload.

“We think that combination of the potential for very high specificity, but with the simplicity of delivery, and that any single protein that we make has the potential to do everything we need it to do, might get us to efficiencies that are very high,” Gregory told BioCentury. “That’s how we think we might be able to separate from other genome editing technologies.”

Gregory said the gene therapies in the clinic use adeno-associated viral (AAV) vectors to deliver the corrected Factor VIII gene, which do not integrate into the genome. “So, over time, the vector has the opportunity to be diluted out as cells grow and divide,” he said. bluebird’s tech would be directly inserted into the genome of liver cells, which would then divide as the patient grows, making it ideal for treating infants.

“I think the field is skeptical that non-integrating approaches such as AAV could treat patients at an early stage and support the degree of Factor VIII expression that would be necessary as an adult,” he said.

bluebird acquired the megaTAL technology through its 2014 takeout of Pregenen Inc., which was founded by researchers at the Seattle Children’s Research Institute, the Fred Hutchinson Cancer Research Center and the University of Washington. The company has applied the tech for ex vivo editing of preclinical therapies.

bluebird gained $1.42 to $90.13 on Wednesday.

User Sign In

Article Purchase

This article may not be distributed to non-subscribers

PURCHASE THIS ARTICLE FOR LIMITED ONE-TIME DISTRIBUTION AND WEBSITE POSTING $995.00 USD

PURCHASE