Biogen is making a big bet on gene therapies for neurodegenerative diseases. The firm will pay Sangamo Therapeutics $350 million upfront to develop zinc finger gene therapies for Alzheimer’s disease, Parkinson’s disease, and an undisclosed neuromuscular disease. Unlike most gene therapies, which upload new genes into cells, Sangamo’s tool tunes the expression of existing genes that are linked to disease.
Sangamo is best known for pioneering the development of zinc finger nucleases, proteins that its scientists have engineered to cut precise sequences of DNA for gene editing. The company was founded in 1995, more than 15 years before CRISPR gene editing was invented. In 2018, Sangamo became the first group to attempt gene editing directly in a human body.
Sangamo’s deal with Biogen highlights a different use of zinc fingers. The company starts with zinc finger proteins designed to target and bind a specific DNA sequence without cutting it. Next, it attaches another protein called a transcription factor, which turns a gene on or off. The result, dubbed a zinc finger protein transcription factor (ZFP-TF), is what Biogen hopes will shut down the production of proteins implicated in neurological diseases.
Sangamo also has partnerships with Gilead Sciences, Pfizer, Sanofi, and Takeda Pharmaceutical. The deal with Biogen is yet another validation that zinc fingers, though older, are competition for CRISPR.
The lead program in the Biogen collaboration is a ZFP-TF designed to reduce levels of tau, a protein that is known to accumulate in the brains of people with Alzheimer’s disease. At scientific conferences and investor meetings, Sangamo has showed that its experimental therapy reduces levels of tau in rodent and monkey brains. While many companies, including Biogen, are developing small molecules and antibodies to reduce tau, those therapies typically target only a particular variant of tau. In theory, Sangamo’s approach should reduce all kinds of tau.
Another program in the collaboration is a ZFP-TF that reduces levels of α-synuclein, a protein that accumulates in the brains of people with Parkinson’s disease.
The deal gives Biogen the exclusive rights to 9 additional targets. If Biogen follows through on those programs, Sangamo could earn up to $2.37 billion in milestone payments, including up to $925 million for preclinical work.
For Biogen, the deal fits squarely with its neuroscience focus and expands upon its existing gene therapy investments. Last year, it acquired the gene therapy firm Nightstar Therapeutics for $800 million. Nightstar uses adeno-associated viruses (AAVs) to deliver whole genes into the eye to treat inherited visual diseases.
Sangamo also uses AAVs to deliver genes encoding its ZFP-TFs into neurons of the brain or spinal cord, where the ZFP-TFs are expected to be expressed permanently. The two approved gene therapies in the US use AAVs as well, and demand is growing for new AAV variants that are better at delivering their cargo to specific cell types. Sangamo is using directed evolution to develop such AAVs, including ones that are good at reaching parts of the brain most affected by Alzheimer’s disease.
Biogen will have nonexclusive access to new AAV variants owned by Sangamo. In a call with investors, Sangamo CEO Sandy Macrae said this was an important part of Biogen’s interest in working with Sangamo.
Clinical trials for the ZFP-TFs are at least a year away. The companies plan to ask the US Food and Drug Administration for permission to start the Alzheimer’s trial in 2021 and the Parkinson’s trial in 2022. Biogen will pay Sangamo to manufacture the experimental therapies for the first three clinical trials. After that, Biogen will manufacture the therapies itself.
In the investor call, Macrae emphasized that pharma partnerships are an important part of Sangamo’s growth. He said the firm has raised almost $700 million from licensing fees, milestones, and equity investments from pharma partnerships. It could earn more than $6.3 billion through milestone payments from Biogen, Gilead, Pfizer, and Sanofi.
Despite those high-profile partners, Sangamo’s market capitalization of around $1 billion is below that of several smaller CRISPR gene-editing companies—including CRISPR Therapeutics, Editas Medicine, and even the recently public Beam Therapeutics.
Macrae said 2020 marks a new phase for Sangamo as its first Phase III clinical study—a gene therapy for hemophilia partnered with Pfizer—begins. Macrae also emphasized that Sangamo will continue to apply its zinc fingers and AAV expertise to more common diseases. For instance, the company has begun work on gene-edited cell therapies for irritable bowel disease and multiple sclerosis.