Abstract
A string of recent deals suggests gene therapy is finally becoming a hot prospect for big pharmas seeking to shore up their pipelines. Over the last few months, Bayer, Eli Lilly, Novartis, and UCB all made hefty deals for proprietary gene therapy technologies addressing a range of indications. In the biggest of these, in October Bayer acquired gene therapy firm Asklepios BioPharmaceutical, Inc (AskBio) for $2 billion upfront, with an additional potential $2 billion in milestone payments. Ask-Bio's pipeline includes pre-clinical and clinical-stage candidates for the treatment of neuromuscular, central nervous system, cardiovascular, and metabolic diseases.
The spate of deals cover a range of technologies and indications, demonstrating that the field has matured to a point where companies have multiple technologies to choose from to address genetic errors. And these therapies no longer just show potential, they are making their way into the clinic. This includes U.S. approval of the first in vivo gene therapies: Spark Therapeutics' Luxturna, a treatment for biallelic RPE65 mutation-associated retinal dystrophy approved in 2017; and Novartis' Zolgensma, approved in 2019 and which targets SMN1 gene function to treat children under two-years-old with spinal muscular atrophy.
Today the development pipeline is robust, including cell therapies in which cells are removed then genetically modified and returned to the patient. There are also gene editing technologies, such as CRISPR, that can revise, or “edit,” genes as well as remove or replace them. CRISPR engineering for gene therapies is progressing quickly. Recently CRISPR Therapeutics and Vertex Pharmaceuticals released data that showed a sustained response using the gene editing therapy CTX001 in patients with beta thalassemia and sickle cell disease—two common genetic disorders.
Sangamo's collaboration with Novartis could generate as much as $795 million for the company and shows the premium pharma is willing to pay for promising candidates in the cell and gene therapy area.
The Novartis/Sangamo collaboration announced in July was one of the first in the string of deals and has a maximum potential value to Sangamo of $795 million. It covers neurodevelopmental disorders, which many would consider a long shot because of the complexity of the underlying genetics. Sangamo's ZFP-TF genome regulation technology is not a gene therapy per se, but it is delivered by adeno-associated viruses (AAVs) to selectively repress or increase the expression of specific genes. After about 50 years of study, AAVs have emerged as the preferred method of delivery for transgenes for gene therapy, with more than 150 current clinical trials using AAVs.
ZFP-TFs are a class of transcription factors that recognize and bind to specific sequences of DNA. “We have a long history,” says Sangamo's chief medical officer Bettina Cock-roft, M.D. “We were pioneers and we can land in precisely the right spot and upregulate or suppress the gene in question.” Further, ZFP-TFs can be created to address genes of any size, a limitation with other technologies. Meanwhile, Novartis thinks it has a corner on some of the most desirable genes involved in neurodevelopmental disorders, which would give it an important edge.
Bettina Cockroft, M.D., Sangamo Thereapuetics
In addition, in 2018 Novartis merged with gene therapy pioneer AveXis, for about $8.7 billion in cash. AveXis, now called Novartis Gene Therapies, is a pioneer in AAV gene therapy, including its manufacturing and research and development. AAV9, AveXis' lead delivery vehicle has been well studied in diseases of the central nervous system (CNS).
Bayer AG also signaled its intention to be a player in the cell and gene therapy arena, launching a new Cell and Gene Therapy platform in December. “This is a defining moment for Bayer. Cell and gene therapies are leading innovation in healthcare, and it is our goal to be at the forefront of this revolution in science,” says Stefan Oelrich, member of the board of management, Bayer AG and president pharmaceuticals division, in a company statement. “This will complement our existing C> pipeline which already includes five advanced assets with at least three investigational new drugs annually for the next years.”
Bayer's pipeline was stocked in part with the acquisition of cell therapy company Blue-Rock Therapeutics in 2019 as well as the recent AskBio acquisition. Further, in December of 2020, AskBio announced a deal with Brain Neurotherapy Bio to expand AskBio's clinical pipeline for neurodegeneratives diseases, particularly neurotrophic factor gene therapy for Parkinson's, multiple system atrophy, and other conditions.
Lilly's December $880-million acquisition of Prevail Therapeutics came just three years after the company was founded by OrbiMed's co-head of private equity Jonathan Silverstein. The company specializes in AAV9-based gene therapies and aims to tackle Parkinson's disease (PD) caused by mutations in the glucocerebrosidase (GBA1) gene.
Prevail's lead therapies are PR001, which is in phase 1/2 testing for GBA1-positive PD as well as neuronopathic Gaucher disease, and PR006 for patients with frontotemporal dementia with GRN mutations (FTD-GRN). The startup's preclinical pipeline includes PR004 for patients with specific synucleinopathies, as well as potential gene therapies for Alzheimer's disease, PD, ALS, and other neurodegenerative disorders.
Lilly, meanwhile, in November announced it would pay $135 million upfront for an alliance with gene-editing specialist Precision Biosciences to develop in vivo therapies for three diseases, starting with Duchenne muscular dystrophy.
“Gene-edited therapies are emerging as a promising approach to help patients afflicted with genetic conditions,” says Ruth Gimeno, vice president of diabetes and metabolic research at Lilly. ARCUS nucleases, Precision says, can deliver safer, more specific genetic edits because of the properties of a naturally occurring gene editing enzyme—the homing endonuclease I-CreI.
With the recent buyout of Handl, Belgian pharma UCB gains an AAV technology platform with a neurodegenerative focus, and two research programs. Handl's gene therapy platform was built with technology licensed from four universities in Europe, the UK, and Chile. Its new collaboration with Lacerta, meanwhile, aims to support research, preclinical activities, and early manufacturing process development, while UCB will carry out studies to prepare for an Investigational New Drug application (IND). Currently, Lacerta is focused on gene therapy for Sanfilippo Syndrome Type B, Friedreich's ataxia, spinocerebellar ataxia, Pompe disease, and Alzheimer's.
Some challenges remain of course, especially since gene therapy is a relatively new clinical approach. Novartis, for example, wants to expand the market for Zolgensma to include a product that could be delivered by injection directly into the spine for children up to age 5, the drug is currently approved as an infusion only up to age 2. But the FDA put a partial clinical hold on the company's trial in October 2019, citing safety concerns related to a preclinical trial in which some animals developed dorsal root ganglia (DRG) mononuclear inflammation. Despite such setbacks, the industry is speaking with its wallet, which portends a promising future for cell and gene therapies.