April 15, 2024

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The fast-growing gene therapy has come to the crossroads after a series of setbacks

The fast-growing gene therapy has come to the crossroads after a series of setbacks


The fast-growing gene therapy has come to the crossroads after a series of setbacks

In September 1990, William French Anderson led the first successful clinical trial of gene therapy approved for use in humans. This is an exciting time for the scientific community, patients and pharmaceutical companies, marking the transition from concept to reality for gene therapy .


But since then, gene therapy, like Anderson himself, has gone through a series of ups and downs.


In 2017, the US FDA approved the first gene therapy to treat amaurosis congenita via adeno-associated virus (AAV) , and since then, the pace of gene therapy approvals has accelerated rapidly. Today, more than 10 gene therapies have been launched around the world for the treatment of cancer, viral infections, hereditary diseases, etc.

After decades of tortuous development, gene therapy has grown into a large scale of nearly 10 billion US dollars per year. market, becoming one of the most concerned pharmaceutical fields.


Recently, however, the field of gene therapy has suffered a series of failures and setbacks.


Next month, the FDA will hold an advisory panel meeting to review two of Bluebird Bio ‘s lentiviral gene therapies: Zynteglo (betibeglogene autotemcel , which treats transfusion-dependent beta-thalassemia) and Lenti-D (elivaldogene autotemcel , which treats transfusion-dependent beta-thalassemia). cerebral adrenoleukodystrophy) .


As a flagship company in the field of gene therapy, Bluebird Bio used to be very popular, with a market value of more than 16 billion US dollars at one time, but today, its market value is less than 300 million US dollars. If these two gene therapies fail again, then Bluebird Bio is likely to fall with it.


The fast-growing gene therapy has come to the crossroads after a series of setbacks



After decades of research and thousands of human trials, the field of gene therapy has finally gained commercial recognition and success, and has also sparked a wave of acquisitions by major pharma companies: Bamboo Therapeutics, AveXis, Spark Therapeutics, Nightstar Therapeutics Biotech companies in the gene therapy field, including Audentes Therapeutics, Asklepios BioPharmaceutical, Juno Therapeutics and Kite Pharma, have been acquired for a total value of more than $41 billion.


However, a series of recent setbacks has brought the field of gene therapy back to reality, with an analysis published in Nature Reviews Drug Discovery last year showing serious adverse events in 35% of the 149 ongoing AAV gene therapy clinical trials 【1】.

In February this year, a report released by Jefferies Investment Bank showed that 40% of the clinical trial suspension in 2021 will come from the field of nuclear gene therapy [2] .


In September last year, the FDA had to set up a special response team to deal with the frequent adverse events related to AAV gene therapy.

The FDA suspended AAV gene therapy for Audentes Therapeutics (a subsidiary of Astellas) for Duchenne muscular dystrophy (DMD) in a clinical trial that resulted in severe liver toxicity and death in 2 patients a year earlier .


In addition, dose-limiting hepatotoxicity has also been observed in clinical trials of AAV gene therapy conducted by Solid Biosciences, Sarepta Therapeutics, Pfizer, and Homology Medicines, among others.


However, the problem does not end here.


Thrombotic microangiopathy , a form of complement activation leading to platelet depletion and acute kidney injury, was identified in a clinical trial of AAV gene therapy for Duchenne muscular dystrophy (DMD) conducted by Solid Biosciences , after receiving Novartis’ AAV gene The disease has also been found in spinal muscular atrophy (SMA) patients treated with the therapy Zolgensma.


In addition, a clinical trial of AAV gene therapy with an AAVrh10 vector at Massachusetts General Hospital in patients with familial amyotrophic lateral sclerosis showed neuronal loss in the dorsal root ganglia at subsequent autopsy [3 ] ] .


In November 2020, a research paper published by Nature Biotechnology showed [4] that a decade-long observation of AAV gene therapy in dogs with hemophilia A found that the therapeutic gene carried by AAV virus Some of the fragments are integrated into the dog’s chromosomes near growth-controlling genes, potentially causing cancer.


Lentiviral vectors also have concerns about potential toxicity. In August last year, Bluebird Bio ’s lenti-D for adrenoleukodystrophy showed patients with myelodysplastic syndrome in Phase 3 clinical trials, and the FDA immediately suspended this clinical trial.


The recurring problem in AAV gene therapy is mainly that the increase of injection dose leads to adverse consequences. At low doses (10E10-10E11vg/kg) , it is mainly used for local injection in the eyes and ears, or for systemic applications such as secreted proteins and antibodies.

But in order to reach the deep brain, motor neurons or muscles and other tissues, thousands of times higher doses (2×10E13-3×10E14vg/kg) are required .

These high doses of AAV are prone to toxicity, but the specific reasons behind this are The reason is not very clear, it may be related to the high expression of the target gene or the pre-existing antibody to AAV virus in vivo.


Currently, there are many companies including 4DMT, 64×Bio, Affinia Therapeutics, Capsida Biotherapeutics, Dyno Therapeutics, Generation Bio, StrideBio, VIVEbiotech, Vectalys, etc. trying to avoid these problems by modifying and designing AAV capsids.

There are also companies using dual AAV vectors to overcome the length limitations of the gene fragments delivered by AAV, and there are studies that hide AAVs in extracellular vesicles to evade immune system attack.

In addition, there are new types of in vivo applications such as virus-like particles (VLPs) and lipid nanoparticles (LNPs) .


With an estimated 380 trillion viruses living on and in the human body, researchers are increasingly interested in exploring the human virome for novel viral vectors other than lentiviruses and AAVs for gene therapy .


For example, the start-up company Ring Therapeutics is developing the human symbiotic Anellovirus as a gene therapy vector that can evade the body’s immune system.

Krystal Biotech recently announced the results of a Phase 1/2 clinical trial of its herpes simplex virus type 1 (HSV-1) vector for the treatment of dystrophic epidermolysis bullosa.

Amarna Therapeutics is exploring polyoma vectors. Pfizer is working with the University of Iowa to develop a Bocavirus/AAV hybrid virus vector with a larger gene loading capacity (5.2Kb) .


However, these R&D efforts require substantial funding, and successive failures, coupled with the continuation of the stock market downturn, have forced layoffs at Bluebird Bio, Amicus Therapeutics, Sigilon Therapeutics, Freeline Therapeutics, Gemini Therapeutics, and Passage Bio in recent times.


Following the recent spate of problems with lentivirus and adeno-associated virus (AAV) gene therapy, the gene therapy industry desperately needs a win to boost the industry.


Will the FDA have good news for the gene therapy industry next month?





References :
1. https://www.nature.com/articles/d41573-021-00017-7
2. https://endpts.com/hold-the-phone-biopharma-fda-imposed-clinical-holds-are-on-the-rise/
3. https://www.nejm.org/doi/10.1056/NEJMoa2005056
4. https://www.nature.com/articles/s41587-020-0741-7

The fast-growing gene therapy has come to the crossroads after a series of setbacks

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