COVID is a global health crisis, the virus infecting hundreds of millions and killing hundreds of thousands worldwide. The vaccines developed in rapid order may save millions of lives and are a wonder of modern science. But in rare instances the vaccines may cause safety issues due to undesirable responses to polyethylene glycol (PEG) and AdenoAssociated Virus (AAV). These immune responses to the vaccine nanoparticles or viral vectors could have implications beyond treating COVID and may prevent safe and efficacious delivery of life saving biotherapeutics and gene therapies. Are we immunizing hundreds of millions of people against PEGylated drugs and AAV gene therapies? 

Both the Moderna and Pfizer COVID vaccines contain PEG in their formulations to create stable nanoparticles containing viral mRNA. PEG is a common additive in food, cosmetics and pharmaceuticals. PEG, when conjugated to protein therapeutics enhances pharmaceutical kinetics, pharmacodynamics and can reduce immunogenicity. However, people can and do create anti-PEG antibodies. According to a publication cited below, there is a 22 – 25% occurrence of anti-PEG in healthy blood donors, compared with a very low 0.2% occurrence two decades earlier. This increase may be due to an improvement of the limit of detection of antibodies during the years and to greater exposure to PEG and PEG-containing compounds. These results raise obvious concerns regarding the efficacy of PEG-conjugated drugs for a subset of patients. (https://www.tandfonline.com/doi/full/10.1517/17425247.2012.720969). Anti-PEG antibodies can cause skin rashes and more severe allergic responses, including anaphylaxis. Anti-PEG antibodies may cause rapid clearance, poor uptake and decreased efficacy of PEGylated biotherapeutics. There are over a dozen PEGylated biotherapeutics on the market for many diseases (see below and cited above). Will a significant number of people getting the COVID vaccine develop anti-PEG antibodies? Will COVID vaccination status need to be considered when prescribing PEGylated drugs?

What about the impact of COVID vaccination on gene therapy drugs? Two adenoviral vector COVID-19 vaccines are now being used to protect people from COVID. The first, Ad5-nCoV from CanSino, uses a human adenovirus 5 (AAV5) vector; the second, AZD1222, licensed by AstraZeneca from University of Oxford, uses a chimpanzee adenovirus vector. At least seven adenovirus vector vaccines are in development for COVID-19. The AAV5 serotype, is used for gene therapy, and has double-digit pre-existing antibody prevalences that presents challenges to effective treatment.  AAVs are used for the few approved gene therapies and many more in development. Gene therapy may be the future of medicine and save millions with rare genetic diseases. But now AAVs are being leveraged to strongly activate both B and T cells against COVID-19 (https://www.biocentury.com/article/305392/aav-covid-19-vaccine-aims-for-the-sweet-spot-between-antibody-and-t-cell-immunity). Will gene therapy developers need to find ways to avoid these antibodies and T-cells once hundreds of millions of people have been immunized against COVID? Pre-existing antibodies to certain AAV serotypes are common and sometimes neutralizing antibodies develop. These neutralizing antibodies can be tested in functional bioassays. Clever ways to engineer AAVs or reduce the immune response to the gene therapy are being explored. This may be increasingly important once millions of people are immunized with AAV-SARS-CoV-2.

By Erik Foehr

BioTether Sciences

Last year saw the approval and marketing of the most expensive drug ever created. Zolgensma, by Novartis, is a one time gene therapy for the rare condition, spinal muscular atrophy. The therapy costs $2.125 million and may be used to treat children around 2 years of age stricken with the disease. Other new drugs with large price tags also added to the growing class of cell and gene therapies that are ‘The Most Expensivest’ drugs ever developed. Spark Therapeutics gene therapy drug for a rare form of blindness, is called Luxturna, and is priced at $425,000 per eye.  A few CAR-T therapies have been approved for cancer over the last couple years,  including Novartis Kymriah for non-Hodgkin Lymphoma.  CAR-T therapies are complex and cost nearly $500,000 for the treatment. 2020 is likely to see several more cell and gene therapy approvals ignite costs like a pile of cash on fire. Million dollar drugs may become commonplace someday.

Cell and Gene Therapy drugs have enormous potential to treat and even cure disease. For instance, Zolgensma, was shown to keep some of the treated children free of the devastating neuromuscular disease years after the therapy was administered. CAR-T therapies have demonstrated astonishing successes curing people of deadly cancers. The FDA projected that 10-20 gene and cell therapies will be approved per year by 2025. That would indicate 3-5 approvals this year, 5-10 next year and so on until cell and gene therapies become a significant part of the biopharmaceutical ecosystem. Hundreds of genetic diseases are being targeted for gene therapy treatment by small biotech start-ups to large multinational biopharmaceutical companies.

How will cell and gene therapies impact the biopharmaceutical and healthcare ecosystems? On the one hand fortunes will be made on the new discoveries, break-throughs, and mega-mergers. Intractable diseases, many rare genetic diseases, with no other treatment option may be ameliorated or even cured. This new class of therapy could improve and save many lives and may even reduce the long term cost burden on the healthcare system. But no one has a clear answer for how to pay for these new million dollar therapies. Cell and gene therapy drugs are being developed for rare diseases, with thousands, hundreds, or even a few dozen treatable patients in the USA. But some new cell and gene therapies may be used on a larger population of patients. Will insurance companies be able to absorb the costs of these million dollar drugs? Can the system find a solution to a low probability, but high impact claims?

These drugs are also extremely expensive to develop, manufacture, and test. CAR-T therapies require highly specialized manufacturing and quality testing systems. Similarly, gene therapies have shown great potential, but have significant challenges relating to vector delivery, immunogenicity, and other safety concerns. Cell and gene therapies are only a small fraction of the overall drug development spend with small molecule and biotherapeutics accounting for over 95% of development dollars. But this new class of drug is going to grow rapidly and will require significant expenditures on in-house and outsourced activities. The outsourced analytical chemistry services spend alone will reach into the hundreds of millions in 2020 and beyond. But that may just be the price to pay for the best, most effective, and expensivest drugs ever developed.