March 15, 2023
The FDA was always operated on a single foundational doctrine: Ensuring drug safety and protecting human life.
While much has changed since its founding in 1906, this guiding principle still holds true and shapes many of today’s drug approval decisions.1 It’s why review time, statistically-significant data, and carefully controlled trials are all part of releasing a drug for clinical use to treat harmful diseases effectively.
But for patients and their caregivers, particularly those with no FDA-approved treatment options, there’s a tension with the regulatory agency that has long been palpable. To them, the FDA acts as a sluggish gatekeeper, sometimes shutting the door on their future. In the past, with the HIV crisis and cancer, this tension has reached a boiling point, with public outcry for the FDA to enact shorter review processes, push faster approvals, and give patients a shred of hope.2,3
The FDA responded to these pleas with new initiatives, such as expanded access and accelerated approval programs. These programs were successful, enabling those willing to accept an experimental drug's risk to access potentially helpful drugs.
With the state of drug development today, we’ve reached the next boiling point.
The appeals come from the “rare” diseases community, who want access to the possibility of help or a cure. We use “rare” in quotes because, as a recent opinion article in STAT reminded us, this collection of diseases is anything but: They affect 10% of Americans.4
That’s a scary thought considering their destructive nature: 3 in 10 children with a rare disease won’t live to see their 5th birthday. This unfortunate and tearful truth comes down to the lack of safe and effective treatments and the need for traditional – and hence, time-consuming – clinical testing.
For Chairman and Founding Director of the Beyond Batten Disease Foundation, Craig Benson (and many others), asking patients and caregivers to accept the sluggish pace of drug approval for rare diseases is a bridge too far. In a recent webinar, Craig called the need for a placebo arm in rare disease clinical trials and other FDA clinical trial regulations unethical.5
With Batten disease primarily affecting children, it’s easy to see why: The idea of a child, who may not live to see their next birthday, being enrolled in a placebo arm is unthinkable.6
Moreover, there is promising evidence that off-label use of an approved drug called miglustat (currently safe and efficacious for treating Niemann-Pick disease type C) may be effective for Batten disease.7 However, this approach causes complications with insurers, who want the FDA’s stamp of approval before they choose to cover the astronomical costs of some therapeutics.
Together, this paints a bleak picture for those living with Batten and other rare diseases. Why should a potentially efficacious drug be withheld from families and physicians that have collectively decided that the risk of experiencing an adverse event is worth it?
Repurposing currently approved drugs is just one path to developing rare disease treatments. There are also many innovative, new therapeutic classes being explored, including clinical trials with gene therapies, which offer the possibility of a one-time cure for rare genetic diseases.
While powerful, these treatments also have drawbacks for patients, and their caregivers, as experimental gene therapies have been found to have numerous safety problems. Delivery of many gene therapies rely on viral vectors, such as adenovirus and adeno-associated viruses (AAVs), which have a tumultuous clinical history and, recently, caused clinical holds, severe adverse events, and even mortality during clinical trials.8–11
Much like the therapeutic crisis of the past, the FDA is beginning to take action for the rare disease community, by hastening the path to approval for repurposed drugs and gene therapies. The Director of the FDA’s Center for Biologics Evaluation and Research, Peter Marks, announced recently that a pilot program, the next generation of Operation Warp Speed, for rare diseases with no treatments would be rolled out soon12. Promising treatments could be granted breakthrough or advanced therapy designation during clinical development, while remaining in close and transparent communication with the FDA to ensure vigilant monitoring of adverse events.
The other avenue for furthering the development of gene therapies is by addressing the current safety concerns head-on. With AAV-based vectors, which make up a large percentage of the gene therapies in development, safety issues have been linked to quality issues due to poor AAV manufacturing processes. More specifically, AAV preparations can be contaminated with non-therapeutic capsids. These capsids can be empty or contain truncated viral vectors and thus don’t contribute to a potential therapeutic effect.
Impurities of viral capsid production lead to the higher relative dosing of an AAV-based drug, which can induce an inflammatory immune response in patients.13
For gene therapy, dose is determined by the number of full viral genomes the patient is supposed to receive. Therefore, if the manufacturing run results in 25% of capsids filled with truncations or contaminants (helper plasmids), the patient would receive well over that number of viral particles in their dosing regimen.
This significant increase in the number of viral particles the patient receives leads to an increase of likelihood that an inflammatory immune response is made and is detrimental to the patient. This type of intense negative immune response is what stopped gene therapy development in the late 1990s8.
Also, if there are truncated proteins developed, they may be foreign enough that a specific immune response could be made to them, that would lead to a very directed immune response to the cells that were treated with the gene therapy and the immune system may kill those cells.
These points were also addressed in the FDA’s recent advisory meeting, “...empty capsids increase overall antigenic load and potentially exacerbate capsid-triggered innate and adaptive immune responses. The empty capsids can contribute to the peptides presented by major histocompatibility complex molecules, with consequent recognition and clearance of transduced cells by capsid-specific cytotoxic T cells…In addition to stimulation of innate and adaptive immune responses, AAV empty capsids may compete with full capsids for receptor binding on target cells, which could necessitate an increase in the required vector dose.”14,15
To address all these complications, a draft guidance, “Testing of Adeno-Associated Viral (AAV) Vector-Based Human Gene Therapy Products for Empty Capsids During Product Manufacture” has been submitted for approval by the FDA.
The draft guidance defines the process impurities that result from AAV-based therapeutics manufacturing and recommends several methods for detecting non-therapeutic capsids and the critical quality attributes for manufactured gene therapies.
As stated in the document, “This guidance provides sponsors of AAV vector-based human gene therapy products with the recommendation to establish a maximum release criterion for empty AAV capsids to better control immunogenicity that may be due to empty capsid product impurity and provide for improved product safety in the context of systemic administration.”
The guidance also recommends that sponsors investigate other process impurities, such as truncated and partial genomes, which aren’t currently included in any other Chemistry, Manufacturing, and Control (CMC) recommendations for gene therapies in development.
While the FDA hasn’t entirely accepted the draft guidance yet, optimizing the production process, implementing stringent quality control measures for the defined attributes, and conducting rigorous preclinical and clinical studies to evaluate the safety and efficacy of a product, can enable gene therapy companies to reduce the risk of non-therapeutic capsids and increase the commercial viability of their products.
Based on the draft guidance, here are several strategies gene therapy developers should consider:
For gene therapy companies, considering these recommendations early in the development of AAV-based gene therapies will be necessary for a successful path to market, particularly as the FDA formulates its position on protecting the safety of clinical trial participants and manufacturing details. As noted in the recent Endpoints piece, clinical holds for gene therapies are often due to incomplete Investigational New Drug (IND) applications that are missing a manufacturing section12. Therefore having a well-defined and optimized manufacturing process is of utmost importance to get your gene therapy through to the IND approval process.
As the draft AAV guidance mentioned, AAV capsids with partial genomes are impurities that can cause non-therapeutic products and clinical safety issues in the patient. These particular impurities can arise through genome truncation during viral packaging.
Purification processes are useful, but the gene therapy industry needs a capsid that can form and replicate without fail. Fortunately, artificial intelligence (AI) strategies are coming to the rescue. These tools have been and will continue to be helpful for gene therapy developers to optimize construct design, validate therapeutic candidates, and improve pre-clinical development and manufacturability.
At Form Bio, we are engineering state-of-the art solutions for gene therapy discovery and AAV manufacturing. Our research teams have combined artificial intelligence techniques with our deep biological and bioinformatic expertise to accelerate the process from development to market in ways previously thought impossible. Our work has shown that truncation can be reduced by as much as 70% in the coding region for some transgenes18.
Building upon the AI research of DeepMind, we are taking their work to new heights and using AI advancements such as those described in our recent publications 19, 20, 21 to stretch limited AAV data resources further. Our tailored solutions for data scarce environments maximize efficiency, coupled with a customized optimization to prescriptively solve the problem on AAV capsid truncations.
These existing improvements, our continued advancement of predictive AI algorithms, and the ongoing push – by patients, caregivers, doctors, patient advocacy groups, and the FDA – for safe and efficacious gene therapies will help clear a path for successful clinical trials and bring more viable and accessible patient care.
1. FDA History. FDA. Published March 29, 2021. Accessed March 8, 2023. https://www.fda.gov/about-fda/fda-history
2. Gyawali B, Hey SP, Kesselheim AS. Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval. JAMA Intern Med. 2019;179(7):906-913. doi:10.1001/jamainternmed.2019.0462
3. Aids I of M (US) R for the D of D and VA, Nichols E. Historical Perspective. National Academies Press (US); 1991. Accessed March 8, 2023. https://www.ncbi.nlm.nih.gov/books/NBK234129/
4. Skerrett P. My son’s time is running out due to a rare disease. The FDA needs to add more clinical trial flexibility. STAT. Published February 28, 2023. Accessed March 8, 2023. https://www.statnews.com/2023/02/28/fda-needs-to-build-in-more-flexibility-for-rare-disease-clinical-trials/
5. Rare Disease Day 2023: The Future of Rare Disease R+D. Accessed March 8, 2023. https://www.formbio.com/webinars-resources/rare-disease-day-2023-the-future-of-rare-disease-r-d
6. Batten Disease. National Institute of Neurological Disorders and Stroke. Accessed March 8, 2023. https://www.ninds.nih.gov/health-information/disorders/batten-disease
7. PhD PI. Phase 1/2 Trial of Juvenile Batten Disease Therapy Fully Enrolled | Batten-1 Therapy in Testing Aims to Slow CLN3 Progression | Batten Disease News. Published September 22, 2022. Accessed March 8, 2023. https://battendiseasenews.com/news/trial-testing-juvenile-batten-disease-therapy-fully-enrolled/
8. The Death of Jesse Gelsinger, 20 Years Later | Science History Institute. Accessed March 8, 2023. https://www.sciencehistory.org/distillations/the-death-of-jesse-gelsinger-20-years-later
9. Astellas Announces Positive Safety Data from the FORTIS Study of AT845 in Adults with Late-Onset Pompe Disease. BioSpace. Accessed March 8, 2023. https://www.biospace.com/article/astellas-announces-positive-safety-data-from-the-fortis-study-of-at845-in-adults-with-late-onset-pompe-disease/
10. Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284-293. doi:10.1016/S1474-4422(21)00001-6
11. High-dose AAV gene therapy deaths | Nature Biotechnology. Accessed March 8, 2023. https://www.nature.com/articles/s41587-020-0642-9
12. Operation Warp Speed for rare diseases: CBER leader says pilot is coming soon. Endpoints News. Accessed March 8, 2023. https://endpts.com/operation-warp-speed-for-rare-diseases-cber-leader-says-pilot-is-coming-soon/
13. Maurya S, Sarangi P, Jayandharan GR. Safety of Adeno-associated virus-based vector-mediated gene therapy—impact of vector dose. Cancer Gene Ther. 2022;29(10):1305-1306. doi:10.1038/s41417-021-00413-6
14. In Vivo Performance of AAV2 Vectors Purified by CsCl Gradient Centrifugation or Column Chromatography. Mol Ther. 2003;7(5):S390-S391. doi:10.1016/S1525-0016(16)41455-3
15. Wright JF. Codon Modification and PAMPs in Clinical AAV Vectors: The Tortoise or the Hare? Mol Ther J Am Soc Gene Ther. 2020;28(3):701-703. doi:10.1016/j.ymthe.2020.01.026
16. Werle AK, Powers TW, Zobel JF, et al. Comparison of analytical techniques to quantitate the capsid content of adeno-associated viral vectors. Mol Ther - Methods Clin Dev. 2021;23:254-262. doi:10.1016/j.omtm.2021.08.009
17. Voineagu I, Narayanan V, Lobachev KS, Mirkin SM. Replication stalling at unstable inverted repeats: Interplay between DNA hairpins and fork stabilizing proteins. Proc Natl Acad Sci U S A. 2008;105(29):9936-9941. doi:10.1073/pnas.0804510105
18. Nipko, J. Developing Machine Learning Powered Solutions for Cell and Gene Therapy Candidate Validation. Form Bio Resource Center. Published November 2022. Accessed February 8, 2023. https://www.formbio.com/white-papers/machine-learning-solutions-cell-and-gene-therapy
19. Ketz, N. Applying DeepMind’s Transformer Architecture to Optimize AAV Constructs. Form Bio Resource Center. Published March 8, 2023. Accessed March 9, 2023. https://www.formbio.com/blog/large-language-model-gene-therapy
20. Ketz, N. Understanding How Best to Allocate Resources When Training Large Language Models in Gene Development Programs. Form Bio Resource Center. Published Jan 31, 2023. Accessed March 14, 2023. https://www.formbio.com/blog/large-language-models-gene-therapy
21. Day, A. Shorting Gene Therapy Development Time with Strategic Use of Large Language Models. Form Bio Resource Center. Published March 2, 2023. Accessed March 14, 2023. https://www.formbio.com/blog/shortening-gene-therapy-development-time
22. The Death of Jesse Gelsinger. Science History Institute. Published June 4 2019. Accessed March 15, 2023. https://www.sciencehistory.org/distillations
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