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Gene Therapy — An Inventory

By Karoline Hahn, Senior Consultant, Advanced Therapies at KCR

The landmark approval of two AAV-based gene therapies, one — Luxturna — to treat vision loss due to inherited retinal dystrophy, and the other — Zolgensma — to manage spinal muscular atrophy, provided definitive proof of gene therapy’s potential. Since then, many biotech and pharmaceutical companies have expanded on the momentum of those successes as their own innovative gene therapies entering late-stage rare disease clinical development, such as hemophilia, sickle cell disease and muscular dystrophy. Advances in understanding the gene sciences expand the drug discovery toolbox.

The achievements hold lessons for the field, though. A series of setbacks have overshadowed the initial optimism. Last year, a gene therapy drug for hemophilia A, which was widely expected to receive U.S. approval, was rejected by FDA. The drug developer, BioMarin Pharmaceutical, was asked for more data to prove durability of the observed benefit. In September, a fourth child died in a trial studying Astella´s gene therapy for X-linked myotubular myopathy. The trial has been halted before, after three deaths occurred between May and August 2020. Back then, Astellas lowered the dose, which was one of the highest being tested in any gene therapy trial, by more than half. Nonetheless, a fourth patient developed signs of liver damage before unfortunately passing away. Signs of liver toxicity, but not patient death, have been reported in other gene therapy trials, too. However, the liver-related effects could effectively be managed with steroid treatment. Pfizer has reported three serious adverse events of muscle weakness, two of which involved myocarditis, which occurred during their gene therapy trial for Duchenne Muscular Dystrophy. Pfizer thinks certain mutations in the dystrophin gene may be associated with a higher risk for adverse events, causing them to exclude patients with certain genetic traits from participation in the trial.

Drug developers are thoroughly investigating safety incidences, grabbing the attention of regulators. In September 2020, the FDA convened a group of gene therapy experts for advice on the risks associated with gene therapy. The meeting discussion made clear that much remains uncertain on the safety and efficacy of the gene therapy, but it gave clues to the direction of the current thinking of the agency.

Hepatotoxicity is the most observed toxicity in AAV-based treatments as the therapies are mostly administered intravenously tend to affect the liver. CNS-directed vectors also cause liver damage as they can escape the CNS and have some systemic side effects. The severity of liver damage may not be correlated to high vector doses as the findings in the Astellas study suggest: the fourth patient received a dose comparable to those in other trials. Preexisting liver conditions may influence how side effects develop. It will be warranted to comprehensively assess patient’s health status and not rely solely on blood liver function test results. It is perceived that the data from Pfizer´s Duchenne trial suggests that the individual’s genetic make-up could modulate the amplitude of side effects, the underlying mechanism remains to be elucidated.

As it is for hepatocellular carcinoma (HCC) caused by AAV-based gene therapies, the initial studies from 20 years ago lead to the plausibility of HCC incurred by AAV genome insertion, as demonstrated by the vector integration in neonatal mice. Integration occurs mostly into the Rian locus, a genomic region unique to rodents, which is transcriptionally active during hepatocyte growth and restoration. In dogs, there are five hotspots of AAV integration, all linked to cancer, but no tumor was detected in any dog as well as no inflammation, hepatitis, or fibrosis. UniQure reported a participant of their hemophilia B trial being diagnosed with liver cancer. The patient had a history of hepatitis B and C infection. The viral infections are linked to 80% of HCC. In contrast, AAV integration was found in 0.027 % of the cells in the tumor sample and were not clustered in genes associated with cancer.

It has become apparent that inconsistent methods to assess the risks of gene therapies makes it hard to draw concrete conclusions. Missing standards in gene therapies, for example, in vector construction and production may cause safety issues. Regulators call for commercial-grade manufacturing process and product at the time of clinical development to unlock any potential risk early.

The increased understanding of the gene therapy field calls for higher standards. Winning approval for a gene therapy based on minimal data from a Phase I/II trial may be hampered. Robust and durable efficacy data as well as long-term safety data must construct evidence to fit the interdiction of use. Adaptability in manufacturing and clinical study design supplemented with real-world evidence is likely required from both drug developers and regulators to account for the clinical utility of each gene therapy designed to target a particular genetic defect.

The learning curve in the field of gene therapy remains steep. As experience accumulates with each new therapy, the redemption of the promise of gene therapy will come sooner.

About the Author: Dr. Karoline Hahn is a Senior Consultant for Advanced Therapies on KCR’s Trial Execution Consulting team with 20 years of experience in the biopharmaceutical industry, devising regulatory strategies and leading interactions with global health authorities. A geneticist by training, Dr. Hahn has extensive expertise in Advanced Therapies and provides top-tier strategic regulatory services in

About KCR:

KCR is a clinical development solutions provider creating value for biotechnology and pharmaceutical organizations. Founded in 1997, our expert teams support clients with full-service clinical development capabilities across three main areas: Trial Execution, Consulting and Placement. KCR operates across North America, Europe, and Australia, with main office locations in Boston, US, Berlin, Germany, and Warsaw, Poland. Our geographical coverage across 25+ countries, cutting-edge technical capabilities and tailored offerings allow for the optimized delivery of solutions to develop life-changing therapies. KCR offers access to an estimated population of 1.1 billion people. For more information visit www.kcrcro.com.

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