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A Tale of Two Clinical Trials: Gene Therapy for a Rare Disease and a Vaccine for COVID-19

Encouraging preliminary findings in a phase I clinical trial for a COVID-19 vaccine were widely reported as soon as the paper appeared in The New England Journal of Medicine July 14. Coverage of the recent deaths of two boys in a clinical trial to test a gene therapy for a rare, devastating muscle disease were more under-the-radar. Comparing the two very different scenarios illuminates the scientific rigor behind the clinical trial process.

The boys had X-linked myotubular myopathy. MTM affects 1 in 50,000 male births. Seventy-five percent of boys die in weeks or months of respiratory failure; average life expectancy is 29 months. Given that prognosis, taking the risk of an experimental treatment in a clinical trial makes sense. Parents of participants as well as physicians know that children can die during the trial, due to the disease or to toxicity at higher doses of a treatment.

In contrast, volunteers in a clinical trial to evaluate a vaccine are healthy.

Although comparing MTM gene therapy and a COVID-19 vaccine is a bit of apples and oranges, those fruits are in the same bin in terms of progression through the three phases of development of a new treatment or preventative:

Phase I tests safety on a small number of individuals to determine the optimal dose and reveal side effects.

Phase II increases that number and evaluates efficacy.

Phase III expands the number further – ultimately thousands of volunteers will receive various COVID-19 vaccine candidates, while at most a few dozen boys will test the MTM gene therapy.

A Dire Diagnosis

The journey to gene therapy for MTM began, as many gene therapy stories do, with pioneering parents.

When Joshua Frase was born on February 2, 1995, it was clear that something was wrong – he was floppy, dusky, skinny and eerily silent. The medical team prepared Alison Rockett Frase and Paul Frase for their newborn’s imminent death even before a diagnosis, but Joshua lived. He went home on his 24th day.

Soon after, a muscle biopsy confirmed that the boy had inherited a mutation in the MTM1 gene from one of Alison’s X chromosomes. Joshua’s skeletal muscle cells couldn’t make the protein myotubularin 1. They were stuck in a fetal state, their nuclei bulging centrally rather than squished to the sides of the pulsating proteins that normally fill the spindly muscle cells. The misplaced nuclei block calcium from entering and the cells can’t contract, like a phone unable to receive signals.

The weak muscles affect development of the skeletal system, leading to scoliosis and a large head. Ability to breathe wanes.

The parents began the Joshua Frase Foundation for Congenital Myopathy Research, launching their relentless search for a team to tackle the disease. They became aware of how gene therapy might work in 1997; I told the story of how Labrador retrievers led to the gene therapy here. The experimental gene therapy came too late for Joshua, but he defied the odds and lived until 2010.

Early Signs of Success for MTM Gene Therapy

The phase I gene therapy trial of AT132 (resamirigene bilparvovec) began in September 2017, sponsored by Audentes Therapeutics.

Eleven boys received copies of the MTM1 gene intravenously in an arm or leg. Adeno-associated virus serotype 8 delivered the genes, 100 trillion viruses per kilogram of weight to 7 boys and triple that dose to four others. Controls were two other boys who weren’t treated, although a natural history study published as the trial began documented the course of disease progression without treatment, for comparison.

Time passed, and parents’ initial observations showed promise. The company presented interim encouraging results at the May 2019 annual meeting of the American Society of Gene and Cell Therapy.

By August 2019, 82 adverse events had been reported that could have been due to the gene therapy, 14 deemed serious. That’s comparable to gene therapies for other diseases given systemically. The serious adverse events were low platelet count, liver problems, and a blood test (high troponin) indicating possible sepsis, which is an extreme immune response to infection.

Then another update came March 26, 2020, when Neurology Live interviewed Perry B. Shieh, MD, PhD, from the department of neurology, Ronald Reagan UCLA Medical Center. He’d been scheduled to present findings at the 2020 Muscular Dystrophy Association Clinical & Scientific Conference until COVID came. Shieh reported better mobility and breathing for 72 weeks, while biopsies showed that skeletal muscle cells were pumping out functional myotubularin.

“We’re seeing rapid improvements in a lot of our patients, and meaningful changes in motor skills—sitting, crawling, standing, walking, and even running. A lot of them are eating normal food, they’re speaking and they’re vocalizing normally. We’ve really been seeing unprecedented reductions in ventilator dependence,” Shieh said.

A Dire Letter to Families

On May 6th, parents in the MTM patient community received a distressing email from Audentes: one of the children in the clinical trial had died, from sepsis. But death from infection or out-of-control response to it in a clinical trial isn’t uncommon.

Then on June 23, the company reported the second death, in a boy being treated for a liver abnormality in the hospital, from the same cause. Liver dysfunction is an early sign of sepsis.

The FDA halted the MTM clinical trial. But the pause may be a time-out, to regroup, more than a final word.

The boys, both of whom had received the higher dose, were older than the boys receiving the lower dose, and obviously weighed more (important in figuring out dosages). They both had pre-existing liver disease. None of the boys receiving lower doses developed sepsis, not even any of four who had a history of liver disease.

The company is thoroughly investigating what went wrong.

Were the viral vectors contaminated, or too revved up by the promoter DNA sequence that sets the activity level of gene expression?

Was the dose simply too high, the flood of viruses triggering an overwhelming immune response? That possibility conjures memory of 18-year-old Jesse Gelsinger, who died 20 years ago just days after receiving gene therapy for another rare genetic disease. His immune response went into overdrive as the torrent of viruses invaded macrophages in addition to the targeted liver cells.

Refining the gene therapy for MTM may be a question of balance.

“We know the immune response is dose dependent. The question is can we reduce the dose and safely get the clinical results we need and maintain them? If not, we need to improve or retool the product,” said Alison Rockett Frase.

COVID-19 Clinical Trials

At the same time that problems were arising in the clinical trial for MTM, the first trials of COVID vaccines were getting underway.

The report in the July 13 New England Journal of Medicine presents interim (day 57) findings of the phase I clinical trial for the mRNA-1273 vaccine, in 45 patients given one of 3 doses. The National Institute of Allergy and Infectious Disease is the sponsor and ModernaTX is the biotech company producing the vaccine.

So far, so good. “The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified,” the researchers write. Three patients receiving the highest dose had serious adverse events, but others had only typical vaccine reactions – fever, soreness at the injection site, fatigue – or no reaction at all. The trial was conducted at Kaiser Permanent Washington Health Research Institute in Seattle and the Emory University School of Medicine.

The ClinicalTrials.gov entry reveals the complexity of the planning.

In phase I, 155 healthy volunteers, aged 18 through 99, receive one of 5 doses of the vaccine in injections given 28 days apart, at several clinical centers. The trial is assessing safety, “reactogenicity” (normal vaccine indicators of innate immune response, such as inflammation and low fever), and “immunogenicity” (antibody production).

The definition of “healthy” emerges from a list of 31 exclusion criteria in the protocol, which minimize confounding factors. A volunteer for the mRNA-1273 vaccine can’t have: cardiovascular disease, a psychological condition, cancer, respiratory disease, an autoimmune condition, immunodeficiency, chronic kidney or liver disease, or blood clotting issues, and must not have been exposed to COVID-19 or work in a high-risk area, like a hospital.

The phase I trial is still listed as slated for conclusion in November 2021, so it’s hard to imagine how a much larger phase III trial is going to be done by early next year, even with overlapping phases and proclamations of warp speed acceleration.

Differences Between the Two Trials

The rare disease gene therapy clinical trial has very few participants who are very sick facing a poor prognosis. The goal is to help individuals with this one disease. The preclinical research and clinical trial unfurled over 15 years.

The COVID-19 vaccine trial will ultimately have many participants who are the healthiest of the healthy. The goal is to vaccinate enough people to reach herd immunity so that the “R-naught” value of how many people each infected person infects dips below 1 and spread trickles away and stops. Planning and recruiting for the first trials took mere months.

What the clinical trials for the two conditions – MTM and COVID-19 – share is clear thinking of the planners, based on knowledge of science; understanding of the process of scientific inquiry; experience in setting up, conducting, and interpreting findings of experiments; and logic.

Not faith. Not hope. Not magic. Not wishing. Not denial of a problem or false promises that the virus will disappear. Science isn’t that simple.

One benefit from the pandemic will be a new appreciation for the reasoning that lies behind understanding nature.

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