An Investigational Drug Offers Hope to Patients with a Disabling Neuromuscular Disease
Robert Thomas was a devoted runner, gym goer, and crew member on a sailing team in San Diego when, in his 40s, he noticed that his range of movement was becoming more limited.
He thought he was just getting older, but when he was hiking an uphill trail in Lake Tahoe, he kept tripping over rocks. "I'd never had this happen before," Robert says. "I knew something was wrong but didn't know what it was."
It wasn't until age 50 when he was diagnosed with Charcot-Marie-Tooth disease. The genetic disorder damages the peripheral nerves, which connect the brain and spinal cord to the rest of the body. This network of nerves is responsible for relaying information and signals about sensation, movement, and motor coordination. Over time, the disease causes debilitating muscle weakness and the loss of limb control.
Charcot-Marie-Tooth usually presents itself in childhood or in a person's teens, but in some patients, like Robert, onset can be later in life. Symptoms may include muscle cramping, tingling, or burning. Many patients also have high foot arches or hammer toes — toes that curl from the middle joint instead of pointing forward. Those affected often have difficulty walking and may lose sensation in their lower legs, feet, hands, or forearms. One of the most common rare diseases, it affects around 130,000 people in the United States and 2.8 million worldwide.
Like many people with Charcot-Marie-Tooth, or CMT, Robert wears corrective braces on his legs to help with walking. Now 61, he can't run or sail anymore because of the disease, but he still works out regularly and can hike occasionally. CMT also affects his grip, so he has to use special straps while doing some exercises.
For the past few years, Robert has been participating in a clinical trial for an investigational CMT drug. He takes the liquid formulation every morning and evening using an oral syringe. Scientists are following patients like Robert to learn if their symptoms stabilize or improve while on the drug. Dubbed PXT300, the drug was designed by French biopharmaceutical company Pharnext and is the farthest along in development for CMT. If approved, it would be the first drug for the disease.
Currently, there's no cure for CMT, only supportive treatments like pain medication. Some individuals receive physical and occupational therapy. A drug for CMT could be a game-changer for patients whose quality of life is severely affected by the disease.
Genetic Underpinnings
CMT arises from mutations in genes that are responsible for creating and maintaining the myelin sheath — the insulating layer around nerves. Pharnext's drug is meant to treat patients with CMT1A, the most common form of the disease, which represents about half of CMT cases. Around 5% of those with CMT1A become severely disabled and end up in wheelchairs. People with CMT1A have an extra copy of the gene PMP22, which makes a protein that's needed to maintain the myelin sheath around peripheral nerves.
Typically, an individual inherits one copy of PMP22 from each parent. But a person with CMT1A receives a copy of PMP22 from one parent and two copies from a parent with the disease. This extra copy of the gene results in excess protein production, which damages the cells responsible for preserving and regenerating the myelin sheath, called Schwann cells.
The myelin sheath helps ensure that a signal from the brain gets carried to nerves in the muscles so that a part of the body can carry out a particular action or movement. This sheath is like the insulation on an electrical cord and the action is like a light bulb. If the insulation is fine, the light bulb turns on. But if the insulation is frayed, the light will flicker.
"The same happens to these patients," says David Horn Solomon, CEO of Pharnext. "The signal to their muscle is weak and flickers." Over time, their muscles become weaker and thinner.
The PMP22 gene has proven difficult to target with a drug because it's located in a protected space — the Schwann cells that make up the insulation around nerves. "There's not an easy way to tamp it down," Solomon says.
Another company, Acceleron Pharma of Cambridge, Massachusetts, was developing an injectable CMT drug meant to increase the strength of leg muscles. But the company halted development last year after the experimental drug failed in a mid-stage trial. While the drug led to a statistically significant increase in muscle volume, it didn't translate to improvements in muscle function or quality of life for trial participants.
Made by Design
Pharnext's drug, PXT3003, is a combination of three existing drugs — baclofen, a muscle relaxant; naltrexone, a drug that decreases the desire for alcohol and opioids; and sorbitol, a type of sugar alcohol.
The company designed the drug using its artificial intelligence platform, which screened 20,000 existing drugs to predict combinations that could inhibit the PMP22 gene and thereby lower protein production. The AI system narrowed the search to several hundreds of combinations and Pharnext tested around 75 of them in the lab before landing on baclofen, naltrexone, and sorbitol. Individually, the drugs don't have much effect on the PMP22 gene. But combined, they work to lower how much protein the gene makes.
"How the drug inside the cell reduces expression isn't quite clear yet," says Florian Thomas, director of the Hereditary Neuropathy Center, and founding chair and professor in the department of neurology at Hackensack University Medical Center and Hackensack Meridian School of Medicine in New Jersey (no relation to Robert Thomas, the CMT patient). "By reducing the amount of protein being produced, we hopefully can stabilize the nerves."
In rodents genetically engineered to have the PMP22 gene, the drug reduced protein levels and delayed onset of muscle weakness when given to rats. In another animal study, the drug increased the size of the myelin sheath around nerves in rats.
"Like humans with CMT, one of the problems the animals have is they can't grip things, their grip strength is poor," Solomon says. But when treated with Pharnext's drug, "the grip strength of these animals improves dramatically even over 12 weeks."
Human trials look encouraging, too. But the company ran into a manufacturing issue during a late-stage trial. The drug requires refrigeration, and as a result of temperature changes, crystals formed inside vials containing the high dose of the drug. The study was a double-blind trial, meaning neither the trial participants nor investigators were supposed to know who received the high dose of the drug, who received the low dose, and who received a placebo. In these types of studies, the placebo and experimental drug should look the same so that investigators can't tell them apart. But because only the high dose contained crystals, not the low dose or placebo, regulators said the trial data could be biased.
Pharnext is now conducting a new randomized, double-blind trial to prove that its drug works. The study is recruiting individuals aged 16 through 65 years old with mild to moderate CMT. The company hopes to show that the drug can stop patients' symptoms from worsening, or in the best case scenario, possibly even improve them. The company doesn't think the drug will be able to help people with severe forms of the disease.
"In neurologic disease, you're looking for plasticity, where there's still the possibility of stabilization or reversal," Solomon says. Plasticity refers to the ability of the nervous system to change and adapt in response to stimuli.
Preventing Disability
Allison Moore, a CMT patient and founder and CEO of the Hereditary Neuropathy Foundation, has been following drug development for CMT since she founded the organization in 2001. She says many investigational drugs haven't moved forward because they've shown little success in animals. The fact that Pharnext's drug has made it to a late-stage human trial is promising, she says.
"It's really exciting," Moore says. "There's a chance that if you take the drug early before you're very severe, you'll end up not developing the disease to a level that's super disabling."
CMT has damaged Moore's peroneal nerve, a main nerve in the foot. As a result, she has foot drop, the inability to lift the front part of her foot, and needs to wear leg braces to help her walk. "The idea that you could take this early on and that it could stop progression, that's the hope that we have."
Thomas, the neurologist, says a drug doesn't have to be a cure to have a significant impact on patients. "If I have a CMT patient who's 50 years old, that patient will be more disabled by age 60," he says. "If I can treat that person with a drug, and that person is just as disabled at age 60 as they were at age 50, that's transformative in my mind."
While Robert Thomas says he hasn't noticed a dramatic improvement since he's been on the drug, he does think it's helping. Robert is now in an open-label study, which means he and his health provider are aware that he's receiving the drug.
When the COVID-19 pandemic hit, manufacturing and supply chain disruptions meant that Robert was without the trial drug for two months. When his medication ran out, his legs felt unstable again and walking was harder. "There was a clear distinction between being on and off that medication," he says.
Pharnext's current trial will take about a year and a half to complete. After that, the FDA will decide on whether to approve the drug for CMT patients.
As scientists learn more about the PMP22 gene and the more than 100 other genes that when mutated cause CMT, more precise treatments could be possible. For instance, scientists have used the gene-editing tool CRISPR to correct a CMT-causing mutation in human cells in the lab. The results were published August 16 in the journal Frontiers in Cell and Developmental Biology.
Pharnext is also interested in pursuing genetic treatments for CMT, but in the meantime, repurposed drugs may be the best shot at helping patients until more advanced treatments are available.
If you were one of the millions who masked up, washed your hands thoroughly and socially distanced, pat yourself on the back—you may have helped change the course of human history.
Scientists say that thanks to these safety precautions, which were introduced in early 2020 as a way to stop transmission of the novel COVID-19 virus, a strain of influenza has been completely eliminated. This marks the first time in human history that a virus has been wiped out through non-pharmaceutical interventions, such as vaccines.
The flu shot, explained
Influenza viruses type A and B are responsible for the majority of human illnesses and the flu season.
Centers for Disease Control
For more than a decade, flu shots have protected against two types of the influenza virus–type A and type B. While there are four different strains of influenza in existence (A, B, C, and D), only strains A, B, and C are capable of infecting humans, and only A and B cause pandemics. In other words, if you catch the flu during flu season, you’re most likely sick with flu type A or B.
Flu vaccines contain inactivated—or dead—influenza virus. These inactivated viruses can’t cause sickness in humans, but when administered as part of a vaccine, they teach a person’s immune system to recognize and kill those viruses when they’re encountered in the wild.
Each spring, a panel of experts gives a recommendation to the US Food and Drug Administration on which strains of each flu type to include in that year’s flu vaccine, depending on what surveillance data says is circulating and what they believe is likely to cause the most illness during the upcoming flu season. For the past decade, Americans have had access to vaccines that provide protection against two strains of influenza A and two lineages of influenza B, known as the Victoria lineage and the Yamagata lineage. But this year, the seasonal flu shot won’t include the Yamagata strain, because the Yamagata strain is no longer circulating among humans.
How Yamagata Disappeared
Flu surveillance data from the Global Initiative on Sharing All Influenza Data (GISAID) shows that the Yamagata lineage of flu type B has not been sequenced since April 2020.
Nature
Experts believe that the Yamagata lineage had already been in decline before the pandemic hit, likely because the strain was naturally less capable of infecting large numbers of people compared to the other strains. When the COVID-19 pandemic hit, the resulting safety precautions such as social distancing, isolating, hand-washing, and masking were enough to drive the virus into extinction completely.
Because the strain hasn’t been circulating since 2020, the FDA elected to remove the Yamagata strain from the seasonal flu vaccine. This will mark the first time since 2012 that the annual flu shot will be trivalent (three-component) rather than quadrivalent (four-component).
Should I still get the flu shot?
The flu shot will protect against fewer strains this year—but that doesn’t mean we should skip it. Influenza places a substantial health burden on the United States every year, responsible for hundreds of thousands of hospitalizations and tens of thousands of deaths. The flu shot has been shown to prevent millions of illnesses each year (more than six million during the 2022-2023 season). And while it’s still possible to catch the flu after getting the flu shot, studies show that people are far less likely to be hospitalized or die when they’re vaccinated.
Another unexpected benefit of dropping the Yamagata strain from the seasonal vaccine? This will possibly make production of the flu vaccine faster, and enable manufacturers to make more vaccines, helping countries who have a flu vaccine shortage and potentially saving millions more lives.
After his grandmother’s dementia diagnosis, one man invented a snack to keep her healthy and hydrated.
On a visit to his grandmother’s nursing home in 2016, college student Lewis Hornby made a shocking discovery: Dehydration is a common (and dangerous) problem among seniors—especially those that are diagnosed with dementia.
Hornby’s grandmother, Pat, had always had difficulty keeping up her water intake as she got older, a common issue with seniors. As we age, our body composition changes, and we naturally hold less water than younger adults or children, so it’s easier to become dehydrated quickly if those fluids aren’t replenished. What’s more, our thirst signals diminish naturally as we age as well—meaning our body is not as good as it once was in letting us know that we need to rehydrate. This often creates a perfect storm that commonly leads to dehydration. In Pat’s case, her dehydration was so severe she nearly died.
When Lewis Hornby visited his grandmother at her nursing home afterward, he learned that dehydration especially affects people with dementia, as they often don’t feel thirst cues at all, or may not recognize how to use cups correctly. But while dementia patients often don’t remember to drink water, it seemed to Hornby that they had less problem remembering to eat, particularly candy.
Where people with dementia often forget to drink water, they're more likely to pick up a colorful snack, Hornby found. alzheimers.org.uk
Hornby wanted to create a solution for elderly people who struggled keeping their fluid intake up. He spent the next eighteen months researching and designing a solution and securing funding for his project. In 2019, Hornby won a sizable grant from the Alzheimer’s Society, a UK-based care and research charity for people with dementia and their caregivers. Together, through the charity’s Accelerator Program, they created a bite-sized, sugar-free, edible jelly drop that looked and tasted like candy. The candy, called Jelly Drops, contained 95% water and electrolytes—important minerals that are often lost during dehydration. The final product launched in 2020—and was an immediate success. The drops were able to provide extra hydration to the elderly, as well as help keep dementia patients safe, since dehydration commonly leads to confusion, hospitalization, and sometimes even death.
Not only did Jelly Drops quickly become a favorite snack among dementia patients in the UK, but they were able to provide an additional boost of hydration to hospital workers during the pandemic. In NHS coronavirus hospital wards, patients infected with the virus were regularly given Jelly Drops to keep their fluid levels normal—and staff members snacked on them as well, since long shifts and personal protective equipment (PPE) they were required to wear often left them feeling parched.
In April 2022, Jelly Drops launched in the United States. The company continues to donate 1% of its profits to help fund Alzheimer’s research.