Gene Therapy & Antibodies: Five Takeaways from an Immunologist
Or, some thoughts on how to wipe out antibodies
Last week, I published an interview with Michelle Rengarajan, an immunologist and DMD mom.
Not only was the conversation illuminating, but the subject is relevant to all of us: Gene therapy has the potential to one day be a life-transforming option for everyone with a genetic disease, but our immune systems are undoubtedly one of the the biggest roadblocks. It's why gene therapy can be unsafe for many patients, it’s why people with antibodies can’t safely get treatment. It’s why we can’t redose patients who’ve already had a gene therapy treatment.
In case you missed the full conversation, here are five takeaways from my chat with Michelle:
1. As many as half of eligible Duchenne patients have antibodies to gene therapies
Somewhere between a third and a half of eligible Duchenne patients have natural antibodies to the viruses that are used as part of gene therapies. But it varies quite a lot—by age, by geographic region, and possibly by race.1 Rates are higher in Europe, for instance, than in the US.
Companies working in Duchenne are all using slightly different viruses, too. And that seems to make a difference, too. (Some studies have found that rates are ever so slightly higher for AAV8, for instance, than for AAV9 or AAVrh74.)
2. All the gene therapy companies are using different antibody cut-offs
Some companies, like Regenx, are not including kids who have any antibodies at all. Others, like Sarepta, are including kids with higher antibody levels. Part of the reason is that there’s no universal test; the other part is that we don’t understand exactly why or where the cut-offs should be.
Michelle’s insight: “I think everyone's justifiable fear is that if you include patients who have antibodies above a threshold, and if you are wrong and the product doesn't work, then that patient is going to have gotten a dose of AAV that essentially did nothing because their antibodies interfered. And you've taken away their once-in-a-lifetime shot at gene therapy for no benefit. I think that's why everyone is being quite cautious.”
3. Companies and researchers are trying three different strategies to reduce antibodies that are already in the body
Plasmapheresis: A process where patients are hooked up to a machine via IV, which clears out plasma, the part of blood that contains antibodies. Michelle’s insight: This would probably need to be done repeatedly as part of a course of hospitalization.
Vyvgart: a drug that inhibits the recycling of antibodies, reducing their levels. (This is an approach being supported by DMD patient-advocacy groups)
Imlifidase, a drug that cuts up antibodies. (This is an approach being used by Sarepta-Roche in Europe.)
4. Can we pre-treat and block the formation of antibodies in the first place? (And maybe allow for redosing in the future?)
Plasma cells are little antibody-production factories. Gene-therapy companies are starting to test the use of drugs for multiple myeloma (a cancer of plasma cells) as a way to block the formation of antibodies before giving a gene therapy. Those drugs kill plasma cells, and the thinking is that you if you kill a lot of plasma cells before giving a treatment, your body won’t be able to make antibodies once the treatment has started.
Michelle’s insight:" “[Multiple myeloma drugs raise] some interesting possibilities, like maybe we could start splitting up your dose. So instead of getting a massive dose, which is right at the edge of what’s safe and is pretty high risk, you could split up that dose over multiple sessions over a three month period.”
5. Trials are already starting to treat patients with antibodies
There’s a Sarepta Imlifidase trial in Spain to treat seropositive kids before giving them Elevidys.
There is another trial planned to dose seropositive patients with Crigler-Najjar syndrome.
Read the full interview here.
ICYMI:
PTC announced that the FDA would review its drug application for ataluren, a drug that treats boys with nonsense mutations. It has been a roller coaster for this drug, both in the US and Europe, where authorities had initially approved the drug in 2014 before changing their mind earlier this year. This saga is one to keep following.
Sarepta announced it was not moving forward with its next-generation exon-51 skipper. This was due to a side effect of the drug (hypomagnesemia, aka low magnesium levels). Plus, there are now other companies working on exon-51 skipping, a factor the company cited in its decision.
Capricor announced that it had started filing an application with the FDA for its drug Deramiocel, a cell-based therapy that the company believes improves heart health.
Regenxbio said that it was launching its pivotal trial, following good results in its dose-finding trial. A pivotal trial is supposed to prove whether the drug works, before going to the FDA.
Solid started dosing boys with their new gene therapy. A few years ago, the company paused their early microdystrophin trial to create a new viral vector, the envelope that delivers their manufactured gene into cells. The company believes its newly engineered vectors are far superior at getting into muscle cells. Though they are still working with a miniature version of the DMD gene, I've been thinking about it as a sort of 1.5-generation product.
Satellos, a Canadian pharma company whose medication has promisingly regenerated skeletal muscle in DMD dogs, has started dosing healthy volunteers, the first step for establishing the safety of any new compound. The company said that it expects to dose 10 adults living with DMD in early 2025.
Roche is screening boys aged 8-15 to try its repurposed anti-inflammatory and bone-strength drug. Sites are open in Virginia, Michigan, and Poland.
Novartis (famous in the rare disease world for the SMA gene therapy Zolgensma) bought Kate Therapeutics, a Duchenne biotech pioneering highly muscle-targeted AAV vectors for gene therapy. Watching this space….
Last month, Netflix released The Remarkable Life of Ibelin, a documentary about the life of Mats Steen, a young man living with DMD who found community through World of Warcraft. (More on Mats below.) Cure Duchenne has partnered with WoW to raise funds for DMD research via the purchase of an in-game "Reven Pack.” Spread the word with the WoW players in your life.
Here’s what else I’m reading:
Writing in Pictures, by Chris Ware. As a parent of two toddlers, I go through a lot of books. Wordless books, rhyming books, books that I’m reading for the seven-hundredth time. But my hands-down favorites are by the author Richard Scarry and feature a cast of very busy characters. For everyone who grew up loving Lowly Worm in his apple car or the accident-prone Mr. Frumble, this is a fascinating portrait of Scarry and an argument for why his work is so resonant across generations of readers. (The Yale Review).
The Number, by John Lanchester. A couple of newsletters ago, I recommended Michael Lewis’ profile of a mine-safety visionary. This week, I’m recommending a story from the same series by another writer who can make even the most horribly boring subjects surprisingly readable…? (Aspirations!) This one is about the Consumer Price Index, but it’s also a reflection on the nuance, complexity and political life of data. And it doesn’t disappoint. Fellow data nerds, eat your hearts out. (Washington Post)
An I.V.F. Mix-Up, a Shocking Discovery and an Unbearable Choice, by Susan Dominus. Maybe you read this crazy story of coincidences that went viral last week: Two couples gave birth to and began raising each other’s daughters after a mix-up during IVF implantation. (It was only discovered because the couples are different races.) What happened next was the best possible outcome, but utterly painful. A reminder also that human error can always happen, even in tech we trust. (The New York Times.)
One paper found that African Americans were slightly more likely to have antibodies than Caucasian patients.
Most studies have found that younger patients were less likely to have antibodies than older patients.
A very informative article, thank you!