Updated: Sep 22
June 14th, 2020
Maggie Update – Single Patient IND – Epalrestat for the treatment of PMM2-CDG
Disclaimer: I’m mom to Maggie, age 6, PMM2-CDG. I’m not a doctor, or a scientist, and anything in this post should not be taken as medical advice. I’m simply summarizing our experience from my perspective as a parent. I’m happy to answer questions and share what we’ve learned along the way but it’s from a layperson’s point of view and not an expert opinion. My apologies in advance that this is lengthy. This is a way for me to journal our experience so I can look back and recall just as much as it’s an update for other fellow CDG families.
Hi everyone! For those of you just joining or catching up, you can read earlier posts on the single-patient IND (Investigational New Drug) study on this site. The original post is from “day one” on January 29th and answers many of the basic questions about the study. You can watch Ethan Perlstein’s 2020 Conference presentation on the science behind the study here: https://www.mededonthego.com/Pediatrics/Video/program/572/module/4694.
Now for an update -
It has been 139 days since Maggie started taking 5 mg of Epalrestat three times daily, almost 5 months ago. What a different world we live in now?! Dan and I are so excited to share with you our experience so far.
First, and probably most importantly, we haven’t seen any negative side effects and the drug appears to be safe. What we have seen are some HUGE improvements in Maggie’s speech, muscle tone, and balance!! In terms of speech – we’re seeing improved clarity, increased quantity of words, and more thoughtful content in verbal communication. For example, Maggie was playing hide and seek with her older brother Dexter and he said, “Your turn!”. Normally, Maggie would have just parroted him and said “Lor tur!” - but she didn’t. Instead she said, “My tur! You go hide and I will find you!” We’re still working on final consonant deletion in speech therapy but her speech has really blossomed since starting Epalrestat. School personnel noted this as well. Maggie started Epalrestat at the end of January so she was able to spend the first thirty days or so in class. The aide in her classroom shared that during an exercise where they were practicing the phrase, “We go to” they were selecting images like the park, the pool, and the zoo and saying the sentence. Maggie opted to say, “We go to the zoo because I like to see the animals!” The third example I’ll share is that while hanging out watching a movie I got up to refill my water. As I was walking to the kitchen I asked Dan if he’d like me to get him some water and he said yes. Maggie pipes up and says, “I want water as well!”.
Balance and control are another area where Maggie has improved. She had taken acetazolamide for 6 months and we saw gains with that drug. We had to stop taking the acetazolamide to start epalrestat and I was worried about potential regression noted by Mercedes Serrano when patients stopped acetazolamide. You can watch Mercedes Serrano update on acetazolamide at the 2020 Conference here: https://www.mededonthego.com/Pediatrics/Video/program/572/module/4688. We not only didn’t see regression but saw some really big gains when starting on epalrestat. Of note, we notice only a slight improvement in the “pata, pata” test that you see in Mercedes Serano’s presentation. I don’t think in Maggie’s case it fully demonstrates the significant improvements we’ve seen in her speech overall. Here are some pata pata videos of Maggie if you’re interested:
Maggie can sit more controlled, not as wobbly like before. See two videos below, one from Maggie getting ready for Kindergarten practicing her letter names and sounds. Notice how wobbly she is. The second is from a video just recently where we practiced sight words in almost the same sitting position. Her stability in a sitting position has been really impressive and I think it’s allowed her to better focus on some of our educational activities because she isn’t spending her energy focusing on balance as much.
She is cruising furniture much more stably and even sometimes turning around or lifting one leg in the air in a move she calls “ballerina”. Her walking in her walker is more controlled and I’m hopeful that we can eventually use this as her primary mode of transportation. See one walker video pre-acetazolamide about 9 months ago and one from our latest Mayo Clinic trip for the 3-month update on epalrestat.
Her muscle volume, especially in her lower legs, has increased. She doesn’t have chicken legs anymore! We’ve noticed that her orthotics seem tighter around her calves and we’ll need to get her casted for bigger ones soon. She’s also getting really good at riding her bike – last year she couldn’t peddle it on her own! Here’s a video of a recent bike trip – we’re still working on steering.
Probably one of the biggest gains in balance and control we’ve seen is no more face plants! Maggie’s primary mode of transportation around the house is 4-point crawling and about 5-6 times per day when she was tired or just not being careful enough she would face-plant. It’s awful to see and she never gets hurt too badly because she’s pretty low to the ground but it’s just sad to see her cry in pain and frustration. Epalrestat has made it so she can crawl stable enough to no longer face plant! It seems like something so minor but for her quality of life it’s a huge win. Imagine banging your nose 5-6 times/day!
In addition to all that real-world evidence, at Maggie’s 3-month visit the results of several lab tests confirmed that Epalrestat is working. For example, a lab test that measures the glycosylation of a protein in the blood called transferrin showed a trend toward readings in the normal range. Another lab test that measures a biomarker in urine showed a strong positive result. Finally, a scan of Maggie’s liver showed a healthy result that was actually better than the last time this test was administered when Maggie was 3 years old.
We've been extremely excited by the results we've seen. I honestly didn't know what to expect when we first ventured down our PerlQuest with Ethan and Perlara. Part of me expected nothing and part of me thought we’d find a magic bullet to cure CDG. It ended up being somewhere in between. Epalrestat isn’t a cure for CDG but I believe that it is a potential treatment that can improve quality of life. I’m not giving up hope that someday we will cure CDG and I hope it's in Maggie's lifetime. I know it will be hard to undo damage done and that her cerebellum is already significantly atrophied. I will still hope. As a rare disease parent hope is the fuel that drives us. Sometimes it’s the only thing we have. I’ve found that I have to balance hope with acceptance. I have to accept there are some things we may not be able to do for Maggie, some things she’ll never get to experience that I so very much wanted for the little baby girl that grew in my womb. She still has big hopes and dreams – she wants to be a doctor (like Dr. Eva Morava) and a ballerina. We hope that she will be able to do those things but also have acceptance that it may be a difficult path or may not happen at all.
There are two primary ways that PMM2-CDG patients, and really any CDG patient for that matter, can help drive research. One is to enroll in available natural history studies and the second is to collect fibroblast samples for research testing.
Natural History Studies – there are three to my knowledge, Maggie is a patient in each of them and I would recommend them for different reasons.
FCDGC – This is a collaboration across many organizations and observed by Dr. Morava. Many of the sites that support the Glycomine study will also support this study, however, Mayo Clinic is the only location that has been able to successfully enroll patients so far. Dr. Morava covers this in her 2020 CDG Conference presentation here in addition to a slide that talks about the epalrestat trial!
NIH – This is a week long bear of a trip but they go through every system top to bottom. I am happy to send anyone the schedule from when Maggie attended in 2017. I learned a lot about Maggie on this trip, for example – I didn’t realize that she had some minor hearing loss. I also learned more about blood coagulation levels so I could be better informed prior to her strabismus surgery and that her vaccines weren’t as effective as I thought. To enroll you just e-mail Lynne Wolfe at email@example.com or firstname.lastname@example.org. This study is open to all CDGs and you do not have to be a US resident to participate. The NIH covers your travel costs once you arrive on US soil including food and lodging. You can see Lynne presenting at the 2020 conference this year here.
Glycomine – Glycomine is a company that is working on development of a PMM2-CDG therapy (lipid coated mannose-6-phosphate) and they want to learn as much as they can about the natural progression of the disease in the process. There are several sites around the world that are participating in their natural history study. To enroll you just need to be seen at one of the supporting sites through the doctor listed. I enrolled Maggie through Dr. Morava by e-mailing her at Morava-Kozicz.Eva@mayo.edu. Glycomine presented at the latest conference and you can see a video of the presentation here: https://www.mededonthego.com/Pediatrics/Video/program/572/module/4686.
Many of the studies, especially Glycomine and FCDGC, are collecting your information from regular routine care that would be done anyways. In the NIH study there are some tests and scans that wouldn’t “normally” be done as part of routine care, however, I didn’t find it to be extremely invasive and I learned some things about Maggie that we didn‘t know before.
Fibroblasts – These are collected through a skin biopsy outpatient procedure. Fibroblasts are used in research a lot. I went through the biobank Coriell – they house and sell fibroblasts to researchers. If you choose to collect your child’s fibroblasts and submit them to Coriell, they permit you to send one set for free to any place of your choice. Here is the link with info on how to collect and submit. We sent our free copy to Mayo Clinic so that Eva could study the effects of Epalrestat on Maggie’s cells. Her mutations are E139K and R141H and Epalrestat had a 400% boost in enzymatic activity. You can read about it it in the research paper here (see Figure 6). Maggie’s fibroblasts are on sale here!
The fibroblast collection is fairly simple and didn’t seem to cause Maggie any discomfort. They numb a section of the body (usually the forearm) and take a 3mm “punch” of tissue. For reference here is an image of 3mm in earring sizes. The punch does leave a scar but it’s minuscule. See Maggie’s scar pictured below.
When Maggie was first diagnosed, I was terrified. We had already lost our first daughter and I wasn’t, and am not, prepared to lose another. I so badly and desperately scoured the internet in search of answers, in search of treatment options, in search of hope. I would have done anything for someone to give me some guidance on where to start or what I could do. So I hope that this is in some way helpful to other families. Like I said, I’m not a doctor, a scientist, or a researcher and you should consult with your own physician. If your interested in talking more, please feel free to reach out.