I cannot believe we are here, 22 months into an n-of-1 trial using epalrestat to treat Maggie’s rare disease, PMM2-CDG. Quick disclaimer – I’m not a medical physician. I’m mom to Maggie, age 8, PMM2-CDG and co-founder of Maggie’s Cure. Maggie’s Cure was founded by Maggie’s family to help find a cure or treatment for her condition and funded the research that led to the discovery of this potential treatment. Maggie’s Cure partnered with Perlara PBC to found Maggie’s Pearl, an entity working to expand access to treatment for CDGs. Nothing I write should be taken as medical advice.
As a parent, the things you notice are not the same things that others do. We spend nearly every day with her, so gradual changes do not always register with us like they do with those who have infrequent interactions. That very fact is what has made the last twenty-two months so exciting: We have noticed so very much.
Maggie has gotten… well, clever. Clever in so many different facets. We are seeing her draw more and more conclusions on her own, based on the information available to her. She is making her opinions and views more pronounced, specific, and distinguishable. For example, we’ve read the classic children’s book, Guess How Much I Love You? several times and the following conversation ensued at bedtime.
Me: “I love you Maggie!”
Maggie: “I love you to the Moon and back!”
Me: “Well I love you to Pluto and back!”
Maggie: “...well I love you to Mickey Mouse and back!”
(Maggie was apparently unaware of the former planet Pluto, so she assumed I was talking about Disney’s famous animated dog. The next logical step was, of course, Mickey Mouse.)
Her reading has exploded this year. She’s getting much better at her phonics and blending of words and can routinely spell and read any CVC word. It is so much fun to watch.
Maggie’s sense of humor is on-point. She is genuinely funny, can make abstract statements that relate to her life around her that are hilarious, and really enjoys making people laugh.
Even her silliness has become more sophisticated. She will talk to inanimate objects, telling them what she would like them to do. “Come on pink pencil, behave yourself!” she said, pleading with her pencil to not roll off of her desk.
Maggie’s physical development has been progressing fast as well. The communication stuff is so… jarring that sometimes we forget to marvel at the way she is improving physically. For example, in this span we have gone from ‘Difficulty staying upright while sitting on the floor’ all the way to ‘Sits in a standard-issue school chair for hours a day.’ To watch that, and to feel that peace of mind as a parent is wonderful. Her core strength continues to blossom, her balance has never been so good, her endurance has been such a boon for her education: not long ago, a full day of lessons and activities would have almost had to end early, or at the very least would have necessitated a nap directly afterwards. Today, she never naps and is only rarely a bit cranky by the end of the day, maintaining her infectiously positive demeanor.
We have often talked about her improved locomotion- she still mainly four-point crawls around the house- and our big win with that was her lack of face-planting while motoring about the house. Maggie travels fast now. She can get to where she is going almost as fast as we can walk.
You can visually see her progress in these videos, a walking compilation, and a sitting/core compilation. I’m amazed at how scrawny her little chicken legs were pre-epalrestat! Her speed, control, and stability have improved so much over time. We can now use her walker as her primary mode of transportation, where before we were rarely using it. She is getting better control over her body and more stability when we practice walking without her walker. Our goal is that she can someday walk using the support of holding just one hand. Dr. Morava noted at Maggie’s most recent visit, “Wow, she makes steps with minimal support, incredible!”.
Walking Compilation - https://www.youtube.com/watch?v=8fzl5lxWZO0
Sitting Compilation - https://www.youtube.com/watch?v=2espY5kwojQ
In the sitting and core compilation video you see how much her core strength, stability, and balance increase. She more and more often is raising upon her knees to a tall kneel without using any supports. Over this past weekend we even had Maggie utilize a folding chair without any belt or safety strap and as I mentioned before she can sit in a regular school chair at her desk!
One way we notice improvements are in the things we no longer need to do for Maggie. We’re no longer using a bath safety seat, we’re no longer having to dress her or take off her orthotics, no longer strapping her into every chair, no longer feeding her (even cold cereal and milk she eats independently!). While these don’t really appear on any lab test, they are valuable quality of life gains for both Maggie and her family. Maggie has such a sense of pride when she can do things on her own.
From the things we can measure in a lab, things are looking really good. Maggie’s liver enzymes have stayed at or below pre-epalrestat levels. After 6 months of epalrestat treatment, her transferrin normalized while her growth curve has gone up (no more chicken legs!). Mayo Clinic and FCDGC created a poster summarizing the trial results to date that you can see here: https://cdgcare.org/wp-content/uploads/2021/03/NIH-RDD-2021-Epalrestat-Poster.pdf.
Within 3 months of treatment, epalrestat normalized her sorbitol levels which are generally elevated in CDG patients. In this recent paper, Mayo Clinic authors and FCDGC physicians identify sorbitol as a severity biomarker for PMM2-CDG patients: https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.26245. The other really amazing lab work that is published in this paper is epalrestat’s effects on glycosylation over all sugar antennas on proteins in the body, not just improving PMM2.
For those of you anxiously waiting to start the epalrestat trial posted on Clinical Trials.gov, Maggie’s Pearl is hoping to launch very soon. After the initial IND submission, the FDA had feedback on trial design and dosing which have now been adjusted. A resubmission of the IND with a proposed start date of Q1 2021 will be sent to the FDA for final approval soon. The great news is that there will be up to 40 patients instead of the initial proposal of 30. Maggie’s Pearl will host updated family meetings in December and January! In the meantime, do not hesitate to reach out to Ethan Perlstein, CEO of Maggie’s Pearl, directly at firstname.lastname@example.org if you have any questions.