August 26th, 2020
n=1 Epalrestat Trial for the treatment of PMM2-CDG 6-month Update
Disclaimer: I’m mom to Maggie, age 6, PMM2-CDG. This post is based on my interpretation of Maggie’s progress and should in no way be taken as medical advice. You should consult with your doctor about any treatment options or available drug trials.
A little over 6 months ago Maggie began taking 5 mg of epalrestat 3 times daily in a Compassionate Use Single Patient IND (Investigational New Drug) Trial. Epalrestat is a 30-year-old generic Japanese drug and aldose reductase inhibitor used in geriatric patients with diabetes to treat peripheral neuropathy. Peripheral neuropathy is often associated with PMM2-CDG and something Maggie has at a moderate level. We discovered this drug through our partnership with Perlara and Dr. Ethan Perlstein whose team built model organisms of yeast, nematodes (worms), and fruit flies. The team then built assays, which are ways to measure and compare sick organisms to healthy ones. In yeast, the assay was cell growth while in worms growth and developmental timing was used. High-throughput screening showed which small-molecule drugs had a positive impact on the organisms. Epalrestat and naturally occurring aldose reductase inhibitors were hits not only in yeast and worms, but also in patient fibroblasts. In fact, Maggie’s own fibroblasts (skin biopsy cells grown and cultured) showed more than a four-fold increase in PMM2 enzymatic activity after treatment with epalrestat. You can read about the research here: https://dmm.biologists.org/content/12/11/dmm040584.
One important impact this IND study has had is the discovery of a new biomarker for PMM2-CDG patients. Its level is elevated in approximately 70% of PMM2-CDG patients seen at the Mayo Clinic and has not been previously reported. Epalrestat has brought Maggie’s elevated level of this biomarker to a normal range.
To say we’ve seen a positive impact in Maggie’s quality of life would be an understatement. I try to stay level-headed and balanced about gains we’ve seen but at this point the evidence is so overwhelming that I think I can finally allow myself to be excited and happy about her progress and shout it from the rooftops! Here is a summary of progress we’ve seen:
Maggie’s speech has just exploded under epalrestat and has continued to blossom as time goes on. She’s hilarious – and more importantly, intentionally so. I can have conversations with her, something that I couldn’t do before and you simply can’t put a value on that. It’s a huge thing for our lives and I’m so grateful. Maggie now talks about relevant topics with a larger, more robust vocabulary of words. Her response times have improved and there is less processing delay in conversational exchange. The complexity of thought behind her communications continues to wow us each day. Here’s just a few examples of speech that really highlight this:
Dan and I are playing a video game together. Maggie just got up from her nap and comes out to the living room.
Maggie: Mommy, what are you doing?
Me: Playing a game with Daddy.
Maggie: Can I play?
Me: No sweetie, you’re not old enough.
Maggie: Mommy, I am six years old. You have to be five years old to play.
The processing requirements for her to set a fabricated age limit for the game that was less than her age is astonishing!
Just yesterday, Maggie was cleaning her room. She comes out with something in her hand.
Maggie: Mommy, you won’t believe what I found in my room.
Me: What is it sweetie?
Maggie: It’s a screwdriver.
She actually found a screw, but the amazing thing to me is her sentence structure and using the phrase “you won’t believe”. I don’t know where this is all coming from!!!
She’s talking about more relevant topics and is excited that her dad is ordering her and her brother a basketball hoop for the driveway. She asks him each day, “Daddy, how many days until my new basketball hoop gets here?”.
These sentences are so long and complex and so beyond anything like her speech was before.
Maggie’s fine motor has steadily improved while taking epalrestat. She has improved pincer skills and can grab her pill easily. Probably most striking though is her coloring. Maggie only scribbled before – she now colors in the lines! To great detail! You can see before and after pictures in this post. It stopped me in my tracks when I looked at the pictures she’s colored.
She’s also drawing much better. Again – before drawings were just scribbles. Now there are recognizable things that are relevant to and reflective of her life. See this image she drew of Dan. 😊
Most impressively, is this picture she drew after helping prepare scrambled eggs. While cleaning up from breakfast, Maggie opted to sit at her desk to do some free drawing and actually drew out what she had just done with no prompting. She described her drawing in detail afterwards.
See writing samples below. Her letter formation is less shaky and clearer with smoother lines. She did the most recent sample without a model.
She’s able to use more complex apps on the iPad with her improved skills and continues to do better and better.
I’ve talked about in previous updates the progress she’s made by having zero faceplants but it bears repeating because it has such a positive impact on her daily life. Maggie’s primary mode of transportation around the house is four-point crawling. She used to face-plant 5-6 times daily when she would get tired or when she just was going faster than her arms could be securely placed beneath her. This would result in crying and consoling and it’s a miserable thing to witness. I hated the face plants – there was nothing I could do for her. I could put a helmet on her but unlikely one that could protect her face and that she’d tolerate. This quality of life gain in and of itself is worth all of the work it took to get to this point.
Maggie has improved greatly on her bike riding. She switched from a bike with a handle in the back that we would push and steer for her. She was not strong enough to peddle on her own. She’s now in a bike that doesn’t have a push handle and requires her to peddle. She can not only make that thing go but she can steer and is even doing some (with close monitoring and advisement from PT) without being buckled!!
Video riding her new bike: https://youtu.be/kw3-lxFdDgk
She’s asking to walk more and more and we’re able to hold lower on her body to support her – at her pelvis vs. trunk or arms. We’ve installed a railing down the hallway that she now uses multiple times per day and will lift one leg up in what she calls a “ballerina” move.
She’s much faster at crawling now and more stable. She’s also more stable at sitting. She can sit on the edge of the ottoman and balance (without hands) while I brush her hair. Before epalrestat, Maggie needed both hands to support her to sit on the ottoman and even then we would need to be near her to “spot” her. Here she is today sitting with no hands! See this video of her putting arms out and touching nose. Dr. Eva Morava had her do this at her 6-month exam and I couldn’t believe how awesome she did!
She’s getting dressed more independently and just overall has more energy and is more active. Her use of her gait trainer has improved so much that we can now use that as her main mode of transportation when we go to the Mayo Clinic. Check out this compilation video – note Maggie began use of epalrestat January 29th, 2020.
I mentioned the new biomarker that was elevated previously and is now normal but it’s also critical that I note her transferrin levels are NORMAL – that’s right – NORMAL!!!! Transferrin is a common test done in CDGs to compare the ratio of deficient to mature fully glycosylated oligos. I don’t know what exactly an “oligo” is but nevertheless…Maggie has never had a normal result until this last one. It’s important to note that transferrin does typically normalize in PMM2-CDG patients, but this is usually happening after puberty. It is unique that a PMM2-CDG child age 6 years, 11 months would have normal transferrin. In natural history study data, the youngest known PMM2-CDG patient with normal transferrin is age 11 and is very mildly affected with the ability to walk and talk.
Her liver function tests and fibroscan results have remained stable and she does not appear to have any negative side effects of the medication.
She’s seemed to have better growth while taking epalrestat. We notice thicker legs and her IGF-1 (a growth hormone) results have gone from 83 to 111 and Z-Score (standard deviation from 50th percentile) has improved from -0.84 to -0.39. See this chart of her weight (in pounds) over time. This is with no change in diet.
It seems very possible, that based on Maggie’s results, there will be an expanded trial to allow other PMM2-CDG patients (likely age 4-17) to take epalrestat and see if there is safety and improvements. My greatest hope is that others can experience some of the amazing gains we’ve gotten to see in Maggie. Many of these gains are difficult to measure and hard to know what’s a drug’s effects and what is natural development but to my fellow parents out there – sometimes you just know. I know Maggie wasn’t making these types of gains before and I truly believe that this major jump in her progression is because of epalrestat. Additionally, lab results are improving as well and although the natural history of PMM2-CDG is not yet thoroughly studied and documented, I think that these things aren’t part of the typical course.
If you think you might be interested in participating in the expanded trial, my advice (as a parent) is to enroll in the natural history study through FCDGC by e-mailing Dr. Eva Morava at Moravaemail@example.com. You should also get fibroblasts collected if you haven’t done so already.
I’m hoping to host a webinar later this month to go through Maggie’s experience and have lots of Q&A time for any families out there wondering about different aspects of clinical trials or the drug discovery process. I’m not giving up that we can cure CDG. This is just one small step towards that dream.