January 29, 2020
Disclaimer: This post is from me, a mom of a child with PMM2-CDG. This should in no way be construed as medical advice and is my layman’s understanding and interpretation of CDG research and drug development.
Today is the day! Day one of a brand new clinical trial for a potential treatment of PMM2-CDG. It is surreal to be in this moment and is the result of many, many talented and kind people over several years. We have not yet reached the mountain-top but this peak is pretty awesome and worth noting! I would be remiss if I did not thank the following individuals, and I’m likely missing many others – firstly, Ethan Perlstein and his entire team at Perlara including Sangeethaa Iyer, Feba S. Sam, Nina DiPrimio, Kausalya Murthy, Zachary Parton, Hillary Tsang, Jessica Lao, and Josh Mast. Of course, I must thank Dr. Eva Morava who will be the Principal Investigator and whose love and compassion for her patients knows no bounds. Others at Mayo Clinic who have been so helpful in getting us to the finish line
(really the starting line in so many ways) include Connie Kruger, Graeme Preston, Jan Verheijen, Kaitlin Schwartz, Anna Ligezka, Katie Reed, Patrica Graumann, and Joel Reid. Thank you to Hitoshi Yanaihara and Akita Oh who were instrumental in assisting us to get the drug from Japan to the United States, Sigi Caron who assisted in development of the IND to the FDA for approval and continues to consult and guide, and Matt Might, one of the most brilliant and kind humans I know, who first connected us to Perlara. I also need to thank my family who put a lot of their own money towards funding this research and have shown their unwavering support in our quest to find a cure. Bonnie, Thee, John, and Jill – thank you! Natasha Moreno, at times my literal right-hand, for your support both professionally and personally. Last but not least, and I’m sorry for anyone I may have forgotten, Maggie. I must thank Maggie for her tenacity, her never-give-up attitude, her bravery, loving spirit, and making me one of the luckiest moms in the world.
Here we are – IND Day One! Maggie took her first dose of epalrestat at 7:00 AM Central Standard Time this morning – we finished our first blood draw of the day at 8:00 AM which will tell us how much of the epalrestat is in her system. What a historic moment!
What is an IND?
IND stands for “Investigational New Drug” and is the first clinical phase of new drug trials. The general process for drug development is:
Basic Research --> Preclinical Development --> IND --> Clinical Development Phase I (Safety), Phase II and III (Effectiveness) --> NDA --> FDA Review --> Approval
What is Epalrestat? Epalrestat is a Japanese drug developed in the late 90’s that is used to treat geriatric patients for peripheral neuropathy caused by diabetes. It’s never been used in the USA.
Isn’t peripheral neuropathy a symptom of PMM2-CDG? Yes, peripheral neuropathy is when nerves in your extremities are damaged and can cause numbness, pain, lack of sensation, and weakness. It is a symptom of PMM2-CDG and is measured and monitored through EMGs.
Is Epalrestat safe? The drug has been around for a long time, which is reassuring. We’ll be monitoring for any adverse affects closely, especially with the liver. Of note, in Japan it is used for geriatric patients and this is the first known use in pediatrics. Dosing has been adjusted accordingly but safety will be the first priority of the study.
Can other patients take it? Not at this time. The FDA approved a single-patient compassionate use IND. The hope is that if the drug is safe and shows positive clinical outcomes we can expand the IND to allow more PMM2-CDG patients a chance to join the trial. There is no estimate on how long this may be but the shortest timeframe would be 6-12 months minimum.
How will you measure results? The study will look at blood labs, vitals, and the Nijmegen Pediatric CDG Rating Scale (NPCRS). Additionally, clinical evaluations will include ICARS (International Cooperative Ataxia Rating Scale). We’ll also be hoping for our own goals for Maggie which are to walk more steadily with her gait trainer or with one handed assistance, work towards potty training, and have her speech more clearly understood by strangers.
How soon will you see results? We don’t know. Of course, we’re hopeful that results will come soon but we’ll be in the study for 12 months with the NPCRS completed at the start, 6 months, and 12 months.
When will the FDA approve it? Really, the question should be “if”. First, the drug would need to show that it is safe, then it’d have to have some positive clinical impact, then the IND would have to be expanded for more patients that also showed safety and effectiveness. Then…we’d have to submit an NDA (New Drug Application). Likely, all of that would take 2-3 years at the minimum but I am hopeful.
How did you find Epalrestat? Perlara discovered Epalrestat as a potential drug candidate during a research project funded by Maggie’s Cure, a company our family founded to help find a treatment or cure for PMM2-CDG. The research consisted of the creation of model organisms with PMM2-CDG (yeast, worm, and flies) and high throughput screening of compounds to find one that had a positive impact on the model organisms. A high throughput screening, in laymen’s terms is simply a method of “try all the drugs!” to see if anything works. Ethan Perlstein, Founder and CEO of Perlara, led the “Perlquest” and is the commercial sponsor of the IND. You can read and download the published research here for free: https://dmm.biologists.org/content/12/11/dmm040584
How do you know it will work in patients? The short answer is, we don’t. That’s why we’re doing the IND. It worked across multiple model organisms, which is promising. It also worked in patient fibroblasts. Maggie’s fibroblasts in particular showed a 4.06 fold increase in PMM2 enzyme activity. That means that with Epalrestat her fibroblasts had 4x more good PMM2 enzyme activity than without it. This is all positive and supportive that it could work in patients, however, the human body is complex. We simply won’t know until we try.
Is this a cure? Likely not. PMM2-CDG is a multi-system complex rare disease. It is difficult for one thing to be a cure all, however, this drug does appear to address the underlying issue of PMM2 enzymatic activity. If it can successfully boost this in the body globally it could have a positive impact. My personal (and non-medical) opinion is that a “cure” or significant treatment for PMM2-CDG may end up being a cocktail of drugs that support and boost enzymatic activity and production.
How will we stay updated on this study? I will try to keep everyone updated the best I can on Maggie’s journey throughout this study. The study will formally check in at Day 30, 60, 90, 6 months, 9 months, and 12 months after dose one. Maggie will be coming with me, her dad, brother, grandma and grandpa at the CDG Conference in San Diego in February. Ethan Perlstein will be presenting on the research. I’ve tried to have this post cover all of the initial questions I would have if I learned there was a new IND for PMM2. If there are other questions you have, please let me know and I’m happy to add them and answer the best I can. I feel so incredibly lucky, guilty, scared, hopeful, and amazed that Maggie gets to be the first to try something that could help treat CDG.