DRUG REPURPOSING is the use of an FDA approved compound to treat a condition for which the drug was not initially intended.
There is a long record of pharmaceuticals being used for expanded reasons; famously when the glaucoma medication bimatoprost had the side effect of growing longer eyelashes, it was re-branded as Latisse and is now widely available for this purpose.
Drug Repurposing is appealing to rare disease groups like ours because developing a new drug in the United States will cost at least $35 million dollars. In the case of ADSLD with only 150 patients worldwide, the profit margins are just too low for companies to benefit. Not only does repurposing save patient groups a vast amount of money (Phase 2 of this screen cost just over $37,000), but it can shorten the time to treatment by several years. For patient groups like ours that have some very sick kids, this was absolutely our best shot at a life-saving therapy in the shortest amount of time.
In addition, the drug repurposing screen only tested compounds already in use with known safety profiles. Although many of these drugs have not been tested in children, we know they are generally safe for humans.
WHAT WILL WE DO WITH THESE RESULTS?
We received 27 new potential drug therapies for ADSLD in this screen. Fortunately, Rare Birds Foundation is working with research teams who are able to test these compounds in animal models (pending grant funding, fingers crossed!) What we hope is that we receive a "Proof of Concept" for some of these drugs, which simply means we would know whether the drug works in an animal affected by ADSLD. (The screen was performed on a strain of yeast that was given ADSLD by completely 'knocking out' the function of the ADSL gene.)
Once we "prove the concept" we will know what compounds warrant further testing, and we can begin testing in larger animals, like mice, that have bodies more like humans.
WHAT DOES THIS MEAN FOR FAMILIES?
Every family will make their own choices based on what is best for their child. Rare Birds Foundation seeks only to give options to families who have never had them before. Here are some choices that could be made:
ASK FOR A PRESCRIPTION -- Families in the past have been successful getting prescriptions for Allopurinol, a compound that was ultimately proven to be ineffective in the treatment of ADSLD, but was known to be safe. This can be done for any compound we are investigating, if the family and their doctors are comfortable. In the U.S. you can ask your doctor to prescribe a compound as an "I.N.D." or Investigational New Drug. This program is also called "Compassionate Use" and can be approved if your child is very sick and no other options are available. Whether a doctor will choose to do this is based on their own risk level, knowledge of the disorder, and access to data on the efficacy in animals.
WATCH AND WAIT -- Families may choose to wait for more data in animal models, or wait until other children have tried it first. It is a personal choice and depends on factors including the overall health of the child, other medications they are taking, or even parental trust in the scientific method or their medical team. Some may choose to wait until FDA approval of the drug for use in patients with ADSLD.
OPT OUT -- Some families may come to a place of acceptance and decide to let their child live out their natural life with the disorder. This is also a beautiful and valid approach. It should be noted that this has been the only option for families thus far and Rare Birds Foundation seeks to support families in their journeys, no matter what path they choose, or what path chooses them.
SO...WHAT ABOUT DISULFIRAM?
Disulfiram was the winning compound from the first round of screening. Also known in the States as Antabuse, this drug had previously been used for alcohol cessation, as it causes a violent reaction to alcohol. The drug has sat largely unused for many years.
Wendy Hanna-Rose from Penn State has "proved the concept" in worm models, and the data is very striking. Disulfiram seems to improve movement symptoms in the worms, but does not improve other symptoms of ADSLD that are present.
In addition, a Rare Birds family has had their daughter on Disulfiram for nearly 8 months. This is known as an "N of 1" trial because it is only a single participant trialing the drug. Anecdotally, the family reports improvements, but we are awaiting results from urine tests to see if the drug is decreasing toxic compounds. It is vital that children trialing a drug receive this testing before starting the drug and again after, as it is important to illustrate clinical endpoints when we take a drug to the FDA for approval. The FDA does not accept "my child seems better" as strong evidence worthy of drug approval. They need measurable, compelling results. I am so thankful to this family for bravely taking this first step towards a treatment.
It is widely accepted that drug treatment for ADSLD will require multiple compounds. Because the ADSL enzyme works in two places in the purine synthesis pathway, we see multiple issues that need correcting. We are hopeful that Disulfiram, in combination with one or more compounds discovered in our latest Drug Repurposing Screen, will finally offer families a way to help improve the lives of their children.
Comments