A new story from Sounds of Science
And it was actually a very depressing time. Because the we were really weren't addressing the actual viral Lyra load The toxicity of the drugs was terrible. Act Up was protesting and very rightly so and before Internet. If you you think about it they were passing out pamphlets. They were educating themselves on the nature of virology and the difficulties of the immune system. And they we're being extremely effective in getting FDA NIH is attention by that time and so the antivirals group was actually invented to be very. Are you proactive group to embrace. Those patients needs and to speed up. The approval look drugs so I actually cut my teeth in the process of public health the crisis on high risk disease. And I've never left field. I've always felt very strongly that patients had an unmet medical need needed to get the fastest Access to drugs after seeing upfront personal with the what they were up against so why is the FDA's rigorous testing so necessary. Well I I think you're aware that a lot of drugs fail From safety concerns we all know about getting sleepy with antihistamines. Or you know that's the actual aside side effect that comes from the action of the drug on the brain. That's at the senior centers that we would like to counteract allergy. So that's what we call pharmacologic based aced toxicity. It's an effect actually on the target. But it's in a way that we don't want it to act GOTCHA. So as we're working on very new drugs we often don't understand like where there's receptors are in God or the brain or the immune system. There's a lot of things we don't understand about the basic mechanisms of action of disease and there's lot of things that we don't understand sometimes about where the receptors are in the buddy. I mean it seems great. Yeah but that's why. I'm kind of glad if my original training and classic Comic Anthology Because you have to ask questions okay. where else is the receptor? Who else could hit end so? FDA trained to think about those nightmare scenarios of what it could do that. You don't want it to do right and ask those hard questions to make sure that we have the checks and balances right a lot of the early drugs That were used in AIDS. Patients Cause Peripheral neuropathy and that wasn't shown very well in the animal models models but it caused intense pain in the patients at the same doses that was needed for the virus. It wasn't until later that we got the protease inhibitors that really counteracted the road. And that's the basis of the lifesaving therapies that we have today I was really fortunate to be. FDA during that time when the protease inhibitor came through so switching gears a little bit what is personalized medicine. When it comes to patients like for example adjacent armstead and meal Amac? I understand that Jaycee is a twenty five year old with Lou GEHRIG's disease while meal is a young girl with batons disease who have both recently benefited from personalized medicine. He I think we have come to the place in drug development where we understand a lot more about genetics of disease so so yes switching away from viruses and into genetic Madison we have a lot of inborn errors when we learned that there is an inborn Gene that was missing in a patient has always been there born like that and as soon as we can diagnose them and with that replacement gene product or the enzyme of interest interest. We can save their lives so. LS has also been learned to be a whole series of different mutations responsible for LS Um and so you have to look at those different subsets according to their genetic diagnosis. But we also know that Batten's disease is a specific mutation and there's also something like fourteen different forms of Batten's disease that are mutations in same pathway that result in the same type of phenotype of neurological article degeneration some earlier some younger and some an older kids or adults in the case of Mula. She has two mutations that are different on both of the wheels that caused the dysfunction of a particular protein. Batten's disease six seven and there's only a handful or double handful of kids worldwide. They're known to have that particular subtitled batons and Jaycees case she has a very aggressive form of al it lasts called F s mutation and it has a particularly bad course people with F.. US typically sadly succumbed LS typically approximately a year. Because it's so aggressive. It's very hard to intervene soon enough. And there has never been a medication that could actually address the fundamental gene problems in these two cases so we need to design whole new the truck when we find the particular mutation and it turns out depending on the molecular biology and that control mechanisms around them. A tation some all of them are amenable to go nuclear type therapy and both of these girls have been their particular. Genetics have been amenable to A strategy she of using nuclear tight enter equally sadly we did not know that. JC had this particularly bad ale ass us until she was twenty five. Her family had lost her twin sister at the age of seventeen and Alex add add. Actually he contracted the symptoms of L. S. at age eleven so the two girls were identical. They had the same mutation but one got symptoms at eleven on the other at twenty five. JC I guess Through some grace right. Her symptoms arose during time in which a drug was already available in unaccompanied show that happened to be appropriate for her. So I understand and that in this case she got lucky. Well in a way because the drug already existed otherwise we couldn't have intervened quickly enough. Yeah it was an act of considerable effort on the part of the patient advocacy group project. LS The head of Columbia University's LS LS center. Dr Neil Snider in the company who originated the drug and all of us that were helping around the sides trying to support like an exoskeleton including Charles forever and I was helping with the regulatory strategy and also trying to make sure that the drug that was chosen was actually appropriate to the most expedient animal model so as a result of that we were able to put together a very lean and mean I N D for JC and get her approved through the FDA. I have to say. FDA was understandably cautious but when they heard her situation detail and how she'd lost her twin sister the understood of course about a few and they made a lot of exceptions to the usual toxicology regulations. Well I know that she had been she and her family. They had been advocating pretty publicly for a while up until it was approved. I if I'd been in her mom shoes I would have done the same thing called. She lower local congressman. The Stephen King and there was actually quite a response. In Congress. There is a bill that was put forward to ask. FDA to move expediently for JC. I don't know that that had specific impact but just to say that they got some considerable public discussion. And how Camilla's case different in her case Tim you At Boston Children's Hospital recognized that her condition was suitable for an exon skipping being drug very similar to Isis Been Raza and he was able to use a similar backbone and design a drug from scratch within several months it was quite remarkable global. We've done the testing for it and then we've Were able to get started with just a acute data and then I designed a type of a program in which we would update the FDA very regularly on the progress of the toxicology studies so that we could extend her dosing and again. FDA's group group that does an enzyme replacement was wonderful. In working with us to customize that I approach how do you envision cases like these being handled in the future after all not everyone. Everyone has a congressman. That's willing to go to bat for them. Like Jaycee did not. Everybody should take one. There's definitely a sea-change coming is really exciting. And it goes back to the changes brought about by the AIDS patients who identified that they were an extreme unmet medical. Need we see the finalization of the L. S. guidance. We see a lot of guidances have come out on rare disease from the agency in the past twenty four months. And I'm very excited about this because we're really getting to the place where we custom tailor the amount of upfront non clinical research. That has to proceed to human trials customize. That the patient's situation well do you think that each was going to require its own uniquely designed non clinical research at will or will there kind of. Okay you're not gonna be able to have like a standard version that works for most Aso's typically called platform toxicology in kind of a dream. Right now when you look across all a good nuclear tides you find out remember. I mentioned early in this talk about the pharmacologically driven toxicity. Let's say there's another place in the genome that has has a similar sequence. We end up having the drug acting by its intended action bit at the wrong place which is an off what we call an on target but unwanted toxicity existed that could arise by modulating genome which is a little scary right to put something into the spine or once. You invoke gene therapy. What's done is done so you need to have really careful toxicology evaluations that look at the animal as if it were a miniature clinical trial? And you know you're basically siklie handling the animals has patients and so we get as much information as we can vary from each particular experiment and try to make sure that Ed's translation Lee accurate for predicting patient risk. We need the parents to know that right. If if you were me. Resigning are up to our child. An an in-and-out shoes you have to. You have to feel as if you've done the best job possible to.