Kennedy's Disease Chat Mitschrift (gekürzt) vom 21.01.2006

Besonderer Gast - Di Prospero, M.D., Ph.D. beantwortet Fragen

Leitung: Bruce Gaughran

Leider erlaubt es meine Zeit momentan immer noch nicht, die Texte ins Deutsche zu übersetzen. Daher muss ich diese Mitschrift leider auch wieder vorerst nur in Englisch veröffentlichen. Aber er ist wieder so interessant, dass ich nicht darauf verzichten möchte, ihn auf die Seite zu stellen.

Die wichtigsten Inhalte und Informationen möchte ich trotzdem versuchen, in Kurzform auf Deutsch hier aufzuführen.

Die entscheidende Botschaft dieses Chats ist die Ankündigung einer klinischen Studie über 2 Jahre mit mindestens 50 KDs aus den USA und Kanada, die im März oder April 2006 starten soll.

Die Studie wird “doppelblind” durchgeführt, d. h. die Hälfte der Teilnehmer bekommt das Medikament, die andere ein Placebo (Zuckerpillen). Weder die Patienten noch die Ärzte wissen während der aktiven Phase der Studie, wer das Medikament bekommt und wer nicht.

Eingesetzt wird als Wirkstoff Dutasterid, das unter dem Markennamen Avodart^® bereits zugelassen ist zur Behandlung von gutartigen Vergrößerungen der Prostata.

Der Wirkstoff Dutasterid ist ein 5-Alpha-Reduktase-Hemmer. Dutasterid hemmt die Umwandlung von Testosteron in Dihydrotestosteron durch eine Blockade des Enzyms 5-Alpha-Reduktase. Dieses DHT scheint einen wesentlichen Anteil am Nervensterben bei SBMA zu haben. Dutasterid (Avodart^®) hat eine lange Halbwertszeit von drei bis fünf Wochen, innerhalb von 24 Monaten reduzierte Dutasterid damit den Serum-DHT-Spiegel um mehr als 90%.

Im Gegensatz zur nicht erfolgreichen Studie in Japan mit Lupron wird also nicht das Testosteron, das durchaus auch wichtig für die Erhaltung der Muskeln ist, reduziert, sondern nur das DHT bekämpft, das den Nervenzellen schadet.

Nebenwirkungen: Im Vordergrund stehen die antiandrogene Nebenwirkungen > Impotenz (6%), Libidoverlust (3,7%), Gynäkomastie (1,3%) und Ejakulationsstörungen (1,8%).

Über das Vorkommen von Langzeit-Nebenwirkungen sowie weniger häufiger Nebenwirkungen ist zurzeit nichts bekannt.

Positiv getestet wurde Dutasterid bereits an Fruchtfliegen, Untersuchungen an Mausmodellen folgen - oder laufen bereits.

Wenn die klinische Studie positiv verläuft, ist relativ schnell danach mit einer Freigabe von Avodart für die Anwendung bei SBMA zu rechnen, da das Medikament selbst ja schon seit 3 Jahren im Handel ist.

Dr. DiProspero sind neben seiner geplanten und der beendeten Studie in Japan keine weiteren geplanten Studien bekannt, so dass unsere Aufmerksamkeit ganz besonders auf diesen Versuchen ruht!

Hier nun die gekürzte Chat-Mitschrift auf Englisch

	Bruce	The KDA would like to welcome Dr. Di Prospero to our chat room this morning. Today's topic is the: "NIH Drug Development Programs and the upcoming Kennedy's Disease Trial" For those of you who missed it, here is a brief bio of Dr. Di Prospero. He received his MD from the University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School and his PhD in pharmacology jointly from UMDNJ and Rutgers University. Following training in internal medicine at Georgetown University, he received a fellowship in clinical pharmacology from NIGMS and joined the Neurogenetics Branch with Dr. Fischbeck at NIH in 2003. He currently investigates mechanisms underlying polyglutamine pathogenesis and conducts a variety of clinical trials for neurodegenerative disseases
	Dr_D	Happy to be here in cyberspace.
	murf	How are our flies? LOL
	Bruce	Dr., can you give us an update on current KD research?
	Dr_D	Our lab been studying the androgen receptor for many years and so we were very excited in 1991 when Drs. La Spada and Fischbeck found the mutation that causes Kennedy's disease was in the androgen receptor gene. We study the polyglutamine-expanded receptor protein in cells in the lab.
	murf	So I guess our recycle bins are full??
	Dr_D	In our lab (Fischbeck), there are people looking at different pathways involved in cell death and thereby ways to interrupt the process.
	Bruce	Are you using fruit flies or mice?
	Dr_D	Additionally, Dr. Chen and I are starting the clinical trial using Dutasteride. We should begin end of March/April. We are using a cell line. I do collaborative work with Dr. Taylor using the flies
	Bruce	We know Dr. Taylor well here at the KDA. What is Dutasteride normally used for?
	Dr_D	Dr. Taylor has made a very interesting observation using his flies and ones I have generated as well which we believe may point us to an effective therapy but I will let him chat about this.
	Bruce	Dr. Taylor will join us in June as our guest.
	Dr_D	Dutasteride is marketed for benign prostatic hypertrophy.
	Terryw	So it's already and FDA approved drug?
	murf	If their is anything we can help you with related to the clinical trial please just let us know.
	Dr_D	It is a very safe drug taken once a day
	LouLou	What is prostatic hypertropy?
	Dr_D	prostatic hypertrophy is enlargement of the prostate gland which results in urinary difficulty.
	Bruce	Is there some part of the drug that makes it look advantageous for a treatment for KD?
	Terryw	How many KD individuals do you have signed up for the clinical trials, and how long will it last?
	Dr_D	We hope the KDA will spread the word for the trial and help us get volunteers for the study; the faster we recruit patients the faster we can complete the study.
	Bruce	Dr, we are going to discuss how we can help in today's Board meeting.
	Dr_D	We will need 50 volunteers and it will run for 2 years for each patient.
	Terryw	do clinical trials cover travel expenses?
	Bruce	We believe we can get the word our to several hundred possible candidates.
	Dr_D	We cover travel, lodging, and $20/day for food.
	LouLou	We have been involved with Dr. Chen since she first said she was going to have a clinical trial. How can we help?
	Bruce	all of us at the KDA, we will do everything possible to support your work.
	Terryw	I know that some Canadian KD individuals were interested. Does it cover those in Canada
	Dr_D	Yes. Canadians are welcome
	LouLou	Is there a cap on travel expenses?
	Dr_D	No cap.
	Terryw	how many time a year would travel be for the trial?
	Bruce	For those that joined us late: The KDA would like to welcome Dr. Di Prospero to our chat room this morning. Today's topic is the: "NIH Drug Development Programs and the upcoming Kennedy's Disease Trial" For those of you who missed it, here is a brief bio of Dr. Di Prospero. He received his MD from the University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School and his PhD in pharmacology jointly from UMDNJ and Rutgers University. Following training in internal medicine at Georgetown University, he received a fellowship in clinical pharmacology from NIGMS and joined the Neurogenetics Branch with Dr. Fischbeck at NIH in 2003. He currently investigates mechanisms underlying polyglutamine pathogenesis and conducts a variety of clinical
	Dr_D	would see each patient every 6 months.
	murf	I just talked to John and he said he would shot us an e-mail before the BOD meeting on the conversation he had with NIH. Nick were you in on that conversation?
	LouLou	A lot of KD'ers will be glad to hear that. Many are not well off enough to spend a lot out of pocket to join the trial.
	Terryw	The trial is in MD correct? state
	Dr_D	Dutasteride looks promising because it blocks the formation of the more potent more of testosterone called DHT. This enzyme is found in motor neurons but not muscle. We believe it will protect the neurons while sparing the muscle. Dr. Taylor and I have good evidence in flies that this will be effective. No, murf, I wasn't in that conversation.
	craig_h	when would patients know if they are a part of the trial? Dr. Taylor gave you my name Dr_D
	Bruce	After the BOD meeting today, we hope to put out an email to all registered associates explaining the trial and asking if they are interested.
	Dr_D	As soon as we have NIH approval (probably early March), we will contact everyone in our database and ask the KDA to advertise it.
	LouLou	How soon will they make a list of who they would like to have in the trial? It would be nice to find out if we are included or not.
	Dr_D	If people are interested in having their name in our database, please call Alison La Pean at 301-496-8969.
	Bruce	Dr, this trial sounds promising. Besides trials in Japan that we know about, are there any other trials for KD right now?
	Dr_D	The one in Japan and the one we are panning is the only ones I know of.
	murf	I heard the one in Japan did not bring the results they wanted
	Bruce	Are there any side effects from the drug? Dr., do you see patients with KD as part of a clinic or something like that?
	Dr_D	We think that the problem with Lupron (the Japan trial) is that it shuts down all testosterone whereas we only want to shut it down in the neurons. So, the men in the Japanese trial would lose the benefits of testosterone on their muscles which we would like to preserve.
	craig_h	Dr_D , if this drug is a benefit, do you see a decrease in muscle loss, a stoppage in loss, or (please) a strength increase?
	Bruce	Dr, let's say the trial is conclusively positive, does that mean that because the drug is already FDA approved it will become available as a treatment immediately?
	Dr_D	The major side effects of the drug are decreased libido and impotence. We would expect an increase in muscle strength (fingers crossed).
	Bruce	Would that be great or what!
	Dr_D	If the trial is conclusive, it would be available immediately.
	LouLou	Decreased libido--So what's new!!!
	Dr_D	Please note that side effects are not seen in all patients; maybe around 1 in 10.
	craig_h	impotence versus not the strength anyhow , no brainer trade off
	Bruce	Dr, you being a scientist and a realist, what are the chances that this is going to work? 10% - 25% - 50%???
	Dr_D	I think the chances are around 50%.
	LouLou	Sounds good to me
	Bruce	I believe I can state that everyone with KD is most appreciative of your team's work and also state that you are our hope for us and our families.
	LouLou	How can we help with the everyday struggles in your lab? We want to let the Drs. and researchers that we are here and will do anything to help find a cure.
	Dr_D	The only struggle in the lab is finding more time; anyone want to support my experiments to clone myself - LOL
	mobiusloop	I know that this my be a dumb question but has steroids or growth hormones been tried?
	Dr_D	There are several types of steroids. The one you may be thinking of are anabolic steroids (like athletes) which is really just testosterone.
	gofr	So steroids being testosterone, and the Japanese test kills testosterone - a dead heat?
	Dr_D	Testosterone has been tried in one early trail (Dr. Jerry Mendel in Ohio) which seemed to offer some benefit in the short term which is why we believe we need to preserve testosterone for muscles and shut it off around the neurons.
	murf	I just got of the phone with John and we (KDA) will put out an e-mail to all associates in the next week explaining the upcoming clinical trial and asking for your assistance.
	Dr_D	Sounds good, Murf.
	Bruce	Dr, I am certain that there has to be a degree of excitement and optimism in the lab right now with the upcoming trial.
	Dr_D	We are excited and we are happy to have such support from everyone in the KDA.
	craig_h	Dr_D, will the trial be a blind/placebo group, or varying dosages?
	gofr	Do you find sometimes that the side effects are worse than the disease?
	Dr_D	It is a drug trial. But please realize that it will be a placebo-controlled blinded study. That means that half the patients (25) will be taking "sugar" pills and the other half will be taking actual drug (only one dose). Blinded means neither the patient nor the researchers will know who is taking what until the end of the study; this is done to prevent bias. The think the side effects in the general population are mild, but since some of the KD folks have some of these problems already, I am certain how "bad" they may be.
	Bruce	That is what the trial will also uncover.
	Dr_D	Yes. Additionally, the placebo group will also provide us with EXTREMELY valuable information about what we call natural history.
	Bruce	Dr, besides the trial, is there other news/research taking place that the group might be interested in learning more about? Natural history ... meaning what?
	Dr_D	Natural history is how the disease affects each patient and therefore how to design better/faster trials in the future.
	gofr	What is involved in proving for sure that a person HAS kd?
	Bruce	In the research leading up to the trial, has there been a significant strength improvement in your lab tests?
	Dr_D	Basically, we need to know at what rate muscle function (let's say) changes over a given period of time. It allows us to determine how much a drug needs to do and how quickly to have an effect. To mae sure a patient has KD, we use genetic confirmation from a blood sample.
	craig_h	so, during the trails, you will be measuring muscle strength how?
	LouLou	I am sure that the progression of the disease which is different in all KD'ers will get different results in the trial.
	Dr_D	That's true, LouLou. But by having a mix in both arms of the trial we hope to get a slope of the line through the data points
	billeric	Dr.D. will study participants have to travel to NIH?
	Dr_D	Yes. We will cover travel expenses.
	gofr	Where is NIH?
	murf	Bethesda MD
	LouLou	I'm sure the Drs. and researchers will want to keep track of each individual at least at the 6 months intervals.
	Dr_D	We will measure muscle strength grossly using a functional assessment (asking you do do certain tasks like holding your head up) and then quantitatively by having you pull/push against a machine that has a transducer hooked up to a computer to read the amount of force generated.
	Bruce	Dr, will part of the testing process require something other than taking the drug ... some exercise program for example or a different diet?
	Dr_D	No, Bruce, but those are important questions.
	Bruce	I know some of us exercise every day and others don't.
	Dr_D	I want to investigate exercise in the KD mice.
	Bruce	Those of us who exercise, swear by it, but we might be doing more damage than good.
	Dr_D	We have to accept a certain amount of variability with things like exercise.
	billeric	I think all of us would like guidance on exercise. What kind and how much.
	craig_h	Do those who exercise find that there is an improvement in strength?
	Dr_D	I agree with you; I believe mild exercise is beneficial and this is supported by studies in other populations of patients.
	Bruce	I am an advocate of exercise (the right kind and not too much or too often). It is a balancing act.
	craig_h	I want to get back into the water exercise
	Dr_D	The exact exercise program should probably be developed with a physical therapist.
	Bruce	My brother has KD and is in his mid 70's. He still exercises every day.
	LouLou	LouLou: Some of the guys who exercise regularly, also fall regularly. Can exercise of too much at a time cause more damage than good?
	Dr_D	Yes. As Bruce said it is a balancing act which is why I would advocate it being developed with a physical therapist.
	craig_h	Dr_D, thank you so much for working on KD, it raises my spirits to know that relief could be around the corner
	Dr_D	It is a partnership and I am happy to be on the team.
	Bruce	Most MDA clinics in the country have therapists that are more educated in this area.
	Dr_D	That's right Bruce.
	MikeG	Dr are you familiar with the amino acid Arginine?
	Dr_D	We do have people walk as part of the testing, but it is limited. Yes, I am familiar with Arginine
	MikeG	Do you see any benefit of a person with KD taking it?
	gofr	Arginine was mentioned before. Another trial drug?
	Dr_D	Arginine is a simple amino acid found in protein. There is some data to support that taking supplements in athletes helps with reducing muscle fatigue, but I have not heard of any patint with KD taking it.
	GeryKS	Dr._D, thank you very much!