Hello,my friends,I am a kd patient from china.The questions I need to ask include the following five aspects, A.can therapeutic drugs（AR- Antagonists，PROTAC) for metastatic prostate cancer be used for the treatment of Kennedy's disease.B.if the ar-protac drug such as ARV- 110,766 does work on kd? C. can Enzalutamide be a commonly used drug to delay the development of Kennedy's disease. D. If drug development and clinical trials go smoothly, the first Kennedy disease drug is expected to be available within a few years，How many years will it take? E. how the patients in Chinese Mainland join the clinical trial of AJ-201？

One topic discussed ar-protac can solve Kd problem. https://doi.org/10.1016/j.mce.2019.110452

Hi, welcome to this forum and thanks for your excellent questions. Several androgen blocking prostate drugs have been tested for KD. Enzalutamide is one that shows significant benefit in mouse models of KD although I have not seen reports of it being tested in men with KD. AR-PROTACs have much potential similar to ASOs but I don't think they have been tested yet for KD. Here is a fairly recent paper reviewing recent developments in prostate cancer drugs which suggests PROTACs have poor pharmokinetics especially limited oral bioavailability. https://www.mdpi.com/1422-0067/22/4/2124

My impression is AR blocking drugs show more promise for KD prevention than KD treatment of advanced disease. In animal models such as mice the best results are obtained when treatment is given early before disease onset. In human trials results have been mixed. Even in the trial of leuprorelin which resulted in the approval for KD in Japan the men on the drug showed greater decline in walking performance than the controls not taking the drug.

AJ-201 and Nido-361 are in patient trials for KD here in the US. Both are in phase 1 and have two further more difficult phases they must pass for FDA approval. Each phase tends to take about 2 years.

DEAR Mr.ToddAllen,Thank you for your answer.My KD friend, He took Enzalutamide for a month, CK from 2600 to about 1000, and the symptoms of lameness has improved, i also saw the article of Bicalutamide combined sea sugar treatment of KD , Enzalutamide is the second generation of AR antagonist, more advantages than carutamide, and is a successful drug has been approved by the FDA for ten years, why not used for KD treatment? My KD friends and I are going to test it on KD, but we know several problems, one is the possible emergence of AR varieties, such as AR-V7; the resistance of the drug, which only temporarily delays the development of muscle atrophy; third, the other effects of the variant AR are not known. I heard that the ARV-7661b / 2a clinical trial had good results(ESMO2023), so ARVINASE is ready to start a phase III clinical trial in 2024, and this drug will not be resistant, although bioavailability remains problematic, does that mean that 766 will be the first we see possible treatment on KD.I post the pdf by ARVINAS team on ESMO2023(I CANT post it ）.

Here it is:https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-upcoming-bavdegalutamide-poster-presentation

Sorry for my delayed response. I was hoping to find more information on the potential of ARV-766 and related drugs to treat KD but I have made little progress. It looks like the focus so far has been on prostate cancer. Hopefully success in the prostate cancer trials will lead to further research for KD.

Your friend's results with Enzalutamide sound encouraging. Is he still taking it? Do you have more details such as his age, CAG repeat count, history of KD symptom onset and progression? Is he tracking physical peformance in terms of walking, weight lifting or other measures of strength?

this is my friend response:My age is 35, and I have had three CAG repeat tests for 46,55 and 51 times, respectively. When I was 15, I was found shaking by an old Chinese doctor. The cause was not found. At the age of 16, my legs and neck often cramped. When I was 18, I walked a little more and my legs felt tired, tired of how to rest. I suspect creatine kinase was very high at that time. At the age of 19, the long jump test found that he had failed in jumping ability (from full marks to barely failed), and later found that he could not lift his left hand when lifting weights at the same time. At the age of 26, he could still run, jump and climb mountains normally, but his run and jump ability was significantly worse than ordinary people. At the age of 26, blood indicators showed abnormal liver function, such as lactate dehydrogenase, with creatine kinase as high as 3,000, and testosterone and estradiol by several times. When I was 30 and climbed the sixth floor, I found that I couldn't climb to the fourth floor. Then you began to feel like your legs and ankles were tied when you walked. Gradually, squatting for a long time to stand up need hands to support the knees. Since then, the disease has developed rapidly, in 2022, a long squat and have to rely on both hands. Since the age of 32, creatine kinase has been tested once a month, basically between 2000 and 3000. After the injection of leuprorelin in October 2022, the stair climbing state declined significantly and required the handrail.injection for half a year, found that the strength is still decreased, even much worse than before the injection, before the injection, squat and stand up to do 3,1 after the injection can not get up. And monitoring the creatine kinase index, no decline, the disease continued to develop, serious claudication, so stop the drug. In August 2023, I began to try to eat Enzalutamide, and all the indicators have greatly improved in 2 weeks (see the table for details). Although the upstairs condition has not been significantly improved, the lameness has been greatly improved, and the feeling of sore legs is much better. At present, I can walk about 8,000 steps every day. The side effect of Enzalutamide was a slight loss of sexual function and no discomfort in the rest.
Considering the problem of enzalutamide resistance, the stability of the current state, and I want to see if the disease continues after withdrawal
Zhan, I decided to stop watching for a while. So I chose to stop the drug on November 26,2023. At present, the legs began to feel a little acid distension, limping has not appeared, waiting for further to observe.

my friend continue tests his health data

patient_data.zip (9 Kb, 3 downloads)

Thanks for the detailed response. It is good to see your friend is trying to collect data to evaluate the effects of Enzalutamide and trying periods both with and without the drug. Even if we had human trial data in KD patients showing benefit in most I think it is important we each do our best to evaluate the effects of any drug in ourselves as responses can vary. Developing the skill of self evaluation might be the most important thing we can each do and may put us in a better position to maximize benefits and minimize harms of whatever treatments are eventually developed.

Despite the significant impacts KD has had on your friend at 35 he is still relatively young and I expect he can benefit more from treatments such as Enzalutamide than I expect I might at 59. I think my history is similar to his and I wonder how much better I could have done if I had emphasized developing the skill of self evaluation sooner. Due to my grandfather's disease I became aware of early signs of KD starting around 13 and by 20 was fairly certain I had it. I've only had the genetic test once with a CAG repeat count of 50. Whatever the accuracy I don't think the exact count matters much as there is a lot of evidence of variability in disease progression with the repeat count only weakly correlated to severity. I did quite well in my late teens and early 20s following common guidelines of the time for health and fitness but then suffered noticeable decline that continued accelerating rapidly from there until 50 at which point I could barely walk at all without falling. In my 30s I had similar labs to your friend with respect to high CK, liver enzymes and triglycerides. I also had mildly elevated cholesterol and sex hormones both male and female. As my health and fitness declined in my 30s and 40s my CK dropped a lot although I suspect this was more due to declining muscle mass and use rather than any abatement of KD. My cholesterol and sex hormones slowly dropped while liver enzyymes and triglycerides increased.

At 50 I began altering my approaches to diet, exercise and other lifestyle choices chasing results in terms of how I felt, looked and performed versus following what is supposed to work for others or the desirability of lab results. At 59 my CK and myoglobin are still elevated but continue slowly falling and now I hope it is due to lessening disease as I have been increasing strength, fitness and physical activity. I have achieved desirable lab results for triglycerides, blood glucose and improving results for most others such as liver enzymes. But my cholesterol and sex hormones are very high, 2 to 3 times their reference ranges and still rising. The expectations of harm from this have yet to be seen and so far I am only experiencing increasing vigor and feelings of youthfulness.

Thank you for your reply. We are consulting KD experts in China, but we have no results yet, I would like to ask you to consult your doctor, or convey our ideas to KDA, at least to promote the application research of ENZA drug in KD clinic.Looking forward to your response.

There is awareness of the potential of enzalutamide as there have been studies of it and related drugs such as flutamide and bicalutamide in cell cultures and animal models of KD. I think the expectation is the drug NIDO-361 planned to begin a phase 2 trial in men with KD next year will produce similar or better benefit to those drugs but with less undesirable effects.

quote:

Originally posted by micheldou:
... Enzalutamide is the second generation of AR antagonist, more advantages than carutamide, and is a successful drug has been approved by the FDA for ten years, why not used for KD treatment?

Enzalutamide was first approved for prostate cancer. Despite having significant adverse effects when the benefit is increased survival for a disease producing significant numbers of deaths over the trial period it is easier to show a favorable benefit to risk ratio. Among the adverse effects fatigue, gynecomastia and sexual dysfunction are common and more rarely asthenia, arthralgia and backpain each of which is problematic for KD reducing the odds of a KD patient trial showing a favorable outcome especially if the expected benefits for KD slowly accrue while adverse effects may arise quickly. There are other issues with Enzalutamide such as significant interactions with other drugs which may increase the difficulty of getting sufficient numbers of the small mostly older KD patient population to successfully complete the trials and also limit the already small number who might take it with approval. Drug trials are expensive and mostly funded by profit seeking corporations which aren't interested when they don't see favorable odds for success.