Yesterday a reader left a comment regarding my 2/29/24 post on the ORION trial (of the drug AMX-0035) and I responded on the comments page. But I thought the comment was so well expressed and possibly so widely shared by my readers that it deserved more of a platform. So I turned the question and my response into this post.

Hello Dr. Golbe,

Thank you for the information and data on the AMX-0035 trial. I cannot help but share my thoughts.

The endpoint of this trial, if I understand correctly, is to slow the progression of the disease’s natural course. How is this to be assessed via the PSPRS? An absence of a rise in the score over time or an improvement in the score? If the goal is to prevent a rise in the score over time, is there a known rate at which the PSP-RS usually rises in the absence of any intervention in order to compare this to?

I hesitate to bring this next concern up, however I feel that I need to. In the absence of any known treatment for PSP, if this trial is successful then this is quite good news – anything that helps in any way is good news. However, is it really? The quality of life for a patient with PSP is terrible as you (or anyone who has ever cared for or evaluated a patient or loved one with PSP) know. Therefore is extending this poor quality of life by a year truly a success? The reason I bring this up is because I would like to know if perhaps by targeting these molecular and cellular processes within the mitochondria and endoplasmic reticulum, and thus reducing the stress and burden which is on these patients at the cellular level, is there any hope that perhaps there will also be some symptom improvement as a result of a lessening of burden/overload of the system and the brain’s own immune system and other processes being able to more efficiently function or discard of more abnormal proteins? And therefore some (even small) improvement in quality of life. This very well may be completely unknown. I may have asked you this in a prior post. I ask this not to be dismal or morbid but to see if there is even more hope. As you always say, hope is important.

AF

Dear Ms. F,

I think both of your questions are shared by many others.

The answer to you first question, regarding what the patients on the study drug are compared to, is the placebo group. At the time of enrollment, each patient is randomly assigned to receive either the real study drug or an identical-appearing placebo. Of course, this plan is made quite clear in the informed consent process but only the drug company knows the assignments. For the ORION study, 60% will get real drug and 40% placebo.  At the end of the study, the rates of progression of the PSPRS score for the two groups are compared. In this way, we don’t need to know in advance how rapidly PSP progresses. On completing their 12 months of placebo or real drug, each patient will be offered the chance to take the real drug (called the “open-label phase”).

The second question asks about the likelihood of symptomatic benefit, rather than just slowing the rate of worsening. The chance of that is low, but not zero. If the drugs do improve the function of cells affected by the PSP process, some of them may be able to recover but others (probably most) will be beyond saving. Either way, the treatment may allow cells that are still healthy to avoid becoming involved in the disease process at all, or with a major delay. What we don’t yet have is a way to restore the function of the cells already lost, though researchers are busily working on that.

Your second question implies that it may not be worthwhile merely to slow the progression of a disabling condition without curing it or improving its symptoms relative to the study baseline. That’s a legitimate philosophical and ethical question. My own interactions with patients in my decades of practice and my informal poll of this blog’s readers show that even a 25% slowing of progression (the benefit of AMX-0035 in ALS), which would provide one more year of life for people with PSP, would be worth the hassle and risk of side effects of a new drug. Keep in mind that in prolonging survival from three years to four, the drug would not merely prolong the most advanced, disabled stage for another year. Rather, it would prolong the condition in each of the three years by 33%.

I hope this clarifies things a bit.

Dr. Golbe