What’s good for the goose . . . ?

Biogen is currently testing an anti-sense oligonucleotide drug called BIIB-080 in patients with mild cognitive impairment and very mild Alzheimer’s disease. The goal would be to slow or prevent their conversion to full-blown Alzheimer’s disease. Today someone posted a comment asking if I thought this could work for PSP. I thought this could make a good, brief post:

Biogen has an early-phase trial of BIIB080 in Alzheimer’s, and there’s no reason to think it wouldn’t work as well in PSP.

Actually, the Alzheimer’s trial is mostly for people with “mild cognitive impairment” and the measure of success would be preventing progression (“conversion,” as it’s called) to full-blown Alzheimer’s. They are also enrolling some patients with mild AD, hoping to prevent progression to moderate stages. If the people at Biogen feel that BIIB080 should first be tested in such an early disease phase, that could be why they chose Alzheimer’s over PSP: there is no known equivalent of mild cognitive impairment for PSP.

Another reason Biogen might be starting with AD is the ready availability of a test for beta-amyloid in the brain in the pattern specific for that disease. It’s called an Amyvid scan, and participants in the BIIB080 trial have to show an AD pattern on the scan to qualify. There is no equivalent, road-tested, sensitive and specific diagnostic test for PSP, which means that a much larger trial would be necessary to overcome the “statistical noise” caused by people with a false-positive diagnosis of PSP.

The diagnostic criteria for PSP do define a state called “suggestive of PSP,” but there are still no data on what fraction of those individuals eventually progresses to probable or definite PSP, or how long it takes. On the other hand, there are excellent such data on the conversion of MCI to Alzheimer’s.

A couple of examples of symptoms that would result in a diagnosis of “suggestive of PSP” are repeated falls and slow downward eye movements. As you can tell, such symptoms in isolation are not very specific for PSP, so a trial enrolling such patients would have to have many hundreds of particicpants for a statistically useful fraction of them to convert to possible, probable of definite PSP, especially over only a 12-month period. Furthermore, the size of the trial would have to be large enough for the conversion rate among the recipients of the active drug to be validly compared to the rate among those on placebo.

So, my guess is that if BIIB080 works in mild cognitive impairment and very mild AD, Biogen will test it in PSP. But if a good pre-clinical marker for PSP becomes available, then it would much more practical to try such treatments in pre-clinical PSP.

But there are other drug companies with other anti-tau ASOs. One, from Novartis, is already enrolling patients. Others are approaching clinical trials.

A downside to the back-door approach

Someone wrote asking if they should seek a fecal microbiota transplant (FMT) for their spouse with PSP. (See yesterday’s post, which reports on a favorable double-blind trial.) Of course, I replied that I can’t give individualized medical advice, but it occurred to me to write this post to mention two downsides that I didn’t mention yesterday.

One problem is that drinking the huge volume of fluid for the 3 bowel preps could be very difficult for someone with PSP. It typically requires drinking a 8 full 8-ounce glasses of a salty-tasting stuff over 2 hours (i.e., one glass every 10-15 minutes) the night before the procedure and then repeating the same thing on the morning of the procedure. That’s 64 ounces twice, which totals one gallon. That has to be repeated at 4 weeks and again at 8 weeks for the other 2 coloscopies/transplants. All those fluids could invite aspiration. I don’t know if using a thickener would be permitted, but that’s not a full guarantee against aspiration, and the mere exertion of the swallowing muscles might not be possible for someone with more than mild PSP.

The other issue is finances. Colonoscopies are expensive — my survey on line suggests an average professional fee of $2,000, another fee for the facility and another for the bacteria to be transplanted. Then, multiply by 3 for the 3 steps in the FMT. I doubt that any public or private insurer would pay for this for someone with PSP, where it’s not FDA-approved. The insurers know that quacks offer FMT for many medical conditions with no proper double-blind trials as evidence of benefit and safety. The insurers may simply lump PSP in with those conditions despite the one small positive trial from China, and it’s hard to argue with them on that.

So, I’ll leave this to the judgment of my commenter’s spouse’s own doctor and to that of the gastroenterologist who would be doing the procedures.

A back-door approach

For the past few years, fecal microbiota transplantation (FMT) has been part of mainstream medicine’s treatment for a nasty, antibiotic-resistant intestinal infection by the bacterium Clostridium difficile.  Essentially, the idea is to replace the person’s colonic bacteria with a new set obtained from the stool of healthy people.  The new bacteria are introduced to the junction between small and large intestines via coloscopy after a standard bowel prep.  

On the theory that immune-related diseases could be a result of some poorly-characterized problem in the colonic bacteria, clinics have sprung up to use FMT for things like inflammatory bowel disease and multiple sclerosis.  PSP is a disease for which evidence of abnormal immune function has been accumulating.  Furthermore, constipation occurs in PSP to a far greater degree than abnormalities in other autonomic nervous system abnormalities such as urinary incontinence or low blood pressure.  This vaguely suggests that an abnormality of intestinal bacteria could underlie PSP in some way.

A trial of FMT in PSP appears in the current issue of the prestigious British journal The Lancet from a research group at Zhengzhou University in Zhengzhow, China led by Dr. Haiyan Tian with senior author Dr. Xuejing Wang. They randomly assigned 68 people with newly-diagnosed PSP (averaging 2.6 years since onset) to receive identical bowel preps followed by either FMT or placebo transplant, which was a colored saline solution.  Neither the patients nor the researchers performing the transplantations or evaluations knew the treatment assignments.  That is, it was a proper randomized, double-blind trial. 

Each patient received 3 such transplantation procedures – at 0, 4 and 8 weeks.  The patients were examined periodically over 36 weeks using the PSP Rating Scale (PSPRS) at 16 weeks as the “primary outcome measure.” They also received a long list of other standard tests and chemical measures in the stool as secondary outcome measures. 

The result was that at Week 2 (i.e., 2 weeks after the first procedure), the PSPRS, which averaged 40.1 in each group at the start, improved by 1.5 points in the FMT group and worsened by 0.2 points in the placebo group (as expected), for a total “treatment effect” of 1.7 points.  At Week 7, the treatment effect was 2.8 points; at Week 12, 4.8 points; at Week 16 (the “primary” outcome), 4.3 points; and at Week 36, 3.8 points. 

The researchers confirmed that the FMT group’s post-treatment stool had lower levels of inflammation-related compounds than that of the placebo group.  Side effects, all of them minor and transient gastrointestinal symptoms, occurred in 3 patients in the FMT group and 2 in the placebo group.

Taken at face value, this is good news – the primary outcome measure reduced the PSPRS by 4.3 points relative to placebo, which is (4.3 / 40.1 =) a 10.7% improvement. 

Let’s keep several things in mind:

  • As a comparison, the average person with PSP worsens about 11 PSPRS points per year, so a 4.3-point improvement is the equivalent of erasing about 5 months’ progression.  In these 68 patients, the progression before the trial was much faster, averaging 15.4 points per year, possibly because they all had PSP-Richardson syndrome, the most rapidly-progressing form of PSP.  So for them, a 4.3-point improvement is the equivalent of only 3.4 months of progression.
  • This is not a trial of neuroprotection, where the treatment is attempting to slow the long-term progression of the underlying disease process.  Although FMT, in theory, could do that, this particular trial measured only short-term improvement in outward signs and symptoms. We call that “symptomatic treatment,” and that’s what all existing treatments for PSP do for specific symptoms with various degree of success.
  • As you can see from the PSPRS scores above, the benefit started to wane at about Week 12, which was about 2 months after the third transplant.  We only have subsequent measurements at Weeks 16 and 36, so we don’t know how soon another round of 3 transplants would have to be repeated in order to maintain an acceptable degree of improvement.  Hopefully, these researchers are continuing to observe and examine these 68 patients and will report longer-term results.

Bottom line:  I interpret this as a “proof-of-concept” study.  That means that even though the trial’s procedure might not be practical as routine treatment, the results (assuming they’re confirmed by studies elsewhere) show that revising the colonic bacteria can do good things for PSP, at least in the short term. 

Next steps are to:

  • Measure the duration of benefit from the three FMTs;
  • Devise an orally-administered capsule of bacteria that is safe and can accomplish the same thing;
  • Mount a neuroprotection trial, which requires about 200 patients on FMT and another 200 on placebo to detect a 25% slowing of progression.
  • And most importantly, figure out what biochemical action the old bacteria were doing wrong that the new bacteria are doing right, and accomplish the same effect in a simpler way.

Then there’s this minor question: How and why do some people acquire a set of colonic bacteria that increase PSP risk and how can that be prevented?