Good News (Neurostim) Bad News (FDA)

AFAIK Dispatch #5

Alzheimer’s Families for Action, Innovation and Knowledge

Recent news items have not done much (yet) to change my mind about the dismal state of Alzheimer’s Disease (AD) treatments, nor the FDA, Medicare and the pharmaceutical industry dance. Some recent news below.

But also, some good news on the Neurostimulation front, at the end.

ALS, FDA and Medicare

My focus is AD, but my concerns about improper Pharma influence on FDA decision making are reflected in another cognitive area, that of amyotrophic lateral sclerosis (ALS). Recently, the FDA approved “a drug for amyotrophic lateral sclerosis that by its sponsor’s own admission may or may not work.”

The F.D.A. decided to greenlight the drug instead of waiting until 2024 for results of a large clinical trial partly because the treatment is considered to be safe. The agency said that although the evidence of effectiveness was uncertain, “given the serious and life-threatening nature of A.L.S. and the substantial unmet need, this level of uncertainty is acceptable in this instance

The trial data failed to persuade an independent advisory panel, which last March voted 6 to 4 not to approve the drug without further testing. In an unusual move, the FDA reconvened the advisory committee for another look at essentially the same data. This time, the committee voted 7 to 2 for approval after extracting a pledge from the company’s CEO that he would remove the drug from the market if an ongoing Phase 3 trial turns out negative. (Endpoint News).

So, the FDA decision making, (“after extracting a pledge from the CEO”?) first seemed to me acting to support a questionable treatment, once again with a financial incentive for the pharmaceutical company involved, as the price was quoted as $158,000 per year for treatment. (This is close to the original price for aducanumab which triggered a 15% increase in Medicare premiums — see below.) What was once an agreed upon (by government and medical professionals) standard for approving new drugs, we now have an ad-hoc and arbitrary process.

To be fair, this appears the result not only of pharmaceutical company lobbying, but also lobbying on the patient side.

The FDA had initially asked Amylyx to run a Phase 3 trial, but that met with a torrent of complaints from patients and advocacy groups who are desperate for a treatment. ALS progresses rapidly, leading to paralysis and death usually in two to five years of symptom onset.

All this has raised the question of just how much power advocacy groups hold over the FDA (see reports from The New York Times and Endpoints News).

I wonder who funds those “advocacy” groups…

Along with the aducanumab story, does this signal a new standard of approval for disease treatments — the burden of proof shrinking from 90% clinical evidence of effectiveness down to 50%, or even a single study?

And can we expect much greater percentage increases in Medicare premiums to pay for these $150,000 apiece or more priced-treatments for ALS as well? On that note, also in the news is great fanfare from the Biden Administration to reduce next year’s Medicare premiums

Each year the Medicare Part B premium, deductible, and coinsurance rates are determined according to the Social Security Act. The standard monthly premium for Medicare Part B enrollees will be $164.90 for 2023, a decrease of $5.20 from $170.10 in 2022. The annual deductible for all Medicare Part B beneficiaries is $226 in 2023, a decrease of $7 from the annual deductible of $233 in 2022.

The 2022 premium included a contingency margin to cover projected Part B spending for a new drug, Aduhelm. Lower-than-projected spending on both Aduhelm and other Part B items and services resulted in much larger reserves in the Part B account of the Supplementary Medical Insurance (SMI) Trust Fund, which can be used to limit future Part B premium increases. The decrease in the 2023 Part B premium aligns with the CMS recommendation in a May 2022 report that excess SMI reserves be passed along to people with Medicare Part B coverage.

So, I can tell you the news headlines loudly proclaimed the decrease, and no mention that the $5.20 decrease ($62.40 for the year) gives back only one-fourth the increase assessed in 2022 ($20/month, $240 year), with Medicare arbitrarily deciding it didn’t have to give back most of the “much larger reserves” that resulted from the Aduhelm scandal.

Amyloid “Hypothesis” Possibly Based on Fraud Yet Driving the Research

In the background is earlier news that the initial foundation of the amyloid theory of AD may have been fraudulent. This is not widely acknowledged, either in press or among the financial community. For example, in yet another tentative study of a new AD drug on the heels of aducanumab,

Biogen and Eisai [stock prices] surged after lecanemab slowed cognitive decline in a key Alzheimer’s study, while Eli Lilly and Roche, which are developing rival anti-amyloid treatments, climbed as well.

Lots of cheerleading on the above from researchers who have been plowing the fields of pharmaceutical answers — and nary a mention of the recent scandal over potential fraud, either from FDA or from clinical researchers (who partner w pharma)

As I have noted previously, the pharma-oriented focus of the FDA is more concerning with the emergence of new evidence that the amyloid plaque theory of the disease, which drove most pharmaceutical research over the last ten years, may have been based on fraudulent evidence! More discussion and reaction to this news is here, including thefollowing comments from one researcher (emphases are mine):

In the bigger picture, researchers said the data strengthen the amyloid cascade hypothesis. “This confirms the importance of Aβ in disease pathogenesis,” said David Holtzman at Washington University in St. Louis.

There is an important cautionary note however: The magnitude of the delay — which was a slowing of decline — was small. We can only hope that the benefit is durable and could grow with time. Those long-term properties are unknowable at this time.

Given that this is a press release, not a scientific report, and taking it at face value — often a chancy thing to do — the primary outcome is statistically significant at P < 0.0001. On its face, other things being equal and assuming a low risk of bias, the P value strongly suggests that the CDR-SB primary outcome is robust and not going to be overturned in sensitivity analyses.

It is striking to me that after years of hearing the “cause” of AD is amyloid plaque, that it is still widely understood in the research community to be a hypothesis. The FDA yielding to pharma (and advocacy group) pressure may be even more reason to focus more attention on neuromodulation.

Neuromodulation Good News

The juxtaposition of ALS and AD drug development actually underscores the original point of AFAIK — why, when neurostimulation is an accepted ALS treatment, isn’t a corresponding amount of effort going into neurostimulation treatment for AD. Surely the market is large enough. Is it possible that neurostimulation approaches aren’t easy to patent, and thus are not as economically attractive as drug approaches?

So here is some more good news on this front, not from the major players (Medtronic, Boston Scientific, Abbott), but still from an article in Nature.

According to a new Phase II study, precision-delivered non-invasive brain stimulation could turn out to be a promising approach to help slow the progression of cognitive and functional decline in patients with mild-to-moderate dementia due to Alzheimer’s disease.

Sinaptica is developing what it says is a “next-generation approach to neurostimulation” with its SinaptiStim — AD System product, which was recently awarded a breakthrough designation from the FDA to treat cognitive and functional decline in Alzheimer’s patients. However, the study was carried out using the already cleared Magstim Rapid2magnetic biphasic stimulator.

Sinaptica describes themselves as a clinical-stage one that is leading the development of a new class of personalized integration of neurostimulation and brain wave monitoring technologies in combination with a proprietary artificial intelligence (AI)-derived engine.

Stay tuned.