Most of us would like to think that medical news – new drugs, new treatments – just concerns health care, but again and again we find that other areas of concern intrude. Politics and economics are very much part of the picture, and although Doc Gumshoe, like just about everybody, has his opinions on these subjects, he has to acknowledge that they’re just that – opinions. So in this piece, where a couple of the subjects veer into those contentious areas, I will try to segregate the non-medical aspects.

The first news item we’ll look at concerns a new drug that may slow the progress of Alzheimer’s disease in patients who are in the early stages.

A clinical trial in 1,795 subjects indicates that lecanemab slows cognitive decline

On September 27th two pharmaceutical companies, Biogen and Eisai, announced the results of a multinational clinical trial in which subjects treated with lecanemab experienced 27% less cognitive decline than placebo-treated subjects. The trial, Clarity AD, evaluated lecanemab in persons with mild cognitive impairment due to Alzheimer’s disease (AD) with confirmed presence of amyloid beta (Aβ) in the brain.

The measure used to assess the efficacy of lecanemab is a numeric scale, the Clinical Dementia Scale – Sum of Boxes (CDR-SB) which is used to attempt to quantify the severity of the various symptoms of dementia. The six areas that are assessed are memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care.

At the 18-month conclusion of the study, the difference in the CDR-SB scores between lecanemab and placebo-treated subjects was 0.45 points, which translates to the 27% difference. This difference was evaluated as highly statistically significant, P = 0.00005. Starting as early as six months into the study and at all time points, treatment with lecanemab showed highly significant changes in the CDR-SB scores compared to placebo. All the key secondary endpoints were met with highly significant results. These included Aβ levels in the brain and several other cognitive assessments.

Lecanemab specifically targets amyloid beta, which is generally thought to be one of the two causes of Alzheimer’s disease, the other one being the presence of neurofibrillary tangles caused by misfolded tau protein. Lecanemab selectively binds to and neutralizes the toxic Aβ levels that are thought to interfere with communication between neurons and to contribute to the degenerative process in Alzheimer’s.

Prior to being published in a peer-reviewed journal, the data on lecanemab will be presented at the Clinical Trials on Alzheimer’s Disease (CTAD) conference in San Francisco November 29th through December 2nd. The conference focuses entirely on AD therapeutic trials.

Several researchers have expressed confidence in the robustness of the topline results and agreed that the outcome is strong enough that it is unlikely to be overturned in sensitivity analyses that look for confounding effects. Some also noted, however, that the absolute difference in the scores was small. However, it was pointed out that the point difference in the lecanemab Clarity AD trial was three times the point difference in the aducanumab trial, which is discussed below.

On balance, the trial results were viewed as highly promising. Researchers look forward to the potential benefit of combined therapy with lecanemab and agents that target the tau protein effects.

Previous trials in lecanemab as well as other Aβ inhibitors such as donamemab and aducanumab (Aduhelm) had linked removal of Aβ plaque to slowing of cognitive decline. However, the other Aβ inhibitors, especially aducanumab, have been linked with serious adverse effects such as brain swelling and bleeding. These effects were much less frequent with lecanemab.

On balance, researchers expect that the FDA will grant regular marketing approval to lecanemab, without the restrictions that applied to the Aduhelm approval terms.

The results of the lecanemab trials present a clear challenge to the other Aβ inhibitors. Roche is expected to report data from two trials in their candidate, ganenerumab. Eli Lilly has applied to the FDA for accelerated approval of donamemab early in 2023, and results of a larger trial in donamemab are expected sometime later next year. Several well-informed commentators on Alzheimer’s treatment have observed that it will be difficult for either of those two drugs to meet the treatment standard now set by lecanemab. They note that prior to the introduction of aducanumab (Aduhelm), no new treatment options for Alzheimer’s had emerged in more than two decades. Perhaps it was that aspect of the aducanumab data, in spite of the small clinical benefit and the concerning side effects, that led to the FDA’s controversial approval of Aduhelm.

Some possible downstream implications

Here’s what the FDA said about the terms of the approval of Aduhelm:

“Aduhelm is approved under the accelerated approval pathway, which provides patients with a serious disease earlier access to drugs when there is an expectation of clinical benefit despite some uncertainty about the clinical benefit.

Accelerated approval is based upon the drug’s effect on a surrogate endpoint — an endpoint that reflects the effect of the drug on an important aspect of the disease — where the drug’s effect on the surrogate endpoint is expected, but not established, to predict clinical benefit. In the case of Aduhelm, the surrogate endpoint is the reduction of amyloid beta plaque. The accelerated approval pathway requires the company to verify clinical benefit in a post-approval trial. If the sponsor cannot verify clinical benefit, FDA may initiate proceedings to withdraw approval of the drug.”

Full, unrestricted approval for Aduhelm would have had major implications for Medicare costs. Since Medicare is required to cover FDA-approved drugs, and since Aduhelm was projected to cost somewhere in excess of $50,000 per year, Medicare costs were projected to zoom, and did increase substantially for the year 2022, although not as much as projected. Medicare Part B costs averaged $170.10 per month in 2022, an increase over the ~$155 per month that had prevailed since 2017. In 2023, the average Part B premium will be $164.10, a slight lowering.

A congressman from Florida, Vern Buchanan, who is widely seen as a frontrunner to chair the powerful Ways & Means Committee if Republicans win back the House, recently introduced a bill that would force Medicare to make coverage decisions on individual drugs, not classes of drugs. This is seen as a rebuke to Medicare’s limited approval of Aduhelm, which was based on the mechanism of action rather than on demonstrated clinical benefit. Medicare’s approval of Aduhelm, as noted above, was based on the evidence that it statistically reduced the amount of amyloid plaque, and not on the minor benefit that it brought to the Alzheimer’s patient. The FDA approval of Aduhelm on those terms might imply approval for lecanemab would be granted on similar terms, requiring further data to be submitted before full approval could be granted. The application for full approval rather than accelerated approval for lecanemab is in contrast to the approval process for aducanumab/ Aduhelm.

At this time the projected cost of lecanemab treatment has yet to be disclosed, but if it does receive full FDA approval, and if the costs are comparable to the Aduhelm costs, the impact on Medicare could be considerable.

And what about the fortunes of Biogen and Eisai? Obviously, they are hoping that lecanemab will restore them to robust health, after the Aduhelm disappointment. It all remains to be seen, although present signs are hopeful.

Speaking of Alzheimer’s …

Why do more women than men develop Alzheimer’s disease?

The usual answer is that women tend to live longer than their opposite sex counterparts, and, as we know, Alzheimer’s mostly affects people as they grow older. But it turns out that there’s yet another gene linked with Alzheimer’s, besides the APOEε4 gene. About 60% of people with AD have the APOEε4 gene, meaning that 40% or so of known AD cases have developed the disease without any known genetic cause. In the general population, about 25% carry the APOEɛ4 gene.

Now a gene has been discovered that is strongly associated with the risk of developing Alzheimer’s – the so-called MGMT gene. MGMT is O-6-methylguanine-DNA methyltransferase, which under normal circumstances guards against the formation of toxic substances in the body. However, the gene itself can become corrupted, in which case it attacks other cells in the body.

A research group from the Boston University School of Medicine, the University of Chicago, and the University of Pennsylvania, among others, performed genome-wide sequencing on several groups, including 10,340 women without APOE ɛ4, who were part of the Alzheimer’s Disease Genetics Consortium (ADGC). These included 3,399 AD cases and 6,905 controls. Researchers found that the MGMT gene was significantly associated with AD risk in women lacking the APOE ɛ4 gene.

Another small study in a group of 32 Hutterites, 22 of whom were women, similarly found significant associations between the MGMT gene and AD, but only in women, none of whom had the APOE ɛ4 gene. Hutterites are a small closely-related community sharing genetic characteristics, and therefore preferred subjects for studies in the effects of genetics.

What does this discovery mean – or imply – for the development of treatment options for Alzheimer’s? Researchers can start by studying the mechanisms through which the MGMT gene was turned from a protector to a malefactor, and then take aim at those mechanisms. And, as the research continues, other avenues will likely open. In any case, the more we know about Alzheimer’s, the better.

The FDA approves a new drug for amyotrophic lateral sclerosis (ALS)

Perhaps it’s better known as Lou Gehrig’s Disease, that being the illness that caused Gehrig, a first baseman with the New York Yankees, to retire only 8 games into the 1939 baseball season, at the age of 36. He was known as The Iron Horse, and until that last year, he regularly played in more than 150 games per season. His lifetime batting average was .340, and he hit 493 home runs. He died of ALS just two years after his retirement.

ALS is a devastating disease for which there is no cure. It affects about 30,000 persons in the US every year, with about 5,000 new cases per year. About half of the persons who develop ALS die in less than three years; 20% survive five years or more, and perhaps 10% live ten years after the onset of the disease. The disease affects motor neurons in the brain and the spinal column. The early symptoms include difficulty walking or doing normal daily activities, tripping and falling, weakness in the legs, feet or ankles, slurred speech, trouble swallowing, and cognitive and behavioral changes. Eventually the person with ALS can no longer eat or breathe. Current treatment does not address the underlying disease process, but assists patients in coping with the effects of the disease to whatever extent possible.

The new drug is AMX0035, to be sold as Relyvrio, from Amylyx Pharmaceuticals, a small biotech outfit in Cambridge, Massachusetts. A couple of days ago, as I write this, the FDA granted full approval to the drug, after reversing its previously negative view of the evidence presented by Amylyx. A small, 24-week study did provide evidence that the drug slowed the progression of the neurologic damage caused by ALS. Amylyx is conducting a larger and longer trial, hopefully to confirm the benefits of AMX0035. They have promised to remove the drug from the market if the longer trial does not bear out the data showing that AMX0035 slowed the progression of ALS.

AMX0035 is an oral formulation that combines two non-proprietary small molecules, sodium phenylbutyrate, and tauroursodeoxycholic acid (TURSO). Both drugs inhibit the proteins that cause programmed cell death.

Amylyx is also targeting the Alzheimer’s disease market. AMX0035 met its primary endpoints of safety and tolerability in the PEGASUS test last month and had “significant effects” on AD biomarkers such as tau protein and amyloid beta.
Aside from ALS and Alzheimer’s, Amylyx hopes that AMX0035 might be effective in treating neurodegenerative diseases such as Wolfram syndrome, Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, and multisystem atrophy.

Looking at this from a different perspective

Today, as I am writing this, Amylyx announced the closing of its public offering of 7,697,812 shares of its common stock at a price of $32.00 per share. This includes the exercise by the underwriters of their option to purchase up to an additional 1,004,062 shares of common stock in the offering. The gross proceeds to Amylyx from the offering were $246.3 million, before deducting underwriting discounts and commissions and estimated offering expenses.

As Doc Gumshoe has repeatedly stated, pronouncements about the stock market are well beyond his area of expertise, but the larger economic picture with regard to Aymylix strikes me as open to question. AMX0035 is their only current drug candidate, so far as I can tell, although it is likely that they have others in the works. A likely scenario for Amylyx is acquisition by a larger, wealthier pharmaceutical company that has the resources to market the drug nationally and internationally. Will a big pharma gobble up Amylyx before the full evidence about AMX0035 is in? Or will they gamble that the longer they wait, the higher the price will be?

The FDA’s approval of AMX0035 is based more on a mechanism of action than on evidence of actual benefit. This is much like the FDA’s approval of aducanumab/Aduhelm, and we know where that went. Amylyx announced that the charge for a 28-day supply of AMX0035 (now to be called Relyvrio) will be $12,500, which comes to about $160,000 per year. Will Medicare come up with the cash for the few thousand Medicare patients with ALS? Will the rest of us have to come up with the cash to pay the likely-to-be-increased Medicare charges?

Thoughts on drug pricing

The subject has been on the minds of many, from the Chief Executive all the way through the ranks of Congress and officialdom.

For a start, it is easy – too easy! – to place the blame on the pharmaceutical companies and accuse them of being greedy, end of story. I won’t say they aren’t greedy, but so is just about every business on the face of the planet. Making money is their major objective, no matter what benevolent, community-minded banners they fly.

But pharmaceutical companies have to operate in a rather unique economic straitjacket. First, they have to invest huge sums – several billion dollars – to develop their products. And, from the very beginning of the drug development process, the candidate drug has to be patented. They cannot wait until they are close to bringing it to market to obtain a patent, because if anybody gets wind that Pharma ABC is looking into the possibility that potential drug XYZ might be a useful treatment for some disease or condition that needs treatment options, that “anybody” – another drug company or an independent researcher – might beat Pharma ABC to the punch and get a patent on XYZ, wait and see if Pharma ABC comes up with anything, and then sell Pharma ABC the patent for a hefty mark-up. Or, who knows, develop the drug themselves, leaving Pharma ABC in the lurch.

So the Pharma ABC gets their candidate drug patented, and then they go to work on the difficult and lengthy process of developing and testing the drug, starting with tests in laboratory animals and going all the way through large and hugely expensive Phase 3 clinical trials. The process not only costs billions, but takes time. And the time it takes comes out of the patent life of the candidate drug. Patent life in the US is 20 years, not a day more, from the date the patent application is filed. It can easily take 10 years for a drug to go from the very first test through a Phase 3 trial that is necessary for approval to market the drug. And by the time Pharma ABC is ready to market the drug, they only have 10 years to recover their costs and make a tidy profit. After the patent life expires, there’s a change that the drug will go generic, and Pharma ABC will need to adjust their price downward quite a bit!
What some pharmaceutical companies do to extend the profitable lives of their product is tinker a bit with the molecule, do some trials to see whether it is equally safe / effective, and then attempt to get a fresh patent on the revised molecule. If that strategy succeeds, they have another 20 years of patent and marketing life. Is this legitimate or squirrely?

Another factor that has to be considered is that the pharmaceutical outfits need, somehow, to cover the costs of research, development, and clinical trials of drugs that go nowhere.

Anyhow, that’s the environment in which the pharmaceutical companies exist, and which the rest of us have to navigate in some way. The Congressional Budget Office recently put out a lengthy document (60 dense pages) discussing ways that the cost of drugs might be lowered to some degree. Happily, the CBO summed up their conclusions in one clear and simple graphic, which is reproduced here:

The pharmaceutical industry’s first suggestion was that revealing the price of drugs, whether purchased directly by the public or covered by insurance plans, would mobilize consumers to compare prices and pick the least expensive options. The CBO concluded that such an approach would result in miniscule price reductions.

Their second-favorite suggestion was that more competition among drug makers would have some spill-over effect on the costs of these drugs. The CBO’s opinion was that the price reductions would be small at best.

The third option was imposing actual price controls on pharmaceutical companies. That’s when substantial price reductions would result. And that option, of course, is the one the pharmaceutical industry would like to avoid.

An option that isn’t getting a lot of discussion, at least in elevated government circles, is that the research and development of drugs be somehow covered by government. To a certain degree, that’s happening right now, in the form of research grants to scientists, mostly working in academic environments. For example, a great deal of the research that went into CRISPR development was federally funded. But should the feds also pay for the clinical trials? I have to confess that I’m not qualified to answer that question.

Flu season coming on

I wish I could spare you this, but the signs seem to be that the flu will be somewhat worse than usual this year. This past year’s flu season was the mildest in more than 25 years, but the consensus seems to be that this year’s will be several notches worse.
A principal cause of the uptick will be that masking is way, way down. In the winter of 2021 – 2022, concern over the Omicron variant was very high, and the case load was at all-time high levels, so people were being super-cautious. Now, that level of caution has diminished a great deal. Masks are almost a rarity.

Another reason that an uptick is on its way is that Australia had a particularly severe flu season this year, with about three times the normal number of cases. Their flu season peaks in August. That doesn’t necessarily predict that we will have three times the normal number of cases, but it will be considerably worse than last year’s flu season, or the year before.

We hope that it won’t be worse than a mild case of COVID.

And, speaking of COVID …

What’s happening with the pandemic?

In short, it’s not over.

Currently, the COVID death rate in the US is 11,726 per 28 days. That’s about 425 deaths per day. Granted, most of those deaths are in either the unvaccinated or persons with pre-existing conditions, but still, that’s a high mortality rate. At this point, the total number of COVID deaths in the US is 1,065,414.

Globally, the COVID death rate is 41,249 per 28 days, or about 1,475 deaths per day. COVID has cost 6,561,195 deaths on the planet.

(I should point out here that at its peak, the daily COVID death rate was more than 12 times higher than the current death rate, so it’s definitely tapering down.)
At least two factors fuel the continuation of the pandemic. One, according to the World Health Organization, is the shortage of vaccines in low and middle-income countries. WHO director general Tedros Ghebreyesus points out that the more the virus circulates, the more chances it has to mutate into something of concern. “The refrain of the pandemic has been that no one is safe until everyone is safe,” Ghebreyesus said. “The pandemic is not over, but the end is in sight.”

Professor William Hanage of the Harvard T.H. Chan School of Public Health said that last winter’s Omicron variant provided an unforgettable example of the need to not let our attention wander. Though Omicron does not result in as severe illness as other variants, Omicron’s constellation of mutations stunned scientists when it appeared last fall and fueled its breathtaking spread around the world in the weeks that followed.

“The thing which most people would be nervously looking for is the possibility of a variant that has properties like Omicron, in terms of being able to infect lots of people but which also is more dangerous in the way that Delta was,” Hanage said. “If Omicron had been as virulent as Delta, things would have been much worse.”

There are some 300 Omicron subvariants that are being monitored, including BA.5 (which is widespread in the US), BA.2.75 and its subvariants, BA.4.6 and its subvariants, and BF.7, itself a subvariant of BA.5.

And there’s yet another variant – the XXB strain, another Omicron subvariant, which is causing a small surge in cases in countries like Bangladesh and Singapore. The latter has recorded a daily average of about 5,500 cases over the past week, compared to a daily average of 2,000 cases a month ago.

The XXB strain is a combination of mutations from other Omicron strains, and is considered by some to have the greatest capacity to evade antibody protection of all the newly emerging variants.

As I have observed several times, that’s exactly what the virus “wants” – to infect as many people as possible, and to keep them alive and in contact with other people, so the virus can infect them as well. It doesn’t “want” to make them sick, which would reduce their contact with other people, nor does it “want” to kill them. But, of course, the virus doesn’t always get what it wants!

*******

There’s a good deal more to be said about COVID. For example, there’s a new drug in development, created in the Scripps Research Institute. The drug, NMT5, alters the cells where COVID usually attaches so that the virus is no longer capable of infecting them. That’s an entirely new approach. I’ll dig into that in the next installment.

And I will report on a statement by the American Heart Association on the symptoms and causes of six cardiovascular diseases, and a finding by researchers at the Harvard Medical School that self-employed women enjoy a better quality of life compared with women with jobs and bosses. Not a surprise, you say? But there’s more to it than that. Also, I will attempt to answer a few inquiries that came in the comments thread to my previous piece about Parkinson’s disease.

To all denizens of Planet Gumshoe, Doc Gumshoe sends exhortations of health and happiness. Best to all, Michael Jorrin (aka Doc Gumshoe)