In this installment, we won’t be talking about the two Big C’s – Cancer and COVID-19. I had my say about COVID last time around, and I would be quite happy not to have to deal with that particular blight ever again. As for the other big C, the news has been coming out of the ASCO meeting at a rapid fire pace, and it’s mostly encouraging. There are an increasing number of effective treatments for a great many previously difficult-to-treat subvariants of the disease. Doc Gumshoe will attempt in the next installment to come up with an accurate overview of what’s going on in that front.

For this piece, we’ll be looking at progress in the management of several diseases/conditions that affect a whole lot of us, one way or the other. Here’s a quick list of the subjects I’ll turn my attention to: Alzheimer’s disease, Parkinson’s, respiratory syncytial virus (RSV), atrial fibrillation, migraine, and mammograms.

Alzheimer’s disease

When Doc Gumshoe first addressed Alzheimer’s disease, back in 2013, the piece started out with a bit of history, some of which I will repeat for context:

“Alzheimer’s disease has been recognized as a separate disease entity for over a century. A German physician named Alois Alzheimer had a female patient named Auguste Deter, who became severely demented starting at about age 50, an unusually early onset for senile dementia. Dr Alzheimer carefully followed Auguste for about 5 years, from 1901 to her death in 1906, and then he obtained permission to examine her brain, which he found had been invaded by a dense, whitish substance. Alzheimer recognized that the substance was a form of amyloid, which had been identified and named in the 19th century by the eminent scientist Rudolph Virchow.

For most of the 20th century, the diagnosis of Alzheimer’s disease was applied only to persons who developed the symptoms of dementia prior to old age. Persons who developed those symptoms in old age were described as being affected by “senile dementia.” While there are many possible causes of the loss of mental capacity, old age by itself is not one of them. For about the past 30 years it has been recognized that AD is a principal cause of dementia regardless of age at onset.”

A couple of years later, I followed up with another blog, which almost entirely was about treatment failures in such drug categories as BACE inhibitors and cholesterinase inhibitors, with modestly hopeful bits about agents that directly targeted the neurofibrillary tangles that were also (along with amyloid beta) thought to be causative factors in AD. That was in the era of AD treatment failures. One after another new drug didn’t work, or resulted in the tiniest positive effect – a continuing torrent of dashed hopes.

At this point, ten years after the first Doc Gumshoe on AD, the picture has changed considerably. I would date the beginning of the change as June 6, 2021, when the FDA gave emergency use authorization to Biogen/Eisai’s aducanumab, marketed as Aduhelm. As you may remember, this provoked widespread outrage in the health-care community, since the actual benefit that aducanumab treatment had demonstrated in the clinical trials was miniscule, while the price was the opposite of miniscule – about $56,000 per year. It was estimated that if just one-third of the eligible patients with Alzheimer’s disease were prescribed aducanumab/Aduhelm, the cost to Medicare would be about $112 billion per year, which is far more than Medicare spends on any other medication.

Aducanumab/Aduhelm is a BACE inhibitor, a class of drugs that inhibit the enzymes that cleave amyloid precursor proteins leading to the formation of amyloid beta (Aβ), which is a marker of Alzheimer’s and has long been thought to be a likely contributing factor, if not the sole cause. The particular enzyme that does most of the damage – that is, formation of amyloid beta – is β-secretase (BACE), so the drugs that try to prevent the formation of Aβ are termed BACE inhibitors.

But Aduhelm is not the only BACE inhibitor. A couple of others have emerged, and they may have turned the tide. The first of these is lecanemab, to be marketed as Leqembi, also from Biogen and Eisai, which on January 6th this year got a green light from the FDA via their Accelerated Approval Pathway. This was based on clinical trial data that demonstrated that treatment with lecanemab significantly removed accumulated Aβ from the brains of subjects with mild cognitive impairment.

More recently, on June 7th, the FDA said that lecanemab was expected to get full approval around July 6th. This was based on recent data showing that treatment with lecanemab slowed the rate of cognitive decline by 27% in patients with early AD compared with placebo. This was confirmed on June 9th, when the advisory panel voted 6 to zero for full approval.

Under the current accelerated approval, granted in January, Medicare’s policy is to provide coverage for the drug only to patients in a clinical trial. Currently, no clinical trials are underway with lecanemab/Leqembi. However, full approval would mean that Medicare would cover the costs of treatment with the drug. Most Alzheimer’s patients are enrolled in Medicare. The current estimated cost of Leqembi is $26,500 per year. Based on the 20% coinsurance requirement in traditional Medicare, patients would be responsible for about $5,000 out-of-pocket annually. However, Eisai offers a range of programs that would to a certain extent offset those costs.

The clinical trial that demonstrated the benefits of lecanemab/Leqembi, dubbed the CLARITY AT trial, investigated two kinds of outcomes. One was to see whether the drug led to a cognitive benefit, with tests of memory and active thinking. The other was to see whether there was a benefit in terms of the performance of usual daily activities – what is termed a functional benefit. Lecanemab met both of these standards by slowing the rate of decline by approximately 25% to 35% compared to placebo on measures of cognitive and functional decline over the 18-month studies.

Lecanemab/Leqembi is just one highly promising AD agent. The other one, perhaps even more promising, is donanemab from Eli Lilly. Initially, back in January of this year, the FDA rejected Lilly’s application for accelerated approval of donanemab, based on the fact that in the TRAILBLAZER-ALZ trial, which originally included more than 100 patients, many patients were able to stop taking the drug after only six months of treatment, with the result that the trial could not meet the FDA’s requirement of a trial that followed at least 100 patients for a full year.

Donanemab was compared to placebo in TRAILBLAZER-ALZ-2, a late-stage study of 1,182 subjects in the primary analysis population. Participants in this group had intermediate levels of tau and clinical symptoms of Alzheimer’s, meaning they were at a more advanced disease state. For comparison, Eisai’s study of lecanemab involved patients with mild cognitive impairment due to Alzheimer’s disease.

Data from the TRAILBLAZER-ALZ-2 trial demonstrated that treatment with donanemab resulted in a 35% slowing of cognitive decline and a 39% lower risk of advancing to the next stage of the disease when compared to placebo.

Donanemab also led to a 36% slowing of decline over 18 months on a key secondary endpoint measured by the Clinical Dementia Rating-Sum of Boxes, or CDR-SB, which measures disease severity. That is the endpoint that Eisai used for its phase 3 study of lecanemab, which showed the 27% rate.

A secondary analysis of that donanemab study showed that 47% of the enrolled subjects had no decline on CDR-SB at one year compared to 29% on placebo. More than half of patients, 52%, completed treatment – meaning that they had achieved plaque clearance – by one year, and 72% completed treatment by 18 months. The participants also had a 40% slowing of decline in ability to perform activities of daily living at 18 months, and, finally, they had a 39% lower risk of progressing to the next stage of disease when compared to placebo.

The safety data are certainly a cause for concern. The three BACE inhibitors that work by clearing the brain of amyloid beta share a particular side effect, termed “amyloid-related imaging abnormalities,” or ARIA. There are two principal forms that this takes – brain swelling or small brain bleeds. Two deaths due to ARIA were reported in the TRAILBLAZER-ALZ 2 study and later a third patient died after a serious ARIA, according to Lilly’s release. Brain swelling occurred in 24% of the treated patients in the donanemab group, with 6.1% reported as symptomatic. For brain bleeds, the rate was 31.4% in the donanemab group and 13.6% in the placebo arm. In the majority of cases, these incidents were entirely asymptomatic and could only be detected through diagnostic imaging.

It should be pointed out that these side effects occur only when there is significant amyloid beta in the brain. Patients being considered for treatment with donanemab or Leqembi should be made aware of the risks, which need to be balanced with the risks of letting Alzheimer’s disease progress without any effective intervention.

The results of the lecanemab and donanemab trials regarding both removing Aβ and slowing the progression of Alzheimer’s symptoms might be said to herald a new era in the treatment of Alzheimer’s disease. We’ll see what’s coming down the pike.

A not-so-minor obstacle in the development of Alzheimer’s treatment

The obstacle is the shortage of volunteers to participate in clinical trials. According to the Alzheimer’s Association, 187 trials are now in planning stages. To fill all of the available clinical trials, 57,465 patients are needed. That would mean 41,864 for Phase 3 trials; 13,829 for Phase 2 trials; and 1,772 for Phase 1. For Phase 4 studies, which are conducted after approval – as for Leqembi and its predecessor Aduhelm, for example – 4,632 additional patients will be needed. It generally takes two to four years to get a trial going and recruit the needed number of subjects. A major reason for this difficulty is that many people are simply unwilling to accept the possibility that they may be a part of the population that can benefit from treatment. So why volunteer to be in a clinical trial?

Who should be treated?

Clinical trials do not address this question. Do we focus treatment on persons who are already significantly affected by AD, or do we reserve treatment for those who have early signs of AD in an effort to slow down the progress of the disease? It’s a difficult question, especially since it’s highly likely that Medicare will cover most of the cost, with major consequences for the entire healthcare system, not to mention the taxpayers.

A test that identifies most persons with Parkinson’s disease

Doc Gumshoe most recently took up Parkinson’s disease (PD) in October 2022, at which time this test was still under development. Parkinson’s has mostly been diagnosed through its symptoms, which are many and puzzling. The obvious symptoms are related to movement; sometimes your muscles are doing things without your telling them to, or else failing to do the things you ask them to do. Before motor symptoms manifest, persons with PD may experience a diminished sense of smell, constipation, sleep disorders, pain, fatigue, and rapid eye movements. Persons with PD are most commonly affected by bradykinesia, meaning slowness of movement. Instead of walking with normal steps and a normally erect posture, swinging their arms in contrary motion with their feet, they take small steps and walk with a hunched-over posture. Sometimes it looks as though they are running, although with tiny steps.

The test, developed by a team of scientists with the Parkinson’s Progression Markers Initiative—a longstanding biomarkers study backed by actor Michael J. Fox’s Parkinson’s research nonprofit – detected deposits of a protein called alpha-synuclein, which is found in the cerebrospinal fluid of Parkinson’s early-stage patients. The test was able to distinguish Parkinson’s from non-Parkinson’s subjects 88% of the time, with a specificity of 96%.

In Parkinson’s, misfolded alpha-synuclein accumulates in the brain as part of what are known as Lewy bodies, which leads to the loss of neurons that signal using the neurotransmitter dopamine. Many of these are in the region of the brain that controls movement, which helps explain why the disease manifests in tremors and other motion problems.

Identifying which patients have alpha-synuclein deposits could help researchers find better ways to treat them, potentially before they develop symptoms. That finding would validate the notion that alpha-synuclein is part of the disease process that leads to symptoms, and that it could potentially be targeted to stave off Parkinson’s altogether.

The test was developed by Amprion, Inc. and is marketed under the name SYNTap. In addition to detecting alpha-synuclein, it is also able to detect Parkinson’s about 68% of the time in persons who have a form of the disease involving a mutation of the gene LRRK2, which is found in a small subset of the Parkinson’s population – between 2% and 5% of the total.

There are more than a million US residents with Parkinson’s. Globally, the number is about 10 million.

Vaccines against respiratory syncytial virus (RSV)

Even though RSV was discovered in 1956, it came into the public’s attention only during the COVID19 pandemic, evidently because some cases of RSV were mistakenly blamed on the coronavirus. Initially, RSV was isolated from a group of chimpanzees that seemed to be afflicted with acute inflammation of the upper airways. It was first named “chimpanzee coryza agent,” coryza being the name for stuffed-up nasal passages leading to sneezing and coughing.

It has since been found that most children at some point become infected with the virus, and which mostly results in mild cases of upper respiratory disease. The key word is “most.” Some children experience serious cases. RSV in children under the age of 5 is the cause of 57,000 hospitalizations, 500,000 emergency department visits and 1.5 million outpatient clinic visits. In children, RSV is infrequently fatal, causing between 100 and 500 deaths per year. Among US adults, an estimated 177,000 hospitalizations and 14,000 deaths associated with RSV infections occur annually. Those figures are estimates, and health workers who are familiar with the virus believe that they are underestimates, and that the real toll of RSV is considerably higher.

It’s in this context that we consider the arrival of vaccines against RSV from Glaxo SmithKline and Pfizer. GSK scored FDA approval for its vaccine, Arexvy, on May 8th of this year, for adults aged 60 and over. Overall efficacy in preventing infection was 82.6%, and in adults with at least one comorbidity, its efficacy was 94.6%. GSK has taken on Magic Johnson to help with its forthcoming ad campaign.

Then on June 7th, the FDA approved Pfizer’s RSV vaccine, Abrysvo. This was based on data from a Phase 3 trial called RENOIR, which enrolled about 37,000 participants aged 60 or older. In the study, the vaccine scored 66.7% protection against RSV-associated lower respiratory tract illness. Against more severe illness, the vaccine’s efficacy came in at 85.7%.

Pfizer recently reported positive results from an ongoing Phase 3 study of Abrysvo given with a seasonal flu vaccine in older adults, and they are studying the vaccine in other age groups and in subjects with underlying medical conditions.

The pharmaceutical world has high hopes for the financial potential of RSV vaccines, with analysts putting the market at about $10 billion.

A potentially effective treatment for atrial fibrillation

The way the heart is supposed to work is that the four chambers – two atria and two ventricles – take in blood and pump it to the next station in a closely determined rhythm. But sometimes the atria are not keeping to the rhythm. Instead, they contract and expand at a much more rapid pace. This leads to what we might view as cardiac inefficiency. Atrial fibrillation is not usually fatal, and in many cases persons with atrial fib experience no symptoms, although some people have palpitations, shortness of breath, and fatigue. As a cardiac issue of concern, atrial fib is not in the same league as ventricular fibrillation, which can be fatal in a matter of minutes. But atrial fib is not without consequences.

One consequence of atrial fib that is concerning and can be fatal is that blood may pool in the atrium, forming blood clots. These blood clots can then be expelled into the circulatory system. If they lodge in the brain, they can cause strokes. If they lodge in a coronary artery, they can cause heart attacks.

Acesion Pharma, a Copenhagen-based outfit, has developed an agent that promises to have a significant effect in reducing atrial fib and its adverse consequences. In a Phase 2 clinical trial of their agent, AP 30663, 63 persons currently experiencing an episode of atrial fib received one or two intravenous doses of their drug candidate, or placebo.

In the 90 minutes after infusion, more than half of recipients of the higher dose (5-mg/kg) converted to sinus rhythm, which is the characteristic rhythm of a healthy heart. The placebo cohort, meanwhile, remained in atrial fib. This resulted in the study achieving its primary endpoint. The conversion rate in the low-dose cohort, which received 3 mg/kg, was lower than in the high-dose arm but still significantly higher than in the placebo group.

The candidate drug is an inhibitor of the SK channel, which allows potassium ions to cross the cardiac cell membrane. These channels are involved in regulating the firing frequency of action potentials in the cardiac muscle tissue – in other words, regulating the rhythm of cardiac contractions.

Patients with atrial fib are often treated with drugs meant to inhibit the formation of blood clots – i.e., blood thinners – so as to minimize the risk of strokes or heart attacks related to atrial fib. Taking blood thinners, however, is not without the risk of GI bleeds or even brain bleeds. Acesion’s AP 30663 is a step in the right direction.

About 12 million persons in the US have atrial fib. The number of deaths in which atrial fib was mentioned in death certificates as a possible cause was 183,321 in 2019. The number of persons affected by atrial fib globally is estimated at more than 60 million – certainly an underestimate since many individuals with atrial fib are asymptomatic, and in less developed parts of the world would almost certainly escape notice.

Anything new in the migraine treatment arena?

Migraines used to be called “sick headaches,” and treating a migraine used to consist of taking megadoses of common pain killers (aspirin, etc.), which might damp the pain a bit, but did absolutely nothing for the many nasty symptoms that went with the headache. The headache itself is not considered to be a migraine unless it is accompanied by other symptoms, the most usual of which is nausea, sometimes with vomiting. Migraineurs are also extremely sensitive to light and sound, frequently taking refuge in dark, quiet rooms. In some cases, odors which are not usually thought to be unpleasant are intolerable to the migraineur. And migraineurs may experience blurry vision, stuffy nostrils, diarrhea, stomach cramps, pallor, flushing, or localized swelling of the face, hot or cold sensations, sweating, stiff neck, tenderness of the scalp, and a range of mental symptoms including anxiety, depression, irritability, and impairment of concentration.

Migraine is a lot more common than most people would guess. Globally, the estimate is that 14.7% of the population experience migraines – that’s about a billion of us here on Planet Earth. In the US, 18% of women, 6% of men, and 10% of children are have migraines from time to time – a total of 39 million.

As to what causes migraines, the most successful theory, from a purely pragmatic perspective, is that migraine is a syndrome characterized by low levels of serotonin in the plasma. Serotonin (5-hydroxytryptamine, or 5-HT) has a number of physiologic effects, including the ability to suppress pain and to contribute to normal sleep. Serotonin acts through a number of receptors, classified as 5-HT1 through 5-HT7. The 5-HT1 subclass includes those most likely to be involved in pathophysiology of migraine. Most of the current generation of migraine medications – i.e., the triptans – are activators of those serotonin receptors. They are both potent constrictors of blood vessels in the brain, and, perhaps more important, inhibitors of the inflammatory response.

The first drugs specifically developed to treat migraines drugs were the triptans, which are activators of certain serotonin receptors, designated 5-HT1B/1D. The first of these was sumatriptan (Imitrex, from Glaxo SmithKline), initially marketed as a subcutaneous injection and later as an oral medication.

Most triptans usually provide reasonably prompt headache relief – i.e., within less than 2 hours. However, there are significant drawbacks to triptan use. One is that many migraineurs experience recurrence of headaches after initial relief. In some studies, 40% to 70% of migraineurs reported rebound headaches, and repeated dosing with triptans is usually not recommended. Thus, rather than taking the triptan, some migraineurs prefer to seek relief without any specific drug treatment, using their own strategies – bed-rest in a darkened room, ice-packs, warm compresses, scalp massage, sleep.

Another target in migraine treatment is the calcitonin gene-related peptide, a molecule that triggers migraine attacks. Drugs that inhibit this molecule, CGRP inhibitors, including Amgen’s Aimovig, which they are co-marketing with Novartis; also Emgality, from Eli Lilly; Ajovy, from Teva Pharmaceuticals; and Vyepti, from Lundbeck. These drugs are mostly used to prevent migraines, not necessarily to provide relief from a migraine once underway. Treatment with these agents is considered successful when it significantly reduces the number of days per month that patients experience migraines. Cutting the number of migraine days by as much as one half is a distinct triumph, but even the most successful of these drugs only attains that threshold in a fraction of the patients treated in clinical trials.

About two months ago, the FDA approved expanding the indication of AbbVie’s Qulipta (atogepant) for the preventive treatment of migraine in adults. The approval makes Qulipta the first and only oral calcitonin gene-related peptide (CGRP) receptor antagonist approved to prevent both episodic and chronic migraine. Chronic migraineurs experience headaches for 15 or more days per month, with at least 8 of those days qualifying as migraines.

The approval of Qulipta was based on the PROGRESS clinical trial, which evaluated the drug over 12 weeks in a once-daily 60-mg form and a twice-daily 30-mg form in patients who had been diagnosed with chronic migraines for at least a year. Patients in the 60-mg and 30-mg groups experienced a decrease of 6.88 and 7.46 monthly migraine days, respectively, compared with a decrease 5.05 days in the placebo cohort. The result was judged to be highly significant (P ≤ 0.0001).

Another trial endpoint was the proportion of patients who achieved at least a 50% reduction in mean monthly migraine days. That result was seen in 41% of patients in the 60-mg group and 42.7% in the 30-mg group, compared with around 26% for placebo treated patients.

AbbVie estimates that annual sales of Qulipta will reach $1 billion.

At what age should women start receiving mammograms?

It used to be age 40. Then the US Preventive Services Task Force switched their recommended age to 50. The reason they gave for the switch was that the potential harms outweighed the benefits. Now, they have changed the recommended age back to 40.

But what were those potential harms that made them raise the recommended age to 50? The harms that the USPSTF considered in that decision were things like the psychological impact and anxiety associated with getting a false positive, the risk of a biopsy, or the risk of additional follow-up. Essentially, the USPSTF was saying, “We think causing anxiety for women is a harm, so we’re going to change the age to 50 when the likelihood of finding cancer is a little higher.”

But between 2015 and 2019, the annual incidence of breast cancer in the younger population (age 40 vs. age 50) increased by about 2% each year. That crossed the threshold where the USPSTF felt that starting screening at age 40 made sense, so they switched back.

As we’ve discussed before, the USPSTF has made recommendations about screening that many healthcare professionals strongly disagree with, including opposing prostate-specific antigen (PSA) testing for men as a way of screening for prostate cancer. The harm the USPSTF was balancing against the potential benefit of detecting prostate cancer in early stages was the risk of a biopsy in the event of a positive PSA test. More recently, the USPSTF has waffled on that negative recommendation, leaving the decision up to the patient and physician.

The USPSTF does not usually bring financial questions into their public recommendations, but they always keep an eagle eye on costs. Which, I must acknowledge, are important factors both for the individual patient and for the insurance community. However, it seems to me that the USPSTF does not sufficiently weight the costs of prevention against the costs of treatment – obviously, treatment is vastly more expensive. As it happens, neither mammograms nor PSA tests rank high on the cost scale, and beyond question, they save lives.

The unanswerable question is, at what point it is too expensive to carry out a procedure that might save a life? Not only is that question unanswerable, but it’s almost un-askable.

The AMA finally comes around to Doc Gumshoe’s view on the BMI

On June 13th, the American Medical Association issued the pronouncement that body mass index was not a reliable indicator of health status. Here’s a statement from a report presented at the 2023 AMA Annual Meeting in Chicago:

“Body mass index (BMI) is easy to measure and inexpensive. It also has standardized cutoff points for overweight and obesity and is strongly correlated with body fat levels as measured by the most accurate methods. But BMI is an imperfect measure because it does not directly assess body fat. On top of this, the current BMI classification system is misleading about the effects of body fat mass on mortality rates.”

The AMA report goes on to outline some of the reasons for their edict, namely that the BMI “normal” is based on data from a male, European population and does not take into account gender, race, or body type. I went into considerable detail on this subject in a recent post titled “Weight and Waistline Worries.”

Doc Gumshoe is gratified.

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I’ve been keeping an eye on the flood of news coming out of the American Society of Clinical Oncology. As the huge cancer field gets sliced up into a great number of different and specific patches, treatment increasingly is focused on specific cancers. And many of those narrowly-focused treatments have been found to be effective, to the benefit of cancer patients for whom previously there was little hope. Taking a look at what happened at the recent ASCO meeting will be the subject of the next Doc Gumshoe. Meanwhile, many thanks for comments of all flavors. Be well and best to all, Michael Jorrin (aka Doc Gumshoe)

[ed note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) and shares his commentary with Gumshoe readers once or twice a month. He does not generally write about the investment prospects of topics he covers, but has agreed to our trading restrictions.  Past Doc Gumshoe columns are available here.]