I’m guessing that news about possible Alzheimer’s disease treatments is still relevant to most of us, so I’ll start with that.

The results of the lecanemab trial are published. The reaction is mixed.

In the October “Odd & Ends” piece, I discussed in considerable detail the clinical trial of lecanemab in advance of publication of the study. I am presuming that you will grant me permission to reproduce what I said back then, and then I’ll report on how those results have been received, and also how the makers, Biogen and Eisai, responded.

Here’s the Doc Gumshoe report from October:

“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 at all time points 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.

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.”

The study was just published in The New England Journal of Medicine, on November 29 (CH van Dyck, “Lecanemab in Early Alzheimer’s Disease,” N Engl J Med. 2022 Nov 29. doi: 10.1056/NEJM oa2212948). The publication attracted a good deal of attention, including a nearly full-page article in the N. Y. Times on November 30, with the headline “Alzheimer’s Drug Proves Marginally Beneficial, With Risks.”

Besides describing the results of the clinical trial very much as in my excerpt above, the Times article included comments from several experts who were not involved in the study. Without exception, these comments were cautiously balanced, acknowledging the benefits of lecanemab treatment in the study subject while at the same time pointing out that the treatment was not without risks. For example, Dr Jason Karlawish, who is co-director of the University of Pennsylvania’s Penn Memory Center, said “The benefit is real; so too are the risks.”

Dr Madhav Thambisetty, a neurologist and a senior investigator at the National Institute on Aging, said “From the perspective of a scientist, it is exciting that an experimental treatment targeting brain amyloid in Alzheimer’s disease appears to slow cognitive decline.” But he added that “From the perspective of a physician caring for Alzheimer’s patients, the difference between lecanemab and placebo is well below what is considered a clinically meaningful treatment effect.”

I should point out the difference between statistically significant and clinically meaningful. Statistically significant means that the outcomes are real and are extremely unlikely to be the result of random accident, while clinically meaningful means that the results are likely to have a real effect on patients’ health and well-being. Dr Thambisetty is saying that, despite that 27% difference in the Clinical Dementia Scale – Sum of Boxes, patients won’t experience much difference in their lives.

The NEJM study reported six deaths in the patient group taking lecanemab and seven deaths among placebo patients. The study authors stated that no deaths were considered to have been related to lecanemab, nor had they occurred while the patient was experiencing brain swelling or bleeding.

However, the deaths of two patients were recently reported. These occurred after the 18-month study period and were thus not included in the study results. The patients were taking blood thinners, and both of these patients had other medical complications. One was a 65-year-old woman who had sustained a stroke and was taking medications to prevent stroke-related blood clots. The other case was a man in his 80s with a heart condition and who had experienced falls and mini-strokes.

And a last minute addition to this report: on Wednesday, December 21, Science reported a third fatality in that cohort – a Florida woman, aged 76, who had experienced episodes of brain swelling and several seizures. This patient, unlike the two patients referred to above, had no pre-existing medical conditions that might have caused mortality.

With regard to the first two fatalities, a spokesperson for Eisai stated that “It is Eisai’s assessment that the deaths cannot be attributed to lecanemab.” Thus far, Eisai has remained silent on the third fatality.

It has been observed that if lecanemab were found to be unsafe for persons taking blood thinners, it would exclude thousands from treatment.

After having noted that the benefit of treatment with lecanemab needed to be balanced with safety risks, the need for frequent infusions, and what will be a high cost, Dr Kristine Yaffe, a professor of neurology and psychiatry at the University of California, San Francisco, summed up her views as “of all the amyloid antibody trials, this one seems most clearly positive and convincing.”

I was struck by the differences in the initial response to the lecanemab data in comparison with the initial response to the aducanumab (Aduhelm) data. When the aducanumab data was first made public, a common response was that at last there seemed to be a drug that actually made a difference in the progress of Alzheimer’s, even though that difference was quite small and offset by the incidence of side effects. The aducanumab data was also evidence that the theory that amyloid beta plaque was a significant cause of Alzheimer’s had some merit.

Of course, as more results came to light, the FDA’s initial authorization came to be generally questioned, leading to the FDA’s limited approval of Aduhelm, based on an end point other than patient benefit, namely a reduction in the level of amyloid plaque. Aduhelm’s continued approval will depend on further clinical trials demonstrating genuine patient benefit.

No doubt because of the adverse events and fatalities, the medical community is taking a “wait and see” position with regard to lecanemab. One common response has been that it will be very interesting to see the results if lecanemab is studied in conjunction with an agent that has an effect on tau protein, which is the other brain substance that is thought to lead to Alzheimer’s disease, along with amyloid beta.

Targeting a genetic risk for Alzheimer’s disease

On Friday, December 2nd, at the Clinical Trials on Alzheimer’s Disease conference, the results of a very small, and very preliminary trial were announced. The trial subjects were five individuals who had inherited two copies of the APOE4 gene, which very greatly increased their risk of Alzheimer’s. There are three variants of the APOE gene. APOE3, the most common variant, apparently has no effect on Alzheimer’s disease. Persons with the APOE2 gene are at lower risk of Alzheimer’s. Persons with a single APOE4 gene are at an elevated risk, and persons with two copies of APOE4 have a lifetime risk of developing Alzheimer’s between 30% and 55%.

The five subjects in this trial were already in the early stages of Alzheimer’s. What the researchers did was to inject the brains of the subjects with copies of the APOE2 gene, in the hopes of reducing the high risk associated with two APOE4 genes to the level of risk associated with a single APOE4 gene. In other words, approximately halving the lifetime risk.

The APOE2 gene is transported by the adeno-associated virus, which is also used in CAR-T gene therapies.

The preliminary trial we’re talking about here was a test of safety only, and the trial, which employed a low dose of the APOE2 gene, met the safety standard. Two markers of Alzheimer’s disease, amyloid beta and tau protein, in the cerebral spinal fluid of the trial participants declined after the infusion of the APOE2 gene.

Another small trial, employing a higher dose of the APOE2 gene is now underway. The work is funded by the Alzheimer’s Drug Discovery Foundation and supported by Lexeo Therapeutics, a new company founded by Dr Ronald Crystal, chairman of the department of genetic medicine at Weill Cornell Medicine in New York.

A potential universal flu vaccine

On Friday, December 6, the National Institutes of Health issued a release which led off with these two statements:

“A vaccine using mRNA technology induced an immune response in mice and ferrets against 20 different types of influenza.

It also provided the animals protection against death from flu strains not included in the vaccine, showing its potential to help prevent future flu pandemics.”

The usual flu vaccine, which I regularly get every year along about Thanksgiving, usually provides specific protection against three variants, generally two type A variants and one type B. The vaccine makers try to figure out which variants are going to be the most menacing in a coming flu season, but they don’t always make an accurate prediction. For instance, in 2009, there was a global pandemic of H1N1 swine flu, and the vaccine did little to prevent it.

However, some older adults who had experienced bouts of H1N1 earlier in life and were infected with the 2009 version only had mild symptoms. Because we all have had flu infections, dating from early childhood, we do have a degree of basic immunity against the flu. As with the immunity provided by the COVID-19 vaccines and boosters, the current flu shots, even if they miss their target with regard to preventing infection, mostly reduce the incidence of serious illness and death.

The notion of a universal vaccine that would provide protection against all flu variants and prevent flu pandemics has been around a long time, and there have been efforts, so far fruitless, to induce the immune system to recognize those parts of the virus that are common to all flu variants.

A different strategy was tested by an NIH-funded research team led by Dr. Scott Hensley from the University of Pennsylvania. Using mRNA technology, as in the COVID-19 vaccines, they put together a vaccine that included a virus protein from each of 20 distinct influenza variants.

The team made a vaccine using mRNA for a key virus protein called hemagglutinin (HA) from all 20 influenza types. The mRNA was packaged in protective fatty nanoparticles. The researchers then tested the vaccine in mice and ferrets.

The antibody levels in these mice were measured, and the vaccinated mice produced robust levels of antibodies against both the hemagglutinin levels that were common in the 20 different influenza types, and also the hemagglutinin levels that were unique to each variant. The antibody levels remained unchanged for months after the vaccination, and robust antibody production occurred whether or not the mice had previously been exposed to any of those flu strains.

When vaccinated mice were exposed to a flu strain similar to one of those in the vaccine, they stayed relatively healthy, and all survived the viral challenge. In contrast, unvaccinated mice exposed to the same flu strain did not survive.

Vaccinated mice exposed to a flu strain that was different from the ones in the vaccine were infected, but recovered much faster than the unvaccinated mice. Most of the vaccinated mice survived, but the unvaccinated mice all died.

Finally, the researchers tested a two-dose vaccination strategy. A month after the second dose, they challenged the ferrets with an avian flu strain that was distinct from the ones used in the vaccine. Vaccinated animals got sick, but recovered quickly and all survived. In contrast, half of the unvaccinated animals died, and those that survived took longer to clear the virus from their bodies.

Dr Hensley emphasized the importance of working with mRNA in developing the flu vaccine. He said, “For a conventional vaccine, immunizing against all these types would be a major challenge, but with mRNA technology it’s relatively easy.”

The vaccine has not yet been tested in humans. Dr Richard J. Webby, an expert in influenza viruses at St Jude’s Children’s Hospital in Memphis, observed that “The proof of the pudding will be what happens when it goes into humans and how going into a pre-immune population skews the response to it.”

Designing clinical trials to evaluate a vaccine against virus variants that are not currently circulating will be a major challenge. One approach might be to test the vaccine in the context of small, local sporadic outbreaks of flu variants that are not the principal ones at that time.

A major take-away from this work so far is that working with mRNA greatly facilitates vaccine development and widens the scope of vaccines.

Is a cancer vaccine a possibility?

That depends on what is meant by the word “vaccine.” If we stick with the conventional understanding, which is that it’s a substance administered for the prevention of an infectious disease, then what the current announcement from Moderna and Merck is talking about is not really a vaccine. For a start, cancer is not an infectious disease, and the Moderna/Merck candidate does not actually prevent cancer.

But that doesn’t mean that their announcement that they are working on a cancer vaccine is a hoax. A less confusing label would be “immunotherapy,” which is, in fact, what Moderna called its candidate. It is a personalized mRNA therapy tailored to the neoantigens found in a patient’s tumor and identifying mRNA that can trigger an immune response. The mRNA molecules are encased in lipid nanoparticles for administration to the patient.

The candidate, labeled mRNA-4157/V940, is given post-surgery, after the removal of tumor, and in combination with Merck’s Keytruda, a blockbuster cancer drug. The combination results in a 44% reduction in the risk of cancer recurrence and death. The 44% risk reduction represents the improvement in efficacy when compared with Keytruda alone.

Those results came from an open-label phase 2b trial in 157 subjects with stage 3 or 4 melanoma. Trial subjects received either mRNA-4157 and Keytruda or Keytruda alone. The finding of a 44% risk reduction was hailed by Moderna and Merck as the first demonstration of efficacy for a mRNA cancer treatment in a randomized clinical trial. The trial laid the groundwork for a move into phase 3 and expansion into other cancers.

That expansion could well prove challenging. Melanoma is a particularly immune-responsive cancer, and the tumors can regress spontaneously. As Merck and Moderna move into indications for other cancers, they may see the impact of mRNA-4157 diminish.

Keytruda is used for more than melanoma, however, including for cancers that affect the breasts, skin, colon, uterus, cervix, stomach, kidney, gut, liver, bladder, as well as Hodgkin’s lymphoma and B-cell lymphoma. The Moderna-Merck immunotherapy candidate will have to be tested in the context of each of those other cancers.

Whether prevention of cancer recurrence is an outcome that justifies calling this candidate agent a vaccine, I will leave to a higher authority to decide. But the work so far has had a very positive outcome, and it testifies to the prospects that mRNA vaccines offer.

The JYNNEOS vaccine provides strong protection against mpox (formerly known as monkeypox)

While we’re still on the subject of vaccines, let’s take a look at this one. According to the Morbidity and Mortality Weekly Report, put out by the U. S. Department of Health and Human Services Centers for Disease Control and Prevention, this vaccine provided robust protection against infection with that pathogen.

The JYNNEOS vaccine, from Bavarian Nordic, is a modified vaccinia Ankara vaccine, meaning that it is based on the same mechanism as the smallpox vaccine. It is given in either one or two doses. It was approved by the FDA in 2019 to prevent smallpox and mpox disease, and then on August 9 of this year Emergency Use Authorization was issued by the FDA to permit intradermal administration of 0.1 mL per dose, which stretched the available supply so that more persons would be vaccinated. From September 4 to October 1, 2022 a total of 205,404 persons received the JYNNEOS two-dose vaccine in the US.

The CDC’s Morbidity and Mortality report cites the evidence for the assertion of the efficacy of the JYNNEOS vaccine, comparing the infection rates for vaccinated versus unvaccinated persons in three different cohorts. In the first comparison, between July 31 and September 3, 2022, mpox incidence in men aged 18-49 years was 14 times higher among the unvaccinated than among the vaccinated.

A second comparison looked at mpox incidence during the period from July 31 to October 1, 2022. There were 9,544 cases among men aged 18 to 49, from 43 US jurisdictions. During that period, mpox incidence was 7.4 times higher in the unvaccinated than among men who had received only one dose of the JYNNEOS vaccine.

A third comparison in the same cohort was between the unvaccinated and men who had received a second dose of the vaccine at least two weeks earlier. In that comparison, the rate of infection among the unvaccinated was 9.6 times higher than in those who had received the second dose.

Whichever ratio of incidence between the unvaccinated and single or double-dose vaccinated we use – 14, 7.4, or 9.6 times higher – the evidence for the effectiveness of the JYNNEOS vaccine is pretty strong.

Obviously, this was not a randomized, double-blind, placebo-controlled clinical trial, but an after-the-fact assessment of mpox incidence in a cohort of vaccinated individuals compared with a cohort of unvaccinated individuals who got mpox. It seems obvious that the 200,000-plus men who got themselves vaccinated had assessed their risk of acquiring mpox and decided to go for the vaccine. But what were the characteristics of the unvaccinated cohort? Were they also aware of their risk of getting mpox? Is the comparison strictly between the vaccinated and the unvaccinated, or also, to some degree at least, a comparison between a cohort that was being careful to avoid behaviors that would risk becoming infected and another cohort that was less aware of the risks and taking fewer precautions?  If the latter, which to me seems likely, then part of the reason that the vaccinated cohort got fewer mpox infections is because they were behaving more cautiously with regard to the behaviors where transmission is likely. These are, as by now very solidly established, sexual contacts between men.

So at least part of the reason for the protection offered by the JYNNEOS vaccine is probably that the vaccinated population is being more careful than the unvaccinated. Perhaps one could say the same about other vaccines, including COVID-19. But avoiding COVID infection is quite a bit more difficult than avoiding the behaviors that lead to monkeypox transmission.

And, in a related bit of mpox news…

Monkeypox declared a Public Health Emergency of International Concern (PHEIC)

The WHO Director General Tedros Adhanom Ghebreyesus announced the declaration back on July 23, 2022. According to WHO regulations, a PHEIC should be declared if a disease outbreak is an extraordinary event; when it constitutes a public health risk to other states through international spread; and when a coordinated international response is potentially required. At this time, WHO’s International Health Regulations Emergency Committee has not approved the PHEIC declaration, likely due to bureaucratic impediments.

(By the way, WHO refers to the disease as monkeypox, so in this discussion I will stick with the earlier appellation.)

The six previous PHEICs were the 2009 H1N1 influenza pandemic, poliovirus in 2014, Ebola virus disease in west Africa in 2014, Zika virus disease in 2016, Ebola virus disease in the Democratic Republic of the Congo in 2019, and COVID-19 in 2020.

A number of concerns have been expressed about the declaration, among which were that it would increase stigma and have no added benefit in quelling the monkeypox epidemic’s trajectory.

One question that is uncertain at this stage is will the PHEIC declaration work to help tackle monkeypox? Will nations pay any attention to the PHEIC declaration and follow WHO guidance, despite the decision not being rubber-stamped by due process of the Emergency Committee? Nonetheless, in the press conference announcing the monkeypox PHEIC, the WHO Director-General expressed optimism that the PHEIC declaration might lead to increased support, increased vaccine production, more equitable access to vaccines, and global coordinated action to combat the spread of monkeypox.

Monkeypox requires international attention. In more developed parts of the world, it has not been of major consequence. However, we in the developed world have a vaccine that works pretty well, and in most cases the consequences of the disease, although unpleasant, are not catastrophic. In the parts of the world where it is more prevalent, such as in Africa, neither vaccination nor treatment are as readily available as in Europe and North America, and monkeypox is taking a severe toll. And it is exactly in those areas that infectious diseases spread and morph into variants that are more threatening and more difficult to treat. If for no other reason than for our own protection – to repeat the words of the WHO Director-General – global coordinated action to combat the spread of monkeypox is necessary.

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I would have preferred to end this offering on a more upbeat note, in harmony with the spirit of the holidays. However, I have a repository of mostly positive developments that I can digest and regurgitate for you in my next post. In the meantime, do please enjoy the holidays! I will certainly try to do the same. Many thanks for all the comments. Stay well, best to all, see you next year! 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.]