Lilly In Radiopharma Deal With Radionetics, Secures Right to Buy Biotech

 Eli Lilly on Monday signed a strategic partnership with Radionetics Oncology, which not only provides the pharma with a pipeline of promising cancer radiotherapeutics but also gives it the exclusive right to buy the San Diego biotech down the line.

The agreement includes a $140 million upfront payment from Lilly as well as the potential right to acquire Radionetics for $1 billion. The companies did not provide specific details or a timeline for the potential buyout but said that it would occur “upon the conclusion of an exercise period.”

Jacob Van Naarden, president of Lilly oncology, in a statement said that the partnership with Radionetics gives the pharma “access to novel GPCR targets” and the robust discovery capabilities of the biotech.

Radionetics focuses on the development small molecule radiopharmaceuticals. The biotech targets GPCRs, a large family of membrane proteins that help transmit signals from outside the cell inside. According to its website, GPCRs represent a “vast and largely unexplored” class of targets for radiopharmaceuticals.

Radionetics contends it leverages a “vast knowledge of GPCR biology” combines it with its platform’s “unrivaled proficiency” in designing small molecule drugs, resulting in highly selective radiopharma therapies.

The approach “uniquely pairs the power of radiopharmaceuticals with the precision of small molecule targeting to novel GPCRs,” COO Brett Ewald said in a statement.

Radionetics’ GPCR-targeting drug development technology has resulted in its lead candidate 68Ga-R8760, a gallium-based radioligand conjugate that targets the MC2R protein, which is highly expressed in the rare cancer adrenocortical carcinoma. The biotech kicked off the Phase I study of 68Ga-R8760 in October 2023 and announced plans to launch clinical programs in breast and lung cancer.

For Lilly, Monday’s partnership with Radionetics continues its recent investment spree in the radiopharma space. In October 2023, the pharma snapped up Point Biopharma for $1.4 billion. The acquisition, closed in December 2023, gave Lilly ownership of PNT2002, Point’s lead asset and an investigational radioligand therapy for metastatic castration-resistant prostate cancer.

At the time, Van Naarden said that the Point acquisition signaled the “beginning of our investment in developing multiple meaningful radioligand medicines for hard-to-treat cancers.”

In May 2024, Lilly partnered with Aktis Oncology for $60 million upfront and the promise of $1.1 billion in royalties. The deal gave Lilly worldwide rights to develop certain radiopharma therapies and diagnostics discovered by Aktis based on specific targets.

https://www.biospace.com/article/lilly-inks-radiopharma-deal-with-radionetics-secures-right-to-buy-biotech/

Two Senior Cassava Employees Subjects in Federal Probes After Former Advisor Indicted for Fraud

 Cassava Sciences disclosed on Monday that two of its senior employees are under investigation by federal agencies in connection with alleged scientific misconduct in its Alzheimer’s disease studies.

The Department of Justice (DOJ) and the Securities and Exchange Commission (SEC) are both investigating the two senior employees, according to Cassava. As part of the federal probes, Cassava’s board of directors has created an ad hoc committee of independent directors to conduct its own internal investigation.

“Cassava is cooperating with the DOJ and SEC in connection with these investigations,” the company said in a statement.

Monday’s announcement comes after a federal grand jury in the District Court of Maryland last week indicted Hoau-Yan Wang, who previously acted as a scientific collaborator and advisor at Cassava. Wang allegedly “caused Cassava to submit grant applications … that contained false and fraudulent representations about his research,” according to the company’s SEC filing.

 The indictment against Wang alleged that he made “materially false, fraudulent and misleading” claims regarding the mechanism of action of simufilam, Cassava’s Alzheimer’s disease candidate. According to the indictment, he also allegedly “manipulated or otherwise fabricated research results” including Western Blot data.

Wang worked with Cassava for more than a decade, during which time he was paid a “cash stipend” of $2,000 per month, according to the company’s SEC filing.

Simufilam is an investigational small molecule drug that works by binding to altered filamin A, which is involved in the neurodegeneration process typically seen in Alzheimer’s disease. Cassava is currently running two Phase III trials for simufilam in mild-to-moderate Alzheimer’s disease.

In late 2021, Cassava and simufilam became embroiled in controversy after a whistleblower alleged that that biotech had doctored some of its data. Questions about Cassava’s data manipulation continued over the following months, eventually involving both the SEC and DOJ. In June 2022, the controversy forced journal publisher Springer to pull a paper co-authored by Wang.

Cassava has always maintained that it did not engage in questionable scientific practices. In August 2022, the Journal of Prevention of Alzheimer’s Disease took Cassava’s side, saying that it had found no evidence to support the allegations of data manipulation by the company. Cassava in November 2022 claimed the controversy was started by short-sellers to manipulate the company’s stock price.

Since then, the biotech has doubled down on its defense of simufilam and insisting that it is “confident in the underlying science” of the candidate.

https://www.biospace.com/article/two-senior-cassava-employees-subjects-in-federal-probes-after-former-advisor-indicted-for-fraud/

Which Executive Agency Has the Most to Lose by SCOTUS’ Decision to Overturn Chevron?

 Nature abhors a vacuum. So do bureaucrats. When the vacuum is statutory silence or ambiguity, bureaucrats are quick to fill it in ways that give themselves more power. Nowhere is this more evident than “Chevron deference,” which has now been overruled.

Chevron deference, named after a Supreme Court case from 1984, has led to all sorts of administrative abuse across the spectrum of executive agencies. This is because the Court gave agencies the ability to identify “ambiguous” statutes that give that agency some sort of authority. Once identified, the agencies have made it a pattern to “interpret” the statute to mean whatever the agency wants it to mean.

This is exemplified in the Loper and Relentless cases that challenged Chevron deference. There, Congress had set forth a statute that permitted the National Oceanic and Atmospheric Administration (NOAA) to require fishermen to carry observers on fishing vessels to monitor their fishing practices. The NOAA felt that the statute was ambiguous as to who foot the bill for these observers and “interpreted” it to mean that the fishermen must pay. The Courts, feeling that Chevron deference tied their hands, agreed and allowed the NOAA’s interpretation of the statute to remain.

This has been common practice across the executive. But the question now exists: which agencies will suffer the most from the Supreme Court’s ruling? Which ones will be forced to return to the checks and balances originally intended by the Constitution? Which ones will be forced to abandon policies that only exist because of Chevron?

The candidates are numerous.

For example, the Department of Agriculture attempted to classify a small puddle as a “wetland” under the Swampbuster Act. Such a designation is subject to review. But the Department of Agriculture, conveniently, interpreted “such time as the person affected by the certification requests review” to mean that review can only happen after a natural event occurs. Clearly, the language does not contain that qualifier, yet lower courts deferred to that interpretation.

Elsewhere, the Food and Drug Administration (FDA) took it upon itself to seize power under the Tobacco Control Act. Congress granted the FDA authority to ensure addicted, adult, cigarette smokers had access to lower risk tobacco products, such as e-cigarettes, to move away from cigarettes. Part of that process included evaluating the program’s effect on minors. The FDA took this and effectively banned flavored e-cigarettes, which was never a stated goal in the legislation.

Even the Department of Veterans Affairs misuses its authority under the guise of Chevron. In one example, a veteran who had qualified for disability benefits was denied three years of benefits. There, the veteran had gained employment with the National Guard, thus pausing his benefits. But when he left the National Guard, the benefits never resumed. When he made a claim, he was told that only one year of benefits could be credited to him, citing its own policy. But the statute never stated such an arbitrarily rigid one-year figure. But this interpretation was given deference by the courts.

Agencies still attempt to stretch these statutory interpretations all the time, even if they know the interpretation may be struck down in court later. For recent examples, the CDC tried to issue an eviction moratorium during covid, the Department of Health and Human Services tried to force nuns to purchase birth control coverage, and the EPA tried to regulate greenhouse gas emissions in industries not under its jurisdiction. Each of these actions were taken despite the statutory authorities giving no such power or wide discretion.

The Supreme Court did correct these bad interpretations, but not until years of litigation had occurred and some damage had already been done. Because courts side with government in more than 70 percent (more if Chevron is invoked) of interpretation disputes, agencies are incentivized to press the envelope.

The answer is that all agencies stand to lose. All of them utilize this de facto loophole in the law that allows agencies to make up authority to their own benefit. And all of them will be forced to justify their interpretations moving forward. In this case, when the agencies lose, the American people stand to win. 

Pete McGinnis is director of communications at the Functional Government Initiative.

https://www.realclearpolicy.com/articles/2024/07/01/which_executive_agency_has_the_most_to_lose_by_scotus_decision_to_overturn_chevron_1041631.html

Xylitol is prothrombotic and associated with cardiovascular risk

 Marco Witkowski 1, Ina Nemet 1, Xinmin S Li 1, Jennifer Wilcox 1, Marc Ferrell 1, Hassan Alamri 1, Nilaksh Gupta 1, Zeneng Wang 1, Wai Hong Wilson Tang 1 2, Stanley L Hazen 1 2

• DOI: 10.1093/eurheartj/ehae244

Abstract

Background and aims: The pathways and metabolites that contribute to residual cardiovascular disease risks are unclear. Low-calorie sweeteners are widely used sugar substitutes in processed foods with presumed health benefits. Many low-calorie sweeteners are sugar alcohols that also are produced endogenously, albeit at levels over 1000-fold lower than observed following consumption as a sugar substitute.

Methods: Untargeted metabolomics studies were performed on overnight fasting plasma samples in a discovery cohort (n = 1157) of sequential stable subjects undergoing elective diagnostic cardiac evaluations; subsequent stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses were performed on an independent, non-overlapping validation cohort (n = 2149). Complementary isolated human platelet, platelet-rich plasma, whole blood, and animal model studies examined the effect of xylitol on platelet responsiveness and thrombus formation in vivo. Finally, an intervention study was performed to assess the effects of xylitol consumption on platelet function in healthy volunteers (n = 10).

Results: In initial untargeted metabolomics studies (discovery cohort), circulating levels of a polyol tentatively assigned as xylitol were associated with incident (3-year) major adverse cardiovascular event (MACE) risk. Subsequent stable isotope dilution LC-MS/MS analyses (validation cohort) specific for xylitol (and not its structural isomers) confirmed its association with incident MACE risk [third vs. first tertile adjusted hazard ratio (95% confidence interval), 1.57 (1.12-2.21), P < .01]. Complementary mechanistic studies showed xylitol-enhanced multiple indices of platelet reactivity and in vivo thrombosis formation at levels observed in fasting plasma. In interventional studies, consumption of a xylitol-sweetened drink markedly raised plasma levels and enhanced multiple functional measures of platelet responsiveness in all subjects.

Conclusions: Xylitol is associated with incident MACE risk. Moreover, xylitol both enhanced platelet reactivity and thrombosis potential in vivo. Further studies examining the cardiovascular safety of xylitol are warranted.

https://pubmed.ncbi.nlm.nih.gov/38842092/

Neuromuscular Training Decreased Incidence of Chemo-Induced Peripheral Neuropathy

 Neuromuscular training decreased the onset of chemotherapy-induced peripheral neuropathy (CIPN) in cancer patients, a randomized trial showed.

Among patients who were receiving either oxaliplatin or vinca alkaloids in the intention-to-treat analysis, the incidence of CIPN was 30% for those participating in sensorimotor training (SMT) and 41.2% for those participating in whole-body vibration (WBV) training compared with 70.6% for those receiving usual care (P=0.002), reported Fiona Streckmann, PhD, of the University of Basel in Switzerland, and colleagues.

Furthermore, results were more pronounced in a per-protocol analysis (>75% participation in the intervention):

• SMT group: 28.6%
• WBV group: 37.5%
• Usual care group: 73.3%

"Based on our results as well as the current literature, this specific exercise regimen not only presents potentially the best current treatment option for CIPN but also has the potential to prevent CIPN, improve quality of life, and have a positive impact on the course of oncological treatment," Streckmann and team wrote in JAMA Internal Medicineopens in a new tab or window.

They noted that CIPN is a "highly prevalent and clinically relevant" adverse effect of chemotherapy, and oxaliplatin and vinca alkaloids induce acute CIPN, with incidences of 70% to 90%, and chronic CIPN, with incidences of 50%. Symptoms, including loss of sensation, tingling, dysesthesia, pain, and loss of balance, affect activities of daily living and reduce quality of life.

"Positive results have been achieved with specific exercise interventions due to their wide range of proregenerative effects, including expression of growth factors, altered blood perfusion, and enhanced mechanoreceptor sensitivity," they added. "Neuromuscular stimulating interventions, such as SMT or WBV training, seem especially beneficial because they address both sensory and motor symptoms."

SMT is focused on balance and increasing mobility, while WBV training is believed to improve gait stability and muscle strength.

In an accompanying commentaryopens in a new tab or window, Arjun Gupta, MD, of the University of Minnesota in Minneapolis, and colleagues wrote that the study "supports the use of supervised exercise and physical medicine programs in reducing the risk of incident CIPN while receiving chemotherapy. As the evidence supporting these interventions grows, we must ensure that we have the capacity and incentives in place so patients can harness these benefits and live their fullest lives."

The study included 158 patients (mean age 49 years, 59% men) from four German centers, most of whom had lymphoma or colorectal cancer. They were randomized into three groups: supervised SMT or WBV training sessions twice a week for about 15 to 30 minutes or usual care.

SMT consisted of balance exercises on progressively unstable surfaces that increased with difficulty. Each patient performed four exercises per session, with each performed three times for 20 seconds, allowing a 40-second rest between each set and a 1-minute rest between each exercise. WBV training took place on a side-alternating vibration platform with patients standing on their forefeet, performing four sets of 30- to 60-second vibration periods.

Training sessions started 24 to 72 hours after randomization and were continued until completion of medical therapy. The primary aim of the study was to reduce the incidence of CIPN, as detected via a thorough neurological assessment.

The mean compliance rates were 68% for usual care, 78.2% for SMT, and 71.7% for WBV training. Patients in the intervention groups performed an average of 18 of 20 training sessions.

Streckmann and colleagues also reported differences in secondary outcomes between the groups.

For example, in the SMT group, there were fewer dose reductions of medical therapy compared with the usual care and WBV groups (31.6% vs 56.4% and 53.8%, respectively). Moreover, they noted that there was lower mortality in the 5 years after completion of chemotherapy in the SMT group that reached statistical significance compared with the usual care group -- 1.9% versus 17.1% (P=0.04).

Patients in the SMT group also reported significantly less pain and burning sensation than in the WBV or usual care groups.

Both the SMT and WBV groups improved balance control in bipedal stance. Patients in the SMT group also had improved bipedal stance with eyes closed and monopedal stance.

The editorialists noted that while the results of the study were encouraging, it came with some limitations.

They observed, for example, that the median age of the study cohort was 49 years -- a full two decades younger than the median age of people with cancer diagnoses in the U.S.

They also pointed out that one-fourth of trial participants in the intervention arms did not meet the criteria for the per-protocol analysis.

"This highlights how delivering the intervention can be challenging, but demonstrating benefits in the intention-to-treat analysis despite suboptimal adherence speaks to the possible efficacy of the interventions," they wrote.

Disclosures

The study was funded by the German Cancer Aid.

Streckmann had no disclosures. Co-authors reported receiving speaker fees from AbbVie/Allergan and Bristol Myers Squibb.

Gupta is supported by a grant from the Pancreatic Cancer Action Network. A co-author reported grants from the National Cancer Institute.

Primary Source

JAMA Internal Medicine

Source Reference: opens in a new tab or windowStreckmann F, et al "Preventive effect of neuromuscular training on chemotherapy-induced neuropathy: a randomized clinical trial" JAMA Intern Med 2024; DOI: 10.1001/jamainternmed.2024.2354.

Secondary Source

JAMA Internal Medicine

Source Reference: opens in a new tab or windowGupta A, et al "Exercise and physical medicine interventions for managing chemotherapy-induced peripheral neuropathy" JAMA Intern Med 2024; DOI: 10.1001/jamainternmed.2024.2367.

https://www.medpagetoday.com/hematologyoncology/chemotherapy/110904

Meds Tied to Higher Risk of Liver Injury

 Real-world data can be used to identify the most potentially hepatotoxic medications based on incidence rates of severe acute liver injury among patients without pre-existing liver or biliary disease, according to a series of cohort studies.

Of 194 suspected hepatotoxic medications, 17 dispensed in VA outpatient settings came with rates of severe acute liver injury at 5.0 or more events per 10,000 person-years, 11 of which were not included in the highest hepatotoxicity category by case reports, reported Vincent Lo Re III, MD, MSCE, of the University of Pennsylvania's Perelman School of Medicine in Philadelphia, and colleagues in JAMA Internal Medicineopens in a new tab or window.

"We identified multiple medications that are significantly higher or lower risk than previously suggested by case-based analyses," Lo Re told MedPage Today.

"We were not surprised by our findings," he added. "Case reports place the onus on the practitioner to publish the clinical findings from the case, which undoubtedly leads to underreporting. Case reports may also vary in the quality of the data and do not rely on standard definitions of acute liver injury."

Seven of the 17 medications -- stavudine, erlotinib (Tarceva), lenalidomide (Revlimid) or thalidomide, chlorpromazine, metronidazole, prochlorperazine (Compazine), and isoniazid -- were found to be the most hepatotoxic, with rates of 10.0 or more hospitalizations for severe acute liver injury per 10,000 person-years. The highest rate was observed with the HIV nucleoside reverse transcriptase inhibitor stavudine, at 86.4 events per 10,000 person-years.

The other 10 medications -- moxifloxacin, azathioprine, levofloxacin, clarithromycin, ketoconazole, fluconazole, captopril, amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, and ciprofloxacin -- had rates between 5.0 and 9.9 events per 10,000 person-years.

Antimicrobial medications, particularly antifungal medications and older antiretroviral drugs, represented 64% of those with the highest rates of severe acute liver injury.

After adjusting for diabetes, obesity, hyperlipidemia, and polypharmacy, rates of severe acute liver injury remained similar.

Aside from the 11 of 17 medications with the highest incidence of hepatotoxicity not being included in LiverToxopens in a new tab or window, a database of drug-induced liver injury case reports, seven medications in the study that had lower incidences of severe acute liver injury -- fewer than 1.0 event per 10,000 person-years -- were included in the highest risk category in LiverTox, noted Grace Zhang, MD, and Jessica Rubin, MD, MPH, of the University of California San Francisco, in an accompanying editorialopens in a new tab or window.

"What explains this difference in findings between the present study and LiverTox?" they asked. "Despite its undisputable value, the ability of LiverTox to capture the true incidence of drug-related hepatotoxic effects is limited because of its reliance on published case reports."

Lo Re and colleagues also pointed out that "categorizing hepatotoxic drugs using case reports does not consider the number of individuals exposed and may not accurately reflect incidence of severe ALI [acute liver injury]."

Another notable finding from the study was that statins, frequently thought to be linked to adverse hepatic effects, were in the lowest risk category for severe acute liver injury.

"Their hepatic adverse effects have long been feared by practitioners and patients alike," Zhang and Rubin wrote. "LiverTox has designated nearly all statins as category A [high] risk medications," but the database "fails to consider the denominator -- the nearly 100 million patients in the U.S. ... prescribed statins each year."

The study has important implications for clinical care, Lo Re and colleagues stressed, noting that there is currently no systematic approach to classifying drug-induced hepatotoxicity.

"Patients initiating a medication with a high rate of severe acute liver injury might require closer monitoring of liver-related laboratory tests to detect evolving hepatic dysfunction earlier, which might improve prognosis," Lo Re explained. "Moreover, within electronic health record systems, automated messages could alert clinicians ordering a medication with a high rate of severe acute liver injury to the potential risk of this outcome and to consider laboratory monitoring."

For this study, the researchers evaluated 194 medications used in the VA health system that had four or more published case reports of hepatotoxicity. They retrospectively analyzed VA electronic health record data for nearly 8 million people without pre-existing liver or biliary disease who began outpatient treatment with a medication suspected of causing hepatotoxicity from October 2000 through September 2021; 55% were taking multiple medications. Most (92.5%) were men, and the mean age across the medication cohorts was 64.4 years.

Lo Re and team identified 1,739 hospitalizations for severe acute liver injury, defined by either inpatient alanine aminotransferase level greater than 120 U/L plus a total bilirubin level greater than 2.0 mg/dL, or an international normalized ratio of 1.5 or higher plus a total bilirubin level greater than 2.0 mg/dL, recorded within the first 2 days of admission. Of these patients, 27.2% died within 180 days of hospitalization, and five patients underwent a liver transplant.

Disclosures

The study was funded by grants from the National Cancer Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases.

Lo Re reported receiving personal fees from Entasis Therapeutics and Urovant Sciences. Several other co-authors reported multiple ties to industry.

Zhang and Rubin reported no conflicts of interest.

Primary Source

JAMA Internal Medicine

Source Reference: opens in a new tab or windowTorgersen J, et al "Severe acute liver injury after hepatotoxic medication initiation in real-world data" JAMA Intern Med 2024; DOI: 10.1001/jamainternmed.2024.1836.

Secondary Source

JAMA Internal Medicine

Source Reference: opens in a new tab or windowZhang GY, Rubin JB "Rethinking drug-induced liver injury -- a new era of pharmacovigilance" JAMA Intern Med 2024; DOI: 10.1001/jamainternmed.2024.1833.

https://www.medpagetoday.com/gastroenterology/generalhepatology/110808

Alzheimer's Gets a New Definition

 Alzheimer's disease has a biologically based definition, according to criteria developed by an Alzheimer's Association workgroup.

The new criteria include biomarker classifications and a revised disease staging system, reported Clifford Jack Jr., MD, of the Mayo Clinic in Rochester, Minnesota, and co-authors in Alzheimer's & Dementiaopens in a new tab or window.

They define Alzheimer's disease as a process detectable by abnormal biomarkers when patients do not have cognitive symptoms -- a point of contention among some in the Alzheimer's community.

"Alzheimer's pathology, which we consider represents Alzheimer's disease, begins to appear in the brain at least 15 to 20 years prior to the onset of symptoms," Jack told MedPage Today. "To be scientifically accurate, we therefore define high-quality biomarker evidence of Alzheimer's pathology to represent Alzheimer's disease, including in people who are presently asymptomatic."

Defining diseases biologically is standard in cancer, heart disease, and diabetes, Jack pointed out. "Symptoms from Alzheimer's disease occur because affected individuals have already undergone substantial and irreversible death of brain cells," he said. "Ultimately, the most effective treatment for Alzheimer's disease must begin while affected individuals are still asymptomatic. This is axiomatic for every disease in medicine for which biomarkers exist."

The field is still awaiting clinical trial evidence about whether treating asymptomatic patients will prevent cognitive decline, Jack added.

Not Clinical Practice Guidelines

The new criteria do not constitute clinical practice guidelines. They are intended to help evaluate symptomatic adults, not those who are cognitively unimpaired, the workgroup committee emphasized. Testing cognitively unimpaired individuals outside of research studies is not recommended at this time.

"Our criteria are intended to serve as a bridge between clinical practice and research, not as a step-by-step manual for general clinical practice today," Jack said. "Formal clinical practice guidelines around treatment and testing will be forthcoming from the Alzheimer's Association."

In the revised criteria, the committee outlined three broad categories of biomarkers: those specific to Alzheimer's changes like amyloid and tau, referred to as "core" biomarkers; those important to Alzheimer's but not specific to the disease, like neurodegeneration and inflammation; and those that reflect conditions that commonly co-exist with Alzheimer's, like vascular pathology and alpha-synuclein.

Core 1 Alzheimer's biomarkers become abnormal early in the disease course and include amyloid PET, approved cerebrospinal fluid biomarkers, and certain plasma biomarkers like phosphorylated tau 217 (p-tau217) that map into either the amyloid-beta or Alzheimer's tauopathy pathway. Core 2 biomarkers reflect aggregated tau deposits and include biofluid and tau PET.

"An abnormal Core 1 biomarker result is sufficient to establish a diagnosis of Alzheimer's disease and to inform clinical decision-making throughout the disease continuum," the committee wrote. Later-changing Core 2 biomarkers can provide prognostic information and increase confidence that Alzheimer's is contributing to symptoms, they added.

The same Alzheimer's biology may result in different phenotypic presentations, the committee noted, depending on co-pathologies, cognitive reserve, resistance, and other factors that may influence relationships between clinical and biological Alzheimer's stages.

Criteria Critiques

The revised criteria updates the 2018 Alzheimer's research frameworkopens in a new tab or window. Early versions of the new criteria were presented at meetings last year and posted for public comment, and groups like the American Geriatrics Society (AGS) reacted quickly to draft versions.

"The AGS position is that the framework proposes a clinical diagnosis of Alzheimer's disease in biomarker-positive asymptomatic individuals with insufficient attention to the potential impact on their personal identity or social and fiscal consequences," the organization wrote in a commentopens in a new tab or window last November. "While AGS understands that defining Alzheimer's disease as a biological construct has advantages for research, the current evidence base is underdeveloped to support clinical utility."

Some criticisms contradicted fundamental positions of the committee, Jack and colleagues noted in a Nature Medicineopens in a new tab or window commentary. One was whether the term "Alzheimer's disease" should be used to describe all-cause dementia and whether distinctions between etiology and symptoms should be ignored to avoid confusion among the general public -- which the committee said was not only inaccurate, but harmful. "The etiology or etiologies underlying clinical symptoms must be understood and accurately diagnosed to enable effective treatments," they wrote.

Another was whether a diagnosis of Alzheimer's disease should require the presence of both abnormal biomarkers and clinical symptoms, as some people with amyloid deposits may not experience cognitive decline. "Over half of individuals newly diagnosed in their mid-70s may not experience symptoms in their lifetime, but nearly half will," the committee pointed out. "The position of the committee is that asymptomatic individuals who may experience symptoms deserve treatment once these are approved for the preclinical population."

Critics also zeroed in on references to blood-based biomarkers, saying they are too new to be used. Recognizing that "plasma biomarkers are a recent development, we also outline rigorous criteria that plasma biomarkers need to meet to be considered fit for the purpose of diagnosis," the committee noted.

The revised criteria are intended to reflect current scientific knowledge, Jack observed. "Some of the biomarker tests described in the diagnosis and staging criteria are not available at this time in general medical settings, but will be in the future as the infrastructure for testing is built out," he said.

Disclosures

Jack reported serving on a data safety monitoring board for Roche pro bono, and holding index funds. He also reported grant funding from the NIH, the Alexander family professorship, and the GHR Foundation. In addition, he received funding from the Alzheimer's Association for travel.

Co-authors reported relationships with pharmaceutical companies, nonprofit organizations, and others. One co-author is an Alzheimer's Association employee and two are employed by the National Institute on Aging.

Primary Source

Alzheimer's & Dementia

Source Reference: opens in a new tab or windowJack CR, et al "Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup" Alzheimer's Dement 2024; DOI: 10.1002/alz.13859.

Secondary Source

Nature Medicine

Source Reference: opens in a new tab or windowJack CR, et al "Revised criteria for the diagnosis and staging of Alzheimer's disease" Nat Med 2024; DOI: 10.1038/s41591-024-02988-7.

https://www.medpagetoday.com/neurology/alzheimersdisease/110912