Clinical Trial Fundamentals

Asked. Answered. Big happenings last week. Eli Lilly and Company published data on its anti-amyloid drug donanemab, confirming that another drug removes plaques from the brain, and most importantly, helps slow cognitive decline. Lilly’s presenter could not get in a word edgewise, as their data reveal slide was met with thunderous applause. I was most impressed with two of Lilly’s senior scientists, the first being Dr. Mark Mintun, who ended the presentation stating, “early diagnosis now becomes the key to holding off Alzheimer’s.” The second being Dr. Dan Skovronsky, who 20+ years ago at UPenn, worked on a “crazy idea” for a PET scan that could detect plaques in the brain. That crazy idea was spun out into the company called Avid Radiopharmaceuticals, ultimately bought by Lilly. Lilly’s flagship Amyvid PET Scan was integral in detecting plaques and measuring Leqembi and donanemab’s success in clinical trials. We all owe Mark, Dan, and the Alzheimer’s team at Lilly our gratitude for proving that innovation and persistence go hand in hand. So, what does this all mean? This past spring, we were in Palm Beach hosting an event, when someone asked, “why would anyone want to know if they were at risk of developing Alzheimer’s, since there’s nothing you can do about it?” It’s always fun to watch Dr. Howard Fillit patiently answer this question. The good news is with two drugs, there is no longer a need to ask the question. Thank you, Eisai US & Lilly. So, what does this all really mean? Both drugs have a “modest effect” on slowing cognitive decline, meaning they can delay the progression of Alzheimer’s by about 30-35%. Any delay is important given Alzheimer’s is a fatally progressive disease. With these new treatments, patients can expect about a six-month delay in cognitive decline (important note: length of time and impact are expected to increase as more people stay on the drugs for longer.) Think of these two new drugs as the “first cracks in the wall.” Howard stated it best to the Financial Times, “This is a watershed moment but it is just a start. We must continue advancing the drug pipeline to develop the next class centered around the biology of aging to ultimately stop Alzheimer’s in its tracks.” And stop it we will. 75% of the drugs in the pipeline have nothing to do with amyloid. Instead, these therapies are looking at novel targets to complement the anti-amyloids. These drugs will support prevention, combination therapy, and precision medicine by moving the needle from the 30-35% provided by the anti-amyloid drugs, to 50-75%—or even 100%—effectiveness. For the past year I’ve been telling our supporters, “If I start having cognitive issues tomorrow, I’ll have options.” Looking forward, my children will have treatments in their lifetime, and my grandsons will have protocols (meaning so long as stay on the precision treatments they will remember their grandkids until the day they pass). What a great time to be in this field….

A look at the Scales, Immunoreactivity, and Aβ42 levels in #Alzheimers trials suggests the risks of #lecanemab and #donanemab exceed the benefits. ·     𝐒𝐜𝐚𝐥𝐞𝐬. The effect size is smaller for objective tests (MMSE Cohen’s d = 0.12; ADAS-Cog13 = 0.18) than for the more subjective ones used as primary endpoints (CDR-SB = 0.30) ·     𝐈𝐦𝐦𝐮𝐧𝐨𝐫𝐞𝐚𝐜𝐭𝐢𝐯𝐢𝐭𝐲. anti-Aβ antibodies with the highest reactivity induce ARIA and paradoxically (via unblinding, see below) correlate with benefits using scales with subjective components. ·     𝐂𝐒𝐅 𝐀β𝟒𝟐 𝐥𝐞𝐯𝐞𝐥𝐬. Most monoclonal antibodies reduce amyloid AND increase CSF levels of Aβ42, a desirable effect. Does this end (increasing the pool of a normal protein) justify the means (removing amyloid plaques)? Probably not. There is a correlation between amyloid reduction and cognitive outcomes 𝐚𝐜𝐫𝐨𝐬𝐬 studies, not 𝐰𝐢𝐭𝐡𝐢𝐧 them. There is also an 𝐚𝐜𝐫𝐨𝐬𝐬-𝐭𝐫𝐢𝐚𝐥 benefit of ARIA-E (see figure), which doesn't make sense --unless ARIA unblinds. ARIA is caused by local amyloid removal, so ARIA cannot be separated from efficacy. When a patient develops ARIA, the dosing of the antibody is halted, and the patient is asked to undergo more frequent MRI scans until the ARIA resolves. These protocol changes almost certainly unblind the patient and physician, who may be 'positively' impressed during the CDR-SB interview –thus explaining the association between ARIA and ‘benefits.’ https://lnkd.in/gH_tW2Yw Conclusion: anti-Aβ antibodies with the highest reactivity induce ARIA and paradoxically (likely via unblinding) correlate with benefits on scales with subjective components. Despite desirable increases in levels of CSF Aβ42, the net risk/benefit balance is unfavorable. This analysis is available here: https://lnkd.in/g2kAvydG KARL HERRUP, Bruno P. Imbimbo, Kasper Planeta Kepp, and Timothy Daly.

BREAKING: Donanemab, an antibody drug, is showing remarkable results in clearing brain plaque linked to Alzheimer’s disease. Researchers report that plaque removal was so effective that some patients may not require ongoing treatment—a potential shift from lifelong therapy approaches. Brain scans reveal significant reductions in amyloid levels, suggesting the treatment could be time-limited rather than permanent. Experts caution this is not a complete cure; cognitive outcomes still vary, and safety and long-term benefits are under close review. Nonetheless, this represents a major breakthrough in neurodegenerative disease research.

Three years ago I wrote a piece in City AM arguing that donanemab wasn't the Alzheimer's miracle the headlines claimed. This week's Cochrane review reached the same conclusion: anti-amyloid drugs have "no clinically meaningful effect on cognitive decline." [links in comments] I run clinical trials, so the gap between the data and the reporting was hard to miss. The trial missed its primary endpoint. The actual difference was 3.25 points on a 144-point scale where the researchers themselves defined "meaningful change" as 5 points. 25% of patients had brain swelling or bleeding. But the headlines said "35% improvement." Two things bother me beyond this one drug: 1. The massive harm caused by scientific fraud. The 2006 Nature paper that identified the amyloid fragment supposedly causing memory loss was retracted last year after investigators found the images were fabricated. That paper helped steer billions in funding toward one hypothesis while alternatives were starved. 2. The way we report trial results to the public is broken. Relative risk reductions make marginal effects sound dramatic. Side effects get buried. When NICE pushed back on these drugs, the political pressure to override them was immediate. This is dangerous. Even the two approved drugs show an absolute benefit of ~0.4 points on a scale where 1-2 points is the minimum noticeable difference. They clear amyloid. They just don't help patients in a way anyone can detect. Alzheimer's families deserve honest data, not false hope. Life sciences needs to reckon with how a fabricated paper went unchallenged for 16 years because it was too useful to too many grant applications.

📢 Positive CHMP opinion for Eli Lilly and Company's Kisunla (donanemab) in early Alzheimer’s disease 📢 🗞️ Today, the committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending EU approval of Kisunla (donanemab) for adults with early symptomatic Alzheimer’s disease who are ApoE ε4 non-carriers or heterozygotes🧬and have confirmed amyloid brain pathology🧠. 🔬 Kisunla is a monoclonal antibody that binds to amyloid plaques, supporting their clearance through microglial activity. Its clinical benefit is based on the TRAILBLAZER‑ALZ 2 study, where donanemab slowed cognitive decline by 35 % compared to placebo over 18 months (as measured by the iADRS scale, Sims et al., 2023). ⚠️ Amyloid-related imaging abnormalities (ARIA) with edema/effusion (ARIA-E) and with hemorrhage/ hemosiderosis (ARIA-H) are side effects within the class of therapies that do not usually cause any symptoms, but serious and life-threatening symptoms can occur. ARIA can be fatal. Carriers of one or two copies of the ApoE4 gene may be at higher risk of developing Alzheimer's disease and experiencing ARIA. ❗ Notably, this positive opinion follows a re-examination: 🔄 In March 2025, the CHMP initially rejected the application, expressing concerns that the benefits of donanemab did not outweigh the risks in the broad patient population. ✅ Following re-evaluation, the Committee limited the indication to a narrower group, excluding ApoE ε4 homozygotes, who are at higher risk of ARIA, thereby shifting the benefit–risk balance favorably for this subgroup. ❓ However, it is important to note that not all patients who meet these criteria will go on to progress clinical Alzheimer’s dementia clinical symptoms if not treated, and the individual benefit-risk balance remains unclear for these patients, highlighting the need for personalized treatment decisions. 🧭 This underlines the growing urgency of a precision medicine approach to Alzheimer's disease that goes beyond amyloid status (Souchet et al., 2023). The field urgently needs new biomarkers, particularly multiomics, that are more predictive of cognitive decline (Braudeau et al., 2025), to better identify those who will need to benefit from this class of therapies. 📩 The final decision now rests with the European Commission. ➡️ A significant milestone for Alzheimer’s treatment in Europe, based on a more targeted and risk-managed approach. 📚 All sources and references are shared in the first comments.

An analysis in Alzheimer's & Dementia revisits the TRAILBLAZER-ALZ 2 trial to ask how donanemab's benefit varies with disease stage. Examining treatment effects on the CDR-SB across baseline tau PET, plasma p-tau217, and predicted progression, the authors found donanemab slowed decline across the spectrum of tau burden, with the greatest slowing in participants who had lower baseline tau and were treated earlier. The results reinforce that anti-amyloid benefit in early symptomatic AD is shaped by underlying pathological severity and timing, informing how future trials and analyses stratify participants. https://lnkd.in/e7wANnMF

How durable are the effects of donanemab in early symptomatic Alzheimer's Disease (AD) after treatment is completed? 🧠 Eli Lilly and Company presented data at CTAD 2025 from the TRAILBLAZER-ALZ 2 Long-Term Extension (LTE) study, which evaluated 325 participants who received an early start of donanemab and achieved the treatment completion criteria by 52 weeks in the placebo-controlled (PC) period. These participants were in an early symptomatic stage of AD. At the start, this subgroup, with a mean age of 74.8 years, had a mean score of 23.9 on the Mini-Mental State Examination (MMSE). 19.1% of participants were classified as having MCI (MMSE 27+) and 80.9% as having Mild Dementia (MMSE 20-26). Participants in this cohort were 60.9% female, 51.4% heterozygous APOE ε4 carriers, and 9.5% homozygous APOE ε4 carriers. 61.5% of participants were on standard of care (AChEI and/or memantine). Their mean initial amyloid level was 90.8 (SD 30.6) Centiloids (CL), which is a measure of plaque burden in the brain assessed using Amyloid PET imaging. The mean Tau PET SUVR was 1.3 (SD 0.2). Treatment completion required amyloid levels to drop below 24.1 CL. Once this threshold was met, participants were switched to blinded placebo infusions, meaning they stopped receiving the active investigative drug donanemab. For this specific subgroup, the mean time they were on active donanemab treatment before the switch was 47 weeks. Amyloid PET data showed that the mean amyloid level for this group remained below the completion threshold for up to three years after they stopped active infusions. The observed rate of amyloid plaque reaccumulation (2.4 CL per year) was comparable to the natural rate of accumulation seen in other studies. Clinical benefits, measured using the Clinical Dementia Rating – Sum of Boxes (CDR-SB), showed increasing slowing of disease progression over three years. At 36 months, the difference in LS mean change in CDR-SB between the early-start completers and a weighted comparison group from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort was Δ−1.3 (95% CI, −1.9, −0.7). Regarding safety, after participants switched to placebo infusions, the frequency of Amyloid-Related Imaging Abnormalities (ARIA) was comparable to the frequency seen in the initial placebo group during the original PC period: 28.4% of total ARIA events occurred prior to switching and 20.3% after switching to the end of the LTE. Some limitations apply, including small sample size and the use of an external ADNI comparator for long-term clinical comparison. Real-world evidence will shed more light on these findings from the LTE study. These results suggest that achieving early amyloid clearance with limited-duration dosing could provide sustained amyloid lowering and may translate to increasing clinical benefits long after active donanemab treatment has been discontinued. #neurology #dementia #alzheimers #donanemab #CTAD2025

Donanemab in early Alzheimer's - the less tau at baseline the more impact https://lnkd.in/egaSDsFv A new post-hoc analysis from the TRAILBLAZER-ALZ 2 trial adds a data point worth taking seriously as we are moving forward with rationally-guided anti-Alzheimer strategies, perhaps toward multi-pronged management strategies which are precision-medicine guided by rationally-selected markers. This study represents yet another clinically relevant analysis of TRAILBLAZER-ALZ brought to our attention by Mark Mintun's dedicated team. The finding: donanemab's clinical benefit on the cognition-function scale CDR-SB is not uniform — it's stage-dependent, and it records inversely with baseline tau burden in the brains of treated early Alzheimer's subjects. Participants in the lowest P-tau217 tercile showed 46% slowing of decline vs. placebo, compared to 26% in the highest tercile. A latent-time disease progression model (Kühnel et al., 2021) sharpens this further: initiating treatment at the 25th percentile of predicted disease progression was associated with a 60% delay in decline over 76 weeks (95% CI 50–70%), versus 17% at the 75th percentile. Extrapolated, the model projects delays to more disabling dementia (CDR-SB=16) of 26.1 months (over 2 years) at the earliest stage vs. 5.5 months at the latest (a mere 1/2 year). Two things: This is consistent with mechanism, not just curve-fitting. Once tau burden is high, decline is increasingly driven by neuroinflammation and neurodegeneration less dependent on aggregated amyloid (Hyman, 2011; Ismail et al., 2020) — so a therapy targeting amyloid clearance would be expected to lose leverage as tau accumulates. This new biomarker-stratified result is exactly this. The methodological honesty here matters. The authors are explicit that this is post-hoc, exploratory, and models population-level dynamics — not a basis for individual treatment decisions. That's a reasonable level of calibrated qualifier, and it's why the primary TRAILBLAZER-ALZ 2 endpoints (Sims et al., JAMA 2023) remain the actual evidence base, with this analysis as a complementary lens what factors predispose to a stronger response to donanemab. This prompts the overriding question "in whom, and at what disease stage, does donanemab [standing in for depletion of aggregated amyloid] work best ?" Plasma P-tau217 — now clinically practical at scale — looks like a reasonable stratification tool for identifying patients most likely to benefit, of course pending prospective validation. One last question: their Table 1 shows ApoE4 carrier >65% in all pTau 217 terciles. Do the ApoE4 carriers fare differently vs the non-carriers, when sticking with the pTau 217 baseline terciles ? #Alzheimers  #Donanemab  #TauPET  #amyloid #amyloidimmunotherapy John Sims

New data from the TRAILBLAZER-ALZ 2 extension study offer an intriguing signal: some benefits of donanemab may persist long after treatment stops. In a subgroup of early symptomatic Alzheimer’s patients who cleared amyloid plaques and completed therapy within 12 months, cognitive and functional outcomes remained better than matched external controls for up to two additional years without active treatment. By year 3, these patients showed a 1.3-point advantage on the CDR-SB, a clinically meaningful measure of both cognition and daily function. Notably, amyloid levels remained low and re-accumulated at the natural background rate. The study has limitations — no true placebo group in the extension, exploratory analyses — but the findings raise an important question: Could short-course immunotherapy provide durable disease modification in a subset of patients? If validated, this would mark a meaningful shift toward more efficient, targeted, and time-limited Alzheimer’s treatments. The field is moving fast. Thoughtful mechanistic work and rigorous long-term trials remain essential, but signals like this underscore a hopeful trend: for some patients, early intervention may change the trajectory of the disease, not just slow it.