The main purpose of this study is to investigate the safety and efficacy of the study drug solanezumab in participants with prodromal Alzheimer's disease (AD).

Start Date01 Jun 2016

Sponsor / Collaborator

Eli Lilly & Co.

NCT02614131

/ TerminatedPhase 1

Single-Dose and Multiple-Dose, Dose-Escalation Study With LY2599666 to Evaluate the Safety, Pharmacokinetics, and Tolerability in Healthy Subjects and Patients With Mild Cognitive Impairment Due to Alzheimer's Disease and Mild-to-Moderate Alzheimer's Disease

The main purpose of this study is to evaluate the safety and tolerability of the study drug known as LY2599666 in different groups of people - those who are healthy, those who have mild cognitive impairment due to Alzheimer's Disease (AD), and those with mild-to-moderate AD. The study will measure how much LY2599666 gets into the bloodstream and how long it takes the body to get rid of it. It will also evaluate how LY2599666 affects the body. The study has three parts. Part A will last about 2 months. Parts B and C will each last about 23 weeks. Participants may only enroll in one part.

Start Date01 Dec 2015

Sponsor / Collaborator

Eli Lilly & Co.

100 Clinical Results associated with Solanezumab

100 Translational Medicine associated with Solanezumab

100 Patents (Medical) associated with Solanezumab

287

Literatures (Medical) associated with Solanezumab

01 Mar 2025·Interdisciplinary Sciences-Computational Life Sciences

ABTrans: A Transformer-based Model for Predicting Interaction between Anti-Aβ Antibodies and Peptides

Article

Author: Zeng, Xincheng ; Su, Yuhong ; Zhang, Lingfeng ; Bian, Yanlin ; Wang, Yangjing ; Ma, Buyong

Antibodies against Aβ peptide have been recently approved to treat Alzheimer's disease, underscoring the importance of understanding their interactions for developing more potent treatments. Here we investigated the interaction between anti-Aβ antibodies and various peptides using a deep learning model. Our model, ABTrans, was trained on dodecapeptide sequences from phage display experiments and known anti-Aβ antibody sequences sourced from public sources. It classified the binding ability between anti-Aβ antibodies and dodecapeptides into four levels: not binding, weak binding, medium binding, and strong binding, achieving an accuracy of 0.83. Using ABTrans, we examined the cross-reaction of anti-Aβ antibodies with other human amyloidogenic proteins, revealing that Aducanumab and Donanemab exhibited the least cross-reactivity. Additionally, we systematically screened interactions between eleven selected anti-Aβ antibodies and all human proteins to identify potential off-target candidates.

01 Feb 2025·Neurology and Therapy

Lecanemab’s Path Forward: Navigating the Future of Alzheimer’s Treatment in Europe Amidst the EMA's Rejection

Article

Author: Di Donna, Martina Gaia ; Motta, Caterina ; Bonomi, Chiara Giuseppina ; Martorana, Alessandro

Lecanemab (Leqembi^©, Biogen), a humanized anti-amyloid-beta monoclonal antibody, has been approved for early-stage Alzheimer's disease (AD) in several countries, including the US and Japan. However, the European Medicines Agency (EMA) recently issued a negative opinion on its marketing authorization, reflecting concerns over the clinical value and manageability of anti-amyloid treatments. This decision highlights the ongoing disconnect between research advancements and clinical practice, where the focus on biological markers over tangible clinical improvements remains contentious. Despite promising biological effects, lecanemab's clinical outcomes have been modest, raising questions about its therapeutic role. The EMA's refusal underscores the need to address doubts surrounding the real-world effectiveness and safety of such treatments, especially concerning amyloid-related imaging abnormalities (ARIAs), a common side effect observed in clinical trials. The recent approval of lecanemab by the UK's Medicines and Healthcare products Regulatory Agency, despite the National Institute for Health and Care Excellence's rejection on cost-effectiveness grounds, further fuels the debate on the feasibility of anti-amyloid therapies. This commentary emphasizes the importance of real-world data on lecanemab's impact on cognitive decline, daily functioning, and side-effect management. As the global clinical use of lecanemab increases, continuous and standardized reporting on its outcomes is crucial for guiding future regulatory decisions and for potentially bridging the gap between research and practice in AD treatment.

29 Jan 2025·JOURNAL OF NEUROSCIENCE

Acute Communication Between Microglia and Nonparenchymal Immune Cells in the Anti-Aβ Antibody-Injected Cortex

Article

Author: Foley, Kate E ; Sudduth, Tiffany L ; Johnson, Sherika N ; Krick, Katelynn E ; Wilcock, Donna M ; Weekman, Erica M

Anti-Aβ immunotherapy use to treat Alzheimer's disease is on the rise. While anti-Aβ antibodies provide hope in targeting Aβ plaques in the brain, there still remains a lack of understanding regarding the cellular responses to these antibodies in the brain. In this study, we sought to identify the acute effects of anti-Aβ antibodies on immune responses. To determine cellular changes due to anti-Aβ antibody exposure, we intracranially injected 14 mo APP male and female mice with anti-Aβ IgG1 (6E10) or control IgG1 into the cortex. After 24 h or 3 d, we harvested the cortex and performed a glial cell-enriched preparation for single-cell sequencing. Cell types, proportions, and cell-to-cell signaling were evaluated between the two injection conditions and two acute timepoints. We identified 23 unique cell clusters including microglia, astrocytes, endothelial cells, neurons, oligos/OPCs, immune cells, and unknown. The anti-Aβ antibody-injected cortices revealed more ligand–receptor (L–R) communications between cell types, as well as stronger communications at only 24 h. At 3 d, while there were more L–R communications for the anti-Aβ antibody condition, the strength of these connections was stronger in the control IgG condition. We also found evidence of an initial and strong communication emphasis in microglia-to-nonparenchymal immune cells at 24 h, specifically in the TGFβ signaling pathway. We identify several pathways that are specific to anti-Aβ antibody exposure at acute timepoints. These data lay the groundwork for understanding the brain's unique response to anti-Aβ antibodies.

News (Medical) associated with Solanezumab

12 Jun 2024

·firstwordpharma.com

With fresh $100M, Alzheon lays out strategy for Alzheimer’s approval next year

Despite a pair of drug approvals within the last three years and millions of patients in need, Alzheimer’s disease treatments have struggled with a gamut of safety, efficacy, and accessibility problems. As a third anti-beta amyloid antibody – Eli Lilly’s donanemab – nears FDA clearance, Alzheon is taking a different tack with its lead programme that it thinks will address all three pain points that have plagued drug development in the field.On Wednesday, the biotech raised a $100-million series E to wrap up the APOLLOE4 Phase III study of valiltramiprosate (ALZ-801) in patients with early Alzheimer’s, and ready it for commercialisation. The round, led by Alerce Medical Technology Partners, brings Alzheon’s total equity financing to $185 million.The pivotal trial is expected to read out in the third quarter, and the company plans to begin a regulatory submission to the FDA by year-end. If all goes well, CEO Martin Tolar expects the oral small molecule to be available to US patients in 2025. “We truly are at the dawn of a new era,” he said. “We understand the biology [of Alzhiemer’s] and we have an opportunity to transform the standard of care with our treatment.”Genetically defined diseaseAlzheon was founded over a decade ago to develop a treatment for Alzheimer’s by methodically determining which toxic agent is driving the disease, and which biomarkers are effective at tracking progression and gauging the efficacy of a given treatment.Notably, Alzheon’s clinical programme is initially enrolling patients who are homozygous for APOE4, a strong genetic risk factor of the disease.Around two-thirds of patients with Alzheimer’s have one copy of the gene, but in people with two copies, “virtually everybody” will develop the disease, Tolar said. About 15% of Alzheimer’s patients are homozygous for APOE4. While the high-risk group might seem the most likely to benefit from treatment, both of Biogen and Eisai’s anti-beta amyloid antibodies, Leqembi (lecanemab) and the now-abandoned Aduhelm (aducanumab), as well as Lilly’s donenamab, have not been as effective in APOE4-homozygous patients and in fact had increased side effects in this population. Plaque precursorsWhile Alzheon has also landed on beta amyloid as the main cause of Alzheimer’s, the team importantly singled out small, soluble amyloid aggregates – the precursors of the plaques targeted by most antibody therapeutics – as the molecules responsible for disease pathology. Beta amyloid is a key neurological protein that responds to damage, but as we age, levels of the monomer increase and the brain becomes less efficient at clearing it. As the molecule accumulates, it can misfold and begin aggregating into toxic, soluble oligomers that cause damage to the brain, Tolar explained.The brain will then sequester these aggregates into insoluble amyloid plaques, which have been the target for much of the drugs in development for Alzheimer’s.But, Tolar said, plaques are “the wrong target” to achieve cognitive and functional improvement, which the company says it has demonstrated in multiple published studies. Rather, the key is to prevent these plaques from forming in the first place – valiltramiprosate accomplishes by blocking beta amyloid from clumping into oligomers.Positive safety, efficacy signsSo far, clinical data seem to support Alzheon’s tactic. While Leqembi and donanemab led to patient improvements of 27% and 29%, versus placebo, respectively, on the Clinical Dementia Rating scale, Phase II results for valiltramiprosate demonstrated an 81% functional benefit on the same measurement. “These patients usually are at the edge of a cliff. They are a little forgetful. But in a year and a half they don't recognise their children, their spouses. And we can keep them stable for two years,” Tolar commented. “These are the data that really gave us confidence [in valiltramiprosate], and in fact helped us raise $100 million at a time where nobody can raise money.”Additionally, because plaques can occur in blood vessel walls, they could also be the reason why amyloid-related imaging abnormalities (ARIA), which can cause both brain oedema and haemorrhage, are a serious side effect associated with both Leqembi and donanemab. However, since valiltramiprosate doesn’t act on plaques, it could be a safer option. “We have shown in over 3000 patients, in a three-year follow-up, that we don't have an increase in brain haemorrhages,” Tolar said. Another potential benefit of valiltramiprosate is simply by virtue of its oral administration, which would make it cheaper and easier for patients to take for years to stave off disease progression, rather than an antibody IV infusion.

Phase 2Phase 3Clinical ResultDrug Approval

10 Jun 2024

·firstwordpharma.com

FDA advisory panel backs Lilly's Alzheimer's therapy

Eli Lilly’s anti-beta amyloid antibody is a step closer to FDA approval after an advisory committee for the US regulator voted unanimously in favour of both the safety and efficacy of donanemab to treat Alzhiemer’s disease. Although briefing documents released ahead of Monday’s meeting flagged safety concerns with donanemab, the advisory committee ultimately supported the treatment’s risk-benefit profile in an 11-0 vote.In particular, FDA staff had noted that patients who received the experimental monoclonal antibody (mAb) had a higher rate of amyloid-related imaging abnormalities (ARIA) – and three ARIA-related deaths – versus the placebo arm. The safety data for donanemab so far is not as strong as demonstrated by Eisai and Biogen’s Leqembi (lecanemab). For more, see Spotlight On: Donanemab briefing docs bode well for Leqembi.To manage these risks, panel participants emphasised that patient and provider education will be necessary.Committee member Kathleen Poston, neurological sciences director at the Stanford Movement Disorders Center, noted that frequently requiring patients to undergo MRI scans to check for ARIA is not an insignificant burden.“Also, the interpretation of those MRI scans, it's not a black-and-white super easy thing to always interpret. And if areas don't have access to a neuroradiologist, they might have challenges knowing what's sort of just normal for age versus what's changed and could be evidence of ARIA,” Poston added. “So again, I think education around the interpretation of monitoring risk needs to be taken into consideration because it's non-trivial.”Colette Johnston, the committee’s patient advocate, argued that any potential benefit to people with Alzheimer’s is worth a risk, and should be up to the individuals to decide. “When you get a diagnosis of Alzheimer's, you don't have anything but risk,” said Johnston, whose father had the disease. “We live in a society now where we get to have clinicians and caregivers and family members help us make choices, and it's up to the patient to be their own advocate and have their own advocates there to really research those risk-benefit ratios…. When you think of risk-benefit, we tend to… look at it as scientists, but my role here is to get you to look at it as caregivers. And so, inasmuch as it is not perfect [for donanemab], it is acceptable as far as I'm concerned.”Tau testing The panel did not raise concerns with the efficacy data supporting donanemab’s use in patients with mild cognitive impairment and mild dementia, voting 11-0 in its favour, though several participants called for more data in underrepresented patient populations, particularly African Americans and Hispanics. That additional subgroup data, Poston said, “will be important in the future… to make sure that these encouraging findings can be extrapolated to everyone with Alzheimer's disease.”In the 18-month Phase III TRAILBLAZER-ALZ 2 study, donanemab slowed cognitive and functional decline by 29% based on Clinical Dementia Rating-Sum of Boxes (CDR-SB), similar to Leqembi's 27% result.However, in addition to being positive for amyloid, trial participants also had to test positive for tau on PET scans in order to be included in Eli Lilly's study. Two main groups based on tau imaging were analysed; those with low/medium tau levels and the overall population consisting of patients with low, medium or high tau levels.Some analysts speculated that, if approved, donanemab might carry a more restrictive label than Leqembi that requires patients to undergo tau-detecting PET scans. However, the advisory committee seemed overwhelmingly against adding an additional burden to patients seeking Alzheimer’s treatment. “Access to a tau PET scan would be virtually impossible for a lot of these communities,” said committee member Cynthia Carlsson, a professor of medicine and Alzheimer'sdisease at the Wisconsin Alzheimer's Institute at the University of Wisconsin School of Medicine and Public Health. “I think that, given the data that we have, and the scientific knowledge that we have of how amyloid and tau progress, that I would say we do not need tau PET in this population.” Summing up the panel's stance, chair Thomas Montine said “the vast majority of the committee feels as though imposing a requirement for tau imaging is not necessary and would raise serious practical concerns and access concerns to the treatment."

Clinical ResultPhase 3Drug Approval

10 Jun 2024

·www.biopharmadive.com

Lilly Alzheimer’s drug gets unanimous backing of FDA panel

An experimental and closely watched medicine for Alzheimers disease is one step closer to approval, after receiving support from a panel of experts who advise the Food and Drug Administration.On Monday, the panel unanimously voted that the medicine, developed by Eli Lilly and known as donanemab, appears to be an effective treatment for certain Alzheimers patients. The experts also concluded, by an 11-0 vote, that the drugs benefits outweigh its risks, despite some safety concerns.I thought the evidence is very strong and the trials [show] the effectiveness of the drug, said Dean Follman, a panelist and assistant director of biostatistics at the National Institute of Allergy and Infectious Diseases.Though the FDA isnt required to follow the recommendations of its advisory committees, it typically does. Should the agency grant approval, donanemab would be the third Alzheimers therapy of its kind cleared for the U.S. market. These medicines work by breaking up sticky, toxic collections of amyloid beta, a protein many researchers believe to be a root cause of the memory-robbing disease.Whether Lillys drug can avoid the obstacles that have held back its predecessors remains unclear. The first product in this class, Biogen and Eisais Aduhelm, was mired in controversy and eventually withdrawn from market. A second, newer option from those companies called Leqembi is faring better commercially. But both Biogen and Eisai acknowledge Leqembis launch has been more challenging than they anticipated.Lilly built its approval application around a placebo-controlled clinical trial that enrolled nearly 1,700 people in early stages of Alzheimers disease. The trial found participants who were given donanemab declined 22% slower than those who were in the control group, as measured by a rating scale that combines two well-known scoring systems for evaluating the severity of Alzheimers symptoms.FDA advisers acknowledged the positive results, yet questioned how applicable they would be to the broader Alzheimers population. All study participants were in earlier stages of the disease, and most were white.Additionally, Lillys study had unique design elements that made evaluating the results trickier. For example, in order to enroll, participants had to test positive not only for amyloid, but also for another protein tied to the development of Alzheimers. The trial found the disease progressed even slower among donanemab-treated patients with low to medium levels of this tau protein.FDA advisers therefore wanted more clarity about the role tau would play in prescribing the drug if it were approved especially since testing for tau requires PET scans, which can be costly and time-consuming.Inclusion of requirements for [tau testing] will further limit the number of patients who can have access to these types of medications, said Cynthia Carlsson, a panelist and a professor of medicine at the University of Wisconsin School of Medicine and Public Health.So it's a nuanced situation where, on the one hand, we do need to have additional data on the no and very low tau population. And on the other hand, we should not require having [tau testing] for access to this medication.Teresa Burrachio, the director of FDAs neuroscience office, noted early on in the meeting that tau burden wouldnt necessarily affect the agencys approval decision, but could potentially be a consideration for labeling.Another distinctive choice Lilly made in running its study was to have participants discontinue donanemab if amyloid levels dropped below a certain threshold. While some panelists described this design as innovative, they still questioned how it would translate to real-world treatment. What would happen, they asked, if amyloid began accumulating again in patients brains?I love the idea of being able to stop the treatment, said Colette Johnston, the panels patient representative. But I am concerned about what happens if we're not following up, and we're not getting that information once we discontinue the dosing.Both FDA staff and panelists were also focused on a type of brain swelling and bleeding, known as ARIA, that occurred in people treated with donanemab and other drugs like it. ARIA is quite often asymptomatic and is only identified via magnetic resonance imagingBut at least two donanemab-treated participants, and possibly a third, died as a result of ARIA episodes, raising questions about the drugs safety if approved for general use.Lilly executives said that, later in the trial, they were able to better identify asymptomatic cases by having patients undergo more frequent MRIs. In these people, the company delayed additional drug infusions until brain swelling subsided to prevent it from becoming more serious.For people at high risk of ARIA, such as those with a genetic marker named APOE4, Lilly executives said they would recommend closer monitoring.Patients, caregivers and physicians testified at the hearing, almost all of whom asked the committee to recommend an approval. One, a 75-year-old man who participated in Lillys trial, said he had an infusion-related side effect that ended with an emergency room visit. Even so, he said he concluded donanemabs benefits still counterbalanced its risks and decided to remain in the study.“The community understands that donanemab is not curative, but has shown in promising clinical trials it can delay progression of disease,“ Sue Peschin, CEO of the Alliance for Aging Research, said. “This is of key importance to people living with early Alzheimer's where quality of life outcomes such as cognition, personality, and the ability to care for oneself are the ones that matter most.Estimates hold that roughly 6 million to 7 million people in the U.S. have Alzheimers. The disease is a leading cause of death, and inflicts an immense physical, mental and emotional toll on patients and their caregivers. It is also extremely expensive. Research published in the American Journal of Managed Care noted how, in 2022, the estimated healthcare costs associated with Alzheimers treatment were $321 billion.For Lilly, approval would cap off a decades-long mission to get an Alzheimers medication on the market. The company came somewhat close years ago with a similar drug called solanezumab, though clinical failures led to the therapy getting scrapped.On Wall Street, analysts expect an approval would add another blockbuster product to Lillys portfolio, which has been buoyed by the success of the companys GLP-1 drug for obesity. As of early March, the average analyst estimate had donanemab generating close to $3 billion in annual sales at its peak, according to the investment firm Jefferies.Editors note: This story has been updated with additional detail from the meeting. '

Drug Approval

100 Deals associated with Solanezumab

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KEGG	Wiki	ATC	Drug Bank
D10058	Solanezumab	-	DB11756

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Amnesia, Anterograde	Phase 3	United States	Eli Lilly & Co.	28 Feb 2014
Amnesia, Anterograde	Phase 3	Japan	Eli Lilly & Co.	28 Feb 2014
Amnesia, Anterograde	Phase 3	Australia	Eli Lilly & Co.	28 Feb 2014
Amnesia, Anterograde	Phase 3	Canada	Eli Lilly & Co.	28 Feb 2014
Cognition Disorders	Phase 3	United States	Eli Lilly & Co.	28 Feb 2014
Cognition Disorders	Phase 3	Japan	Eli Lilly & Co.	28 Feb 2014
Cognition Disorders	Phase 3	Australia	Eli Lilly & Co.	28 Feb 2014
Cognition Disorders	Phase 3	Canada	Eli Lilly & Co.	28 Feb 2014
Alzheimer Disease	Phase 3	United States	Eli Lilly & Co.	01 May 2009
Alzheimer Disease	Phase 3	Japan	Eli Lilly & Co.	01 May 2009

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04623242 (Pubmed)	Phase 2/3	Alzheimer Disease	-	Solanezumab	mighwxyjdg(rnhauahqzm) = bkmuivsinq nwbbiexdnm (mbwwocsphf, 0.43)	-	29 Apr 2024
NCT02760602 (ExpeditionPRO, CTgov)	Phase 3	Alzheimer Disease	26	Solanezumab (Solanezumab)	mbqnueraff(yoigihpkzf) = oddvujoxgi rfigmzyshf (jwcaevixae, tzylwfuqvs - qpqvvnccrd) View more	-	24 Jul 2018
				Placebo (Placebo)	mbqnueraff(yoigihpkzf) = gxxhnxfwya rfigmzyshf (jwcaevixae, fzklhgpslm - vcrazfnogm) View more
NCT01127633 (EXPEDITION EXT, CTgov)	Phase 3	Alzheimer Disease	1,457	Placebo (Placebo)	bhzbjlhwvk = koxdphejkf tlbtchzfka (wkxqasqpek, obrawidikl - lypowyfplx) View more	-	03 May 2018
				Solanezumab (Solanezumab)	bhzbjlhwvk = biplolegqh tlbtchzfka (wkxqasqpek, fnkuntszjl - apcgkufatv) View more
NCT01900665 (EXPEDITION3 \| EXPEDITION 3, CTgov)	Phase 3	Alzheimer Disease	2,129	Solanezumab (Solanezumab)	irsbuvdqfc(gvzdfxqmrh) = nazpvwmfjl myuksmosgp (itmkttrllx, 0.355) View more	-	14 Mar 2018
				Placebo (Placebo)	irsbuvdqfc(gvzdfxqmrh) = lsfnpphpvm myuksmosgp (itmkttrllx, 0.356) View more
NCT01900665 (EXPEDITION3, Pubmed \| Br Dent J \| N Engl J Med) Manual	Phase 3	Alzheimer Disease \| Dementia	2,129	Solanezumab	blhqzsdpyn(dzjygjezgy) = uxpsfyezpc rouegluwrt (ksejbggcps ) View more	Negative	25 Jan 2018
				Placebo	blhqzsdpyn(dzjygjezgy) = hluovervwf rouegluwrt (ksejbggcps ) View more
NCT00904683 \| NCT01900665 \| NCT00905372 (EXPEDITION3, AAIC2017)	Phase 3	Alzheimer Disease amyloid pathology	-	Solanezumab	pymximadwd(pivdvqpjny) = tjniqrvrkv vldsqdiwiz (wczodcyqoh ) View more	-	01 Jul 2017
NCT01900665 (EXPEDITION3, AAIC2017)	Phase 3	Alzheimer Disease	2,129	Solanezumab	xywnahoakh(klgfhzpfoi) = lovpukifsa rgsvhxzosk (jmimmyyshd ) View more	-	01 Jul 2017
EXPEDITION and EXPEDITION2 (AAIC2014)	Not Applicable	Alzheimer Disease CSF Aβ 1-42 \| florbetapir imaging	-	Solanezumab	ahebegvzcw(hnfnqoyftd) = yijyxmrnln eodfrcrpqk (tpcktmaiah ) View more	-	01 Jul 2014

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