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Revision as of 16:02, 6 December 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 460514779 of page Solanezumab for the Chem/Drugbox validation project (updated: 'CAS_number').  Latest revision as of 04:49, 27 March 2024 edit Citation bot (talk | contribs)Bots5,429,146 edits Removed parameters. | Use this bot. Report bugs. | Suggested by Susmuffin | Category:CS1 maint: PMC embargo expired | #UCB_Category 2/2 
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{{Short description|Monoclonal antibody medication}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{cs1 config|name-list-style=vanc}}
{{Drugbox {{Drugbox
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 450329408 | verifiedrevid = 464404831
| image = | image =

<!--Monoclonal antibody data--> <!-- Monoclonal antibody data -->
| type = mab | type = mab
| mab_type = mab | mab_type = mab
| source = zu | source = zu
| target = ] | target = ]
⚫ <!-- Clinical data -->

⚫ <!--Clinical data-->
| tradename = | tradename =
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X --> | pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category = | pregnancy_category =
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> | legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_status = | legal_status = Investigational
| routes_of_administration = | routes_of_administration =
⚫ <!-- Pharmacokinetic data -->

⚫ <!--Pharmacokinetic data-->
| bioavailability = | bioavailability =
| protein_bound = | protein_bound =
| metabolism = | metabolism =
| elimination_half-life = | elimination_half-life =
| excretion = | excretion =
⚫ <!-- Identifiers -->

⚫ | CAS_number_Ref = {{cascite|changed|??}}
⚫ <!--Identifiers-->
⚫ | CAS_number = 955085-14-0
⚫ | CAS_number_Ref = {{cascite|correct|??}}
⚫ | CAS_number = <!-- blanked - oldvalue: 955085-14-0 -->
| ATC_prefix = none | ATC_prefix = none
| ATC_suffix = | ATC_suffix =
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| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 5D6PWO0333 | UNII = 5D6PWO0333
| KEGG = D10058
| KEGG_Ref = {{keggcite|changed|kegg}}
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA | ChemSpiderID = none
⚫ <!-- Chemical data -->

⚫ | C=6396 | H=9922 | N=1712 | O=1996 | S=42
⚫ <!--Chemical data-->
⚫ | C=6396 | H=9922 | N=1712 | O=1996 | S=42
| molecular_weight = 144.1 ]
}} }}

'''Solanezumab''' (proposed ], LY2062430<ref name="Farlow_2012">{{cite journal | vauthors = Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, Friedrich S, Dean RA, Gonzales C, Sethuraman G, DeMattos RB, Mohs R, Paul SM, Siemers ER | display-authors = 6 | title = Safety and biomarker effects of solanezumab in patients with Alzheimer's disease | journal = Alzheimer's & Dementia | volume = 8 | issue = 4 | pages = 261–271 | date = July 2012 | pmid = 22672770 | doi = 10.1016/j.jalz.2011.09.224 | s2cid = 12755108 }}</ref>) is a ] being investigated by ] as a ]<ref>, ''World Health Organization''.</ref> for patients with ].<ref>{{ClinicalTrialsGov|NCT00749216|Solanezumab Safety Study in Japanese Patients With Alzheimer's Disease}}</ref><ref>{{ClinicalTrialsGov|NCT00905372|Effect of LY2062430 on the Progression of Alzheimer's Disease (EXPEDITION)}}</ref> The drug originally attracted extensive media coverage proclaiming it a breakthrough, but it has failed to show promise in Phase III trials.<ref>{{cite journal | vauthors = McCartney M | title = Margaret McCartney: The "breakthrough" drug that's not been shown to help in Alzheimer's disease | journal = BMJ | volume = 351 | pages = h4064 | date = July 2015 | pmid = 26208710 | doi = 10.1136/bmj.h4064 | doi-access = free }}</ref><ref>{{cite web | vauthors = Meglio M |date=March 10, 2023 |title=Solanezumab Fails Phase 3 A4 Study of Preclinical Alzheimer Disease |url=https://www.neurologylive.com/view/solanezumab-fails-phase-3-a4-study-preclinical-alzheimer-disease |access-date=August 1, 2023 |website=NeurologyLive}}</ref>

== Medical uses ==
Solanezumab was safely used in combination with approved Alzheimer's disease treatment, such as ]s or ], in the clinical trials.<ref name="Farlow_2012" /><ref name="Siemers_2010" /><ref name="Bates_2014" />

Aside from Alzheimer's disease, there are other amyloid beta related diseases, in which solanezumab could be used, e.g., ] or ].<ref name="US7195761" /> However, this has not been studied so far.

== Adverse effects ==
No safety concerns were detected in any of the studies.<ref name="Farlow_2012" /><ref name="Siemers_2010" /><ref name="Bates_2014" /><ref name="Siemers_2016" /> A few patients suffered from mild infusion reactions that resolved on their own.<ref name="Farlow_2012" /><ref name="Siemers_2010" /> The measured laboratory values and vital signs, showed no changes.<ref name="Siemers_2010" /> Other adverse events that occurred, e.g., ] or ], were not considered as related to treatment.<ref name="Farlow_2012" /><ref name="Siemers_2010" />

Other anti-amyloid beta antibodies caused ],<ref name="Farlow_2012" /> which is not the case for solanezumab.<ref name="Farlow_2012" /><ref name="Siemers_2010" /><ref name="Bates_2014" />

==Pharmacology==
=== Mechanism of action ===
Solanezumab binds the ] ] that aggregate and form plaques in the brain that are an early pathological feature of Alzheimer's disease.<ref>{{cite journal | vauthors = Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL | display-authors = 6 | title = Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study | journal = The Lancet. Neurology | volume = 12 | issue = 4 | pages = 357–367 | date = April 2013 | pmid = 23477989 | doi = 10.1016/S1474-4422(13)70044-9 | s2cid = 18181917 | collaboration = Australian Imaging Biomarkers Lifestyle (AIBL) Research Group }}</ref> Solanezumab binds the central ] of monomeric ], ], (PDB ID 4XXD<ref>{{cite journal | vauthors = Crespi GA, Hermans SJ, Parker MW, Miles LA | title = Molecular basis for mid-region amyloid-β capture by leading Alzheimer's disease immunotherapies | journal = Scientific Reports | volume = 5 | pages = 9649 | date = April 2015 | pmid = 25880481 | pmc = 4549621 | doi = 10.1038/srep09649 | bibcode = 2015NatSR...5E9649C }}</ref>) with picomolar ].<ref>{{cite journal | vauthors = Watt AD, Crespi GA, Down RA, Ascher DB, Gunn A, Perez KA, McLean CA, Villemagne VL, Parker MW, Barnham KJ, Miles LA | display-authors = 6 | title = Do current therapeutic anti-Aβ antibodies for Alzheimer's disease engage the target? | journal = Acta Neuropathologica | volume = 127 | issue = 6 | pages = 803–810 | year = 2014 | pmid = 24803227 | doi = 10.1007/s00401-014-1290-2 | hdl-access = free | s2cid = 20139520 | hdl = 11343/198431 }}</ref> This epitope is known as the nucleation site for Aβ oligomerization, and it is these oligomers of Aβ that are thought to be toxic to neurons.

Solanezumab is thought to act as an “amyloid beta sink”<ref name="DeMattos_2001" /> that is “facilitating flux of amyloid beta from a central to peripheral compartment”.<ref name="DeMattos_2001" /> This increases the peripheral elimination of both amyloid beta and the antibody. Amyloid beta plaques mostly consist of amyloid beta42. Solanezumab binds free amyloid beta which causes amyloid beta42 to solubilize to reestablish the equilibrium in the cerebrospinal fluid.<ref name="Farlow_2012" />

== Manufacturing ==
Solanezumab is expressed in ]s. The produced antibodies are extracted and purified according to the standard procedures of the art.<ref name="US7195761" />

== Society and culture ==
=== Commercial aspects ===
Solanezumab is developed and investigated by ], Indianapolis, IN.<ref>{{cite web|url=https://www.lilly.com/_assets/pdf/integrated-report.pdf|title=Lilly Integrated report 2015 | date=2016-11-10|website=lilly.com|publisher=Eli Lilly|access-date=2016-11-10}}</ref> It is covered under the ] US 7,195,761 B2, which was filed in 2002 by Eli Lilly, Indianapolis, IN, and ].<ref name="US7195761">{{cite patent | title = Humanized antibodies that sequester abeta peptide | Holtzman DM, DeMattos R, Bales KR, Paul SM, Tsurushita N, Vasquez M |url= https://www.google.com/patents/US7195761| country = US | number = 7195761 | gdate = 27 March 2007 | assign1 = Eli Lilly and Co. | assign2 = Washington University in St Louis }}</ref>

In 2011, TPG-Axon Capital funded part of the phase 3 trials. It will receive an estimated $70 million of based on sales milestones after the launch of the product.<ref>{{cite web|url=http://files.shareholder.com/downloads/LLY/3183010514x0x882148/56D78424-8D60-470D-BE5D-975D890947A4/English.PDF|title=Eli Lilly Annual Report 2015 | date=2016-11-10|publisher=Eli Lilly|access-date=2016-11-10}}</ref>

== Preclinical trials ==
The first evidence that antibodies binding the central ] domain are effective in the treatment of Alzheimer's disease was found in transgenic mice, which express the human amyloid beta precursor protein. Treatment with a murine analog of solanezumab (m266) lead to an increase in ] amyloid beta, which was all bound to m266. Additionally, the amount of both free amyloid beta in the brain and amyloid beta in plaques was significantly decreased.<ref name="DeMattos_2001">{{cite journal | vauthors = DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM | title = Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 15 | pages = 8850–8855 | date = July 2001 | pmid = 11438712 | pmc = 37524 | doi = 10.1073/pnas.151261398 | doi-access = free | bibcode = 2001PNAS...98.8850D }}</ref>

Due to those results, it is postulated that m266 binds free amyloid beta in the plasma and, therefore, changes the amyloid beta equilibrium between plasma and brain.<ref name="DeMattos_2001" />

== Clinical trials ==

=== Phase 1 ===
In a single-dose, placebo-controlled study (H8A-LC-LZAH) in 19 patients with mild-to-moderate Alzheimer's disease, solanezumab was well tolerated over the whole dose range. There were no severe ]s. All patients showed dose-dependent amyloid beta responses, but no change in ]. This negative outcome was expected after only a single dose.<ref name="Siemers_2010">{{cite journal | vauthors = Siemers ER, Friedrich S, Dean RA, Gonzales CR, Farlow MR, Paul SM, Demattos RB | title = Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease | journal = Clinical Neuropharmacology | volume = 33 | issue = 2 | pages = 67–73 | year = 2010 | pmid = 20375655 | doi = 10.1097/WNF.0b013e3181cb577a | s2cid = 43700412 }}</ref>

=== Phase 2 ===
52 patients with mild-to-moderate Alzheimer's disease underwent a parallel group, double-blind, randomized, placebo controlled phase 2 trial. They received weekly infusions of either saline or antibody for 12 weeks. The placebo group received only saline, whereas the antibody groups received four different concentrations of solanezumab infusions or saline. They were dosed with either 100&nbsp;mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks or 400 mg weekly.<ref name="Farlow_2012" />

Plasma amyloid beta levels increased dose dependently over the course of treatment. In the cerebrospinal fluid amyloid beta40 increased, whereas amyloid beta42 increased. This could be due to a change in equilibrium between plasma, ] and amyloid beta plaques. However, there were no significant changes in cognition and memory.<ref name="Farlow_2012" />

=== Phase 3 ===
Solanezumab was tested in two phase 3 clinical trials, EXPEDITION 1 and 2 (NCT00905372 and NCT00904683). Both were randomized, double-blind and placebo-controlled. Patients with mild-to-moderate Alzheimer's disease received either placebo or 400 mg solanezumab infusions every 4 weeks over 18 months.<ref name="Bates_2014">{{cite journal | vauthors = Bates ML, Farrell ET, Eldridge MW | title = Abnormal ventilatory responses in adults born prematurely | journal = The New England Journal of Medicine | volume = 370 | issue = 6 | pages = 584–585 | date = February 2014 | pmid = 24499235 | pmc = 4769592 | doi = 10.1056/nejmx140041 }}</ref>

A total of 1012 patients participated in EXPEDITION 1, EXPEDITION 2 enrolled another 1040 patients. Both studies were not able to show a difference in cognition and memory between the treated and the placebo group.<ref name="Bates_2014" /> However, a subgroup analysis of only patients with mild Alzheimer's disease showed less worsening of cognition in patients receiving solanezumab compared to placebo, which means the progression of the disease was slowed down. There was no effect on disease progression in patients with moderate symptoms.<ref name="Siemers_2016">{{cite journal | vauthors = Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, Dowsett SA, Pontecorvo MJ, Dean RA, Demattos R | display-authors = 6 | title = Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients | journal = Alzheimer's & Dementia | volume = 12 | issue = 2 | pages = 110–120 | date = February 2016 | pmid = 26238576 | doi = 10.1016/j.jalz.2015.06.1893 | s2cid = 19557687 | doi-access = free }}</ref>

Since the first two EXPEDITION trials show a positive effect in patients with mild Alzheimer's disease, Lilly launched another phase 3 trial, EXPEDITION 3 (NCT01900665). Patients with mild Alzheimer's disease received 400&nbsp;mg solanezumab every 4 weeks for 80 weeks. Afterwards they can continue treatment for a total of 208 weeks, if wanted.<ref name=NCT01900665>{{ClinicalTrialsGov|NCT01900665|Progress of Mild Alzheimer's Disease in Participants on Solanezumab Versus Placebo}}</ref> This trial failed to show positive results,<ref>{{cite web|title=Lilly Announces Top-Line Results of Solanezumab Phase 3 Clinical Trial|url=https://investor.lilly.com/releasedetail.cfm?ReleaseID=1000871|website=Eli Lilly|access-date=23 November 2016}}</ref> despite the high expectations. The trial will be finalized in 2020.<ref name=NCT01900665 />

The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study is a phase 3 clinical trial to evaluate whether solanezumab can slow cognitive decline in cognitively unimpaired older adults with elevated levels of amyloid β.<ref>{{cite journal | vauthors = Sperling RA, Donohue MC, Raman R, Sun CK, Yaari R, Holdridge K, Siemers E, Johnson KA, Aisen PS | display-authors = 6 | title = Association of Factors With Elevated Amyloid Burden in Clinically Normal Older Individuals | journal = JAMA Neurology | volume = 77 | issue = 6 | pages = 735–745 | date = June 2020 | pmid = 32250387 | pmc = 7136861 | doi = 10.1001/jamaneurol.2020.0387 }}</ref><ref>{{cite journal | vauthors = Insel PS, Donohue MC, Sperling R, Hansson O, Mattsson-Carlgren N | title = The A4 study: β-amyloid and cognition in 4432 cognitively unimpaired adults | journal = Annals of Clinical and Translational Neurology | volume = 7 | issue = 5 | pages = 776–785 | date = May 2020 | pmid = 32315118 | pmc = 7261742 | doi = 10.1002/acn3.51048 | doi-access = free }}</ref> In July 2023, the final data showed that it did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease.<ref>{{cite journal | vauthors = Sperling RA, Donohue MC, Raman R, Rafii MS, Johnson K, Masters CL, van Dyck CH, Iwatsubo T, Marshall GA, Yaari R, Mancini M, Holdridge KC, Case M, Sims JR, Aisen PS | display-authors = 6 | title = Trial of Solanezumab in Preclinical Alzheimer's Disease | journal = The New England Journal of Medicine | volume = 389 | issue = 12 | pages = 1096–1107 | date = September 2023 | pmid = 37458272 | doi = 10.1056/NEJMoa2305032 | pmc = 10559996 }}</ref>

== References ==
{{reflist|30em}}
{{Monoclonals for bone, musculoskeletal, circulatory, and neurologic systems}}

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