Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Pertuzumab: Difference between pages

{{Short description|Pharmaceutical drug}}

{{Use dmy dates|date=January 2022}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 464199526

| image = Pertuzumab-HER2 complex 1S78.png

| alt =

| caption = The structure of [[HER2]] and pertuzumab

<!-- Monoclonal antibody data -->

<!-- Clinical data -->

| pronounce =

| tradename = Perjeta

| Drugs.com =

| MedlinePlus =

| DailyMedID = Pertuzumab

| pregnancy_AU = D

| pregnancy_AU_comment = <ref name="Perjeta PI" />

| pregnancy_category =

| routes_of_administration = [[Intravenous infusion|Intravenous]]

| class =

| ATC_prefix = L01

| ATC_suffix = FD02

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref name="Perjeta PI">https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropperje11013 {{bare URL inline|date=April 2023}}</ref>

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = <ref name="Perjeta SmPC" />

| legal_US = Rx-only

| legal_US_comment = <ref name="Perjeta FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Perjeta EPAR">{{cite web | title=Perjeta EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/perjeta | access-date=3 January 2022}}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = <!-- For countries not listed above -->

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| bioavailability =

| protein_bound =

| metabolism =

| metabolites =

| onset =

| elimination_half-life =

| duration_of_action =

| excretion =

<!-- Identifiers -->

| CAS_number = 380610-27-5

| CAS_supplemental =

| PubChem =

| IUPHAR_ligand =

| DrugBank = DB06366

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = none

| ChEBI_Ref =

| ChEBI =

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 2007641

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = 2C4

<!-- Chemical and physical data -->

'''Pertuzumab''', sold under the brand name '''Perjeta''', is a [[monoclonal antibody]] used in combination with [[trastuzumab]] and [[docetaxel]] for the treatment of metastatic [[HER2]]-positive breast cancer; it also used in the same combination as a [[neoadjuvant]] in early HER2-positive breast cancer.<ref name="Perjeta FDA label"/>

Side effects in more than half the people taking it include diarrhea, hair loss, and [[neutropenia|loss of neutrophils]]; more than 10% experience [[anemia|loss of red blood cells]], hypersensitivity or allergic reaction, infusion reactions, decreased appetite, insomnia, distortions in the sense of taste, inflammation of the mouth or lips, constipation, rashes, [[nail disease]], and muscle pain.<ref name="Perjeta SmPC"/> Women who are pregnant or planning on getting pregnant should not take it, it was not studied in people with certain heart conditions and should be used in caution in such people, and it should not be used with an [[anthracycline]].<ref name="Perjeta SmPC"/> It is unknown if pertuzumab interacts with [[doxorubicin]].<ref name="Perjeta SmPC"/>

It is the first-in-class of a kind of drug called a "[[Epidermal growth factor receptor|HER]] dimerization inhibitor" — it inhibits the [[protein dimer|dimer]]ization of HER2 with other HER receptors, which prevents them from [[HER2/neu#Signal transduction|signalling]] in ways that promote cell growth and proliferation.<ref name=Harbeck2013rev/>

It was discovered and developed by [[Genentech]] and was first approved in 2012.<ref>{{cite web | title=Drug Approval Package: Perjeta (pertuzumab) Injection NDA #125409 | website=U.S. [[Food and Drug Administration]] (FDA) | date=3 August 2012 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125409Orig1s000TOC.cfm | access-date=3 January 2022}}</ref><ref name=FDA2012/>

==Medical uses==

Pertuzumab is administered as an intravenous infusion in combination with [[trastuzumab]] and [[docetaxel]] as a first line treatment for HER2-positive metastatic breast cancer.<ref name="Perjeta FDA label">{{cite web | title=Perjeta- pertuzumab injection, solution, concentrate | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=17f85d17-ab71-4f5b-9fe3-0b8c822f69ff | access-date=3 January 2022}}</ref><ref name="Perjeta SmPC">{{cite web | title=Perjeta 420 mg Concentrate for Solution for Infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=2 July 2021 | url=https://www.medicines.org.uk/emc/product/2993/smpc | access-date=3 January 2022}}</ref> It is also used in the same combination as a [[neoadjuvant]] (given to reduce the size of a tumor, prior to surgery or radiation) for HER2-positive early breast cancer; as of 2016 this use had not been shown to increase survival.<ref name="Perjeta FDA label"/>

{{Asof|2016}}, pertuzumab has not been studied in people with a [[left ventricular ejection fraction]] value of ≤ 50% normal, a prior history of congestive heart failure, or conditions that could impair [[left ventricle|left ventricular]] function like uncontrolled hypertension, recent heart attacks, or serious cardiac arrhythmia.<ref name="Perjeta SmPC"/> Caution should be used combining pertuzumab with an [[anthracycline]].<ref name="Perjeta SmPC"/> There is also no safety data available for use of pertuzumab in combination with [[doxorubicin]].<ref name="Perjeta SmPC"/>

Women of child-bearing age should use contraception while taking pertuzumab; it may damage the fetus in pregnant women, and it may be secreted in breast milk.<ref name="Perjeta SmPC"/>

==Adverse effects==

In clinical trials of the three-agent combination therapy in metastatic breast cancer, adverse effects occurring in more than half the people taking it included diarrhea, hair loss, and [[neutropenia|loss of neutrophils]]; more than 10% of people experienced loss of neutrophils with fever, and [[leucopenia|loss of leukocytes]].<ref name="Perjeta SmPC"/> After docetaxel was dropped in some people, the most common adverse effects were diarrhea (28.1%), upper respiratory tract infection (18.3%), rash (18.3%), headache (17.0%), fatigue (13.4%), swelling of nasal passages and throat (often due to catching the common cold) (17.0%), weakness (13.4%), itchiness (13.7%), joint pain (11.4%), nausea (12.7%), pain in an extremity (13.4%), back pain (12.1%) and cough (12.1%).<ref name="Perjeta SmPC"/>

In clinical trials of the neoadjuvant use of the combination, more than 50% of people had hair loss and [[neutropenia|loss of neutrophils]].<ref name="Perjeta SmPC"/>

In both uses, more than 10% of people additionally experienced: [[anemia|loss of red blood cells]], hypersensitivity or allergic reaction, infusion reactions, decreased appetite, insomnia, distortions in the sense of taste, inflammation of the mouth or lips, constipation, rashes, [[nail disease]], and muscle pain.<ref name="Perjeta SmPC"/>

==Pharmacology==

The metabolism of pertuzumab has not been directly studied; in general antibodies are cleared principally by [[catabolism]]. The median clearance of pertuzumab was 0.235 liters/day and the median half-life was 18 days.<ref name="Perjeta SmPC"/>

==Mechanism of action==

[[HER2/neu|HER2]] is an extracellular receptor—a [[receptor tyrosine kinase]] - that when activated, sets off [[signal transduction]] through [[HER2/neu#Signal transduction|several pathways]] that stimulate cell proliferation and cell growth; if overexpressed it can cause uncontrollable growth. HER2 positive breast cancer is caused by ERBB2 gene amplification that results in overexpression of HER2 in approximately 15-30% of breast cancer tumors.<ref name=HER2rev2012>{{cite journal | vauthors = Mitri Z, Constantine T, O'Regan R | title = The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy | journal = Chemotherapy Research and Practice | volume = 2012 | pages = 743193 | year = 2012 | pmid = 23320171 | pmc = 3539433 | doi = 10.1155/2012/743193 | title-link = doi | doi-access = free }}</ref>

Like many receptors, HER2 normally combines another protein in order to function (a process called [[Protein dimer|dimerization]]); it can bind with a second HER2 receptor (acting as a [[homodimer]]) and it can heterodimerize with a different receptor of the [[Epidermal growth factor receptor|HER family]]. The most potent dimer for activating signalling pathways is HER2/HER3.<ref name=Harbeck2013rev/>

The [[epitope]] for pertuzumab is the domain of HER2 where it binds to HER3, and pertuzumab prevents the HER2/HER3 dimer from forming, which blocks signalling by the dimer.<ref name=Harbeck2013rev/><ref>{{cite journal | vauthors = Badache A, Hynes NE | title = A new therapeutic antibody masks ErbB2 to its partners | journal = Cancer Cell | volume = 5 | issue = 4 | pages = 299–301 | date = April 2004 | pmid = 15093533 | doi = 10.1016/s1535-6108(04)00088-1 | title-link = doi | doi-access = free }}</ref> [[Trastuzumab]] is another monoclonal antibody against HER2; its epitope is the domain where HER2 binds to another HER2 protein.<ref name=Harbeck2013rev>{{cite journal | vauthors = Harbeck N, Beckmann MW, Rody A, Schneeweiss A, Müller V, Fehm T, Marschner N, Gluz O, Schrader I, Heinrich G, Untch M, Jackisch C | display-authors = 6 | title = HER2 Dimerization Inhibitor Pertuzumab - Mode of Action and Clinical Data in Breast Cancer | journal = Breast Care | volume = 8 | issue = 1 | pages = 49–55 | date = March 2013 | pmid = 24715843 | pmc = 3971793 | doi = 10.1159/000346837 }}</ref> The two mAbs together prevent HER2 from functioning.<ref name=Harbeck2013rev/>

==Chemistry and manufacturing ==

Pertuzumab is an immunoglobulin G1 with a variable region against the human HER2 protein, a human-mouse monoclonal 2C4 heavy chain, disulfide bound with a human-mouse monoclonal 2C4 κ-chain.<ref>{{cite journal|title=Proposed INN: List 89|journal=WHO Drug Information|date=2003|volume=17|issue=3|url=https://www.who.int/medicines/publications/druginformation/innlists/PL89.pdf}}</ref>

It is manufactured recombinantly in [[Chinese hamster ovary|CHO]] cells.<ref name="Perjeta FDA label"/>

==History==

The monoclonal antibody 2C4 appears to have first been published in 1990 by scientists from Genentech,<ref>{{cite journal | vauthors = Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A | title = Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product | journal = Cancer Research | volume = 50 | issue = 5 | pages = 1550–1558 | date = March 1990 | pmid = 1689212 | url = http://cancerres.aacrjournals.org/content/canres/50/5/1550.full.pdf }}, referenced in {{cite journal | vauthors = Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J | title = Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells | journal = Cancer Research | volume = 61 | issue = 12 | pages = 4744–4749 | date = June 2001 | pmid = 11406546 | url = http://cancerres.aacrjournals.org/content/canres/61/12/4744.full.pdf }}</ref> the same year that [[Hoffmann-La Roche|F. Hoffmann-La Roche AG]] acquired a majority stake in Genentech.<ref name=NYTroche>{{cite news| vauthors = Fisher LM |title=Genentech: Survivor Strutting Its Stuff|url=https://www.nytimes.com/2000/10/01/business/genentech-survivor-strutting-its-stuff.html |work=The New York Times|date=1 October 2000 }}</ref>

By 2003, Genentech understood that 2C4 prevented HER2 dimerizing with other HER receptors and had begun Phase I trials, aiming for a broad range of cancers, not just ones overexpressing HER2. It was the first known HER dimerization inhibitor.<ref>{{cite book| vauthors = Albanell J, Codony J, Rovira A, Mellado B, Gascón P |title=New Trends in Cancer for the 21stCentury |chapter=Mechanism of Action of Anti-Her2 Monoclonal Antibodies: Scientific Update on Trastuzumab and 2c4 |series=Advances in Experimental Medicine and Biology |date=2003|volume=532|pages=253–68|pmid=12908564|doi=10.1007/978-1-4615-0081-0_21|isbn=978-0-306-47762-1 }}</ref>

In 2005, Genentech presented poor results of Phase II trials of pertuzumab as a single agent in prostate, breast, and ovarian cancers, and said that it intended to continue developing it in combination with other drugs for ovarian cancer.<ref>{{cite web|title=Press Release: Data From Omnitarg Clinical Program Presented at American Society of Clinical Oncology Meeting|url=https://www.gene.com/media/press-releases/8431/2005-05-15/data-from-omnitarg-clinical-program-pres|publisher=Genentech|date=15 May 2005|access-date=2 November 2016|archive-date=6 April 2017|archive-url=https://web.archive.org/web/20170406222655/https://www.gene.com/media/press-releases/8431/2005-05-15/data-from-omnitarg-clinical-program-pres|url-status=dead}}</ref><ref>{{cite news|title=Genentech's Omnitarg fails in Phase II|url=http://www.pharmatimes.com/news/genentechs_omnitarg_fails_in_phase_ii_998265|work=Pharma Times|date=16 May 2005}}</ref>

In 2007, Genentech dropped the trade name Omnitarg.<ref>{{cite journal|title=Correction: Letter from the Editor|journal=Cancer Oncology News|date=February 2012|page=3|url=https://issuu.com/mcmahongroup/docs/con0212_de/3}}</ref><ref>{{cite web|title=Press release: Roche in the first half of 2007|url=http://www.roche.com/investors/updates/inv-update-2007-07-19.htm|publisher=Roche|date=19 July 2007}}</ref>

In March 2009, Roche acquired Genentech.<ref name=Morse_WSJ2006>{{cite news | vauthors = Morse A | date=10 May 2006 | title =Chugai Shares Post Healthy Gain On Prospects for Cancer Drug | work=The Wall Street Journal | access-date=26 September 2008 | url = https://www.wsj.com/articles/SB114720225204948046?mod=googlenews_wsj}}</ref><ref name="Staff_GEN2008">{{cite news|date = 21 July 2008|access-date = 26 September 2008|title = Roche Makes $43.7B Bid for Genentech|work = [[Gen. Eng. Biotechnol. News|Genetic Engineering & Biotechnology News]]|url = http://www.genengnews.com/news/bnitem.aspx?name=39080941|archive-date = 3 February 2009|archive-url = https://web.archive.org/web/20090203010727/http://www.genengnews.com/news/bnitem.aspx?name=39080941|url-status = dead}}</ref>

In 2012, the results were published of the CLEOPATRA trial, a randomized placebo-controlled Phase III trial of pertuzumab in combination with [[trastuzumab]] and docetaxel in HER2-positive metastatic breast cancer.<ref>{{cite journal | vauthors = Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM | display-authors = 6 | title = Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer | journal = The New England Journal of Medicine | volume = 366 | issue = 2 | pages = 109–119 | date = January 2012 | pmid = 22149875 | pmc = 5705202 | doi = 10.1056/nejmoa1113216 }}</ref> Pertuzumab received US FDA approval for the treatment of HER2-positive metastatic breast cancer later that year.<ref name=FDA2012>{{cite web | title=FDA approves Perjeta for type of late-stage breast cancer | website=U.S. [[Food and Drug Administration]] (FDA) | date=8 June 2012 | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm307549.htm | archive-url=https://web.archive.org/web/20121101092633/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm307549.htm | archive-date=1 November 2012 | url-status=dead | access-date=3 January 2022}}</ref> Results of a Phase II trial in the neoadjuvant setting, NeoSphere, published in 2012,<ref>{{cite journal | vauthors = Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P | display-authors = 6 | title = Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial | journal = The Lancet. Oncology | volume = 13 | issue = 1 | pages = 25–32 | date = January 2012 | pmid = 22153890 | doi = 10.1016/s1470-2045(11)70336-9 }} cited in {{cite journal | vauthors = Mates M, Fletcher GG, Freedman OC, Eisen A, Gandhi S, Trudeau ME, Dent SF | title = Systemic targeted therapy for her2-positive early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline | journal = Current Oncology | volume = 22 | issue = Suppl 1 | pages = S114–S122 | date = March 2015 | pmid = 25848335 | pmc = 4381787 | doi = 10.3747/co.22.2322 }}</ref> and results of a Phase II cardiac safety study in the same population, Tryphaena, published in 2013.<ref>{{cite journal | vauthors = Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J | display-authors = 6 | title = Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA) | journal = Annals of Oncology | volume = 24 | issue = 9 | pages = 2278–2284 | date = September 2013 | pmid = 23704196 | doi = 10.1093/annonc/mdt182 | title-link = doi | doi-access = free }}</ref> The FDA approved the neoadjuvant indication in 2013.<ref>{{cite press release | title=FDA approves Perjeta for neoadjuvant breast cancer treatment | website=U.S. [[Food and Drug Administration]] (FDA) | date=30 September 2013 | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm370393.htm | archive-url=https://web.archive.org/web/20131010072515/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm370393.htm | archive-date=10 October 2013 | url-status=dead | access-date=3 January 2022}}</ref>

Pertuzumab was approved for medical use in the European Union in 2013.<ref name="Perjeta SmPC"/><ref name="Perjeta EPAR" />

==Society and culture==

=== Economics ===

{{Asof|2016}}, in the US each cycle of the three-drug combination given every three weeks costs around {{US$|8,500}}, not including ancillary care costs.<ref>{{cite journal | vauthors = Durkee BY, Qian Y, Pollom EL, King MT, Dudley SA, Shaffer JL, Chang DT, Gibbs IC, Goldhaber-Fiebert JD, Horst KC | display-authors = 6 | title = Cost-Effectiveness of Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer | journal = Journal of Clinical Oncology | volume = 34 | issue = 9 | pages = 902–909 | date = March 2016 | pmid = 26351332 | pmc = 5070553 | doi = 10.1200/jco.2015.62.9105 }}</ref>

In the UK, a [[NICE]] evaluation in 2015, made a preliminary finding that the drug combination was not cost effective, and NICE rejected the drug in the neoadjuvant setting in May 2016, primarily because it was unknown if the drug combination provided a survival benefit.<ref>{{cite journal | vauthors = Fleeman N, Bagust A, Beale S, Dwan K, Dickson R, Proudlove C, Dundar Y | title = Pertuzumab in combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic or locally recurrent unresectable breast cancer | journal = PharmacoEconomics | volume = 33 | issue = 1 | pages = 13–23 | date = January 2015 | pmid = 25138171 | doi = 10.1007/s40273-014-0206-2 | s2cid = 8470253 }}</ref><ref>{{cite web|title=Breast cancer (HER2 positive, metastatic) - pertuzumab (with trastuzumab and docetaxel) [ID523]|url=https://www.nice.org.uk/guidance/indevelopment/gid-tag322|publisher=NICE|access-date=2 November 2016|date=1 September 2016}}</ref><ref>{{cite news| vauthors = McKee S |title=NICE rejects Roche's breast cancer drug Perjeta|url=http://www.pharmatimes.com/news/nice_rejects_roches_breast_cancer_drug_perjeta_1026018|work=Pharma Times|date=20 May 2016 }}</ref> This decision was subsequently reversed six months later and pertuzumab became the first new breast cancer drug to be approved by NICE for routine [[NHS]] funding in almost a decade

after Roche pledged to provide the drug to the NHS at an undisclosed discount for patients in the neoadjuvant setting and to share the long–term financial risks.<ref>{{cite news| vauthors = Yip A |title=NICE U-Turns and Backs Approval of Roche's Perjeta for HER2-Positive Breast Cancer|url=http://www.pharmalive.com/nice-u-turns-and-backs-approval-of-roche-s-perjeta-for-her2-positive-breast-cancer/|work=Pharmalive|date=22 November 2016 }}</ref>

== References ==

{{reflist}}

== Further reading ==

* {{cite book | title=Medical Genetics Summaries | chapter=Pertuzumab Therapy and ERBB2 (HER2) Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK315949/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2015 | pmid=28520364 | id=Bookshelf ID: NBK315949 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}

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