Lutetium (177Lu) vipivotide tetraxetan

Short description: Radiopharmaceutical medication

Lutetium (177Lu) vipivotide tetraxetan

Clinical data
Trade names| Pluvicto
Other names| 177Lu-PSMA-617, Lutetium Lu 177 vipivotide tetraxetan (USAN US)
License data|

* US DailyMed: Pluvicto

Routes of
administration| Intravenous
Drug class| Radiopharmaceutical
ATC code|

* V10XX05 (WHO)

Legal status
Legal status|

* CA: ℞-only / Schedule C[1][2]
* US: ℞-only [3][4]
* EU: Rx-only [5]

Identifiers
CAS Number|

* 1703749-62-5

PubChem CID|

* 122706785

DrugBank|

* DB16778

ChemSpider|

* 58828499

UNII|

* G6UF363ECX

KEGG|

* D12335

Chemical and physical data
3D model (JSmol)|

* Interactive image

SMILES

* [177Lu+3].OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)[C@@H]3CC[C@@H](CNC(=O)CN4CCN(CC(=O)[O-])CCN(CC(=O)[O-])CCN(CC(=O)[O-])CC4)CC3)C(=O)O)C(=O)O

InChI

* InChI=1S/C49H71N9O16.Lu/c59-40(28-55-17-19-56(29-42(62)63)21-23-58(31-44(66)67)24-22-57(20-18-55)30-43(64)65)51-27-32-8-12-35(13-9-32)45(68)52-39(26-33-10-11-34-5-1-2-6-36(34)25-33)46(69)50-16-4-3-7-37(47(70)71)53-49(74)54-38(48(72)73)14-15-41(60)61;/h1-2,5-6,10-11,25,32,35,37-39H,3-4,7-9,12-24,26-31H2,(H,50,69)(H,51,59)(H,52,68)(H,60,61)(H,62,63)(H,64,65)(H,66,67)(H,70,71)(H,72,73)(H2,53,54,74);/q;+3/p-3/t32-,35-,37-,38-,39-;/m0./s1/i;1+2

* Key:RSTDSVVLNYFDHY-BGOLSCJMSA-K

Lutetium (177Lu) vipivotide tetraxetan, sold under the brand name Pluvicto, is a radiopharmaceutical medication used for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).[3][4] Lutetium (177Lu) vipivotide tetraxetan is a targeted radioligand therapy.[4][6]

The most common adverse reactions include fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.[4][5]

Lutetium (177Lu) vipivotide tetraxetan is a radioconjugate composed of PSMA-617, a human prostate-specific membrane antigen (PSMA)-targeting ligand, conjugated to the beta-emitting radioisotope lutetium-177, with potential antineoplastic activity against PSMA-expressing tumor cells.[7] Upon intravenous administration of lutetium (177Lu) vipivotide tetraxetan, vipivotide tetraxetan targets and binds to PSMA-expressing tumor cells.[7] Upon binding, PSMA-expressing tumor cells are destroyed by 177Lu through the specific delivery of beta particle radiation.[7] PSMA, a tumor-associated antigen and type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells.[7]

Lutetium (177Lu) vipivotide tetraxetan was approved for medical use in the United States in March 2022,[4][8] and in the European Union in December 2022.[5] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[9][10]

## Contents

* 1 History
* 2 Society and culture
* 2.1 Regulatory status
* 3 References
* 4 External links

## History

In 2006, scientists from Purdue University designed a targeting ligand that bound with high affinity and specificity to PSMA on prostate cancer cells and patented[11][12] its ability to target attached radionuclides such as 177Lu, 99mTc, 68Ga, etc. to prostate cancers. The patents were licensed to Endocyte in 2007. In 2012, scientists at German Cancer Research Center and University Hospital Heidelberg improved the drug's affinity, patented,[13] and licensed to ABX advanced biomedical compounds, a small German pharmaceutical company, for early clinical development. In 2017, the ABX patent was also acquired by Endocyte[14] and Endocyte together with the above two sets of patents was acquired by Novartis in 2018.[15]

Efficacy and safety was initially investigated as a compassionate access treatment in Germany with high tumor targeting and low doses to normal organs.[16] Physician-scientists from the Peter MacCallum Cancer Centre conducted a phase 2 trial demonstrating high response rates, low toxicity and reduction in pain in men with metastatic castration-resistant cancer who progressed after conventional treatments.[17] The ANZUP co-operative trials conducted the first randomized, multicentre, trial comparing lutetium vipivotide tetraxetan to cabazitaxel chemotherapy.[18] This trial demonstrated higher PSA response and fewer adverse effects with lutetium vipivotide tetraxetan.

Efficacy was evaluated in VISION,[19] a randomized (2:1), multicenter, open-label trial that evaluated lutetium (177Lu) vipivotide tetraxetan plus best standard of care (BSoC) (n=551) or BSoC alone (n=280) in men with progressive, prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC).[4] All participants received a GnRH analog or had prior bilateral orchiectomy.[4] Participants were required to have received at least one androgen receptor pathway inhibitor, and 1 or 2 prior taxane-based chemotherapy regimens.[4] Participants received lutetium (177Lu) vipivotide tetraxetan 7.4 GBq (200 mCi) every 6 weeks for up to a total of 6 doses plus BSoC or BSoC alone.[4]

The U.S. Food and Drug Administration (FDA) granted the application for lutetium (177Lu) vipivotide tetraxetan priority review and breakthrough therapy designations.[4]

## Society and culture

### Regulatory status

On 13 October 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Pluvicto, intended for the treatment of prostate cancer.[20] The applicant for this medicinal product is Novartis Europharm Limited.[20] Lutetium (177Lu) vipivotide tetraxetan was approved for medical use in the European Union in December 2022.[5][21]

## References

1. ↑ Advanced Accelerator Applications USA. "Pluvicto Product Monograph". Government of Canada. https://pdf.hres.ca/dpd_pm/00067158.PDF.
2. ↑ "Summary Basis of Decision - Pluvicto". 23 October 2014. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00621&lang=en.
3. ↑ 3.0 3.1 "Pluvicto- lutetium lu 177 vipivotide tetraxetan injection, solution". 23 March 2022. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fb973a8d-7fea-4a7a-963f-2a8e67a46e55.
4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 "FDA approves Pluvicto for metastatic castration-resistant prostate can". 23 March 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer. This article incorporates text from this source, which is in the public domain.
5. ↑ 5.0 5.1 5.2 5.3 "Pluvicto EPAR". 12 October 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/pluvicto. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
6. ↑ "Radiolabeled PSMA Inhibitors". Cancers 13 (24): 6255. December 2021. doi:10.3390/cancers13246255. PMID 34944875.
7. ↑ 7.0 7.1 7.2 7.3 "Lutetium Lu 177 Vipivotide Tetraxetan (Code C148145)". NCI Thesaurus. 28 February 2022. https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI Thesaurus&code=C148145. This article incorporates text from this source, which is in the public domain.
8. ↑ "Novartis Pluvicto approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer" (Press release). Novartis. 23 March 2022. Archived from the original on 23 March 2022. Retrieved 23 March 2022.
9. ↑ "Advancing Health Through Innovation: New Drug Therapy Approvals 2022". 10 January 2023. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022. This article incorporates text from this source, which is in the public domain.
10. ↑ (PDF) ﻿New Drug Therapy Approvals 2022﻿ (Report). January 2024. https://www.fda.gov/media/164429/download. Retrieved 14 January 2024. This article incorporates text from this source, which is in the public domain.
11. ↑ Low PS, Kularatne SA, "PSMA binding ligand-linker conjugates and methods for using", US patent 11318121, issued 3 May 2022, assigned to Purdue Research Foundation
12. ↑ Low PS, Kularatne SA, "PSMA binding ligand-linker conjugates and methods for using", US patent 10406240, issued 10 September 2019, assigned to Purdue Research Foundation
13. ↑ Eder M, Kopka K, Schäfer M, Bauder-Wüst U, Haberkorn U, Eisenhut M, Mier W , Benesova M, "Labeled inhibitors of prostate specific membrane antigen (psma), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer", US patent 20160228587, published 11 August 2016, assigned to Deutsches Krebsforschungszentrum DKFZ, Universitaet Heidelbergand Molecular Insight Pharmaceuticals Inc.
14. ↑ "Endocyte Announces Exclusive License of Phase 3 Ready PSMA-Targeted Radioligand Therapy for Development in Prostate Cancer". https://www.isotope.com/corporate-overview/news.cfm?nid=Endocyte Announces Exclusive Worldwide License of Phase 3 Ready PSMA-Targeted Radioligand Therapy for Development in Prostate Cancer.
15. ↑ "Novartis inks $2.1B Endocyte buyout, furthering radiotherapy push" (in en). 18 October 2018. https://www.fiercebiotech.com/biotech/novartis-inks-2-1b-endocyte-buyout-furthering-radiotherapy-push.
16. ↑ "The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions". Journal of Nuclear Medicine 56 (11): 1697–1705. November 2015. doi:10.2967/jnumed.115.161299. PMID 26294298.
17. ↑ "[177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study". The Lancet. Oncology 19 (6): 825–833. June 2018. doi:10.1016/S1470-2045(18)30198-0. PMID 29752180.
18. ↑ "[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial". Lancet 397 (10276): 797–804. February 2021. doi:10.1016/s0140-6736(21)00237-3. PMID 33581798.
19. ↑ Clinical trial number NCT03511664 for "Study of 177Lu-PSMA-617 In Metastatic Castrate-Resistant Prostate Cancer (VISION)" at ClinicalTrials.gov.
20. ↑ 20.0 20.1 "Pluvicto: Pending EC decision". 13 October 2022. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/pluvicto. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
21. ↑ "Pluvicto Product information". https://ec.europa.eu/health/documents/community-register/html/h1703.htm.

## External links

* "Lutetium lu 177 vipivotide tetraxetan". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/unii/G6UF363ECX.

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