Abituzumab

Abituzumab

Monoclonal antibody
Type	Whole antibody
Source	Humanized
Target	CD51
Clinical data
ATC code	none
Identifiers
CAS Number	1105038-73-0
ChemSpider	none
UNII	724QD330RD

Abituzumab is a humanized IgG2 monoclonal antibody (mAb) targeted at CD51 (an integrin) currently in development by Merck KGaA Darmstadt, Germany in an attempt to prevent bone lesion metastases in castration-resistant prostate cancer.^[1][2]

Pharmacology

Pharmacokinetics

Early results from clinical trials show that there are no severe dose-dependent adverse effects up to 1500 mg IV administration of Abituzumab. Maximum serum concentrations were observed one to two hours after the onset of administration, with a Cmax that increased proportionally with dose. Serum half-life is also dose-dependent, at 35 mg the half-life is 19.3 hours, and at 1500 mg half-life is 246.1 hours. Clearance of Abituzumab began to stabilize at 250 mg, which may suggest saturable first-order elimination kinetics. Volume of distribution remained constant between 4.1 - 5.9 L at all doses of Abituzumab, which indicates minimal distribution in the tissue. Anti-abituzumab antibodies were observed in 19% of patients, however, researchers believe the development of these antibodies did not alter the pharmacokinetic profile of Abituzumab.^[3]

Society and culture

In 2014 Merck KGaA acquired Sigma-Aldrich Corp. for approximately $17 billion. Before the acquisition, Sigma-Aldrich Corp. primarily produced laboratory testing and research materials.^[4] During the purchase, Merck KGaA agreed to pay $140/share, which was 37% above the valued share price at the time. Merck KGaA cited the purchase as an opportunity to increase their platform of novel drug discovery.^[5] In a 2015 Annual Report, Merck KGaA proposed that the acquisition of Sigma-Aldrich Corp. would have a negative impact on earnings and net income during the 2016 fiscal year, however, they proposed no risks to jeopardize the continued existence of the company.^[6] Despite the negative impact on earnings and net income, Merck KGaA observed an 18.2% increase in net sales during the second quarter of 2016, with EBITDA pre-exceptionals rising 28.8% and EBITDA margin rising 30.4%^[7]

Patents

On December 14, 2009 Merck KGaA filed a patent application citing Abituzumab as a novel treatment and diagnostic tool for patients with tumor induced angiogenesis or another angiogenic-associated disorder. Ideally the therapy would target patients with an alteration in the expression of genes related to cell proliferation and angiogenesis.^[1]

Research

Randomized Phase I/II POSEIDON Trial

This multiphase trial aimed to further evaluate the safety of tolerability of Abituzumab in combination therapy with cetuximab and irinotecan in the Phase I portion of the trial.^[8] Cetixumab, a monoclonal antibody, that targets epidermal growth factor receptor (EGFR), and irinotecan, a topoisomerase I inhibitor, can be used in combination as standard of care for treating colorectal cancer.^[9][10][8] The Phase II portion of the trial sought to compare the efficacy of Abituzumab, cetuximab, and irinotecan compared to cetuximab and irinotecan in patients with KRAS (exon 2) wild-type metastatic colorectal cancer. Patients included in the study failed treatment with oxaliplatin, and initial safety studies included comparing Abituzumab, cetuximab, and irinotecan with standard of care. The Phase I study showed that doses up to 1000 mg of Abituzumab, cetuximab, and irinotecan were well tolerated. The results of Phase II showed that the primary endpoint of progression-free survival was not met, but overall survival improved in patients receiving Abituzumab compared to standard of care. The researchers postulate that this could be due to increased expression of αvβ6 integrin in tumors.^[8]

Randomized Phase II PERSEUS Trial

Based on the positive results of the Phase I trial, an additional Phase II clinical trial investigating Abituzumab's ability to extend progression free survival (PFS) in metastatic castration-resistant prostate cancer was conducted.^[11] This trial utilized Abituzumab in combination with luteinizing hormone antagonist/agonist treatment every three weeks in patients with confirmed bone lesions in metastatic castration-resistant prostate cancer. During this study, the researchers did not see an overall improvement in prostate cancer, but they did observe a partial response in relation to the bone lesions. However, further study is warranted to determine the efficacy of Abituzumab in treating bone lesions in metastatic castration-resistant prostate cancer.^[2]

References

1. EP 2706358, Behrens J, "Biomarkers for inhibitors with anti-angiogenic activity", published 12 March 2014, assigned to Merck Patent GmbH 
2. Hussain M, Le Moulec S, Gimmi C, Bruns R, Straub J, Miller K (July 2016). "Differential Effect on Bone Lesions of Targeting Integrins: Randomized Phase II Trial of Abituzumab in Patients with Metastatic Castration-Resistant Prostate Cancer". Clinical Cancer Research. 22 (13): 3192–200. doi:10.1158/1078-0432.CCR-15-2512. PMID 26839144.
3. Uhl W, Zühlsdorf M, Koernicke T, Forssmann U, Kovar A (April 2014). "Safety, tolerability, and pharmacokinetics of the novel αv-integrin antibody EMD 525797 (DI17E6) in healthy subjects after ascending single intravenous doses". Investigational New Drugs. 32 (2): 347–54. doi:10.1007/s10637-013-0038-5. PMC 3945639. PMID 24242902.
4. Mahadevan N, Walker J (2014-09-22). "Germany's Merck to Buy Sigma-Aldrich for $17 Billion". Wall Street Journal. ISSN 0099-9660. Retrieved 2016-11-14.
5. Serafino P (2014-09-22). "Merck KGaA to Buy Sigma-Aldrich for to Add Chemicals". Bloomberg.com. Retrieved 2016-11-14.
6. "Annual Report 2015" (PDF). Merck KGaA. Archived from the original (PDF) on 2017-04-13.
7. Talanow M. "Merck KGaA, Darmstadt, Germany, Lifts Forecast Following Good Second Quarter" (PDF). Merck KGaA. Archived from the original (PDF) on 2017-04-13.
8. Élez E, Kocáková I, Höhler T, Martens UM, Bokemeyer C, Van Cutsem E, et al. (January 2015). "Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial". Annals of Oncology. 26 (1): 132–40. doi:10.1093/annonc/mdu474. PMID 25319061.
9. "Cetuximab (Erbitux)". Cancer Research UK. 2015-11-18. Retrieved 2016-11-20.
10. "Irinotecan Injection". MedlinePlus Drug Information. U.S. National Library of Medicine. Retrieved 2016-11-20.
11. Levitan D (16 February 2016). "Abituzumab Improves Bone Lesion Progression, not PFS in CRPC". Cancer Network. UBM Medica, LLC. Archived from the original on 2 March 2016.