The Possible Neuroprotective Effect of Ocrelizumab Via VEGF Protein Expression in Relapsing Multiple Sclerosis Patients

Multiple Sclerosis Relapse Clinical Trial

Official title:

An Observation Monocentric Study to Analyse the Possible Neuroprotective Effect of Ocrelizumab Via VEGF Protein Expression in Relapsing Multiple Sclerosis Patients

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04902690
• Other study ID #: VEGF Study
• Status: Not yet recruiting
• Start date: May 31, 2021
• Est. completion date: July 31, 2024

Study information

• Verified date: May 2021
• Source: IRCCS National Neurological Institute "C. Mondino" Foundation
• Contact: Cinzia Fattore, MD
• Phone: 0382 380385
• Email: cinzia.fattore[@]mondino.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Ocrelizumab (OCR) is a humanized anti-CD20 antibody approved for Relapsing Multiple Sclerosis (RMS) and Primary Progressive Multiple Sclerosis (PPMS), due to neuroprotective effects of partially unknown origin. While its mechanism of action is mainly thought to occur via B cell depletion, previous studies on rituximab, another anti-CD20 drug, showed that CD20 binding elicits several intracellular signalling pathways, also including Protein Kinase C (PKC) activation. Of interest, the β isoform of PKC is known to modulate, through the RNA-binding protein ELAV/HuR, the expression of Vascular Endothelial Growth Factor (VEGF), a signaling protein that has been suggested to play deleterious effects in the first phases of MS. Therefore, the hypothesis is that part of the neuroprotective effects exerted by OCR may also be due to the modulation of VEGF expression via PKCβ /HuR cascade. The primary objective is to evaluate the variation of the expression of VEGF (protein and mRNA) in Peripheral Blood Mononuclear Cells (PBMCs) induced by OCR therapy. No additional visits will be required outside of clinical practice. Additional laboratory testing (VEGF protein expression and PKCbeta/HuR cascade) will be performed on extra blood which will be taken during the routine blood exams.

This study is an observational, longitudinal, monocenter and single arm study, in patients with RMS who are newly prescribed with OCR as per clinical practice.

The study consists of the following visits as per clinical practice

• T0 visit: at the first dose of OCR, blood sample and clinical/radiological MS data will be collected.

• T6: after 6 months of OCR treatment, blood samples and clinical MS data will be collected.

• T12 visit: after 12 months of OCR treatment, blood samples and clinical MS data will be collected.

Description:

Ocrelizumab (OCR) is a humanized monoclonal anti-CD20 antibody approved by the FDA in 2017 and by the European Medicines Agency in 2018 for treatment of adult patients with Relapsing Multiple Sclerosis (RMS). In addition, having shown neuroprotective effects, OCR is the first drug ever approved for early treatment of Primary Progressive MS (PPMS). Currently, OCR is thought to mostly act via the rapid depletion of the B cells expressing CD20. Additionally, this depletion most likely causes long-lasting changes in the profile of B cells, characterized by a reduction of their pro-inflammatory phenotype, as demonstrated with other anti-CD20 antibodies.

Of interest, previous studies on other anti-CD20 drugs, mainly rituximab, have shown that anti-CD20 agents also exert interesting effects on additional intracellular signaling pathways, such as those involving serine/threonine and tyrosine kinases, as well as c-myc. Considering the structural, pharmacokinetic and pharmacodynamic similarities between OCR and rituximab, it can be hypothesized that the efficacy of OCR in delaying disease progression and neuroprotection might also stem from such intracellular effects.

Among the various intracellular effects elicited by rituximab through the binding with CD20, stimulation of the Protein Kinase C (PKC) pathway is of potential significance. The term PKC encompasses a family of several serine/threonine protein kinases of which the isoform β has been implicated in pathological processes, such as diabetic retinopathy, via a specific PKCβ/HuR/Vascular Endothelial Growth Factor (VEGF) pathway (Amadio et al. 2010). Notably, HuR belongs to a family of RNA-binding proteins, named ELAV, which are able to influence virtually any aspect of the post-synthesis fate of the targeted transcripts, including VEGF.

VEGF is a signaling molecule involved in vital processes such as angiogenesis, endothelial proliferation and cellular response to hypoxia. The possible role of VEGF in MS pathogenesis and evolution has not been explored until recently, but mounting evidence points to the conclusion that VEGF might play a significant noxious role in the relapsing stage of MS, for instance by mediating an increase in blood-brain barrier (BBB) permeability, while playing a beneficial, neuroprotective role in the late, progressive stage of the disease. Of note, VEGF has a primary role in promoting vascular hyperpermeability, indeed via phosphorylation of endothelial tight junction proteins modulates their degradation, finally leading to BBB disruption. Further, it also regulates vessel growth and is chemotactic for monocytes and lymphocytes, promoting neuroinflammation.

Of interest, a significant increase in VEGF was observed in mice in the acute phase of murine MOG-induced MS, which correlates to the clinical score, and in sera of MS patients during clinical disease relapses.

Based on these considerations, it can be possible that OCR exerts an additional beneficial effect in MS therapy by modulating VEGF content.

With this project, we aim to explore the effects of OCR on intracellular signaling pathways by assessing VEGF expression in Peripheral Blood Mononuclear Cells (PBMCs) of RMS patients at the beginning of OCR therapy, as well as at 6 and 12 months of ongoing treatment.

In particular, ther purpose of the study is to focus on the pro-angiogenic VEGF-A 165, which seems the isoform mainly involved as mediator of inflammation and cellular immunity.

Further, the PKCβ/HuR cascade will be investigated in the same conditions. Secondly, disease activity during OCR treatment will be examined at every step, and also compared with VEGF and PKC levels.

The results will also possibly demonstrate a necessity of further determining the extent and significance of intracellular effects of anti-CD20 therapy in MS.

This study is an observational (phase 4) , longitudinal, monocenter and single arm study, in patients with RMS who are newly prescribed with OCR as per clinical practice.

The study consists of the following visits as per clinical practice:

• Baseline/start (T0): informed consent signature, inclusion/exclusion criteria verification, demographical characteristics, clinical medical history recording, concomitant therapies, neurological history recording (MS history), number of relapses from MS onset, neurological examination, the Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Score (MSSS), blood sample, ocrelizumab administration.

• T6: (after 6 months of OCR treatment) adverse events (including relapses), neurological examination, therapies changes, EDSS, MSSS, blood sample, ocrelizumab administration.

• T12 (after 12 months* of OCR treatment), adverse events (including relapses), neurological examination, therapies changes, EDSS, MSSS, blood sample, ocrelizumab administration.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 21
• Est. completion date: July 31, 2024
• Est. primary completion date: July 31, 2024
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion criteria

• The participant must have a previous diagnosis of RMS in accordance with the 2017 revised McDonald criteria

• The participant must have been newly prescribed to OCR treatment according to clinical practice

• Absence of high dose of steroid treatment for at least 4 weeks

• The participant must be capable of giving signed informed consent.

Exclusion criteria

• Clinical MS relapse within four-week period prior to inclusion

• Pregnant or nursing (lactating) women.

• Chronic disease of the immune system, other than MS

• Active systemic bacterial, viral or fungal infections

• Allergy to OCR

• Already included in other interventional trials

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis Relapse
• Sclerosis

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS National Neurological Institute "C. Mondino" Foundation

References & Publications (13)

Amadio M, Bucolo C, Leggio GM, Drago F, Govoni S, Pascale A. The PKCbeta/HuR/VEGF pathway in diabetic retinopathy. Biochem Pharmacol. 2010 Oct 15;80(8):1230-7. doi: 10.1016/j.bcp.2010.06.033. Epub 2010 Jul 1. — View Citation

Di Girolamo F, D'Amato A, Lante I, Signore F, Muraca M, Putignani L. Farm animal serum proteomics and impact on human health. Int J Mol Sci. 2014 Sep 1;15(9):15396-411. doi: 10.3390/ijms150915396. Review. — View Citation

Girolamo F, Coppola C, Ribatti D, Trojano M. Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol Commun. 2014 Jul 22;2:84. doi: 10.1186/s40478-014-0084-z. Review. — View Citation

Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234. doi: 10.1056/NEJMoa1601277. Epub 2016 Dec 21. — View Citation

Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, Moore CS, Michel L, Althekair F, Rajasekharan S, Gommerman JL, Prat A, Fillatreau S, Bar-Or A; Canadian B cells in MS Team. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med. 2015 Oct 21;7(310):310ra166. doi: 10.1126/scitranslmed.aab4176. — View Citation

Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS; ORATORIO Clinical Investigators. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21. — View Citation

Moran EP, Wang Z, Chen J, Sapieha P, Smith LE, Ma JX. Neurovascular cross talk in diabetic retinopathy: Pathophysiological roles and therapeutic implications. Am J Physiol Heart Circ Physiol. 2016 Sep 1;311(3):H738-49. doi: 10.1152/ajpheart.00005.2016. Epub 2016 Jul 29. Review. — View Citation

Pascale A, Govoni S. The complex world of post-transcriptional mechanisms: is their deregulation a common link for diseases? Focus on ELAV-like RNA-binding proteins. Cell Mol Life Sci. 2012 Feb;69(4):501-17. doi: 10.1007/s00018-011-0810-7. Epub 2011 Sep 10. Review. — View Citation

Riley JK, Sliwkowski MX. CD20: a gene in search of a function. Semin Oncol. 2000 Dec;27(6 Suppl 12):17-24. Review. — View Citation

Roscoe WA, Welsh ME, Carter DE, Karlik SJ. VEGF and angiogenesis in acute and chronic MOG((35-55)) peptide induced EAE. J Neuroimmunol. 2009 Apr 30;209(1-2):6-15. doi: 10.1016/j.jneuroim.2009.01.009. Epub 2009 Feb 23. — View Citation

Roxburgh RH, Seaman SR, Masterman T, Hensiek AE, Sawcer SJ, Vukusic S, Achiti I, Confavreux C, Coustans M, le Page E, Edan G, McDonnell GV, Hawkins S, Trojano M, Liguori M, Cocco E, Marrosu MG, Tesser F, Leone MA, Weber A, Zipp F, Miterski B, Epplen JT, Oturai A, Sørensen PS, Celius EG, Lara NT, Montalban X, Villoslada P, Silva AM, Marta M, Leite I, Dubois B, Rubio J, Butzkueven H, Kilpatrick T, Mycko MP, Selmaj KW, Rio ME, Sá M, Salemi G, Savettieri G, Hillert J, Compston DA. Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity. Neurology. 2005 Apr 12;64(7):1144-51. — View Citation

Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene. 2003 Oct 20;22(47):7359-68. Review. — View Citation

Theoharides TC, Konstantinidou AD. Corticotropin-releasing hormone and the blood-brain-barrier. Front Biosci. 2007 Jan 1;12:1615-28. Review. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	VEGF protein levels	To evaluate the expression of VEGF protein in PBMCs from patients with RMS	Month 12 versus baseline (T0)
Secondary	VEGF protein levels	To evaluate the expression of VEGF protein in PBMCs from patients with RMS before and after OCR treatment.	Month 6 versus baseline (T0)
Secondary	VEGF mRNA levels	To evaluate the expression of VEGF mRNA in PBMCs from patients with RMS before and after OCR treatment	Change from baseline (T0) to Month 6 and Month 12
Secondary	PKCß protein levels	To evaluate the expression of PKCß protein in PBMCs from patients with RMS before and after OCR treatment	Change from baseline (T0) to Month 6 and Month 12
Secondary	PKCß mRNA levels	To evaluate the expression of PKCß mRNA in PBMCs from patients with RMS before and after OCR treatment	Change from baseline (T0) to Month 6 and Month 12
Secondary	Expanded Disability Status Scale (EDSS)	To evaluate whether the expression of VEGF and PKCß affects MS severity before and after OCR treatment.; The Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability.	Change from baseline (T0) to Month 6 and Month 12
Secondary	Multiple Sclerosis Severity Score (MSSS)	To evaluate whether the expression of VEGF and PKCß affects MS severity before and after OCR treatment.; The Multiple Sclerosis Severity Score (MSSS) relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations.	Change from baseline (T0) to Month 6 and Month 12