Mavrilimumab at the 2020 EULAR Online Meeting

Mavrilimumab has my interest for about a decade now. There have been two studies at the 2020 EULAR Online Meeting. I am suprised! My last entry here on the blog concerning mavrilimumab dates back to January 17^th 2019 under the title: „Mavrilimumab discontinued“ [1].

Mavrilimumab is a human monoclonal antibody tht targets the GMCSF [Granulocyte macrophage colony stimulating factor] receptor and alpha-chain.

G. De Luca and colleagues presented the following study [2]: “CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION”. The study is single-center, non-randomized, open-label, single active arm intervention (N=13) with comparison to “contemporaneous patients (N=26) with similar baseline characteristics”. The patients in the active arm received a non-disclosed single dose of mavrilimumab. In “results” the authors tell us: “Death occurred in 0% (n=0/13)

of mavrilimumab recipients and 27% (n=7/26) of comparison-group patients (log rank p=0.046) during the 28-day follow-up. 100% (n=13) of mavrilimumab recipients and 65% (n=17) of comparison-group patients achieved clinical improvement (p=0.018) at Day 28, with earlier improvement (median 8.0 [IQR, 5.0–11.0] days vs 18.5 [11.0–NE] days) (p<0 -="" .001="" 1.0="" 14="" 61="" 7.0="" 91="" by="" compared="" comparison="" controls="" day="" days="" faster="" febrile="" fever="" group="" had="" in="" lang="en-US" mavrilimumab="" median="" n="11/18" ne="" of="" p="0・009)." patients="" recipients.="" recipients="" resolution="" resolved="" respectively="" span="" the="" to="" versus="" vs="" was="">was well tolerated in all patients.” The authors concluded: “Patients with severe COVID-19 pneumonia and systemic hyper-inflammation who received treatment with mavrilimumab had better clinical outcomes compared to patients receiving routine care. … Randomized controlled trials are warranted to confirm our findings.”

It is unclear, how patients were chosen to get mavrilimumab. Did the “26 contemporaneous patients with similar baseline characteristics” also showed “severe COVID-19 pneumonia (as evaluated by CT scanning), hypoxia (PaO2:FiO2 ratio ≤ 300 mmHg), and systemic hyper-inflammation (increased C-reactive protein [CRP] ≥ 100 mg/mL and/or ferritin ≥ 900 μg/L, increased lactate dehydrogenase [LDH])”?

In former studies the most common adverse event of mavrilimumab had been a decrease in CO diffusing capacity. So why choose an investigational drug instead of an IL-6-inhibitor already on the market in other indications?

The study by M. C. Cid and colleagues is a cell sttudy{3]: “CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION”. The authors looked at “expression of GM-CSF and GM-CSF-Rα proteins in temporal artery biopsies (TABs) from GCA and controls (patients with suspected but not confirmed GCA and a negative TAB).” The authors concluded: “Increased GM-CSF, GM-CSF-Rα, and downstream pathway-associated protein levels in GCA biopsies were consistent with previously-observed increased transcriptome signature. Expression of genes associated with inflammatory cells was suppressed by mavrilimumab in cultured GCA arteries. These data implicate the GM-CSF pathway in GCA pathophysiology and increase confidence in rationale for targeting the GM-CSF pathway in GCA.”

Adis Insight reports a phase II trial in B-cell lymphoma (Second-line therapy or greater, Combination therapy) in the second half of 2020 (17.06.2020) and phase II trial in Giant cell arteritis in Australia, Belgium, Croatia, Estonia, Germany, Italy, Ireland, Netherlands, New Zealand, Poland, Serbia, Slovenia, Spain, USA and United Kingdom (NCT03827018) (13.03.2020) [4].

I am still not convinced that mavrilimumab will become a drug in rheumatology. Kiniksa Pharmaceuticals should clarify how comparable the patients in the COVID-19 study were and why there hasn't been a randomization.

Links and References:

[1] http://rheumatologe.blogspot.com/2019/01/mavrilimumab-discontinued.html

[2] G. De Luca1,2, G. Cavalli1,2, C. Campochiaro1,2, E. Della Torre1,2, P. Angelillo1, A. Tomelleri1,2, N. Boffini1, S. Tentori1, F. Mette1,2, P. Rovere-Querini1,2, A. Ruggeri1, T. D’aliberti1, P. Scarpelllini1, G. Landoni1,2, F. De Cobelli1,2, J. F. Paolini3, A. Zangrillo1,2, M. Tresoldi1, B. C. Trapnell4, F. Ciceri1, L. Dagna1,2. CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION. DOI: 10.1136/annrheumdis-2020-eular.6858

[3] M. C. Cid1, S. Muralidharan2, M. Corbera-Bellalta1, G. Espigol-Frigole1, J. Marco Hernandez1, A. Denuc3, R. Rios-Garces1, N. Terrades-Garcia1, J.

F. Paolini2, A. D’andrea2. CO0001 MAVRILIMUMAB IMPROVES OUTCOMES IN SEVERE COVID-19 PNEUMONIA AND SYSTEMIC HYPER-INFLAMMATION. DOI: 10.1136/annrheumdis-2020-eular.4984

[4] https://adisinsight.springer.com/drugs/800014624

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Mavrilimumab discontinued

Adisinsight updated its information on Mavrilimumab on Dec. 12^th 2018. I’ve just checked this source as I wanted to know more about the fate of Mavrilimumab after having listened to a talk by Prof. G.R. Burmester, one of the chief investigators on Mavrilimumab, last weekend.

Mavrilimumab is a human MAB for the treatment of rheumatoid arthritis. It targets the GMCSF [Granulocyte macrophage colony stimulating factor] receptor and alpha-chain. I’ve written about Mavrilimumab for the first time after the 2012 EULAR Meeting in Berlin.

I already harbored concerns about the drug: “Mavrilimumab did better than placebo, but the effect didn't last as long as the follow-up period after stopping the drug. The most common adverse events had been a decrease in CO diffusing capacity. Did any reader, who worked on studies, ever have to monitor CO diffusing capacity? As I haven't, this point leaves me a little bit uneasy.” Or: “My opinion: this doesn't seem to be the start of a success story. But still, as we need new drugs: All the best, Mavrilimumab!”

In January 2018 ME Weinblatt and colleagues published study details on: “A Randomized Phase IIb Study of Mavrilimumab and Golimumab in Rheumatoid Arthritis.” The authors concluded: “The findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA. Both regimens were well-tolerated in patients who had shown an inadequate response to DMARDs and/or other anti-TNF agents.”

In June 2017 GR Burmester and colleagues published study details on: “A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis.” The authors concluded: “Mavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential.” Oh, with persuasive therapeutic potential! We’ll look into the persuasion quickly!

What is the news on this persuasive therapeutic potential? What does Adis Insight tell us? The indication of rheumatoid arthritis is discontinued. Adis Insight: “The US FDA places a clinical hold on a submitted IND application for a phase II trial in Giant cell arteritis, as additional information has been requested regarding the delivery device to be used in the trial”.

I’m still not convinced that Mavrilimumab could be a drug to treat inflammatory rheumatic diseases, though I am in favor for new ways of action as we already have enough TNF-alpha-inhibitors or IL-6-inhibitors. Maybe GMCSF [Granulocyte macrophage colony stimulating factor] simply isn’t a good target. Let’s hope that other targets work better.

Links:

https://adisinsight.springer.com/drugs/800014624

https://rheumatologe.blogspot.com/2012/07/mavrilimumab-at-eular-2012.html

https://www.ncbi.nlm.nih.gov/pubmed/28941039

https://www.ncbi.nlm.nih.gov/pubmed/28213566

https://rheumatologe.blogspot.com/2014/06/mavrilimumab-at-eular-2014-meeting-in.html

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