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 17th
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:
[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
.
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