The documentation of Workbooks.Open says:

By default, macros are enabled when opening files programmatically. Use the AutomationSecurity property to set the macro security mode used when opening files programmatically.

This works for me:

use warnings;
use strict;
use Win32::OLE ();
use Win32::OLE::Const 'Microsoft Excel';
$Win32::OLE::Warn = 3;  # die on errors

my $Excel = Win32::OLE->new('Excel.Application', 'Quit') or die "Faile
+d to open Excel";
# or to get running Excel instance: Win32::OLE->GetActiveObject('Excel
+.Application')

my $const = Win32::OLE::Const->Load('Microsoft Office '.$Excel->{Versi
+on}.' Object Library');
$Excel->{AutomationSecurity} = $const->{msoAutomationSecurityForceDisa
+ble};

$Excel->{Visible} = 1;
my $Book = $Excel->Workbooks->Open("filename.xlsm");
$Book->Activate;
# ...
$Excel->Quit;
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