Trial hints at improved safety for novel psoriasis drug
ISA247, a novel calcineurin inhibitor, is safe and effective in the
treatment of patients with moderate to severe psoriasis and may have
an improved safety profile compared with ciclosporin, according to the
authors of a phase III study published in The Lancet (2008;371:1337).
However,
an editorial warns that the two drugs need to be compared directly
before conclusions can be drawn.
ISA247 differs from ciclosporin by a chemical modification of the
functional group of the aminoacid-1 residue (see Panel below).
ISA247 and ciclosporin
The chemical modification of ISA247 means that it
binds more tightly to calcineurin than does ciclosporin, leading
to greater inhibition.
In addition, the metabolism of ISA247 has
been shifted away from aminoacid-1, resulting in faster elimination
of metabolites
and
a lower drug and metabolite load after administration, leading
to improved pharmacokinetic and pharmacodynamic predictability,
say the researchers. |
Tracy Hebden/Dreamstime.com
Plaque psoriasis improved with ISA247 |
The researchers conducted a study of 451 patients with
plaque psoriasis involving at least 10 per cent of the body surface area.
Participants
were randomised to receive placebo or ISA247 at 0.2mg/kg, 0.3mg/kg or
0.4mg/kg orally twice daily for 12 weeks. The primary endpoint was a
75 per cent reduction in the psoriasis area and severity index (PASI75)
score at week 12.
PASI75 scores were achieved in 16 per cent of the 0.2mg/kg group (95
per cent confidence interval 9–24), 25 per cent of the 0.3mg/kg
group (17–24; P=0.0085), and 47 per cent of the 0.4mg/kg group
(27–57; P<0.0001) compared with 4 per cent of the placebo group
(0–8).
Adverse events were reported by 368 (82 per cent) of 451 patients, with
headache,
nasopharyngitis and upper respiratory tract infections the most frequent.
Mild to moderate reductions in glomerular filtration rate were seen in
eight (2 per cent) patients — one in the ISA247 0.3mg/kg group
and seven in the ISA247 0.4mg/kg group.
This contrasts with the 10–27 per cent of patients who developed
30 per cent or more reductions in renal function when given ciclosporin
in a previous study, say the researchers.
“Pharmacokinetic data show a strong correlation between response and drug
concentrations, raising the potential for precise titration of dosing
in clinical practice,” say the researchers. They add that ISA247
could therefore provide effective immunosuppression without many of the
dose-limiting side effects associated with other calcineurin inhibitors.
However, the author of an accompanying editorial (ibid, p1311) says that
the claim that ISA247 is safer than ciclosporin should be viewed cautiously
because it is based on external comparisons. |
The
Pharmaceutical Journal
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