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Psoriasis treatment is about
to enter a new era - that of biological therapy. This was
the message delivered to dermatologists at the 60th Annual
Meeting of the American Academy of Dermatology, held in
New Orleans in February 2002.
Outside of the labs, these
new treatments have been the focus of much investor and
analyst interest, and some company fortunes have fluctuated
with their successes and failures. Genentech and Xoma's
product faces a delay in filing, monoclonal antibodies from
both Abgenix and Protein Design Labs have failed in psoriasis,
and the FDA advisory panel opinion on Biogen's Amevive
has generated many column inches: Biogen is seen to be reliant
on Amevive to bolster growth now its major product, Avonex
for multiple sclerosis, faces
increased competition in the US.
The 'Holy Grail' of dermatology
Craig Elmets of the University
of Alabama, introducing the symposium on psoriasis at the
AAD meeting, described the hunt for a successful psoriasis
treatment as a search for the "Holy Grail of dermatology".
It was stressed that current
therapeutic options
available for moderate-to-severe
psoriasis have limited efficacy due to a variety of factors,
including:
- short duration of efficacy
- inconvenient administration
schedules
- unacceptable toxicity profiles
- an adverse impact on quality
of life
- lack of patients’ knowledge
of the disease and expectations for successful treatment
- non-compliance - the most
frequent reason for treatment failure.
New developments in psoriasis
discussed at the AAD meeting included:
- topical tacrolimus (Protopic)
- an immunomodulator cream currently marketed by Fujisawa
for the treatment of eczema - as a potential psoriasis
therapy
- use of new vehicles, such
as foam, for the delivery of corticosteroids
- development of topical and
systemic retinoids for use in combination with radiation
therapy or topical immunomodulators
- improvements in phototherapy
- use of excimer laser treatment
A new treatment paradigm
The newest and most exciting
developments in psoriasis are the ‘biologic therapies’ according
to Alice Gottlieb of the University of Medicine and Dentistry
of New Jersey, who described them as "a new paradigm for
treatment". These therapies have the potential to provide
a safe and effective treatment for all psoriasis sufferers,
especially those with moderate-to-severe psoriasis, Gottlieb
believes.
Advances in studies of the
immunological basis of psoriasis, combined with progress
in genetics, microbiology and bioengineering have resulted
in a shift in therapeutic focus towards agents that interfere
with the psoriatic disease process at the cellular level.
Molecules that interfere with important co-stimulatory signals
involved with T-cell activation (for example Xanelim
and Amevive), and monoclonal antibodies targeted against
pro-inflammatory cytokines (such as Remicade) have
been developed, all of which interrupt the disease pathway.
All biologic therapies are
parenteral, delivered by subcutaneous or intramuscular injection,
usually weekly or bi-weekly. This mode of treatment may
be more acceptable to patients than current twice-daily
application of cosmetically unacceptable creams and ointments,
and could thus improve compliance. Analysts believe the
annual market could be worth $2 billion.
Some promising results...
According to IMS' LifeCycle R&Dfocus,
the new biologics are showing promise.
Biologic
psoriasis therapies
|
Trade
name
|
Generic
name
|
Phase
(for psoriasis)
|
Company
|
|
Amevive
|
alefacept
|
Filed
|
Biogen
|
|
Xanelim
|
efalizumab
|
III
|
Genentech/Xoma
|
|
Enbrel
|
etanercept
|
II/III
|
Immunex/Wyeth
|
|
Remicade
|
infliximab
|
II
|
Centocor (J&J)
|
Source: IMS LifeCycle R&Dfocus
Amevive (alefacept),
from Biogen, is a recombinant human fusion protein that
binds to the T-cell CD2 receptor.
- in clinical trials a statistically
significant number of patients achieved clear or almost
clear endpoints
- long duration of remission
- the median time to re-treatment was 10 months, with
some patients maintaining remission for over 18 months
- importantly, patients receiving
further courses of treatment continued to respond,
and duration of remission remained long.
Amevive was reviewed by an
FDA advisory panel in May 2002 - a high profile meeting,
the verdict of which was awaited by the entire biotech community
after a series of product setbacks. The committee decided
8-2 that Amevive was effective, with its benefits outweighing
the possible risks: Amevive has been linked to the development
of infections and lymphoma due to its suppression of T-cell
activity. Biogen says T-cell levels are higher to begin
with in many psoriasis patients, and that there was no difference
in infection rates between those given Amevive or a placebo.
Some biotech experts worried that as psoriasis is a chronic,
non-life-threatening disease, a cautious FDA was likely
to set the bar high for any possible adverse effects - the
panel suggested close monitoring of patients, but Amevive
is certainly less toxic than some of the traditional psoriasis
treatments. A final FDA decision is expected by August 2002.
Xanelim (efalizumab),
developed by Xoma and Genentech, is a humanised
monoclonal IgG antibody that binds to CD11a, the alpha chain
of lymphocyte-function associated antigen-1 (LFA-1).
- it appears very effective
and higher treatment success rates are seen with longer
treatments
- this has led to comparisons
with insulin for diabetes treatment, in that long-term
treatment may be the key to efalizumab therapy to
maintain remissions
- the agent can also be administered
by patients at home with weekly subcutaneous injections.
In April 2002, Genentech and
Xoma announced that a pharmacokinetic study on Xanelim had
revealed that materials produced by the two different companies
were not comparable. Xoma has produced the drug for trials,
while Genentech would be responsible for manufacturing after
approval. The two companies were discussing next steps with
the FDA, but the news means the BLA filing will be delayed
past summer 2002 - leading to a 42% drop in Xoma's share
price.
Enbrel (etanercept) is
a soluble human tumour-necrosis factor (TNF)-alpha receptor,
widely marketed by Immunex and Wyeth for rheumatoid
arthritis. Early in
2002, it also received FDA approval for psoriatic arthritis.
Phase II/III trials are continuing in psoriasis. Enbrel
is associated with a higher risk of infection, particularly
upper respiratory tract infections, sinusitis and tuberculosis.
- it is administered by patients
via subcutaneous injection
- in a phase II trial, 58%
of patients showed at least 50% improvement in Psoriasis
Area Severity Index (PASI) scores after 36 weeks of treatments,
and 37% of these showed a 75% improvement.
Remicade (infliximab),
developed by Johnson & Johnson's Centocor subsidiary,
is a chimaeric humanised monoclonal antibody targeting the
TNF-alpha receptor. It is already marketed (by Schering-Plough
outside the US) for Crohn's disease and rheumatoid arthritis.
- In a phase II trial in psoriasis
patients, 80% achieved 75% improvements in PASI scores,
and remissions lasted for several months in many
patients.
...and some failures
Not all the biological therapies
have made it to late-stage clinical trials. In May 2002,
Abgenix announced that its anti-interleukin-8 monoclonal
antibody, ABX-IL8, did not result in a significant
improvement in PASI scores in a Phase IIb trial, and development
was discontinued. In March 2002, Protein Design Labs said
Zenapax (daclizumab), which is marketed by Roche
for the prevention of kidney transplant rejection, did not
significantly prolong remission in a Phase II trial for
psoriasis, particularly in patients with more severe disease.
PDL said it would therefore not pursue the development of
Zenapax as a maintenance agent in psoriasis following treatment
with other agents, and that it would consider its options
for other psoriasis indications. The monoclonal antibody
targets the interleukin-2 (CD25) receptor.
A new era?
Results for the biologic agents
in clinical trials conducted so far indicate that they offer
a long remission time. Improvements effected by Amevive
treatment lasted up to 18 months. All treatments appear
to be safe and well-tolerated, with typical adverse events
of injection site reactions and mild infusion-related adverse
effects. These are much milder than the kidney and liver
toxicities associated with older drugs such as cyclosporine
and methotrexate. The biologic therapies, when available,
will offer an exciting new option in the treatment of psoriasis.
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