The
dearth of new drugs is one of the major challenges facing
the pharmaceutical industry, with the number of new active
substances launched dropping to a 20-year
low of just 36 in 2002.
It
is perhaps therefore not surprising that when a company
does have a promising drug, it pulls out all the stops to
promote it. Hence the publicity over products such as AstraZeneca's
Crestor (rosuvastatin), and Zetia
(ezetimibe) from Schering-Plough and Merck & Co. Abbott,
the world's 12th largest pharmaceutical company in 2002,
according to IMS
World Review, is putting its marketing muscle
behind Humira (adalimumab), a new biological
therapy for rheumatoid arthritis that received FDA approval
earlier than expected, on New Year's Eve 2002.
Abbott is so determined to make Humira a success that it
warned investors in January 2003 earnings would be affected
by the heavy promotion planned for product - and froze salaries
for six months in order to focus on Humira's launch, the
company's biggest ever.
M1C
(Specific antirheumatic agents) class sales*
US retail
market - 12 months to March 2003
*Note:
For IMS' data collection purposes, Remicade is in the L4A
immunosuppressive agent category, so its sales have been
inserted separately. Also, because of the nature of administration
of Remicade (via clinics and hospitals etc.), the retail
market is not entirely representative
Source: IMS
MIDAS Monthly
The
market for RA is a competitive one, but growing and lucrative.
Up to the launch of Humira, the biological response modifier
sector was dominated by Amgen's Enbrel
(etanercept), co-marketed by Wyeth. According to Abbott,
Enbrel held more than 94% of weekly new prescriptions in
the RA injectables market: by April 2003, Humira had captured
nearly 20% of new prescriptions, having been launched in
January.
Demand
for Enbrel had long outstripped supply, but an Amgen manufacturing
facility in Rhode Island received FDA clearance in December
2002, boosting first quarter 2003 sales of Enbrel to $274
million. For the full year 2003, Amgen predicts Enbrel sales
of $1.2-1.4 billion, up from $802 million in 2002. Merrill
Lynch analysts believe the anti-tumour necrosis factor market
will be worth $3.2 billion in 2003.
In second
place in the M1C specific antirheumatic agent class, according
to IMS, is Aventis' Arava (leflunomide),
a non-biological disease-modifying antirheumatic drug (DMARD).
Third is Kineret (anakinra), a BRM also
from Amgen, but an interleukin-1 receptor antagonist. In
fourth place, above Humira at number five in the US retail
market for the year to March 31, comes Sanofi-Synthelabo's
Plaquenil (hydroxychloroquine), another
non-biological DMARD. If included in the M1C class by IMS,
Johnson & Johnson's (Centocor) Remicade
(infliximab) would appear in fourth place; IMS classifies
it as an immunosuppressive agent (L4A), and it is also indicated
for Crohn's disease.
First
fully human antibody for RA
Humira
was the first fully human monoclonal antibody approved for
RA; humanised antibodies, as opposed to murine or chimaeric,
can reduce the development of an immune response in patients,
which can affect safety and efficacy. It was co-developed
by Cambridge Antibody Technology and BASF's Knoll unit,
acquired by Abbott in March 2001. The small UK firm saw
its chances of acquiring compatriot Oxford
GlycoSciences evaporate in March 2003 after its share
price dropped 25% when it revealed that its royalties on
Humira's sales might be lower than expected due to royalty
offset provisions; CAT is expecting its first royalties
from Abbott in October 2003.
One
of Humira's main selling points is its convenience. Like
Remicade, it is a monoclonal antibody targeting TNF, an
inflammatory mediator over-expressed in RA; Enbrel is a
fusion protein that targets TNF. Humira, however, is delivered
by subcutaneous injection every other week (self-administered),
whereas Enbrel is given twice a week; Remicade is only dosed
every eight weeks, but by infusion, requiring a trip to
a special facility. Humira has been priced at a similar
level to Enbrel, and is 25-30% less expensive than Remicade;
Medicare covers Remicade, but not Enbrel or Humira.
In the
first quarter of 2003, Humira's initial sales reached $26
million. Abbott increased its sales forecast for the full
year from $150 million to over $200 million, and many analysts
believe Humira will eventually achieve sales in excess of
$1 billion. Abbott is giving Humira away to Medicare-eligible
seniors until a Medicare drug benefit is enacted - a generous
act, but one that may also help gain market share. Abbott
has a direct-to-consumer advertising campaign for Humira
planned, and has 100-200 sales representatives concentrating
on its most important new drug. It is also developing Humira
for Crohn's, psoriasis
and psoriatic arthritis.
Safety
concerns no problem so far
Because
they work by inhibiting TNF, the biological RA agents are
associated with an increased risk of infection, including
tuberculosis. Abbott lists upper respiratory infection as
Humira's most frequent adverse event, at a rate of 17%;
Amgen puts the general infection rate with Enbrel at 35%
in placebo-controlled trials. The BRMs have also been linked
to a worsening of congestive heart failure.
In March
2003, the FDA asked an advisory panel to review the evidence
linking the TNF-blockers to an increased risk of lymphoma.
Summarising the panel's findings, the chairman stated, "There
are not enough numbers to say there's causality, but there's
enough to say there may be a signal." RA patients are
at a higher risk for lymphoma, and Amgen, J&J and Abbott
all believe the benefits of their products outweigh the
risks. In trials, however, a small percentage of treated
patients developed lymphoma, compared with none in those
patients given a placebo. All parties concurred that more
long-term data was needed, which the companies have agreed
to provide.
Newer
products on the horizon
A number
of companies are developing new biological therapies for
RA. Most advanced is Celltech's
CDP 870, a PEGylated, humanised MAb fragment
directed against TNF-alpha. This began Phase III trials
in October 2002 with partner Pharmacia; since their merger,
it now has the backing of the world's largest pharmaceutical
company, Pfizer. Launch is predicted in 2005. The PEGylation
(using Nektar's technology) of CDP 870 means it will only
need to be dosed monthly. Celltech is also developing CDP
484, a PEGylated antibody fragment against IL-1
beta, for RA, with Phase I trials scheduled for mid-2003.
Other
products in the pipeline include:
- MRA:
a Chugai/UK MRC-developed humanised MAb against
the IL-6 receptor, in global Phase II trials and licensed
to Roche
in February 2003
- eculizumab:
Alexion completed enrollment for a Phase IIb trial in
RA in January 2003 for this humanised MAb against Complement
C5
-
HuMax-IL15:
under the terms of a licensing agreement with Amgen, Genmab
is developing this human antibody against IL-15 in Phase
II trials in Europe. Approval for US Phase II trials was
received in January 2003
- Vitaxin:
a humanised MAb against alpha5beta3 (VNR) integrin in
Phase I trials for RA with MedImmune and Applied Molecular
Evolution
There
are also other types of new RA therapy in development. Industry
observers believe one of the main reasons J&J acquired
Scios in April 2003 was SCIO-469, an oral
p38 MAP kinase inhibitor in Phase II trials for RA. Similar
compounds are in development with GlaxoSmithKline, Vertex,
Sankyo and ArQule, and one analyst described p38 as "one
of the most exciting things" in current R&D; it
affects TNF-alpha, IL-1 and COX-2. Scios also has a second-generation
product, SCIO-323.
One
less competitor for Humira will be Genentech and XOMA's
Raptiva (efalizumab), a MAb against CD11a
antigens on human T-cells, licensed to Serono for Europe.
It is pending approval with the FDA for use in psoriasis,
but was discontinued from Phase II trials in RA in May 2003
due to poor efficacy. Genentech, however, is planning to
run Phase III trials with its cancer antibody Rituxan
(rituximab), co-developed with Idec, in RA following positive
Phase II results; Genentech's majority owner Roche markets
rituximab in Europe as MabThera.
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