MERIT trial leaves role of
Pfizer's Celsentri unclear
With Pfizer's novel HIV treatment
Celsentri failing to demonstrate non-inferiority to Bristol-Myers Squibb's
Sustiva in the MERIT trial, the drug's chances of easily securing a first-line
use indication look rather bleak. Given this, Pfizer must now establish
whether Celsentri should be used for first-line therapy and the best context
for this use if so.
A product and a class beset by problems
Celsentri (maraviroc) received an FDA approvable letter in June 2007, with a
request for additional information (rather than further trials). This must
have been a small relief, in the context of the tribulations that the CCR5
inhibitor class as a whole, and Celsentri in particular, has experienced. New
HIV classes are in much demand, but both GlaxoSmithKline and Schering-Plough
faced major problems with their CCR5-inhibitor candidates. GlaxoSmithKline's
aplaviroc was discontinued, and malignancies continue to dodge Phase II trials
of Schering-Plough's Vicriviroc.
CCR5-inhibitors are only active in so-called R5-tropic strains of HIV,
limiting the patient population for any drug in this class. CCR5 tropic
strains are much more common in treatment-naive patients (80-85%) than in
treatment-experienced patients (50-60%), making early lines of therapy the
natural home for this drug class. Pfizer therefore undertook the MERIT trial
to evaluate Celsentri's potential to be positioned against Sustiva in
treatment-naive patients.
MERIT trial results raise more questions: further trials needed
Unfortunately for Pfizer, the results are mixed at best. The trial did provide
some promising safety data: Celsentri patients experienced fewer grade three
or four adverse events (non-AIDS cancer or events causing or prolonging
hospitalization) or class C adverse events (i.e. those severely symptomatic of
late-stage disease). These results are valuable in allaying fears over the
safety of the CCR5-inhibitor drug class. Furthermore, compliance in first-line
treatment is key, and there were fewer discontinuations in the Celsentri group
than the Sustiva group. In addition, discontinuations were more likely to be
due to efficacy than side effects and adverse events.
However, in efficacy terms, Celsentri results were less positive; while Pfizer
managed to demonstrate Celsentri's desired non-inferiority against Sustiva in
achieving fewer than 400 copies of HIV/mL, it failed to do so in suppressing
the viral load to fewer than 50 copies of HIV/mL. Accordingly, non-inferiority
could not be proven in this study, implying that Pfizer's ability to go
head-to-head with Sustiva in the battle for treatment-naive patients will be
severely handicapped. Importantly, Pfizer had failed to determine whether
treatment failures in the Celsentri group were due to reservoirs of CXCR4
reactivating once CCR5 levels fell - something that the screening tools used
would be incapable of identifying at low viral concentrations.
On a more positive note, Pfizer pre-specified two subgroups, a northern and a
southern hemisphere cohort, which provided a very interesting result that
needs to be examined further. At first glance, the northern hemisphere
patients did not appear to suffer from the reduced efficacy seen in southern
hemisphere patients. The study investigators will need to dig deeper into the
analysis of the distinction between the two groups, but Pfizer will probably
not be able to use these results without a further confirmatory Phase III
trial in a northern hemisphere population.
Avoiding efficacy comparisons with protease inhibitors
Celsentri's initial positioning as an alternative in third-line treatment
neglects the drug's ideal patient population, given that these
treatment-experienced cases are less likely to be purely CCR5 tropic.
Unfortunately, Pfizer risks comparison with protease inhibitors (PIs), which
are highly effective drugs. However, if instead used in combination with PIs
such as Boehringer Ingelheim's Aptivus (tipranavir) or Tibotec's Prezista (darunavir),
Pfizer has the opportunity to establish combinations that have potential
against other new market entrants, such as Merck & Co.'s integrase inhibitor
MK-0518, or Tibotec's TMC125.
Another alternative would be to exploit the emerging philosophy of hitting
treatment-naive patients hard and fast (i.e. as early as possible, with the
strongest possible regimens), and trialing Celsentri as an add-on to
first-line, NNRTI-based regimens. This would limit the total number of
patients to which Celsentri is exposed, but it would avoid direct first-line
competition with Sustiva.
The direct challenge: price and tolerability versus efficacy
A renewed challenge for Sustiva in treatment-naive patients would be to
compare a combination of Celsentri and Truvada (tenofovir and emtricitabine)
with Atripla (Truvada plus Sustiva). Such a trial would be a real world 'all
or nothing' test against the market leader in the US.
An alternative approach, however, would be to position Celsentri as part of a
combination regimen other than Truvada. The main potential selling point of
this option would be improved tolerability, albeit likely limited to the
northern hemisphere. The MERIT trial demonstrated higher proportions of
treatment discontinuations in the Sustiva group due to adverse events and
higher discontinuations due to lack of efficacy in the Celsentri group, but
overall, a lower discontinuation rate in the Celsentri group.
Given the importance of compliance in treatment-naive groups, this is
conceivably a realistic option, but only if combined with further advantages.
This could mean major compromise on price points.
In markets like the US, Atripla's status as a single prescription item
translates into fewer co-payments than a combination of multiple brands. To be
able to compete, Pfizer would have to reduce total patient outlays. These
already include upfront tropism testing to confirm CCR5 status. This cost of
between $1,000 and $1,500 would be absorbed over time if Celsentri was
combined with one of a number of forthcoming generic antiretrovirals.
Making the best of a bad lot
In summary, the MERIT trial has all but cut off Celsentri's easiest route to
use as a first-line treatment. As such, Pfizer's options for Celsentri are
relatively limited, and a number of less attractive alternative positioning
strategies will all require supplemental trial data if regulators, patients
and physicians are to be convinced. While the trial may have allayed safety
concerns for this drug, Pfizer needs to establish whether Celsentri's profile
is conducive to first-line therapy in the northern hemisphere, and if it is,
the best context for its use.
Related research:
Commercial Insight: HIV - Reshaping Treatment Paradigms
Commercial Insight: HIV - Change of guard
Pipeline Insight: HIV - Extending treatment options
