Biotechnology R. Mehrotra
Multiple Sclerosis - Some thoughts on 3rd Laquinimod PIII, More of a FINALE than a CONCERTO
Yesterday Teva and Active Biotech announced the initiation of a 3rd oral laquinimod PIII study under a SPA. The new
disability focused trial is aptly named CONCERTO, following on from the completed ALLEGRO and BRAVO PIII studies. In
the unlikely event that a fourth trial is started, we suggest it gets called FINALE. Our initial thoughts are that this study is
actually a subtly important and interesting development for the MS space:
Relapse vs. Disability-unearthing an age-old debate. Steeping back from the minutia of the trial for one moment, we remind
ourselves that the ultimate goal of physicians and patients in treating MS is the prevention of long-term disability. The
evolution of relapse rates/counts as the principal primary endpoint in the majority of clinical studies conducted over the last
two decades is a reflection of a focus on relapsing/remitting MS development for the ABCRs in the early 90s. Statistically
significant disability endpoints in these first pivotal MS studies (typically 250-400 patients) were harder to achieve in 2-year
time frames. Indeed, to this day, only Rebif and Avonex from the 1st-gen ABCR class have delayed progression claims on
their labels. Using an EDSS primary endpoint in PIII is NOT that unusual. Avonex's MS1 pivotal trial and two of three
Betaseron pivotal trials used a dual EDSS primary (time-to-progression & percentage progressed) while Tysabri's AFFIRM
trial used time-to-progression. More recently Lemtrada's CARE-MS1 and -MS2 studies used a reduction in EDSS
progression & annualized relapse rate reduction as co-primary endpoints. Enough of the author's gray-haired stories...
The CONCERTO trial has some important subtleties. Recall, the results of the previous PIII ALLEGRO and BRAVO trials
showed good EDSS but poor RR reduction. Hence, it is understandable why laquinimod's development is now focused on
disability endpoints (let's leave the debate of a putative Copaxone combination trial for another time). We note some
interesting points within the relatively short press release: 1) two doses in CONCERTO, 0.6mg and 1.2mg;
ALLEGRO/BRAVO used 0.6mg and PII studies used 0.1 to 0.6mg , 2) 1,800 patients vs. 1,000/1,200 in
ALLEGRO/BRAVO-understandable reflecting multiple doses and EDSS endpoint, 3) "For up to 24
months"...hmmm...probably reflecting a time to EDSS progression endpoint, 4) the (not-so) specific primary endpoint is
described as "disability progression as measured by EDSS"; we assume CONCERTO will use time-to-progression on
EDSS (secondary endpoint in ALLEGRO/BRAVO), and 5) no mention of secondary endpoints were given; we assume they
will include ARR (another bite at the cherry!) and MRI data. So as a final(e) comment...look a whole note on MS without the
word NIMO or a 3 buckets comment! |
