KLLJ Investments opined in an article here last week that there is zero – not 0.1%, zero – probability that the Food & Drug Administration will reject Arena Pharmaceutical’s (ARNA) lorcaserin drug candidate for weight loss.
That’s disturbing. Short-term presentations of lorcaserin efficacy appear to overstate its two-year efficacy, which may exceed its longer efficacy. Therapeutic value of temporary or long-term lorcaserin treatment appears zero, nearly zero, or worse than zero.
I owned a modest amount of ARNA (in a partnership that I manage and in separately managed accounts) until I saw its two-year trial results in the New England Journal of Medicine. Now I have no position in it, though I would buy ARNA put options if they were substantially less expensive.
Preclinical trials indicated that lorcaserin must be consumed perpetually to maintain its weight loss effect.
Acute oral dosing of APD-356 [lorcaserin] significantly reduced cumulative food intake in non-deprived rats for up to 22 h[ours], although post hoc analysis attributed this observation to potent hypophagia [appetite reduction] during the first 2 hours and the absence of subsequent rebound hyperphagia.... During the 4 week withdrawal period, treated animals exhibited rebound hyperphagia and a subsequent return to control body weight.
That preclinical view accords with Figure 1.C in The New England Journal of Medicine July 2010 report. Subjects who received “Lorcaserin in yr 1, placebo in yr 2” gained a tiny amount of weight relative to subjects on placebo on average. After one year, subjects consistently on lorcaserin appeared to lose about 3.5% of body weight more than subjects on placebo overall.
After two years, that average advantage appeared to be around 2% of body weight. The weight trajectories in that NEJM Figure 1.C suggest that subjects consistently taking lorcaserin might exhibit no weight loss relative to subjects consistently taking placebo through later years.
(a) Therapeutic value of lorcaserin after one year: modest and material.
(b) Therapeutic value of lorcaserin after two years: material and minimal.
(c) Therapeutic value of lorcaserin after more years: unknown, trending toward zero.
(d) Therapeutic value of lorcaserin with discontinued use: zero.
Then, a multiple-choice question for KLLJ: which of (a) through (d) are relevant in evaluating lorcaserin for patients’ benefit?
ARNA pumpers may answer (a), because that is nearest the time over which lorcaserin demonstrated most weight loss effect relative to placebo. (Perhaps it's a coincidence that clinical trials measuring results after one year happened to report maximum efficacy near the one year mark.) And (a), like (b), is the wrong answer.
It must be the wrong answer unless we expect patients to perish soon after one or two years of treatment. (If we do, then noting any health benefits accompanying weight loss would be curious. I ignore temporary weight loss benefits that do not impact health after weight is regained, and that may be associated with depression or other detriments accompanying weight regain.) Only (c) or (d) are relevant in evaluating lorcaserin for patients’ benefit. Patients who stop taking lorcaserin after one year experience (d). Patients who stop taking lorcaserin after two years experience (d). Patients who continue taking lorcaserin experience (c). Consequently, only (c) and (d) are relevant.
Constricting our summary to the only relevant time periods:
(c) Therapeutic value of lorcaserin after two years: about average 2% more body weight loss than with placebo, trending toward zero.
(d) Therapeutic value of lorcaserin with discontinued use: worse than placebo.
Will the FDA approve perpetually disrupting serotonin receptors with unknown post-two-year side effects for that efficacy profile? Perhaps it will. That’s disturbing.
So too is the response to this simple article. Those who are long ARNA may focus mostly on facts not discussed, my motivation or anything other than facts and reasoning herein. Some may split hairs: “2% of body weight advantage? No way! It was almost 3%!” Others may trumpet a percentage of patients achieving some weight loss threshold rather than the all-important average result relative to placebo treatment, which encompasses results both better and worse than average. A precious few will constrict any comment to facts and reasoning in dispassionate prose.
 Alastair Garfield and Lora Heisler, "Pharmacological targeting of the serotonergic system for the treatment of obesity" in The Journal of Physiology 587.1 (2009) page 55.
 Steven Smith et al., “Multicenter, Placebo-Controlled Trial of Lorcaserin for Weight Management” in NEJM 363.3 (2010) page 250.
Disclosure: No position.