Mechanism Of Action
Crofelemer is an inhibitor of both the cyclic adenosine monophosphate
(cAMP)-stimulated cystic fibrosis transmembrane conductance regulator (CFTR)
chloride ion (ClÂ¯) channel, and the calciumactivated ClÂ¯ channels (CaCC) at the
luminal membrane of enterocytes. The CFTR ClÂ¯ channel and CaCC regulate ClÂ¯ and
fluid secretion by intestinal epithelial cells. Crofelemer acts by blocking ClÂ¯
secretion and accompanying high volume water loss in diarrhea, normalizing the
flow of ClÂ¯ and water in the GI tract.
Consistent with the mechanism of action of crofelemer
(i.e., inhibition of CFTR and CaCC in the GI lumen), data suggest stool
chloride concentrations decreased in patients treated with FULYZAQ (500 mg four
times daily) (n=25) for four days relative to placebo (n=24); stool chloride concentrations
decreased in both African American patients treated with FULYZAQ (n=3) relative
to placebo (n=5) and non-African American patients treated with FULYZAQ (n=22)
relative to placebo (n=19).
At a dose 10 times the maximum recommended dose,
crofelemer does not prolong the QTc interval to any clinically relevant extent.
The absorption of crofelemer is minimal following oral
dosing in healthy adults and HIV–positive patients and concentrations of crofelemer
in plasma are below the level of quantitation (50 ng/mL). Therefore, standard
pharmacokinetic parameters such as area under the curve, maximum concentration,
and half-life cannot be estimated.
The distribution of crofelemer has not been determined.
No metabolites of crofelemer have been identified in
healthy subjects or patients in clinical trials.
The elimination route has not been identified in humans.
Administration of crofelemer with a high-fat meal was not
associated with an increase in systemic exposure of crofelemer in healthy volunteers.
In the clinical trial, a single 500 mg dose of crofelemer was administered
one-half hour before the morning and evening meals. Therefore, crofelemer may
be administered with or without a meal.
Results of a crossover study in healthy volunteers showed
crofelemer 500 mg administered four times daily for five days had no effect on
the exposure of zidovudine and nelfinavir when administered as a single dose. A
20% decrease in lamivudine exposure was also observed in the same study but was
not considered to be clinically important.
The efficacy of FULYZAQ 125 mg delayed-release tablets
twice daily was evaluated in a randomized, double-blind, placebo-controlled (one
month) and placebo-free (five month), multi-center study. The study enrolled
374 HIV-positive patients on stable anti-retroviral therapy (ART) with a
history of diarrhea for one month or more. Diarrhea was defined as either
persistently loose stools despite regular use of anti-diarrheal medication
(ADM) (e.g., loperamide, diphenoxylate, and bismuth subsalicylate) or one or
more watery bowel movements per day without regular ADM use.
Patients were excluded if they had a positive
gastrointestinal (GI) biopsy, GI culture, or stool test for multiple bacteria
(Salmonella, Shigella, Campylobacter, Yersinia, Mycobacterium), bacterial toxin
(Clostridium difficile), ova and parasites (Giardia, Entamoeba, Isospora,
Cyclospora, Cryptosporidium, Microsporidium), or viruses (Cytomegalovirus). Patients
were also excluded if they had a history of ulcerative colitis, Crohn's
disease, celiac sprue (gluten-enteropathy), chronic pancreatitis, malabsorption,
or any other GI disease associated with diarrhea.
The study had a two-stage adaptive design. In both
stages, patients received placebo for 10 days (screening period) followed by randomization
to crofelemer or placebo for 31 days of treatment (doubleblind period). Only
patients with 1 or more watery bowel movements per day on at least 5 of the
last 7 days in the screening period were randomized to the double-blind period.
Each stage enrolled patients separately; the dose for the second stage was
selected based on an interim analysis of data from the first stage. In the
first stage, patients were randomized 1:1:1:1 to one of three crofelemer dose
regimens (125, 250, or 500 mg twice daily) or placebo. In the second stage,
patients were randomized 1:1 to crofelemer 125 mg twice daily or placebo. The efficacy
analysis was based on results from the double-blind portion of both stages.
Each study stage also had a five month period
(placebo-free period) that followed the double-blind period. Patients treated
with crofelemer continued the same dose in the placebo-free period. In the first
stage, patients that received placebo were re-randomized 1:1:1 to one of the
three crofelemer dose regimens (125, 250, or 500 mg twice daily) in the
placebo-free period. In the second stage, patients that received placebo were
treated with crofelemer 125 mg twice daily in the placebo-free period.
The median time since diagnosis of HIV was 12 years. The percentage
of patients with a CD4 cell count of less than 404 was 39%. The percentage of
patients with a HIV viral load greater than or equal to 1000, 400 to 999, and
less than 400 HIV copies/mL was 7%, 3%, and 9%, respectively; the remainder had
a viral load that was not detectable. The median time since diarrhea started
was 4 years. The median number of daily watery bowel movements was 2.5 per day.
Most patients were male (85%). The percentage of patients
that were Caucasian was 46%; the percentage of patients that were African- American
was 32%. The median age was 45 years with a range of 21 to 68 years.
In the double-blind period of the study, 136 patients
received crofelemer 125 mg twice daily, 54 patients received 250 mg twice
daily, 47 patients received 500 mg twice daily, and 138 patients received placebo.
The percentages of patients that completed the double-blind period were 92%,
100%, 85%, and 94% in the 125 mg, 250 mg, 500 mg, and placebo arms,
Most patients received concomitant protease inhibitors
(PI) during the double-blind period (Table 2). The most frequently used ARTs in
each group were tenofovir/emtricitabine, ritonavir, and lopinavir/ritonavir.
Table 2: Concomitant ART Use in the Double-Blind
||125 mg BID
(N = 136) n (%)
|250 mg BID
(N = 54) n (%)
|500 mg BID
(N = 46) n (%)
N = 138 n (%)
|Efavirenz/ Tenofovir/ Emtricitabine
|Tenofovir disoproxil fumarate
|Abacavir w/ lamivudine
|Zidovudine w/ lamivudine
|Abbreviations: ART = antiretroviral therapy; PI =
Protease Inhibitor; BID = twice daily.
The primary efficacy endpoint was the proportion of
patients with a clinical response, defined as less than or equal to 2 watery
bowel movements per week during at least 2 of the 4 weeks of the placebo-controlled
phase. Patients who received concomitant ADMs or opiates were counted as
A significantly larger proportion of patients in the
crofelemer 125 mg twice daily group experienced clinical response compared with
patients in the placebo group (17.6% vs. 8.0%, 1–sided p < 0.01).
In the randomized clinical study, examination of duration
of diarrhea, baseline number of daily watery bowel movements, use of protease
inhibitors, CD4 cell count and age subgroups did not identify differences in
the consistency of the crofelemer treatment effect among these subgroups. There
were too few female subjects and subjects with an HIV viral load > 400
copies/mL to adequately assess differences in effects in these populations.
Among race subgroups, there were no differences in the consistency of the
crofelemer treatment effect except for the subgroup of African-Americans;
crofelemer was less effective in African-Americans than non-African-Americans.
Although the CD4 cell count and HIV viral load did not
appear to change over the one month placebo-controlled period, the clinical significance
of this finding is unknown because of the short duration of the
Of the 24 clinical responders to crofelemer (125 mg twice
daily), 22 entered the placebo-free period; 16 were responding at the end of month
3, and 14 were responding at the end of month 5.