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Linzess (Linaclotide) - Description and Clinical Pharmacology

 
 



DESCRIPTION

LINZESS (linaclotide) is a guanylate cyclase-C agonist. Linaclotide is a 14-amino acid peptide with the following chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide).

The molecular formula of linaclotide is C59H79N15O21S6 and its molecular weight is 1526.8. The amino acid sequence for linaclotide is shown below:

Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and aqueous sodium chloride (0.9%). LINZESS contains linaclotide-coated beads in hard gelatin capsules. LINZESS is available as 145 mcg and 290 mcg capsules for oral administration.

The inactive ingredients of LINZESS capsules include: calcium chloride dihydrate, L-leucine, hypromellose, microcrystalline cellulose, gelatin, and titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. The linaclotide-induced reduction in visceral pain in animals is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves.

Pharmacodynamics

Although the pharmacologic effects of LINZESS in humans have not been fully evaluated, in clinical studies, LINZESS has been shown to change stool consistency as measured by the Bristol Stool Form Scale (BSFS) and increase stool frequency.

Pharmacokinetics

Absorption

LINZESS is minimally absorbed with low systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 145 mcg or 290 mcg were administered. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t˝) cannot be calculated.

Distribution

Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues.

Metabolism

Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.

Elimination

Active peptide recovery in the stool samples of fed and fasted subjects following the daily administration of 290 mcg of LINZESS for seven days averaged about 5% (fasted) and about 3% (fed) and virtually all as the active metabolite.

Food Effect

In a cross-over study, 18 healthy subjects were given LINZESS 290 mcg for 7 days both in the non-fed and fed state. Neither linaclotide nor its active metabolite was detected in the plasma. Taking LINZESS immediately after the high fat breakfast resulted in looser stools and a higher stool frequency compared with taking it in the fasted state [see Dosage and Administration (2.1, 2.2)]. In clinical trials, LINZESS was administered on an empty stomach, at least 30 minutes before breakfast.

Specific Populations

Age and Gender

Clinical studies to determine the impact of age and gender on the pharmacokinetics of LINZESS have not been conducted. See Use in Specific Populations for information regarding patients aged 65 years and older.

Hepatic Impairment

LINZESS has not been specifically studied in patients who have hepatic impairment. Hepatic impairment is not expected to affect the metabolism or clearance of the parent drug or its metabolite because linaclotide is metabolized within the gastrointestinal tract [see Use in Specific Populations].

Renal Impairment

LINZESS has not been specifically studied in patients who have renal impairment. Renal impairment is not expected to affect clearance of the parent drug or its metabolite because linaclotide has low systemic availability following oral administration and is metabolized within the gastrointestinal tract [see Use in Specific Populations ].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenesis

In 2-year carcinogenicity studies, linaclotide was not tumorigenic in rats at doses up to 3500 mcg/kg/day or in mice at doses up to 6000 mcg/kg/day. The maximum recommended human dose is approximately 5 mcg/kg/day based on a 60-kg bodyweight. Limited systemic exposure to linaclotide was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure.

Mutagenesis

Linaclotide was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay or in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes.

Impairment of Fertility

Linaclotide had no effect on fertility or reproductive function in male and female rats at oral doses of up to 100,000 mcg/kg/day.

Animal Toxicology and/or Pharmacology

Linaclotide caused deaths in two separate toxicology studies in juvenile mice. The mechanism for these deaths is unknown [see Contraindications and Warnings and Precautions].

Linaclotide caused deaths at 10 mcg/kg/day in neonatal mice after oral administration of 1 or 2 daily doses, starting on post partum day 7. Deaths were also observed in juvenile mice after a single oral administration on post partum day 14 (100 mcg/kg) and post partum day 21 (600 mcg/kg). The deaths were identified in mice with ages approximately equivalent to human infants and children less than 2 years of age. There were no deaths in the control groups. There are currently no data for mice between ages of 21 days and 6 weeks. Linaclotide did not cause death in a study in older juvenile mice age 6 weeks (approximately equivalent to humans age 12 to 17 years) at a dose of 20,000 mcg/kg/day for 28 days. Linaclotide did not cause death in adult mice, rats, rabbits and monkeys at dose levels up to 5,000 mcg/kg/day. The maximum recommended dose in adults is approximately 5 mcg/kg/day, based on a 60-kg body weight. Animal and human doses of linaclotide should not be compared directly for evaluating relative exposure [see Nonclinical Toxicology].

CLINICAL STUDIES

Irritable Bowel Syndrome with Constipation (IBS-C)

The efficacy of LINZESS for the management of symptoms of IBS-C was established in two double-blind, placebo-controlled, randomized, multicenter trials in adult patients (Trials 1 and 2). A total of 800 patients in Trial 1 and 804 patients in Trial 2 [overall mean age of 44 years (range 18 - 87 years with 5% at least 65 years of age), 90% female, 77% white, 19% black, and 12% Hispanic] received treatment with LINZESS 290 mcg or placebo once daily and were evaluated for efficacy. All patients met Rome II criteria for IBS and were required, during the 2-week baseline period, to meet the following criteria:

  • a mean abdominal pain score of at least 3 on a 0-to-10-point numeric rating scale
  • less than 3 complete spontaneous bowel movements (CSBMs) per week [a CSBM is a spontaneous bowel movement (SBM) that is associated with a sense of complete evacuation; a SBM is a bowel movement occurring in the absence of laxative use], and
  • less than or equal to 5 SBMs per week.

The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat IBS-C or chronic constipation.

Efficacy of LINZESS was assessed using overall responder analyses and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries.

The 4 primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment. For the 9 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain, at least 3 CSBMs and an increase of at least 1 CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the 2 components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint.

For the 6 out of 12 weeks combined primary responder endpoint, a patient had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least 1 CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment. To be considered a responder for this analysis, patients did not have to have at least 3 CSBMs per week.

The efficacy results for the 9 out of 12 weeks and the 6 out of 12 weeks responder endpoints are shown in Tables 3 and 4, respectively. In both trials, the proportion of patients who were responders to LINZESS 290 mcg was statistically significantly higher than with placebo.

Table 3: Efficacy Responder Rates in the Two Placebo-controlled IBS-C Trials: at Least 9 Out of 12 Weeks

* Primary Endpoints

Note: Analyses based on first 12 weeks of treatment for both Trials 1 and 2

CI =Confidence Interval


Trial 1 Trial 2
LINZESS
290 mcg
(N=405)
Placebo
(N=395)
Treatment Difference
[95% CI]
LINZESS
290 mcg
(N=401)
Placebo
(N=403)
Treatment Difference
[95% CI]
Combined Responder*
(Abdominal Pain and CSBM Responder)
12.1% 5.1% 7.0%
[3.2%, 10.9%]
12.7% 3.0% 9.7%
[6.1%, 13.4%]
     Abdominal Pain Responder*
      (≥ 30% Abdominal Pain Reduction)
34.3% 27.1% 7.2%
[0.9%, 13.6%]
38.9% 19.6% 19.3%
[13.2%, 25.4%]
     CSBM Responder*
      (≥ 3 CSBMs and Increase ≥1 CSBM from Baseline)
19.5% 6.3% 13.2%
[8.6%, 17.7%]
18.0% 5.0% 13.0%
[8.7%, 17.3%]
Table 4: Efficacy Responder Rates in the Two Placebo-controlled IBS-C Trials: at Least 6 Out of 12 Weeks

* Primary Endpoint, ** Secondary Endpoints

Note: Analyses based on first 12 weeks of treatment for both Trials 1 and 2

CI =Confidence Interval

Trial 1 Trial 2
LINZESS
290 mcg
(N=405)
Placebo
(N=395)
Treatment Difference
[95% CI]
LINZESS
290 mcg
(N=401)
Placebo
(N=403)
Treatment Difference
[95% CI]
Combined Responder*
(Abdominal Pain and CSBM Responder)
33.6% 21.0% 12.6%
[6.5%, 18.7%]
33.7% 13.9% 19.8%
[14.0%, 25.5%]
     Abdominal Pain Responder**
     (≥ 30% Abdominal Pain Reduction)
50.1% 37.5% 12.7%
[5.8%, 19.5%]
48.9% 34.5% 14.4%
[7.6%, 21.1%]
     CSBM Responder**
     (Increase ≥ 1 CSBM from Baseline)
48.6% 29.6% 19.0%
[12.4%, 25.7%]
47.6% 22.6% 25.1%
[18.7%, 31.4%]

In each trial, improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment periods. For change from baseline in the 11-point abdominal pain scale, LINZESS 290 mcg began to separate from placebo in the first week. Maximum effects were seen at weeks 6 - 9 and were maintained until the end of the study. The mean treatment difference from placebo at week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale). Maximum effect on CSBM frequency occurred within the first week, and for change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs per week in both trials.

During the 4-week randomized withdrawal period in Trial 1, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on LINZESS 290 mcg. In LINZESS-treated patients re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM frequency and abdominal pain levels that were similar to the levels observed in patients taking LINZESS during the treatment period.

Chronic Idiopathic Constipation (CIC)

The efficacy of LINZESS for the management of symptoms of CIC was established in two double-blind, placebo-controlled, randomized, multicenter clinical trials in adult patients (Trials 3 and 4). A total of 642 patients in Trial 3 and 630 patients in Trial 4 [overall mean age of 48 years (range 18 - 85 years with 12% at least 65 years of age), 89% female, 76% white, 22% black, 10% Hispanic] received treatment with LINZESS 145 mcg, 290 mcg, or placebo once daily and were evaluated for efficacy. All patients met modified Rome II criteria for functional constipation. Modified Rome II criteria were less than 3 Spontaneous Bowel Movements (SBMs) per week and 1 of the following symptoms for at least 12 weeks, which need not be consecutive, in the preceding 12 months:

  • Straining during greater than 25% of bowel movements
  • Lumpy or hard stools during greater than 25% of bowel movements
  • Sensation of incomplete evacuation during greater than 25% of bowel movements

Patients were also required to have less than 3 CSBMs per week and less than or equal to 6 SBMs per week during a 2-week baseline period. Patients were excluded if they met criteria for IBS-C or had fecal impaction that required emergency room treatment.

The trial designs were identical through the first 12 weeks. Trial 3 also included an additional 4-week randomized withdrawal (RW) period. During the trials, patients were allowed to continue stable doses of bulk laxatives or stool softeners but were not allowed to take laxatives, bismuth, prokinetic agents, or other drugs to treat chronic constipation.

Efficacy of LINZESS was assessed using overall responder analysis and change-from-baseline endpoints. Results for endpoints were based on information provided daily by patients in diaries.

A CSBM overall responder in the CIC trials was defined as a patient who had at least 3 CSBMs and an increase of at least 1 CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period. The CSBM responder rates are shown in Table 5. During the individual double-blind placebo-controlled trials, LINZESS 290 mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with the LINZESS 145 mcg dose. Therefore, the 145 mcg dose is the recommended dose. Only the data for the approved 145 mcg dose of LINZESS are presented in Table 5.

In Trials 3 and 4, the proportion of patients who were CSBM responders was statistically significantly greater with the LINZESS 145 mcg dose than with placebo.

Table 5: Efficacy Responder Rates in the Two Placebo-controlled CIC Trials: at Least 9 Out of 12 Weeks

*Primary Endpoint

CI=Confidence Interval

Trial 3 Trial 4
LINZESS
145 mcg
(N=217)
Placebo
(N=209)
Treatment Difference
[95% CI]
LINZESS
145 mcg
(N=213)
Placebo
(N=215)
Treatment Difference
[95% CI]
CSBM Overall Responder
(≥ 3 CSBMs and Increase ≥ 1 CSBM from Baseline)
20.3% 3.3% 16.9%
[11.0%, 22.8%]
15.5% 5.6% 9.9%
[4.2%, 15.7%]

CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period in Trial 3 and Trial 4. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and LINZESS was approximately 1.5 CSBMs.

On average, patients who received LINZESS across the 2 trials had significantly greater improvements compared with patients receiving placebo in stool frequency (CSBMs/week and SBMs/week), and stool consistency (as measured by the BSFS).

During the 4-week randomized withdrawal period in Trial 3, patients who received LINZESS during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of LINZESS taken during the treatment period. In LINZESS-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline. Patients who continued on LINZESS maintained their response to therapy over the additional 4 weeks. Patients on placebo who were allocated to LINZESS had an increase in CSBM and SBM frequency similar to the levels observed in patients taking LINZESS during the treatment period.

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