Telotristat Ethyl: A Novel Therapy for Carcinoid Syndrome—Not a Panacea but a Step in the Right Direction





The development of telotristat ethyl for treatment of carcinoid syndrome represents a step in the right direction for improving the quality of life of these patients.
— Bhavana Konda, MD, MPH (left), and Manisha H. Shah, MD

The multihumoral manifestations of neuroendocrine tumors include diarrhea, cutaneous flushing, wheezing, and right-sided valvular heart disease.1 Serotonin, a biogenic amine and product of tryptophan metabolism,2 mediates several of these symptoms.3,4 Diarrhea is a cardinal and often disabling symptom that occurs in about 70% of patients with carcinoid syndrome and is primarily mediated by serotonin.5 Therefore, the latter has long been the target of various pharmacotherapies aiming at symptom control in these patients.

Available Therapies

The traditional treatment approach in patients with carcinoid syndrome has been twofold: direct inhibition of hormone hypersecretion and reduction in tumor volume, thereby reducing net hormone production. Somatostatin analogs (octreotide and lanreotide [Somatuline]) are neuroendocrine regulators that inhibit the release of bioactive hormones including serotonin6 and have been shown in pooled analyses to alleviate symptoms of diarrhea and flushing in over 70% of patients with carcinoid syndrome.7 However, long-term use of these agents is limited by tachyphylaxis, leading to loss of symptom control.8

Although peripheral serotonin receptor antagonists such as ketanserin (Sufrexal) and methysergide (Sansert) may provide gastrointestinal symptom control, they have not gained popularity in view of their nonspecific receptor antagonism and formidable side-effect profile. Cyproheptadine, another serotonin receptor blocker, is relatively better tolerated; however, its widespread use is limited by its antihistaminic properties.9,10

Healing a Deranged Metabolism

Tryptophan hydroxylation is the rate-limiting step in serotonin synthesis and is significantly altered in carcinoid syndrome. Although only 1% of tryptophan is hydroxylated in normal cells, more than 50% of the substrate is converted to serotonin and related compounds in carcinoid tumors.2 Parachlorophenylalanine was the first tryptophan hydroxylase (TPH) inhibitor shown to provide symptom control, particularly of diarrhea. However, the initial enthusiasm associated with this drug was dampened by serious toxicities, including depression, delusions, and hallucinations, likely related to central nervous system (CNS) serotonin depletion due to its permeation through the blood-brain barrier.11

This paved the way to the development and study of telotristat etiprate/LX 1606, a small-molecule peripheral TPH inhibitor that acts via its active moiety telotristat (LP-778902). As per the U.S. Food and Drug Administration guidelines, the drug is referred to as telotristat ethyl, the prodrug and neutral form of the salt telotristat etiprate. With a high molecular weight of over 700 dalton, the drug does not cross the blood-brain barrier, thus sparing patients from the side effects of intracranial serotoninergic depletion.12,13

Early-Phase Studies

Telotristat ethyl demonstrated a favorable toxicity profile while significantly reducing blood serotonin and urine 5-hydroxyindoleacetic acid (5-HIAA) levels in early-phase studies.14 The safety and efficacy of the drug in patients with carcinoid syndrome and poorly controlled diarrhea were further clarified in two separate prospective, exploratory phase II trials carried out in Europe and the United States, respectively. Patients had a significant decline in the frequency of bowel movements, and over 50% of patients had an objective decrease in urine 5-HIAA level. Adverse effects included transient abdominal discomfort, nausea, vomiting, and bloating, which resolved with continuation of therapy.15,16

TELESTAR Clinical Trial

The recent double-blind placebo-controlled multicenter international phase III TELESTAR trial,17 evaluating the safety and efficacy of telotristat ethyl in patients with carcinoid syndrome, was reported by Kulke et al and is reviewed in this issue of The ASCO Post. This trial is one of the largest placebo-controlled phase III studies conducted to date for patients with carcinoid syndrome.

A total of 135 patients with at least 4 bowel movements per day despite being on a stable dose of a somatostatin analog were treated over a 12-week period with 1 of 2 doses of telotristat ethyl (250 or 500 mg thrice daily) or placebo. Notably, over 40% of patients enrolled in the study were on above-label doses of somatostatin analogs, and just over one-third of all patients had at least 2 flushing episodes per day.

Overall, patient compliance was excellent, and telotristat ethyl reduced the frequency of bowel movements by about two per day, compared with a decrease by about one bowel movement per day with placebo. Patients with ≥ 30% reduction in bowel movement frequency for at least half of the study period were categorized as bowel movement responders. Not surprisingly, over 40% of patients receiving telotristat ethyl were bowel movement responders, with an objective decrease in mean urine 5-HIAA levels by over 40 mg/d. Interestingly, despite an increase in mean urine 5-HIAA levels by 12 mg/d in the placebo group, 20% of these patients were bowel movement responders.

As stated by the authors, it is unclear whether the benefit in the placebo arm was secondary to a higher use of breakthrough somatostatin analogs, the use of antidiarrheal agents, dietary changes, or placebo effect. Telotristat ethyl was generally well tolerated, with nausea- and depression-related side effects more commonly seen in the higher-dose telotristat ethyl group. Although definitive conclusions cannot be made, it may be reasonable to speculate that telotristat ethyl at a lower dose of 250 mg thrice daily has comparable efficacy and better tolerance than a dose of 500 mg thrice daily.17

Unanswered Questions

Although statistically significant improvement in diarrhea was noted in the 12-week treatment period, long-term durability of this outcome is as yet unknown. Although telotristat ethyl produced no significant changes in abdominal pain scores or flushing, these results should be interpreted with caution, as the majority of patients had a low abdominal pain score and fewer than two flushing episodes per day at baseline. The role of telotristat ethyl in changing the course of mesenteric fibrosis and carcinoid heart disease is of key interest and requires further study. Finally, the best sequence of therapies is an unexplored area that remains to be defined.

In summary, based on the results of this trial, telotristat ethyl may be incorporated in the treatment regimen for patients with uncontrolled diarrhea related to carcinoid syndrome who are on somatostatin analog therapy. Indeed, the development of telotristat ethyl for treatment of carcinoid syndrome represents a step in the right direction for improving the quality of life of these patients. ■

Disclosure: Drs. Konda and Shah reported no potential conflicts of interest.

References

1. Oates JA: The carcinoid syndrome. N Engl J Med 315:702-704, 1986.

2. Sjoerdsma A, Weissbach H, Udenfriend S: A clinical, physiologic and biochemical study of patients with malignant carcinoid (argentaffinoma). Am J Med 20:520-532, 1956.

3. Oates JA, Butler TC: Pharmacologic and endocrine aspects of carcinoid syndrome. Adv Pharmacol 5:109-128, 1967.

4. Maton PN: The carcinoid syndrome. JAMA 260:1602-1605, 1988.

5. Thorson A, Biorck G, Bjorkman, G, et al: Malignant carcinoid of the small intestine with metastases to the liver, valvular disease of the right side of the heart (pulmonary stenosis and tricuspid regurgitation without septal defects), peripheral vasomotor symptoms, bronchoconstriction, and an unusual type of cyanosis: A clinical and pathologic syndrome. Am Heart J 47:795-817, 1954.

6. Reichlin S: Somatostatin (second of two parts). N Engl J Med 309:1556-1563, 1983.

7. Modlin IM, Pavel M, Kidd M, et al: Review article: Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther 31:169-188, 2010.

8. Hofland LJ, Lamberts SW: The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev 24:28-47, 2003.

9. Vroom FQ, Brown RE, Dempsey H, et al: Studies on several possible antiserotonin compounds in a patient with the functioning carcinoid syndrome. Ann Intern Med 56:941-945, 1962.

10. Coupe M, Levi S, Ellis M, et al: Therapy for symptoms in the carcinoid syndrome. Q J Med 73:1021-1036, 1989.

11. Engelman K, Lovenberg W, Sjoerdsma A: Inhibition of serotonin synthesis by para-chlorophenylalanine in patients with the carcinoid syndrome. N Engl J Med 277:1103-1108, 1967.

12. Lamarca A, Barriuso J, McNamara MG, et al: Telotristat ethyl: A new option for the management of carcinoid syndrome. Expert Opin Pharmacother 17:2487-2498, 2016.

13. Margolis KG, Stevanovic K, Li Z, et al: Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut 63:928-937, 2014.

14. Lapuerta P, Zambrowicz B, Fleming D, et al: Telotristat etiprate, a novel inhibitor of serotonin synthesis for the treatment of carcinoid syndrome. Clin Invest 5:447-456, 2015.

15. Wiedenmann B, Pavel ME, Seufferlein T, et al: The effect of telotristat etiprate on clinical and biochemical responses in patients with symptomatic carcinoid syndrome: Preliminary results of an ongoing phase II, multicenter, open-label, serial-ascending dose study. 2012 ASCO Annual Meeting. Abstract e14564.

16. Pavel M, Hörsch D, Caplin M, et al: Telotristat etiprate for carcinoid syndrome: A single-arm, multicenter trial. J Clin Endocrinol Metab 100:1511-1519, 2015.

17. Kulke MH, Hörsch D, Caplin ME, et al: Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol 35:14-23, 2017.


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Telotristat Ethyl Reduces Frequency of Bowel Movements in Patients With Metastatic Neuroendocrine Tumors and Carcinoid Syndrome


Among patients with carcinoid syndrome not adequately controlled by stable-dose somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in [bowel movement] frequency and [urinary] 5-HIAA.
— Matthew ...


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