More Anti-Tumor Activity, Fewer Side Effects for Patients

PCS6422 Targets Colorectal and Metastatic Breast Cancer

PCS6422 (eniluracil) is a potent, irreversible inhibitor of dihydropyrimidine dehydrogenase (DPD) that is intended for use in combination with Xeloda® for the treatment of advanced gastrointestinal (GI) tumors. DPD is an enzyme that rapidly metabolizes 5-FU (a drug that is commonly used to treat multiple solid tumors) into inactive metabolites, such as α-fluoro-β-alanine (F-Bal).

The presence of F-Bal is known to decrease the antitumor activity of 5-FU and cause toxicities and adverse side effects associated with 5-FU, such as Hand-Foot Syndrome (HFS). HFS is a serious condition that affects patients’ quality of life and requires interruptions and adjustments to treatment dosage or even the discontinuation of therapy, thus compromising the efficiency of their anti-tumor treatment.

Xeloda® Combination Therapy

Xeloda® (capecitabine) is an oral prodrug of 5-FU that is used as first-line therapy for metastatic colorectal and breast cancer. However, the use of capecitabine is limited by adverse side effects such as HFS, which develops in up to 60 percent of patients.

Preclinical studies using human breast, pancreatic, and colorectal cancer cells show that the combination of PCS6422 and capecitabine can improve the antitumor activity of capecitabine thanks to PCS6422’s ability to inhibit DPD, reducing the 5-FU side effects related to F-Bal and significantly lowering the dose of capecitabine that’s required to be effective.

Other DPD enzyme inhibitors

Other DPD enzyme inhibitors that act as competitive reversible inhibitors have been approved only for use outside the U.S. These agents, however, must be administered simultaneously with 5-FU or capecitabine to inhibit the breakdown of 5-FU by DPD and improve the efficacy and safety profile of 5-FU. Conversely, there is evidence that suggests administering DPD inhibitors directly with 5-FU may also decrease the antitumor activity of 5-FU.

As an irreversible inactivator of DPD, PCS6422 can safely be administered a day prior to chemotherapy. One dose of PCS6422 irreversibly blocks DPD activity for up to two weeks, resulting in higher potency of 5-FU and better tumor response along with a decrease in F-Bal quantities.

License Agreement

We entered into a license agreement with Elion Oncology, Inc. on August 23, 2020. Under the Elion License Agreement, we received an exclusive contingent license to develop, manufacture, and commercialize PCS6422 globally.

A Promising Asset for Colorectal and Metastatic Breast Cancer


Clinical Development

Previous History

Previous History

Data from preclinical xenograft models suggest that pretreatment with PCS6422 can significantly enhance the anti-tumor activity of capecitabine in breast and gastric tissue while not increasing its toxicity. The combination of PC6422 and capecitabine was also tested in several xenograft animal models with human breast, pancreatic, and colorectal cancer cells to evaluate their antitumor efficacy. Results showed that PCS6422 helped enhance capecitabine’s antitumor activity and significantly reduced the dose of capecitabine that’s needed to be efficacious.

Current Status & Clinical Trials

Current Status & Clinical Trials

On May 17, 2020, the FDA granted IND application for a Phase 1B study to evaluate the safety and tolerability of several dose combinations of PCS6422 and capecitabine in advanced GI tumor patients.

About This Trial

How PCS6422 Works

PCS6422 (eniluracil) is a selective and irreversible inhibitor of DPD, the enzyme that breaks down (metabolizes) 5-FU. We provide a single 40mg dose of 6422 in a combination regimen with Xeloda (or capecitabine) an oral prodrug of 5-FU. By irreversibly inhibiting DPD, the tumor-killing metabolites increase from ~15 minutes to more than four hours and avoid the creation of toxic metabolite F-Bal that gives rise to neurotoxicity and/or HFS.

Benefits of PCS6422

PCS622 improves the efficacy of leading colorectal and breast cancer chemotherapy while reducing toxicities that enable the development of adverse side effects.

  • Lowers side effects with lower 5-FU metabolite F-Bal.
  • Improves capecitabine efficacy.
  • Significantly reduces Hand-Foot Syndrome (HFS).

Market Landscape

A Substantial Opportunity to Help Cancer Patients

More than two million patients annually rely on fluoropyrimidines (5-FU, capecitabine, Xeloda®) as first-line therapies to treat colorectal, breast, lung, and gastric cancers. Of these patients, 50 to 70 percent develop HFS, which commonly leads to dose interruptions, adjustments, or discontinuation of treatment.

About Colorectal Cancer

Most colorectal cancer starts in a polyp on the inner lining of the colon or rectum. The cancer grows from the polyp into the wall of the colon, eventually invading the blood and lymph vessels, where it may spread (metastasize) to distant parts of the body.

 Around 104,270

Estimated new cases of colon cancer in the U.S. for 2021.1 

Around 45,230

Estimated new cases of rectal cancer in the U.S. for 2021.1

About Breast Cancer

Most breast cancers begin in the ducts that carry milk to the nipple, or in the glands that make breast milk. If breast cancer cells get into the blood or lymph tissue, they can spread (metastasize) to other parts of the body. About 99 percent of breast cancers diagnosed in the U.S. are found in women, but men can also get breast cancer.

Around 281,550

New cases of invasive breast cancer will be diagnosed in women in 2021 in the U.S.1

More than 3,800,000

Breast cancer survivors in the U.S., including women still being treated and those who have completed treatment.1

1. Source: American Cancer Society


Stay up to date on our latest publications and findings.

Read Publications

Partner with Us

Let’s work together to benefit patients with high unmet medical needs.

Partnering Opportunities
  • Clinical
    • Cadoo KA, Gajria D, Suh E, Patil S, Theodoulou M, Norton L, Hudis CA, Traina Decreased gastrointestinal toxicity associated with a novel capecitabine schedule (7 days on and 7 days off): a systematic review. NPJ Breast Cancer. 2016 Mar 30;2:16006. doi: 10.1038/npjbcancer.2016.6. PMID: 28721374; PMCID: PMC5515341.
  • Chang AY, Most C, Pandya Continuous intravenous infusion of 5- fluorouracil in the treatment of refractory breast cancer. American Journal of Clinical Oncology. 1989 Oct;12(5):453-455. DOI: 10.1097/00000421- 198910000-00019.
  • Lu Z, Zhang R, Diasio Dihydropyrimidine dehydrogenase activity in human peripheral blood mononuclear cells and liver: population characteristics, newly identified deficient patients, and clinical implication in 5-fluorouracil chemotherapy. Cancer Res. 1993 Nov 15;53(22):5433-8. PMID: 8221682.
  • Grem 5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs. 2000 Nov;18(4):299-313. doi: 10.1023/a:1006416410198. PMID: 11081567.
  • Grem JL, Harold N, Shapiro J, Bi DQ, Quinn MG, Zentko S, Keith B, Hamilton JM, Monahan BP, Donavan S, Grollman F, Morrison G, Takimoto Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors. J Clin Oncol. 2000 Dec 1;18(23):3952-63. doi: 10.1200/JCO.2000.18.23.3952. PMID: 11099325.
  • Guo XD, Harold N, Saif MW, Schuler B, Szabo E, Hamilton JM, Monahan BP, Quinn MG, Cliatt J, Nguyen D, Grollman F, Thomas RR, McQuigan EA, Wilson R, Takimoto CH, Grem Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule. Cancer Chemother Pharmacol. 2003 Jul;52(1):79-85. doi: 10.1007/s00280-003-0613-0. Epub 2003 Apr 18. PMID: 12707718.
  • Hansen R, Quebbeman E, Ausman R, Frick J, Ritch P, Schulte W, Haas C, Beatty P, Anderson Continuous systemic 5-fluorouracil infusion in advanced colorectal cancer: results in 91 patients. J Surg Oncol. 1989 Mar;40(3):177-81. doi: 10.1002/jso.2930400309. PMID: 2645464.
  • Keith B, Guo XD, Zentko S, Harold N, Schuler B, Quinn M, Shapiro J, Grem Impact of two weekly schedules of oral eniluracil given with fluorouracil and leucovorin on the duration of dihydropyrimidine dehydrogenase inhibition. Clin Cancer Res. 2002 May;8(5):1045-50. PMID: 12006517.
  • Milano G, Etienne MC, Renée N, Thyss A, Schneider M, Ramaioli A, Demard Relationship between fluorouracil systemic exposure and tumor response and patient survival. J Clin Oncol. 1994 Jun;12(6):1291-5. doi: 10.1200/JCO.1994.12.6.1291. PMID: 8201391.
  • Milano G, Etienne Individualizing therapy with 5-fluorouracil related to dihydropyrimidine dehydrogenase: theory and limits. Ther Drug Monit. 1996 Aug;18(4):335-40. doi: 10.1097/00007691-199608000-00004. PMID: 8857547.
  • Paff MT, Baccanari DP, Davis ST, Cao S, Tansik RL, Rustum YM, Spector Preclinical development of eniluracil: enhancing the therapeutic index and dosing convenience of 5-fluorouracil. Invest New Drugs. 2000 Nov;18(4):365-71. doi: 10.1023/a:1006401432488. PMID: 11081572.
  • Rivera E, Chang JC, Semiglazov V, Burdaeva O, Kirby MG, Spector Eniluracil plus 5-fluorouracil and leucovorin: treatment for metastatic breast cancer patients in whom capecitabine treatment rapidly failed. Clin Breast Cancer. 2014 Feb;14(1):26-30. doi: 10.1016/j.clbc.2013.08.018. Epub 2013 Nov 1. PMID: 24183612.
  • Schilsky RL, Levin J, West WH, Wong A, Colwell B, Thirlwell MP, Ansari RH, Bell WN, White RL, Yates BB, McGuirt PV, Pazdur Randomized, open-label, phase III study of a 28-day oral regimen of eniluracil plus fluorouracil versus intravenous fluorouracil plus leucovorin as first-line therapy in patients with metastatic/advanced colorectal cancer. J Clin Oncol. 2002 Mar 15;20(6):1519-26. doi: 10.1200/JCO.2002.20.6.1519. PMID: 11896100.
  • Schilsky RL, Bukowski R, Burris H 3rd, Hochster H, O'Rourke M, Wall JG, Mani S, Bonny T, Levin J, Hohneker A multicenter phase II study of a five-day regimen of oral 5-fluorouracil plus eniluracil with or without leucovorin in patients with metastatic colorectal cancer. Ann Oncol. 2000 Apr;11(4):415-20. doi: 10.1023/a:1008356522080. PMID: 10847459.
  • Spector T, Cao A possible cause and remedy for the clinical failure of 5-fluorouracil plus eniluracil. Clin Colorectal Cancer. 2010 Jan;9(1):52-4. doi: 10.3816/CCC.2010.n.007. PMID: 20100689.
  • Mechanism of Action of PCS6422
    • Baccanari DP, Davis ST, Knick VC, Spector 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5- fluorouracil. Proc Natl Acad Sci U S A. 1993;90(23):11064-11068. doi:10.1073/pnas.90.23.11064
    • Baker SD, Diasio RB, O'Reilly S, Lucas VS, Khor SP, Sartorius SE, Donehower RC, Grochow LB, Spector T, Hohneker JA, Rowinsky EK. Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator J Clin Oncol. 2000 Feb;18(4):915-26. doi: 10.1200/JCO.2000.18.4.915. PMID: 10673535.
    • Baker Pharmacology of fluorinated pyrimidines: eniluracil. Invest New Drugs. 2000 Nov;18(4):373-81. doi: 10.1023/a:1006453500629. PMID: 11081573.
    • Cao D, Pizzorno Uridine phosophorylase: an important enzyme in pyrimidine metabolism and fluoropyrimidine activation. Drugs Today (Barc). 2004 May;40(5):431-43. doi: 10.1358/dot.2004.40.5.850491. PMID: 15319798.