large NUC-3373 logo

A transformation of fluorouracil (5-FU)


NUC-3373, our second ProTide to enter clinical development, is specifically designed to overcome the key cancer resistance mechanisms and pharmacologic challenges that limit the clinical utility of 5-FU, with the aim of improving the efficacy, safety and administration challenges.

5-FU (and its other forms including capecitabine) is an inactive pro-drug and its anti-cancer activity is dependent on conversion to the active anti-cancer metabolite (FUDR-MP), which binds to and inhibits thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. TS is required to convert uridine (specifically dUMP) to thymidine (specifically dTMP), one of the four nucleotides that comprise DNA. The inhibition of TS results in an imbalance in the ratio of dUMP and dTMP, disrupting DNA synthesis and repair, ultimately leading to cancer cell death. However, due to multiple limitations, 5-FU is not efficiently converted to FUDR-MP.

NUC-3373 is a ProTide transformation of 5-FU that generates much higher concentrations of FUDR-MP in patients’ cells. NUC-3373 also has a more convenient administration schedule and does not produce toxic levels of metabolites such as FBAL which results in an improved safety profile.

NUC-3373 is a more potent and targeted inhibitor of TS.

First introduced in 1957, 5-FU remains the cornerstone of treatment for patients with many types of cancers, including colorectal, breast, gastric, head and neck and pancreatic.

We are developing NUC-3373 as a more effective and safer medicine for patients with colorectal cancer and other solid tumours.

We believe NUC-3373 has the potential to replace 5-FU as the standard of care in the treatment of patients with a wide range of cancers.

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Reduction in toxic byproducts

More than 85% of administered 5-FU is degraded by the enzyme dihydropyrimidine dehydrogenase (DPD) in the liver. Therefore most of the drug is broken down before it has an opportunity to enter cancer cells. Levels of DPD have also been found to be elevated in tumours that are resistant to 5-FU. In addition to rendering 5-FU inert, this breakdown results in the generation of a toxic by-product, FBAL, which has been associated with off-target toxicity including “hand-foot syndrome” which affects 34% to 72% of patients treated with 5-FU and its other forms such as capecitabine. Hand-foot syndrome is a debilitating side effect and commonly causes dose reductions or discontinuation of therapy for patients receiving 5-FU.
NUC-3373 avoids breakdown by DPD, and therefore does not generate the toxic by-product, FBAL, at clinically significant levels, which we believe will lead to an improved tolerability profile as compared to 5-FU

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Pre-activated and transporter independent

5-FU relies on specific membrane transporters in order to enter cancer cells. If these transporters are not present or are expressed at inadequate levels, 5-FU’s ability to enter cancer cells will be limited. NUC-3373’s phosphoramidate moiety (a specific combination of aryl, ester and amino acid groups) enables it to enter cells independently of these transporters.
Once 5-FU enters cells, it must be processed by a series of enzymes to generate the active anti-cancer metabolite, FUDR-MP. There are several key enzymes involved in the conversion of 5-FU to FUDR-MP including orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP) and thymidine kinase (TK). Lower levels of these enzymes in tumour cells are associated with cancer-cell resistance to 5-FU.
Once NUC-3373 enters the cancer cell, the protective phosphoramidate moiety is cleaved, resulting in the release of the active anti-cancer metabolite, FUDR-MP. This by-passes the need for the activating enzymes required by 5-FU, and results in significantly higher levels of the active metabolite, which we believe will lead to improved efficacy compared to 5-FU.

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More convenient dosing

5-FU has a short half-life of between 8 and 14 minutes in plasma. As a result, healthcare professionals typically administer 5-FU as a continuous infusion over 46 hours. This causes inconvenience to patients and a significant burden to healthcare systems.
As NUC-3373 is resistant to breakdown by DPD, it has a more favourable pharmacokinetic profile than 5-FU with a plasma half-life of approximately 8 hours. This enables NUC-3373 to be administered over much shorter time periods (typically one to four hours). Thus, we believe that NUC-3373 has considerable dosing advantages over 5-FU.

Colorectal cancer


› 1,800,000

New worldwide cases annually

2018

˜ 148,000

New US cases annually

2018

5-FU-containing regimens are the global standard of care for patients with colorectal cancer. NuCana aims to replace 5-FU with NUC-3373.

Our
Clinical Studies

NUC-3373 is currently being evaluated in a Phase I study in patients with advanced solid tumours and in a Phase Ib study in combination with other agents typically combined with 5-FU in patients with advanced colorectal cancer. Once the recommended dose and schedule has been established, in combination with other agents, we intend to initiate a registrational program with NUC-3373 in patients with colorectal cancer.

NuTide:302

Phase

Ib

NuTide:301

Phase

I

NuTide:302 study logo

Phase Ib study of NUC-3373 in combination with agents commonly used with 5-FU to treat patients with advanced colorectal cancer

NuTide:302 is a three-part study enrolling patients with advanced colorectal cancer who have received ≥ 2 prior lines of fluoropyrimidine-based regimens.

Part 1

Assessing weekly (q1w) and alternate weekly (q2w) doses of NUC-3373 with or without leucovorin. The objective of this part of the study is to ascertain whether leucovorin has an impact on the PK and safety profile of NUC-3373.

Part 2

Assessing increasing doses of NUC-3373 in weekly and alternate weekly schedules in combination with leucovorin and either oxaliplatin (NUFOX) or irinotecan (NUFIRI). The objective of this part of the study is to establish the dose and schedule of NUC-3373 in combination with leucovorin and oxaliplatin or irinotecan to be further examined in expansion cohorts in Part 2.

Part 3

Will open in parallel to the expansion cohorts in Part 2 and will establish the optimal combinations of NUFOX and NUFIRI with EGFR and VEGF inhibitors.

Interim data from Part 1 of NuTide:302 demonstrated a positive linear relationship between intracellular FUDR-MP and dUMP, confirming that NUC-3373 effectively inhibits TS and prevents the conversion of dUMP to dTMP in patients.

NuTide:301 study logo

Phase I dose-escalation study in patients with advanced solid tumours

Interim data from this Phase I clinical study in patients with advanced solid tumours demonstrated a favourable pharmacokinetic profile of NUC-3373 compared to 5-FU.

Anti-cancer activity has been observed in patients who had exhausted all standard treatment options.

Metastatic
Colorectal Cancer

70 years, male

6 prior lines
  1. 5-FU:
    based chemoradiotherapy (adjuvant)
  2. FOLFIRI:
    for metastatic disease
  3. CAPOX:
    progressed within 2 months
  4. FOLFIRI:
    progressed within 8 months
  5. LONSURF:
    progressed within 3 months
  6. Irinotecan:
    treatment for 1 month

Metastatic
Basal Cell Carcinoma

55 years, male

2 prior lines
  1. Vismodegib:
    for 11 months
  2. Paclitaxel + carboplatin:
    for 3 months

Metastatic
Cholangiocarcinoma

60 years, female

1 prior line
  1. Gemcitabine + cisplatin:
    progressed within 6 months

Blagden et al (2018). Ann Oncol; 29: Suppl 8 Abstract ID: 442TiP (ESMO poster 442TiP, 22nd Oct, 2018)
Data as of Sept 25, 2018

Safety Profile (interim)

  • NUC-3373 is well-tolerated (n=36)
  • Multiple cycles administered
    (median 2; range 0.25 -11.75)
  • No hand-foot syndrome has been observed
  • No Grade 4 treatment-related AEs
  • Grade 3 treatment-related AEs include:

    • 3 transaminitis
    • 1 fatigue
    • 1 shingles