large NUC-3373 logo

A transformation of fluorouracil (5-FU)


NUC-3373 is specifically designed to overcome the key limitations and pharmacologic challenges that hinder the clinical utility of 5-FU, with the aim of improving 5-FU's efficacy, safety and administration challenges.

5-FU (and its other forms including capecitabine) is an inactive prodrug and its anti-cancer activity is dependent on its 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, thereby 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 or FUTP, a toxic metabolite associated with neutropenia, mucositis and diarrhea, 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 a 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 tumors.

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.

Number 1 in circle
Avoids breakdown & minimizes 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 tumors that are resistant to 5-FU. In addition to rendering 5-FU inert, this breakdown results in the generation of a toxic byproduct, FBAL, which has been associated with off-target toxicity including “hand-foot syndrome” which affects 25% to 75% 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 fluoropyrimidines.
NUC-3373 avoids breakdown by DPD, and therefore does not generate the toxic byproduct, FBAL, at clinically significant levels, which we believe will lead to an improved tolerability profile as compared to 5-FU and capecitabine.

Number 2 in circle
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 enables it to enter cells independently of these transporters.

Number 3 in circle
Pre-activated

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 tumor 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 bypasses the need for the activating enzymes required by 5-FU and results in significantly higher levels of the active aniti-cancer metabolite, which we believe will lead to improved efficacy compared to 5-FU.

Number 4 in circle
More convenient dosing

5-FU has a short plasma half-life of between 8 and 14 minutes. 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 favorable pharmacokinetic profile than 5-FU with a more predictable plasma half-life of between 6 and 14 hours. This enables NUC-3373 to be administered over much shorter time periods (typically two hours). Thus, we believe that NUC-3373 has considerable dosing advantages over 5-FU.

Colorectal cancer


› 1,900,000

New worldwide cases annually

2020

› 155,000

New US cases annually

2021

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 completing a Phase 1 study in patients with advanced solid tumors and is being evaluated in a Phase 1b/2 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 randomized Phase 2 study of NUC-3373 in patients with advanced colorectal cancer.

NuTide:323 study logo

Randomized Phase 2 clinical study of NUC-3373 in combination with leucovorin, irinotecan and bevacizumab (NUFIRI-bev) versus 5 FU in combination with leucovorin, irinotecan and bevacizumab (FOLFIRI-bev) for the second-line treatment of patients with advanced colorectal cancer

This study will include two NUC-3373 treatment arms to evaluate weekly (Q1W) and alternate weekly (Q2W) administration schedules.

NuTide:303 study logo

Phase 1b/2 clinical study to identify additional indications and treatment combinations for further development

This is a modular, multi-arm, parallel-cohort, dose-finding and expansion study of NUC-3373 in combination with other agents for the treatment of patients with different types of advanced solid tumors.

NuTide:302 study logo

Phase 1b/2 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 previously received fluoropyrimidine-based regimens.

Part 1

Assessed weekly (Q1W) and alternate weekly (Q2W) doses of NUC-3373 with or without leucovorin. The objective of this part of the study was to ascertain whether leucovorin has an impact on the PK and safety profile of NUC-3373.

Part 2

Assessing increasing doses of NUC-3373 plus leucovorin in combination with either oxaliplatin (NUFOX) or irinotecan (NUFIRI). The objective of this part of the study is to establish the dose of NUC-3373 in NUFOX and NUFIRI combinations to be further examined in Part 3.

Part 3

Will establish the optimal combinations of NUFOX and NUFIRI with bevacizumab for the second-line treatment of patients with advanced colorectal cancer.

Data from Part 1 of NuTide:302 demonstrated a favorable PK and safety profile compared to 5-FU.

Colorectal Cancer

67 years, female

3 prior lines
  1. CAPOX (adjuvant):
    for 3 months

    RELAPSED 9 months post adjuvant therapy

  2. FOLFIRI:
    progressed within 3 months
  3. Lonsurf:
    progressed within 3 months

RAS unknown

Target lesions: 1 (peritoneum)

Colorectal Cancer

69 years, male

2 prior lines

Diagnosed with metastatic disease

  1. CAPOX:
    progressed within 2 months

    tumor increase of 35%

  2. FOLFIRI:
    progressed within 1.5 months

RAS unknown

Target lesions: 2 (liver)

Colorectal Cancer

52 years, male

5 prior lines
  1. FOLFOX (adjuvant):
    for 4 months

    RELAPSED 4 months post adjuvant therapy

  2. FOLFIRI:
    progressed within 6 months
  3. Irinotecan + panitumumab:
    progressed within 6 months
  4. Irinotecan + panitumumab + telaglenastat:
    progressed within 6 months
  5. Nivolumab + enadenotucirev:
    progressed within 3 months

RAS wildtype; BRAF mutant

Target lesions: 3 (2 lung; 1 liver)

* patient missed 6 consecutive doses due to COVID-19 and progressed, but continued on study for a total of 8 months due to clinical benefit

Colorectal Cancer

47 years, male

4 prior lines
  1. FOLFOX (adjuvant):
    for 5 months

    RELAPSED 8 months post adjuvant therapy

  2. FOLFIRI + bevacizumab:
    progressed within 18 months
  3. FOLFIRI + cetuximab:
    progressed within 8 months
  4. Lonsurf:
    toxicity within 3 months

RAS wildtype

Target lesions: 5 (2 lymph nodes; 2 peritoneum; 1 liver)

Colorectal Cancer

57 years, male

4 prior lines
  1. CAPOX (neoadjuvant/adjuvant):
    for 6 months

    RELAPSED 2 months post adjuvant therapy

  2. FOLFIRI:
    progressed within 3 months
  3. Lonsurf:
    progressed within 2 months
  4. RXC004 (Wnt inhibitor):
    progressed within 1 month

RAS unknown

Target lesions: 3 (lung)

Colorectal Cancer

67 years, female

5 prior lines
  1. FOLFOX (adjuvant):
    for 5 months

    RELAPSED 2 years post adjuvant therapy

  2. FOLFIRI:
    for 5 months
  3. Irinotecan + Lonsurf + bevacizumab:
    for 33 months
  4. CAPOX:
    progressed within 1 month
  5. Regorafenib:
    progressed within 2 months

RAS mutant

Target lesions: 2 (1 liver; 1 abdomen)

Graham et al (2020) Ann Oncol 31: Suppl 4 Abstract ID :464P (ESMO poster September 2020)

Coveler et al (2021) J Clin Oncol 39: Suppl 3 Abstract ID: 93 (ASCO GI poster January 2021)

NuTide:301 study logo

Phase 1 dose-escalation study in patients with advanced solid tumors

Patients


59

Part 1 (n=43) Part 2 (n=16)

Age


59

(range 20-77)

Prior regimens


3

(range 0-11)

Data from this Phase 1 clinical study in patients with advanced solid tumors demonstrated a favorable pharmacokinetic profile of NUC-3373 compared to 5-FU.

Dose proportional increase in AUC (final)

best overall response graph for ABC-08 study

Long plasma half-life compared to 5-FU (6-14 hrs vs 8-14 mins)

• Enables 2-hour infusion vs 46-hour infusion

Anti-cancer activity was 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

Favorable Safety Profile

  • NUC-3373 is well-tolerated (n=59)
  • No Grade 4 treatment-related AEs
  • Grade 3 treatment-related AEs in 10 patients
  • MTD for NUC-3373 monotherapy 2500 mg/m2 Q1W