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A transformation of 3'-deoxyadenosine (3'-dA)


NUC-7738 is a ProTide transformation of 3'-deoxyadenosine (3'-dA), also known as cordycepin. 3’-dA has demonstrated potent anti-cancer activity in non-clinical studies, but has not been successfully developed as a anti-cancer agent due to its rapid breakdown by adenosine deaminase (ADA).

Similar to our other ProTides, NUC-7738 is designed to generate the active anti-cancer metabolite of 3’-dA directly inside cancer cells, thus overcoming 3’-dA's key limitations of breakdown, transportation and activation. The cytotoxic effect of NUC-7738 is largely attributed to the generation of the main active anti-cancer metabolite, 3'-dATP. Primarily, 3'-dATP interferes with RNA polyadenylation, causing changes in the expression of genes involved in metabolism, differentiation and apoptosis, ultimately leading to metabolic stress, cessation of cancer-cell growth and cell death.

In non-clinical studies, we examined the in vitro cytotoxic activity of NUC-7738 in a range of solid and hematological human cancer cell lines, as compared to 3'-dA. In 16 of the 20 cell lines, NUC-7738 was found to be up to 185-times more potent than 3’-dA.

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Resistant to breakdown

3’-dA is rapidly broken down by the enzyme adenosine deaminase, or ADA. This breakdown prevents 3’-dA's generation of the active anti-cancer metabolite. By contrast, NUC-7738 is not a substrate for ADA and is therefore resistant to degradation by this enzyme, thereby also avoiding the generation of breakdown byproducts.

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Transporter independent

Similar to other nucleoside analogs, 3'-dA requires the nucleoside transporter, hENT1, to cross the cancer cell membrane. The ProTide chemistry alters the chemical characteristics of NUC-7738 so that it is able to enter cancer cells independently of nucleoside transporters.

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Pre-activated

The rate-limiting activation step of 3’-dA requires the addition of a phosphate group, by the enzyme adenosine kinase, or AK to generate 3’-deoxyadenosine monophosphate (3’-dAMP). This phosphorylation is the rate-limiting step in the generation of the active anti-cancer metabolite 3’-deoxyadenosine triphosphate (3’-dATP). Once inside the cancer cell, NUC-7738 releases 3’-dAMP and as such does not require AK for the rate limiting first phosphorylation step. 3’-dAMP in turn is rapidly converted into 3’-dADP and 3’-dATP.

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Simplified administration

As NUC-7738 has a more favorable PK profile than 3’-dA, it can be administered via a short infusion. Attempts to improve the PK profile of 3’-dA, with other agents that inhibit its breakdown, were not historically successful.

Our
Clinical Studies


We are developing NUC-7738 for patients with solid tumors or hematological malignancies based on its broad activity observed in non-clinical studies. NUC-7738 is currently being evaluated in a Phase 1/2 study.

NuTide:302 study logo

Phase 1/2, dose-escalation study of NUC-7738 in patients with advanced solid tumors

This study is currently enrolling patients with advanced solid tumors and has two parts.

Phase 1:

Recommended Phase 2 dose, pharmacokinetics and safety

Phase 2:

Efficacy, pharmacokinetics and safety

Exploratory
Endpoints:

Biomarker evaluation, pharmacodynamics

Metastatic
Melanoma

62 years, female

2 prior lines
  1. Nivolumab + ipilimumab:
    discontinued within 1 month
  2. CK7 inhibitor:
    progressed within 1 month

Target lesion: 1 (pelvic side wall)

Metastatic
Melanoma

65 years, female

1 prior line
  1. Nivolumab + ipilimumab:
    discontinued within 1 month

Target lesion: 1 (lung)

Metastatic lung
Adenocarcinoma

65 years, male

2 prior lines
  1. Carboplatin + Pemetrexed:
    progressed at 6 months
  2. Docetaxel:
    progressed at 4 months

Target lesions: 2 (lung)

* Treatment beyond PD allowed per protocol for patients still receiving benefit.

Blagden et al (2021) Ann Oncol: 32: Suppl 5 Abstract ID 566TiP (ESMO poster September 2021)