ProTide Technology

Harnessing the power of phosphoramidate chemistry, we convert nucleoside analogs into activated nucleotide analogs with the addition of a phosphate group, which is protected by specific combinations of aryl, ester and amino acid groupings. By adding and protecting this phosphate group, we design our ProTides to avoid or overcome key cancer resistance mechanisms in the uptake, activation and breakdown of nucleoside analogs. As a result, we believe our ProTides have the potential to generate hundreds of times higher concentrations of the active anti-cancer metabolites inside tumour cells, potentially making our ProTides more effective than the current standards of care. Because our ProTides resist breakdown, and are thus more stable, we believe they are also able to reduce or eliminate the generation of toxic byproducts that can result from the breakdown of nucleoside analogs.

Our most advanced ProTide candidates, Acelarin and NUC-3373, are new chemical entities derived from the nucleoside analogs gemcitabine and 5-fluorouracil, respectively, two widely used chemotherapy agents. Acelarin is currently being evaluated in four clinical studies across several solid tumour indications, including ovarian cancer, biliary cancer and pancreatic cancer. NUC-3373 is currently in a Phase I study for the potential treatment of a wide range of advanced solid tumour cancers. We have retained worldwide rights to these lead product candidates as well as our preclinical product candidates, all of which we refer to as ProTides.

First in Class Nucleotide Analog

Acelarin, our lead product candidate was designed to overcome the key cancer resistance mechanisms associated with the nucleoside analog, gemcitabine, and has been evaluated in over 130 patients with cancer. We believe Acelarin could replace gemcitabine in certain cancer indications and have utility across a range of other cancers.

In a Phase I dose-ranging study in 49 evaluable patients with advanced metastatic solid tumours, Acelarin was well tolerated, achieved a 78% disease control rate and was associated with intracellular levels of active anti-cancer metabolite over 200 times higher than those reported for gemcitabine. A subset of 14 evaluable patients with relapsed/refractory gynecological cancers achieved a 93% disease control rate.

In a Phase Ib dose-ranging study in 23 evaluable patients with recurrent ovarian cancer, Acelarin was combined with carboplatin and achieved a 96% disease control rate. Based on these disease control rates and its tolerability profile, we have begun a Phase II study of Acelarin in patients with platinum-resistant ovarian cancer for which we expect to report interim data in 2018.

Acelarin is also being evaluated in another Phase Ib study in patients with biliary cancer to determine its optimal dose in combination with cisplatin. We expect data to be reported from this study in 2018, after which we plan to commence a multi-national Phase III study.

In addition, the National Cancer Research Institute in the United Kingdom is facilitating a Phase III study of Acelarin for the treatment of patients with pancreatic cancer.

A ProTide Transformation of 5-FU

We designed our second ProTide, NUC-3373, to overcome the key cancer resistance mechanisms, improve upon the safety profile and reduce the dosing administration burdens associated with the nucleoside analog, 5-FU. NUC-3373 is a nucleotide analog that delivers the same active anti-cancer metabolite, FUDR-MP, that 5-FU aims to generate within a cancer cell, but at far higher concentrations.

Unlike 5-FU, NUC-3373 consists of the active anti-cancer metabolite, FUDR-MP, and a protective phosphoramidate moiety. This moiety allows NUC-3373 to enter the cell without the need for any membrane transporters. Once inside the cancer cell, the phosphoramidate moiety is optimally cleaved off, resulting in deprotection and the release of FUDR-MP. This bypasses the need for any activating enzymes, resulting in significantly higher levels of the active anti-cancer metabolite, which we believe should lead to improved efficacy as compared to 5-FU. In addition, because NUC-3373 avoids breakdown by the enzyme DPD, certain toxic byproducts such as F-BAL are not released, which we believe should lead to an improved tolerability profile as compared to 5-FU. Lastly, we believe that the improved pharmacokinetic and pharmacodynamic profile, including the significantly longer half-life of NUC-3373, should result in a more favorable dosing regimen relative to 5-FU.

NUC-3373 is currently being evaluated in a Phase I clinical study of patients with advanced solid tumours. We plan to initiate a number of clinical studies in 2018: a Phase Ib study of NUC-3373 in patients with colorectal cancer together with other agents routinely used in 5-FU combination regimens; a Phase III study in patients with advanced colorectal cancer; and a Phase II study in patients with advanced breast cancer.

A ProTide Transformation of Cordycepin

NUC-7738 is a ProTide transformation of cordycepin, a nucleoside analog that has not been successfully developed or approved as a chemotherapy, but which has shown potent anti-cancer activity in preclinical studies. Similar to our other ProTide products, NUC-7738 is designed to generate the active anti-cancer metabolite of cordycepin directly inside cells, bypassing the resistance mechanisms of transportation, activation and breakdown. The in vitro cytotoxic activity of NUC-7738 was examined across a range of human cancer cell lines, in which it was observed in certain lines that NUC-7738 had more than 50 times greater anti-cancer activity than cordycepin

We are targeting NUC-7738 for development in both solid and hematological tumours based on the broad activity seen with cordycepin in preclinical studies. We are currently evaluating NUC-7738 in preclinical toxicology studies and we expect to initiate a Phase I clinical study in 2018 in patients with solid tumours, with a second Phase I clinical study planned for 2019 in patients with hematological tumours.

NuCana's Pipeline

We take a scientifically driven approach to designing ProTides, which we believe have the potential to result in highly efficacious cancer therapies with improved tolerability.

We are pursuing both the transformation of well-established and widely used nucleoside analogs as well as novel nucleoside analogs, which we believe have the potential to address additional areas of unmet medical need in oncology.