NuCana‘s ProTide™ Technology:
An Independent Review
On behalf of all Contributors:Wolfram C. M . Dempke, MD, PhD, MBAProfessor of Haematology & OncologySaWo Oncology LtdCambridge, July 17, 2018
Table of Contents
•Introduction and Methodology
•Ovarian Carcinoma (OC)
•Non-Small Cell Lung Cancer (NSCLC)
•Biliary Tract Carcinoma (BTC)
•Colorectal Carcinoma (CRC)
•Pancreatic Carcinoma (PC)
•Summary of Statements
Table of Contents
•Introduction and Methodology
•Ovarian Carcinoma (OC)
•Non-Small Cell Lung Cancer (NSCLC)
•Biliary Tract Carcinoma (BTC)
•Colorectal Carcinoma (CRC)
•Pancreatic Carcinoma (PC)
•Summary of Statements
NuCana Plc: ProTide™ Technology
•NuCana Plc (a clinical-stage pharmaceutical company
based in Edinburgh, UK) have established the
ProTide™ technology to develop new chemotherapy
drugs.
•Using this technology, nucleoside analogues can be
transformed into more active compounds with the aim
to overcome key drug resistance mechanisms of
nucleotide-based anti-cancer drugs.
www.nucana.com
NuCana Plc: ProTide™ Technology
• In principle, with the ProTide™ technology the initial
molecule (e.g., gemcitabine, 5-FU) is modified by adding
aryl, ester, and amino acid moieties that protect the
activated or phosphorylated nucleoside analogue.
• Uptake, activation, and breakdown of nucleoside
analogues, are therefore modified.
• As a result, much higher intracellular concentrations of the
active drug can be achieved (e.g., 217-fold increase for
modified gemcitabine).
www.nucana.com
NuCana Plc: ProTide™ Compounds
• Currently NuCana Plc are evaluating three ProTide™-modified
nucleotide analogues with two of them being in clinical trials.
• Lead compound is Acelarin (phase I-III in ovarian, pancreatic, and
biliary tract cancers), a modified gemcitabine molecule. Response
rate in biliary tract cancers: 4/8 patients. Disease control rate in
relapsed/refractory gynecological cancers: 13/14 patients.
• NUC-3373 (phase I in solid tumours, ProTide™-modified 5-FU)
appears to be 300-fold more potent than 5-FU in vitro.
• NUC-7738 (transformation of cordycepin, a novel nucleoside
analogue) is in pre-clinical stage.
www.nucana.com
NuCana’s Portfolio Analysis:Methodology
• The analysis was prompted by an invitation to submit an
article on nucleoside analogues to “Curr Opion Oncol”.
• A systematic literature search (2008-7/2018) was
performed (including AACR, ASCO, ESMO), and data
from NuCana’s website was also analysed.
• Raw data (all available on the public domain) and final
conclusions/recommendations were discussed in great
detail with independent experts in the field.
NuCana’s Portfolio Analysis:Methodology
• Experts from the following study groups were involved in the discussions:
- Arbeitsgemeinschaft Gynäkologische Onkologie (AGO OVAR)
- Gynecologic Oncology Group (GOG)
- CONKO Study Group
- ASCO GI Members
- EORTC-LCG (Lung Cancer Group)
- Independent Analyst (US) & Independent Investor Group (UK)
• Nucana were given the opportunity to provide comments, but did not do so.
However, NuCana attempted in writing to prevent publication of this analysis.
• All contributors vouch for the fidelity of the current analysis.
Table of Contents
•Introduction and Methodology
•Ovarian Carcinoma (OC)
•Non-Small Cell Lung Cancer (NSCLC)
•Biliary Tract Carcinoma (BTC)
•Colorectal Carcinoma (CRC)
•Pancreatic Carcinoma (PC)
•Summary of Statements
Ovarian Carcinoma (OC)
• NuCana are attempting to evaluate Acelarin in the management of
platinum-resistant and platinum-sensitive ovarian carcinomas.
• In the PRO-001 study (relapsed or refractory ovarian cancers; N =
18) the DCR for Acelarin was 13/14 patients.
• In the PRO-002 study (Acelarin plus Carboplatin in platinum-sensitive
and platinum-resistant patients) the DCR was found to be 22/23
patients.
• In the ongoing PRO-105 study Acelarin is evaluated in platinum-
resistant ovarian cancers (≥ 3 prior lines of chemotherapy) (currently
35 patients enrolled).
Blagden et al. 2017Gourley et al. 2018
OC: QUADRA Study
• Phase II study (N = 463) (NCT02354586)
• Patients with ≥ 3 treatment lines and no prior PARP inhibitor
treatment were enrolled.
• Both, platinum-resistant and platinum-sensitive patients were
eligible for recruitment (3rd line or greater).
• 63% of patients received prior Bevacizumab, two-thirds were
platinum-resistant.
• Treatment: Niraparib 300 mg/die
• ORR: 31%, DoR: 9.4 months
Moore et al. 2018
OC: OVARIO Study
•Phase II study (N = 90) (NCT03326193)
•Combination of Niraparib plus Bevacizumab as
maintenance therapy after initial chemotherapy with
Bevacizumab plus Carboplatin/Paclitaxel.
•Primary endpoint: PFS at 18 months.
•Study is active and is recruiting patients.
Hope et al. 2018
OC: TOPACIO Study
•Phase I/II study (N = 121) (NCT02657889)
•The combination of Niraparib plus Pembrolizumab in
platinum-resistant patients was evaluated.
•ORR (all patients): 25%
•ORR (BRCAmut): 45%
•DCR: 67%
Konstantinopolous et al. 2018
OC: AVANOVA Study
• Phase I/II study (N = 108) (NCT02354131)
• Relapsed platinum-sensitive patients received either niraparib
or niraparib plus bevacizumab.
• Three patients had BRCA mutations.
• Patients pre-treated with Bevacizumab had to have progressed
under or after 3 months after Bevacizumab.
• ORR (combination): 45%
• DCR (combination): 91%
• mPFS (combination): 49 weeks
Mirza et al. 2017
OC: Other Studies• MITO16MANGO2b Study: Re-treatment with
Bevacizumab (plus chemotherapy) of patients with a
platinum-sensitive relapse significantly prolongs PFS
(phase III, N = 452, PFS: 11.8 versus 8.8 months, HR =
0.51) (NCT01802749).
• ATALANTE Study: Bevacizumab plus chemotherapy and
Placebo versus Bevacizumab plus Chemotherapy and
Atezolizumab (Phase III, N = 405) (NCT02891824) in
patients with a platinum-sensitive relapse (ongoing).
Pignata et al. 2018Kurz et al. 2018
OC: Caveats
• The FDA approval of Bevacizumab as first-line treatment
(plus maintenance) has somewhat changed the landscape
and the role of earlier clinical trials (e.g., OCEANS,
AURELIA).
• Established second-line treatment for platinum-sensitive
OC patients will be the CAYPSO protocol (plus
Bevacizumab?).
• Niraparib (PARP inhibitor) has been approved without
prior BRCA testing and is undergoing an extensive study
programme.
OC: Caveats
•Niraparib plus immunotherapy will play a significant
role in future treatment protocols for OC and is
expected to be a huge challenge for Acelarin in this
setting.
•DCR percentage rates (e.g., “93%, “96%”) given for
Acelarin in very heterogenous patient populations are
regarded to be misleading since very few patients
have been treated.
www.nucana.com
OC: Caveats• Reported results from the QUADRA, TOPACIO, and AVANOVA
trial (large numbers of patients recruited) demonstrated
outstanding results for Niraparib in indications Acelarin is also
investigated and will be a huge hurdle to clear for Acelarin.
• Putative option for Acelarin: Acelarin plus Carboplatin versus
PLD plus Carboplatin in platinum-sensitive patients (4th line
following PARP inhibitor failure).
• Alternatively: Bevacizumab + Gem/Carbo versus Bevacizmab +
Acelarin/Carbo (2nd line platinum-sensitive relapse).
• Alternatively: Bevacizumab + Gem versus Bevacizumab +
Acelarin (2nd line platinum-resistant relapse).
Treatment Algorithm (> 2018)
OC: III/IV
Bev + CP(+ Bev
mainte-nance)
Pac or PLD or Topo (Bev?) Niraparib
Bev + PLD or Bev +Gem
Niraparib (+ Pembrolizumab?)
Bev + Pt/GemBev + Pt/PLD
or:Niraparib/Bev?
PARP Inhibitor
Trabectidine+ PLD
Trials
1L 2L 3L 4L
Pt-refractory (5%)
Pt-resistant (20%)
Pt-sensitive (75%)
Table of Contents
•Introduction and Methodology
•Ovarian Carcinoma (OC)
•Non-Small Cell Lung Cancer (NSCLC)
•Biliary Tract Carcinoma (BTC)
•Colorectal Carcinoma (CRC)
•Pancreatic Carcinoma (PC)
•Summary of Statements
Non-Small Cell Lung Cancer (NSCLC)
• Immunotherapies have provided substantial OS
benefits in NSCLC (regardless of PD-L1 status).
•TKIs in EGFR-mutated NSCLCs have also shown a
significant OS benefit (e.g., Dacomitinib in the
ARCHER-1050 trial).
•Checkpoint inhibitors are more and more combined
with chemotherapy (e.g., Keynote-189 trial).Dempke & Fenchel 2017Dempke & Fenchel 2018Dempke et al. 2018
NSCLC: Caveats• Based on various studies, doublet regimens containing cisplatin or
carboplatin with paclitaxel, gemcitabine, docetaxel, vinorelbine or
irinotectan are SoC, and several studies have shown similar degrees
of efficacy among different combinations.
• Introducing a novel chemotherapy drug (e.g., Acelarin) will have to
clear a huge hurdle in terms of clinical trial acceptance.
• Putative option for Acelarin: Pembrolizumab plus Platinum/Acelarin
versus Pembrolizumab plus Platinum/X (X = Gemcitabine, Taxanes
etc.).
Schiller et al. 2002
Treatment Algorithm (> 2018)
Met. NSCLC
EGF-R Mutation (10-15%)
Dacomitinib, Osimertinib,
Afatinib
Osimertinib (if T790M)
Chemo-therapy-
based regimes
ALK Re-arrangement
(3-5%)Alectinib
Loratinib(if G1202R)
Pembro-lizumab
(plus doublet?)
Nivolumab
Atezoli-zumab plus Platin/nab-
Pac
Nivolumab
Ceritinib
Adeno-Cell (20-30%)
Squamous-Cell(40-45%)
1L 2L 3L
Independent Experts’ Opinion
Overall role for Acelarin in metastatic non-smallcell lung cancer:
very low
Table of Contents
•Introduction and Methodology
•Ovarian Carcinoma (OC)
•Non-Small Cell Lung Cancer (NSCLC)
•Biliary Tract Carcinoma (BTC)
•Colorectal Carcinoma (CRC)
•Pancreatic Carcinoma (PC)
•Summary of Statements
Biliary Tract Carcinoma
• SoC in the adjuvant setting is Capecitabine (2 x 625 mg/m², d1-
14, qd21 x 8) (BICAP Study: Capecitabine versus Placebo): OS
52.7 versus 36.1 months, HR = 0.75. ACTICCA-1 Study
ongoing.
• SoC in the metastatic setting is CDDP/Gem (Gemcitabine:
1.000 mg/m², d1,8, qd22; Cisplatin 25 mg/m², d1,8, qd22 x 6)
(ABC-02 Study: Gemcitabin/Cisplatin versus Gemcitabine): OS
11.7 versus 8.0 months, HR = 0.64.
• SoC for second-line is not established: Capecitabine may be
used (2 x 650-1.000 mg/m²,d1-14, qd22 until progression)
Pilmrose et al. 2017Valle et al. 2010
BTC: Caveats• Cisplatin is replaced by Oxaliplatin in many EU countries.
• The combination of Cisplatin plus Acelarin might be too
toxic and requires creatinine levels < 1.5 mg/dl.
• Studies with PD-1 checkpoint inhibitors are emerging
(e.g., in patients with microsatellite instability: MSI)
• Novel radio surgery techniques have achieved OS rates
up to 21.6 months.
• The combination of stenting plus photodynamic therapy
has demonstrated a significant PFS benefit (→ OPUS trial
ongoing). Ernst et al. 2010Leggett et al. 2012
Independent Experts’ Opinion
Overall role for Acelarin in metastatic biliary tractcancers:
moderate/good
Table of Contents
•Introduction and Methodology
•Ovarian Carcinoma (OC)
•Non-Small Cell Lung Cancer (NSCLC)
•Biliary Tract Carcinoma (BTC)
•Colorectal Carcinoma (CRC)
•Pancreatic Carcinoma (PC)
•Summary of Statements
Colorectal Carcinoma (CRC)
• NuCana’s concept appears to replace 5-FU as a backbone for
CRC treatment by NUC-3373.
• NUC-3373 is currently in phase I/Ib development (NuTide:301
and NuTide:302 studies).
• Combination therapies with irinotecan, oxaliplatin, cetuximab,
or bevacizumab are planned.
• Interestingly, the toxic metabolite dhFU was not detected
following NUC-3373 exposure suggesting a favourable toxicity
profile.
Blagden et al. 2018
CRC: Caveats
• It might be very difficult to replace 5-FU by NUC-3373 in a
1:1 fashion – interactions between combination partners
need to be established carefully which is time-consuming
and expensive.
• No clinical data is available so far to support this concept.
• Current CRC treatment strategies are moving towards oral
drugs (e.g., Capecitabine, Rigorafenib) – and, most
recently, oral formulations of irinotecan and oxaliplatin are
being developed.
CRC: Caveats• Clinical trials with checkpoint inhibitors are emerging.
• Patients with mismatch repair defects (dMMR) have shown a
huge benefit following pembrolizumab treatment.
• MMR defects = high MSI (microsatellite instability)
• OS (24 months) in CRC patients with dMMR following
pembrolizumab: 66%.
• CheckMate-142 study (Nivolumab): ORR 31.1%; DCR 69%
• The combination nivolumab plus ipilimumab has been
approved by FDA this month for CRC patients with dMMR.
Lee et al. 2015Lee et al. 2016Overman et al. 2017
Independent Experts’ Opinion
Overall role for NUC-3373 in metastatic colorectalcarcinoma:
low/moderate
Table of Contents
•Introduction and Methodology
•Ovarian Carcinoma (OC)
•Non-Small Cell Lung Cancer (NSCLC)
•Biliary Tract Carcinoma (BTC)
•Colorectal Carcinoma (CRC)
•Pancreatic Carcinoma (PC)
•Summary of Statements
Pancreatic Carcinoma
•A phase III study with Acelarin versus Gemcitabine
(ACELARATE trial, N = 328) (136 patients recruited to
date) is ongoing (only UK sites, end of recruitment
expected in 12/2020).
•Primary endpoint is OS: assumed HR = 0.705
corresponding to an OS for the Acelarin arm of 8.5
months.
•ECOG status: 0-2
PC: Caveats• Control arm (just Gemcitabine) is not SoC in the EU and the US (especially
for ECOG 0-1 patients!).
• SoC for ECOG 0-1 patients (with bilirubin < 1.5 ULN) is FOLFIRINOX or
dose-reduced (modified) FOLFIRINOX.
• If (m)FOLFIRINOX appears to be too toxic, SoC is the combination of
Gemcitabine plus nab-Paclitaxel (MPACT Study, ALPACA Study).
• Data from adjuvant trials has indicated that Capecitabine can also been
used as first-line metastatic treatment and may replace Gemcitabine.
• Only 5-10% of all patients with metastatic pancreatic cancers are treated
with Gemcitabine monotherapy.
• Very slow recruitment since only UK centers are participating.
Tong et al. 2018Martin et al. 2018CONKO Group, unpublished
PC: Caveats• Novel immunotherapies are emerging as treatment
options for pancreatic carcinoma with the potential to
replace chemotherapy.
• Bevacizumab is currently being investigated in the
metastatic setting in some trials with some positive results.
• PANTHEON Study ongoing (phase II: OFF versus
FOLFIRI after Gem/nab-Pac failure).
• Regulatory comment: FDA approval based on the
ACELARATE trial: very unlikely; EMA approval: unlikely.Tong et al. 2018Martin et al. 2018
Treatment Algorithm (2018)
Metastatic pancreatic carcinoma
PS 0-1, Bili< 1.5x ULN
PS 0-2, > 75 years, Bili
> 1.5x ULN
PS 0-2, Bili > 1.5x ULN PS ≥ 3
Gem/nab-Pac;
NaL-IRI/5-FU/LV
OFF or XELOX regime;
NaL-IRI/5-FU/LV
OFF or NaL-IRI/5-FU/LV
Best Supportive Care
FOLFIRINOX(modified) Gem/nab-Pac Gem-mono
Erlotinib canbe an option1L
2L
OFF: Oxaliplatin/5-FU/Folinic AcidNaL-IRI: nanoliposomal irinotecan(Onivyde®): NAPOLI-1 Study
Fuchs et al. 2018
3L
Independent Experts’ Opinion
Overall role for Acelarin in metastatic pancreatic carcinoma:
low/moderate
Table of Contents
•Introduction and Methodology
•Ovarian Carcinoma (OC)
•Non-Small Cell Lung Cancer (NSCLC)
•Biliary Tract Carcinoma (BTC)
•Colorectal Carcinoma (CRC)
•Pancreatic Carcinoma (PC)
•Summary of Statements
Summary of Statements
•Analyst’s and Investor’s Opinions:
“sell” and “no further investment”
•Independent Experts’ Opinions:
“interesting approach, but most likely overall
rate of technical success appears to be low in
current indications”