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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

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








Ovarian Carcinoma

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%)

Independent Experts’ Opinion

Overall role for Acelarin in ovarian carcinoma:

very low

Table of Contents








Lung Cancer (NSCLC)

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


Overall role for Acelarin in metastatic non-smallcell lung cancer:

very low

Table of Contents








Biliary Tract CarcinomaBlue Arrow: TumourBlack Arrow: StentGreen Arrow: Concrements

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


Overall role for Acelarin in metastatic biliary tractcancers:

moderate/good

Table of Contents








Colorectal Carcinoma

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


Overall role for NUC-3373 in metastatic colorectalcarcinoma:

low/moderate

Table of Contents








Pancreatic Carcinoma

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


Overall role for Acelarin in metastatic pancreatic carcinoma:

low/moderate

Table of Contents








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”

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