Sareum Regulatory News (SAR)

SAREUM HOLDINGS PLC

("Sareum" or "the Company")

Sareum notes that Sierra Oncology has significantly expanded its clinical development programme for SRA737

· Ongoing SRA737 clinical studies expanded to target aggregate enrolment of 200 patients across ten cancer indications

· Adding new SRA737 monotherapy cohort for CCNE1-driven ovarian cancer

Sareum Holdings plc (AIM: SAR), the specialist cancer drug discovery and development business, notes that Sierra Oncology, the licence holder advancing clinical cancer candidate SRA737, announced that it has significantly expanded its clinical development programme for SRA737. Sierra Oncology issued an announcement today at 07:00 ET ahead of its Program Update event today at which it will provide an update on the progress of its portfolio of assets, with specific reference to its clinical development programme for SRA737. The Sierra management team will be joined by Dr Udai Banerji, Chief Investigator for its ongoing SRA737 Phase 1/2 clinical trials, and Dr Alan D'Andrea, a member of Sierra's DDR Advisory Committee. The event will take place at 10:00 am ET in New York and a live webcast will be available at www.sierraoncology.com.

Sierra Oncology announced noteworthy progress in the Dose Escalation Phase 1 portions for both of its ongoing Phase 1/2 clinical trials evaluating its potential best-in-class Chk1 inhibitor, SRA737. Sierra announced expansion of the efficacy-oriented Phase 2 portions of both trials, which will now target aggregate enrolment of approximately 200 patients across ten cancer indications. Sierra also announced it is planning to initiate a Phase 1b/2 clinical trial in the fourth quarter of 2018 that will evaluate SRA737 in combination with ZEJULA® (niraparib) for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The full announcement can be found at www.sierraoncology.com.

SRA737-01 Phase 1/2 Monotherapy Trial: Trial Update and Expansion Plans

This trial consists of two phases, a safety-oriented Dose Escalation Phase 1 in unselected 'all-comer' patients and an efficacy-oriented Cohort Expansion Phase 2 in patients with genetically-defined tumours that harbour genomic alterations linked to increased replication stress and hypothesized to be more sensitive to Chk1 inhibition. Sierra will provide an update on the Dose Escalation Phase 1 portion today.

• Dose Escalation has proceeded through multiple dose levels and SRA737 has been well-tolerated from 20 mg QD to 1000 mg QD as monotherapy.

• The majority of reported adverse events (AEs) have been Grade 1 or Grade 2 in severity.

• Most commonly observed AEs (≥ 20%; all reported causalities) were fatigue and GI events (diarrhoea, nausea, vomiting).

• Grade 3 adverse events have included neutropenia (2 patients), nausea (2 patients), and diarrhoea (1 patient).

• Serious Adverse Events (at least possibly related by Investigator assessment) included Grade 3 neutropenia (probably related; one patient) and Grade 3 heart failure/cardiomyopathy (possibly related) in a single patient with rapid disease progression.

• Two Dose Limiting Toxicities (DLTs) were reported at 1300 mg QD (inability to receive 75% of the planned SRA737 dose due to GI intolerability).

• No evidence of emergent or cumulative toxicity and/or declining tolerability was observed with up to 8 cycles of drug administered, supportive of potential for extended dosing.

• Dose escalation is now complete; 1000 mg QD & 500 mg BID cohorts are currently being compared in order to optimize the SRA737 dose regimen.

The Cohort Expansion Phase 2 portion of the trial is enrolling genetically-defined patients into indication specific cohorts, including advanced or metastatic:

• castration-resistant prostate cancer (mCRPC);

• high grade serous ovarian cancer (HGSOC);

• non-small cell lung cancer (NSCLC);

• head and neck squamous cell carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA); and

• colorectal cancer (mCRC).

Sierra announced today the addition of a sixth indication specific cohort, CCNE1-driven HGSOC. During the Program Update, Sierra will present preclinical data demonstrating that SRA737 has significant anti-tumour activity and a profound survival benefit in CCNE1-driven HGSOC preclinical models.

Sierra is also expanding the number of sites recruiting patients into the trial from three active sites (as of the third quarter of 2017) to a planned 15 active sites at leading centres across the United Kingdom, to support its increased enrolment to 20 patients in each of the six genetically-defined cohorts. In total, 120 patients are expected to be enrolled into the Phase 2 portion of the trial. Sierra reported that 20 patients had been enrolled into this portion of the study to date and that enrolment was in line with the anticipated prevalence of the gene mutations targeted. The Cohort Expansion Phase 2 portion of the study is expected to report preliminary clinical data in the fourth quarter of 2018.

SRA737-02 Phase 1/2 Low Dose Gemcitabine Combination Trial: Trial Update and Expansion Plans

This clinical trial consists of three phases:

1. A Standard Dose Triplet Combo Dose Escalation Phase 1 evaluating a combination of SRA737 with standard dose gemcitabine and cisplatin in patients with solid tumours.

Sierra reported that this phase has concluded.

2. A Low Dose Gemcitabine (LDG) Combo Dose Escalation Phase 1 evaluating safety in 'all-comer' non-selected patients, where cohorts of 3 to 6 patients are being administered escalating doses of SRA737 on an intermittent schedule in addition to low dose gemcitabine (5-10% of the standard gemcitabine dose) until the combination maximum tolerated dose (MTD) is reached.

Sierra reported that significant progress has been made in the LDG Combo Dose Escalation Phase 1, and the combination regimen has been very well-tolerated.

• The majority of reported AEs have been Grade 1 or Grade 2 in severity.

• Most commonly observed AEs (≥ 20%; all reported causalities) were diarrhoea, anaemia, thrombocytopenia, fatigue, influenza-like illness, nausea, neutropenia and vomiting.

• Only one Grade 3 treatment related AE (neutropenia) was observed, at 40 mg SRA737/300 mg/m2 gemcitabine.

• Related SAEs included a Grade 1 fever (possibly related) and a Grade 2 DVT (possibly related).

• No evidence of emergent or cumulative toxicity and/or declining tolerability was observed with up to five cycles of drug administered, supportive of potential for extended dosing.

• No DLTs have been reported in any LDG dose escalation cohort and dose escalation continues.

3. A Low Dose Gemcitabine Combo Cohort Expansion Phase 2, that will explore the preliminary efficacy of SRA737 plus low dose gemcitabine in prospectively enrolled genetically-defined patients with tumours that harbour genomic alterations hypothesized to confer sensitivity to Chk1 inhibition via synthetic lethality.

Sierra reported that this phase is anticipated to commence in the second quarter of 2018 and has been expanded to target enrolment of 80 genetically-selected patients across four indications, including advanced or metastatic:

• urothelial carcinoma;

• small cell lung cancer (SCLC);

• soft tissue sarcoma;

• cervical/anogenital cancer.

An update on the study is expected to be provided in the fourth quarter of 2018.

SRA737 PARPi Combination Program Initiation and Supply Agreement

Sierra also announced execution of a supply agreement with Janssen Research & Development, LLC for the supply of TESARO's ZEJULA® (niraparib), an orally administered poly ADP-ribose polymerase (PARP) inhibitor, facilitating the initiation of a combination trial of SRA737 with niraparib in patients with prostate cancer, expected in the fourth quarter of 2018.

The trial is to be led by Professor Johann de Bono, Regius Professor of Cancer Research, Head of the Division of Clinical Studies and Professor in Experimental Cancer Medicine at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.

During the Program Update today, Sierra will present preclinical data supporting SRA737's synergistic activity in combination with PARPi in a model of PARPi acquired resistance. Additional preclinical data supporting this combination will be presented at the American Association of Cancer Research (AACR) Annual Meeting 2018.

SRA737 Combination with Immuno-Oncology

During the Program Update today, Sierra will also present preclinical data providing evidence of biological synergy between SRA737 and immune checkpoint blockade. Sierra is currently designing a clinical study for this combination, which potentially could be submitted to regulatory authorities in the fourth quarter of 2018.

For further information, please contact: 

Notes for editors: 

Sareum is a drug discovery and development company delivering targeted small molecule therapeutics, focusing on cancer and autoimmune disease, and licensing them to pharmaceutical and biotechnology companies at the preclinical or early clinical trials stage.

Sareum operates an outsourced research model, working with international collaborators and a world-wide network of research providers. Its most advanced programme (Chk1) commenced clinical trials in May 2016 and was licensed to NASDAQ-listed Sierra Oncology in September 2016.

SKIL® (Sareum Kinase Inhibitor Library) is Sareum's drug discovery technology platform that has so far produced the Company's Aurora+FLT3 and TYK2 kinase cancer and autoimmune disease research programmes, which are in the IND-enabling preclinical and lead optimisation stages respectively. SKIL® can also generate drug research programmes against other kinase targets.

Sareum Holdings plc is listed on the AIM market of the London Stock Exchange, trading under the symbol SAR. For further information, please visit www.sareum.co.uk

Checkpoint Kinase 1 (Chk1) and SRA737 (formerly CCT245737):

SRA737 is a highly selective, orally available, small molecule inhibitor of Checkpoint kinase 1 (Chk1).

DNA is continuously subject to damage through a variety of endogenous and exogenous mechanisms and, in turn, cells have developed complex processes to resolve this DNA damage. Chk1 is a central regulator in the DNA Damage Repair ("DDR") network of cellular pathways that detect and repair DNA damage. Chk1 impacts multiple cell-cycle checkpoints, temporarily inhibiting the progression of cell replication and division in order for DNA repair processes to be undertaken.

Malignant cells tolerate substantially greater levels of DNA damage than would be acceptable in healthy cells. Cancer cells survive and replicate, despite accumulating DNA damage due to replicative stress, via an over-reliance on select components of the DDR network including Chk1. As such, inhibition of Chk1 by SRA737 may be synthetically lethal to cancer cells and of potential benefit in the treatment of certain cancers.

Certain standard chemotherapeutic agents and radiotherapy also induce DNA damage in order to kill cancer cells. There exists potential for synergy between these standard therapies and Chk1 inhibitors such as SRA737.

SRA737 was discovered and initially developed by scientists in the Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research (ICR) in collaboration with Sareum, with funding provided by Cancer Research UK, the ICR and Sareum. The program was licensed by CRT and the ICR to the CRT Pioneer Fund, a specialist cancer investment fund established by Sixth Element Capital LLP (6EC), Cancer Research Technology (CRT) and the European Investment Fund (EIF) and managed by 6EC, in September 2013 and a co-investment partnership with Sareum was formed to progress the candidate drug through clinical trials.

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