Product and Pipeline

More effective combination treatments for cancer

Cancers are complex dynamic and adaptive diseases with the tumor micro-environment comprising many different cell types, matrix proteins and secreted molecules.

The interplay between these elements impacts the responsiveness to therapy and whether there is continued tumor survival and progression, even in the face of continued treatments. We believe that remodelling of the tumor microenvironment and taking a multi-pathway and multi-target approach offers an opportunity to significantly improving response rates and durability of response.

Product Indication Preclinical Phase 1 Phase 2 Status
SP-002: Phase 2A Multi-lesional Basal Cell Nevus Syndrome
On-going and to complete in 2023
SP-002: Phase 2B Locally Advanced BCC
Commence in 2H, 2023
SP-002: Phase 1/2A Squamous Cell Carcinoma
Commence in 1H, 2024
SP-002: Phase 1/2A Cutaneous Breast Cancer
Commence in 1H, 2024
SP-105 Optimization and Clinical Trial enabling Studies
On-going IND enabling Studies
to commence
on-going study

SP-002

SP-002 is a human adenovirus 5 vector encoding Interferon-γ

SP-002 is an adenoviral vector (serotype 5, Ad5) encoding the therapeutic cytokine Interferon-γ. The vector has been engineered to be replication-deficient so it can transduce cells and produce Interferon-γ but not new viral particles (a safety feature not present in oncolytic viruses, which may also replicate in non-cancer cells). Interferon-γ has shown superior potency against tumors compared with Interferon-⍺, however, its successful clinical application in cancer has been hampered by its narrow therapeutic window. The main advance of SP-002 is a wide-therapeutic window where transduced tumors release local sustained IFN-γ allowing for a therapeutically effective dose to be delivered without causing significant systemic toxicities. Interferon-γ is a central orchestrator of an immune response (both adaptive and innate response), can induce programmed cell death in tumors, and restricts neo-vasculature supporting tumor growth.

Clinical Rationale

It is being developed as an effective, durable non-surgical intra-lesional treatment for treating multiple Basal Cell Carcinomas in Basal Cell Nevus Syndrome patients.

SP-002 with a Hedgehog Pathway Inhibitor (HHPI)

The combination regimen is being developed as an effective treatment for Locally Advanced Basal Cell Carcinoma. Basal cell carcinoma is a common skin cancer, with 3-4 million cases arising annually in the US. About 2% of these patients progress to advanced disease (about ~60,000 per yr. in the US). LA BCC comprise unresectable lesions, recurrent (multiple recurrences) lesions and lesions on anatomically difficult surgical sites that would result in significant functional damage upon resection.

Clinical Rationale

The HHPI (Hedgehog pathway inhibitors, e.g., vismodegib and sonidegib) are FDA-approved agents for use in LA BCC when surgery and radiotherapy are not suitable. Of the estimated that of 60,000 LA BCC patients, only a small subset use HHPIs. The primary reason for HHPI’s low adoption rate is the low Complete Response (CR) rate observed. HHPIs are effective at shrinking the majority of LA BCC but a quiescent population of residual BCC persist even while ongoing treament. Combining, SP-002 with an HHPI can improve clinical outcomes via complementary and synergistic mechanisms of action. SP-002, as an add-on to standard of care (SOC) HHPI, vismodegib, is anticipated to improve both CR rate and durability of response.

Rationale for add-on of SP-002 to HHPIs

HHPI Monotherapy – major ‘debulking’ of large BCCs

BCCs are heterogeneous with respects to HHPI responsiveness

BCCs are heterogeneous with respects to HHPI responsiveness 1-3

HHPI highly effective in majority of BCCs

HHPI highly effective in majority of BCCs 1-3

HHPI resistant residual BCC can lead to relapse ~CR~20-30%

HHPI resistant residual BCC can lead to relapse ~CR~20-30% 5

Quiescent residual BCCs express LGR5 cancer stem cell marker 1-3

HHPI & SP-002 Combination Therapy – ‘debulking’ and removal of HHPI resistant residual populations

BCCs are heterogeneous with respects to HHPI responsiveness

HHPI highly effective in majority of BCCs

HHPI

HHPI plus SP-002

HHPI plus SP-002

Interferon – γ ablating residual BCCs (Interferon – γ reported to induce cell death in LGR5 stem cells) 4

Complete Responses Targeting CR >40-50%

1 Eberl et al, Cell 2018 33, 229

2 Biels et al, Nature 2018 562:429

3 Sánchez-Danés, Nature 2018 562:434

4 Takashima, et al Sci Immunol 2019 4:42

5 vismodegib product information sheet

SP-105

SP-105 comprises SP-002 in combination with a controlled-release cox-2 inhibitor to enable the local release profile that can provide a wider therapeutic window.

Scientific Rationale

Cox-2 and PGE2 expression is induced as a broad response to multiple treatment modalities, such as chemotherapy, 1,2 radiotherapy,3–5 immunotherapy,6–11 and viral infections. Cox-2/PGE-2 expression can decrease the efficacy of these modalities leading to treatment resistance through the inactivation of programmed cell death pathways 12,13 and immunosuppression. 6,7,14–17 Cox-2/PGE2 expression is also a key constituent of wound healing 18,19 and regeneration that can then foster persistence, relapse, and recurrence of cancers.20–23 The initial impact of Cox-2/PGE2 can result in dampening of the immune inflammatory response, but subsequent activation of the regeneration program can result in the expansion and mobilisation of stem cells (and cancer stem cells) resulting in the replenishment of the tumor with treatment resistant cancer cells. 11,20,21,24–26

Cox-2 Inhibitors and SP-002 both promote adaptive immune responses and direct anti-tumor effects through complementary pathways. 26,27 A key part of the regulatory feedback that dampens the cellular inflammatory response driven by Interferon-γ signalling, is the induction of Cox-2 expression 28 which suppresses cellular immunity. 26,29 Cyclooxygenase-2 expression within the tumour stroma enhances PDL1 expression in tumour-associated macrophages and myeloid-derived suppressor cells (the PD1/PDL1 nexus is a major regulatory checkpoint that can shut-down T cell responses elicited by Interferon-γ signalling).29 A second major negative regulator of T cell responses elicited by Interferon-γ signalling are regulatory T cells (Tregs). Cox-2 expression has been shown to be potent inducers of regulatory T cells. 17

Stage

Preclinical IND enabling studies.

SP-500 Platform

The SP-500 oncolytic platform has been designed to address the intratumoral heterogeneity present in cancers that can often undermine durable responses.

Scientific Rationale

In multiple cancer settings, early treatment success evidenced by complete responses , can rapidly giveaway to resistant recurrent cancer. 30–34

This, in part, may be attributed to the heterogenous nature of tumours, often comprising subsets of varying susceptibility to therapeutic intervention and cell death. 32,33,35,36 Often, more stem-like/progenitor subsets, which may comprise only a minor fraction have a higher threshold for cell death and retain potent proliferative capacity. 37–40 While, more differentiated populations, that may comprise the bulk of the tumor, can have a lower cell death threshold, resulting in impressive early regressions and clinical responses. The more resistant residual populations can persist, undergo further genetic or epigenetic alteration, and drive resistant recurrences and remodel the tumor microenvironment for progression.

The SP-500 oncolytic platform has been designed to induce programmed cell death across intratumorally heterogeneous tumor by invoking multiple non-redundant effector pathways that can impart varying thresholds for cell death. These vectors also carry payloads that remodel the tumor microenvironment for tumor eradication and aid in efficient viral vector dispersion throughout the tumor microenvironment.

Stage

Lead optimization.

References

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