Oncology SYD003

SYD003 - Oncology candidate

 

Name of the candidate:

SYD003.

 

Orphan indication:

Pancreatic cancer.

Orphan designation:

EMA on 22 August 2014 (EU/3/14/1323).

FDA on 20 October 2014.

Treatment of pancreatic cancer

 

Other potential indications:

Bladder, lymphoma, liver and lung cancer.

 

Description/mode action:

Immune modulator.

 

Stage of development:

Preclinical proof of concept in validated pancreatic cancer murine model.

Orphan designation by EMA and FDA for the treatment of pancreatic cancer.

Development plan consulted with the SAWP CHMP EMA (Protocol Assistance)

 

Clinical safety:

Projected human dose > 80-fold safety margin

(Based on clinical studies).

 

Route of administration:

Oral.

 

Manufacture / Formulation:

Easy and inexpensive formulation.

 

Therapeutic approach:

SYD003 is expected to be effective in the clinic alone but would most likely benefit current chemotherapy and other immunoactivating strategies.

 

Regulatory Status

Synovo has been granted orphan drug designation for SYD-003 by the FDA and the EMA for the treatment of pancreatic cancer. In addition, the company has received protocol assistance from the Scientific Advice Working Party (SAWP) of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency for the clinical development of the drug candidate. The next step in the development of SYD-003 is a Phase I trial in the EU.

 

Preclinical Data in Pancreatic Cancer

In vitro activity

In vitro, SYD003 causes a change in the cytokine production and macrophage phenotype. This data are consistent with the observed from in vivo studies.  

 

In vivo activity

The drug candidate has demonstrated excellent anti-tumor activity in a mouse model of pancreatic cancer which is the gold standard in the industry (murine pancreatic ductal adenocarcinoma model) that clearly shows that drugs that have no efficacy in pancreatic cancer in humans also have no efficacy in mice:

- SYD-003 alone, as well as in combination with Gemcitabine (standard of care), significantly prolonged survival of tumor-bearing animals.

- SYD-003 alone reduced the liver metastasis incidence in about 40% and administrated in combination with Gemcitabine almost 50%.

- Animals treated with SYD-003 showed elevated gene expression levels of IFNg and IL12 while reduced levels of IL10 compared to control mice, which is indicative of a switch from an immunosuppressive milieu towards an immune-stimulatory one.

SYD-003 has shown further impressive results in animal models of other cancers (bladder, lymphoma, liver and lung) so that there is ample scope for developing the drug for other cancer indications as well.

 

SYD003 Survival in KPC mice

 

Repurposing

SYD-003 was initially developed by a third party in the late 1990s for use in rheumatoid arthritis. This drug candidate was subject to studies in phase I in which it demonstrated high oral bioavailability and no adverse effects.  The highest dose tested was 4 g. In a subsequent trial it was then administered to rheumatoid arthritis (RA) patients over a 28 day treatment cycle using doses up to 750 mg/day.   No adverse effects were observed, however, no clinical effect was reported either.  Indeed, based on what is now known about the molecule, one would not expect it to bring clinical benefit in RA.

Given that the active murine dose is 3 mg/kg i.p. – i.e. 210 mg directly scaled to a human patient, it is clear that the dose range already tested probably exceeds that which will be required for use in oncology by far.   Therefore, it is unlikely that one would encounter issues of tolerance in dose finding in oncology trials. Based on these facts SYD-003 promises to have a very wide therapeutic window.

 

Mode of action and relationship to checkpoint inhibitors

SYD-003 modifies the immune-tolerance characteristics of the micro-environment around the tumor, leading to a less immunosuppressive state and, therefore, a more effective anti-tumor response. The influence of myeloid cells (i.e. macrophages) on lymphoid cells (i.e. T-cells and natural killer cells) makes SYD-003 a highly relevant combination therapy for checkpoint inhibitors. Therefore, owners of PD-1 inhibitor programs will have a significant interest in developing combination therapies with the “checkpoint agonist” SYD-003.  

SYD-003 reduces the amount of tumor associated macrophages (TAMs) with M2 phenotype and instead induces tumoricidal and stroma-depleting macrophages with an M1 profile, which enhance the anti-tumor effect.  By activating M1 macrophages, additional cells of the immune system are being recruited and can participate in immune-mediated tumor destruction. SYD-003 causes the accumulation of IL-12 which overrides tumor immune suppression and stimulates T-cells and Natural Killer Cells which attack the tumor.

SYD-003 induces a switch in the tumor cytokine profile, improving the ratio between stimulatory and inhibitory cells in the tumor microenvironment. In the presence of co-signaling factors such as TNFα and TGFβ, SYD-003 causes a change in myeloid signaling leading to increased synthesis of the anti-tumor cytokine IL-12.  Importantly, in the absence of tumor driven pathological co-signaling, SYD-003 appears to exert no obvious pharmacological effects in healthy animals outside of tumor microenvironments; i.e. the tumor-selective action of the drug molecule prevents burdening other, tumor free parts of the body.

While significant competitors of Synovo in the myeloid signaling field find themselves still in the discovery phase with their key assets at this time, SYD-003 is practically ready for clinical testing.

 

Business development

For business development information or other enquiries in relation to this project please contact:

 

United States and Canada:

 

       Mathias Woker

       Head Synovo North America

       mathias.woker (at) synovo.com

 

Europe:

 

       Michael Burnet

       Managing Director

       Synovo GmbH

       Germany

       michael.burnet (at) synovo.com

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