Oncology - tigilanol tiglate

Oncology

 

QBiotics' lead molecule is tigilanol tiglate (EBC-46), a novel signalling molecule in development as an intratumoural treatment for a wide range of solid tumours. While tigilanol tiglate appears to be effective as a single agent treatment (monotherapy), we are also exploring its development in combination with immune check point inhibitor drugs.

Tigilanol tiglate is delivered as an injection directly into the tumour mass, usually without the need for general anaesthetic. Direct intratumoural administration delivers tigilanol tiglate right where it is needed, thus reducing the potential for systemic exposure and off-target toxicity.

Our experience in canine patients and early human clinical trials indicates that tigilanol tiglate is a well-tolerated and straight-forward, treatment regimen.

 

  

Human


Tigilanol tiglate has the potential to treat unresectable tumours that are in difficult to access areas, as well as tumours in patients that cannot

undergo surgery because they are too frail, are immunocompromised or in palliative care.

While our initial focus for the human market is Head and Neck Squamous Cell Carcinoma (HNSCC), Melanoma and Soft Tissue Sarcoma, there is the potential to treat a broader range of solid tumours that are accessible for injection via palpatation, or guided by imaging, such as prostate cancer.

Clinical Programs
Tigilanol tiglate exhibits promise for treating solid tumours in humans.

Clinical trial progress

A Phase Ia/IIb dose escalation safety trial in 22 patients with refractory skin and subcutaneous solid tumours has been completed. The results show that tigilanol tiglate is generally well tolerated with a maximum tolerate dose (MTD) not declared. Clinically-relevant tumour responses were observed across all 9 solid tumour types tested, including squamous cell carcinoma, melanoma, basal cell carcinoma, breast adenocarcinoma, atypical fibroxanthoma, myxoid fibrosarcoma, colorectal adenocarcinoma, adenoid cystic carcinoma and angiosarcoma (Panizza et al 2019).

In addition, 6 of the 22 patients (27%) experienced a treatment response, with 4 of the 6 patients (18%) achieving a complete response (full tumour destruction) in the injected tumour. Two of the patients with melanoma also had a response in a non-injected tumour (anenestic) response (Panizza et al 2019).

These promising results are supported by a strong body of pre-clinical evidence obtained in spontaneous tumours in dogs. (Link to TT vet).

Following these positive results, QBiotics is progressing clinical trials in patients with Head and Neck Squamous Cell Carcinoma, Melanoma and Soft Tissue Sarcoma. (See summary table below)

Tigilanol tiglate human clinical trial summary

 

Market Need

Monotherapy

Surgery is the standard of care for the treatment of solid tumours, however in many cases the tumours are unresectable (unable to be removed by surgery), can be disfiguring, or patients may be too unwell for surgery. Surgery requires not only removal of the tumour mass, but also a large margin of healthy tissue, and often the tumours are located in difficult to access areas. These tumours do not always respond to other treatments such as chemotherapy, radiotherapy and immunotherapy. As a result, there is a significant unmet need for new treatments that can remove unresectable tumours, especially in the head and neck region to preserve a person’s appearance, as well as critical functions such as sight, hearing, speech and swallowing.

Combination with immune checkpoint inhibitors

The immune checkpoint inhibitors (ICIs) such as Keytruda® (pembrolizumab) and Opdivo® (nivolumab) are leading the market for systemic treatment of solid tumour cancers . However, only a minority of patients respond to ICIs (about 20%), and many patients acquire resistance . Therefore, the pharmaceutical industry is focussed on identifying more effective treatment regimens, as well as new therapies to combine with ICIs to increase response rates and patient outcomes, without increasing toxicity .

Combination partners that work via a different mode of action to ICIs are likely to improve efficacy without increasing toxicity.

One possible new combination partner is tigilanol tiglate. Tigilanol tiglate has been shown to synergise with chemotherapy and radiotherapy as well as with checkpoint inhibitors (anti-CTLA-4 and/or anti-PD-1 mAbs) to destroy injected tumours and shrink non-injected tumours in a B16-F10 metastatic mouse model (a CPI refractory model) .

Disease incidence and prevalence 

Head and neck cancer is the 7th most common cancer globally, with ~1.46 million new cases reported in 2018, and ~962,000 deaths. It is associated with tobacco and alcohol use and its incidence is increasing due to human papilloma virus infection.

For melanoma, there were ~287,000 new cases reported globally in 2018, and ~61,000 deaths. The incidence of new cases of melanoma diagnosed each year is rising at 5% per year.

While the initial focus is on head and neck squamous cell carcinoma and melanoma, there is the potential for tigilanol tiglate to be developed to target other solid tumours, such as sarcomas and potentially internally located tumours, such as prostate cancer.

Solid tumours account for 90% of all cancers. In 2018, the World Health Organisation’s International Agency for Research on Cancer estimated that there were 18.1 million newly diagnosed cases of cancer and 9.6 million cancer deaths.

Mode of action

Tigilanol tiglate has a multimodal action, initiated by PKC-dependent and independent cell signalling mechanisms. It (i) induces a rapid, but highly localized, inflammatory response, (ii) significantly increases permeability of the tumour vascular endothelium, and (iii) causes rapid tumour cell death by oncosis. These effects lead to rapid tumour destruction of the treated tumour within 4 to 14 days . Once the tumour is destroyed, the site heals rapidly, generally without the need for sutures, antibiotics or special dressings .

Tigilanol Tiglate complex 2

Tigilanol tiglate is protected by both composition of matter and use patents in all major jurisdictions and extension patents have been filed.
The commercial production and supply of tigilanol tiglate has been secured. The source of tigilanol tiglate, the Blushwood seed (Fontainea picrosperma) , is produced in commercial plantations and is manufactured under c(GMP). Link to Commercial and Partners

Veterinary 


Tigilanol tiglate as an anticancer treatment for companion animals is well advanced. The European Medicines Agency, Switzerland’s Swissmedic and the United Kingdom’s Veterinary Medicines Directorate has approved tigilanol tiglate as a veterinary pharmaceutical for the first-line treatment of unresectable mast cell tumours in dogs.

Tigilanol tiglate, branded STELFONTA®, is marketed across Europe and the United Kingdom in partnership with Virbac, a global animal health company. STELFONTA® is also under late stage review by the US Food and Drug Administration – Center for Veterinary Medicines and the Australian Pesticides and Veterinary Medicines Authority.

In a pivotal, multi centre, randomised, blinded and controlled study conducted in 123 dogs, a single treatment with tigilanol tiglate completely destroyed (Complete Response) 75% of mast cell tumours, compared to the control group (p<0.001). See Figure x. A second tigilanol tiglate treatment increased the Complete Response rate to 88%, with no local tumour recurrence in 93% in dogs at 84 days post treatment. Importantly, tigilanol tiglate was very well tolerated and animals had a good quality of life during and after treatment.

Further clinical trials are in progress in Australia, the USA, Europe and the UK to determine efficacy in other solid tumours and in other veterinary species, for example canine soft tissue sarcoma, and equine sarcoids.

Canine Tumour Volume w legend

Market Need

Dogs

Mast cell tumours are the second most frequent cancer diagnosed in dogs, accounting for up to 21% of skin cancer cases . STELFONTA® is the first pharmaceutical treatment available for all grades of canine non-metastatic mast cell tumours. It represents an attractive additional treatment option for mast cell tumours in dogs, especially where tumours are difficult to remove because of their location and in older dogs, where anaesthesia carries inherent risks. Generally, dogs undergoing treatment do not need to be sedated, or need local or general anaesthesia.

Horses

Sarcoids are locally invasive, fibroblastic skin tumours and represent the most common tumour in horses worldwide , with an incidence ranging from 12.5 to 67% of all neoplasms . Currently, there is no uniformly effective therapy for equine sarcoids. Current treatments involve surgery, cryotherapy, hyperthermia, radiotherapy, chemotherapy, immunotherapy, topical immune modulation and antiviral agents, all with variable degrees of success and adverse event profiles. Consequently, there is significant need for an efficacious and safe treatment for solid tumours in horses.

Preliminary clinical trials with tigilanol tiglate in horses with sarcoids, squamous cell carcinomas and melanoma, have shown promising results and further clinical studies are currently underway.

Cats

Current treatment options for solid tumors in cats are limited. Surgery is the mainstay for solitary tumours and when surgery is not possible, treatment is often palliative at best. Consequently, there is significant need for an efficacious and safe treatment for solid tumours in cats.

Clinical case studies with tigilanol tiglate treatment of a range of tumour types in cats show have shown initial encouraging results, and further investigations are underway.

 


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