Periodic Reporting for period 1 - ADC (Next-Generation Antibody-Drug Conjugates for safer and more effective cancer therapies)
Reporting period: 2016-05-01 to 2016-09-30
Overall objectives: To further advance the technology, OncoLinx will require to produce the High Potency Active Pharmaceutical Ingredient (HPAPI) molecule and to perform preclinical testing in rodents and non-human primates. These assays will be integral in bridging the gap between in vitro and in vivo work. The ultimate goal of the ADC development plan, described below, will be to better understand the compound(s) metabolite‐mediated toxicity and safety profile to make a concrete decision for the purpose of enabling the clinical trial application, which is a crucial part of the drug approval process. A Clinical Trial Application (CTA) package will be based on the Investigational Medicinal Product Dossier (IMPD) that contains previous data from literature and quality/non-clinical data from the following studies: bioanalytical method validation in one rodent and one non‐rodent specie; single and multiple‐dose toxicity and pharmacokinetic in one rodent and one non‐rodent specie; and in vitro CYP inhibition/induction in human liver microsomes. Assessment of the degree of binding of the drug candidate to plasma proteins, and of its metabolism during incubation in vitro with hepatic microsomes or hepatocytes from nonclinical species and human, are expected for non-biological drugs prior to the initial clinical study . The pivotal toxicology studies will be conducted in rat/monkeys as relevant species (predictive for humans) to evaluate potential on-and off-target safety risks. The target profile of this ADC drug candidate will be later stage patients with a specific breast cancer subtype such as HER2- positive, with the pre-clinical plan aiming to assess the safety of the conjugate antibody/drug in order to support first-in-human clinical trials.
2) (In vitro) Azonafide subnanomolar potency evaluated across 60 cancer cell lines
The 60 Human Tumor Cell Lines Screen showed that the Azonafide payload outperformed all other existing payloads on the market, with the ability to completely eliminate almost all tumor cells past the Lethal Dose 50 (LD50) value when most payloads can only inhibit cell growth.
3) (In vitro) ADC development and caracterization: steric hindrance resulting in optimization of linker-drugs
• Biostable, biocompatible, non-immunogenic linker
• Programmable number of attachment sites for a homogenous drug product
• Dramatic prolongation of ADC half-life
• Increases Pharmacokinetics (PK) of ADC, making it more stable in circulation
• Exclusive “click chemistry ” provide strongest linkage to payload
• Not susceptible to high-bioburden or microbial breakdown
• Stable at pH extremes
• Selective/tumor specific enzymatic cleavage/Antibody degradation
• Ensures small ADC structures that are soluble at high concentrations
4) (In vivo) Unique, stable half-life that mirrors naked antibody (Novartis Collaboration):
OncoLinx’s Azonafide ADC is stable in Circulation: this will minimize side effects and anticipated release of the cytotoxin payload (off-target toxicity).
OncoLinx’s previous research and development has addressed one of the greatest technical challenge facing cytotoxin development for use in ADCs: the need to have picomolar potency. In fact only about 1% to 1.5% of the toxin reaches the cancerous cells, and thus cytotoxins need to be 100 to 1,000 times more toxic than traditional chemotherapy compound. Azonafide-ADCs potency could then revitalize previously failed antibodies that exhibited strong antigen binding, but did not provide enough therapeutic effect on their own – perhaps because the targeted antigen was not central to the cancer’s growth. Such already tested antibodies could guide cytotoxic payloads to cancerous cells and this is the strategy OncoLinx wants to pursue for its first Azonafide-ADC to bring to the market.
Exploitation plan: OncoLinx’s ambition is for the Azonafide-ADC platform is to be adopted throughout Europe as first-in-line therapy for oncologic indications. To achieve this goal, OncoLinx needs to carry out successful pre-clinical studies, in rodents and non-human primates by testing the platform in an in vivo setting. In addition, this will allow OncoLinx to confer data on the toxicity, Pharmacokinetics (PK), bioavailability, and other clinically relevant studies that will help OncoLinx to secure approval for a first-in-human trial. These studies will validate the Target Product Profile (TPP) and will make the ADC platform an attractive asset for oncologic players. Once successful accomplished this stage, OncoLinx will be a uniquely differentiated project in strong position to approach a licensing deal for a specific oncologic indication with a big pharma company. Breast cancer is the important go-to market for OncoLinx as the potential to cure these patients with a targeted, long-term, safe therapy is higher than other forms of cancers, since current breast cancer immunoconjugates have demonstrated significant efficacy in progression-free survival (PFS) in and overall survival (OS) paving the way to gain approval of as first-line therapy.
Due to the relevant economic interests related to cancer pathologies, bringing Oncolinx’s therapy to the market will enhance the profitability and growth performance of SMEs and seizing European and global business opportunities.