Periodic Reporting for period 1 - ADC (Next-Generation Antibody-Drug Conjugates for safer and more effective cancer therapies)
Periodo di rendicontazione: 2016-05-01 al 2016-09-30
Non-discriminating cancer therapies, including chemotherapy and radiation, marginally differentiate between tumour and healthy cells. However, these therapies have defined the paradigm of cancer therapy for the last 50 years. Current forms of cancer therapies manifest serious side effects including edema, hair loss, nausea, internal bleeding, vomiting, fatigue, muscle/joint pain and others. Antibody drug conjugates (ADCs) are a class of therapeutics that harness the antigen-selectivity of antibodies to deliver highly potent cytotoxic drugs to antigen-expressing tumour cells. New effective and less-invasive technology are needed: with approximately 14 million new cases and 8.2 million cancer related deaths in 2012 worldwide, there is an increasing urgency to find more cures for more patients. Solutions are needed to improve life quality for patients undergoing treatment and also eliminating cancer, while decreasing rates of recurrence and relapse. OncoLinx has developed an ADC platform that will create the next generation of ADC therapies with Azonafide payloads specifically targeting cancer cells, while sparing healthy cells—resulting in superior treatment and manageable, milder side effects. Oncolinx’s platform is composed of the payload (Azonafide) and a chemical linker sequence, whose technical features make this drug complex when coupled to any antibody and therefore targeting any possible cancer type. The Azonafide platform has the unique ability to both induce cancer cell death and activate the immune system. Furthermore the highly efficient linker technology allows for an easy synthesis and conjugation enabling the commercialization of a cost-effective chemotherapeutic product. No other oncologic drug, currently marketed, is able to address therapy effectiveness, reduction of side effects, and healthcare cost-savings at the same time with an unique product. During the feasibility investigations, OncoLinx established that in order to achieve the target product profile features and the commercialization capacity (license deal) the technology must be optimized and its safe profile extensively proved in in vivo validation studies. A strategic plan will minimize R&D costs by collaborating with strong partners – like Abzena -, and perform the preclinical development in order for the Azonafide-ADC to be approved for the first-in-human clinical studies and other clinical studies.
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.
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.
1) Computational Modeling Generated Portfolio of Potent Azonafides: Azonafide 1 chosen as lead cytotoxic candidate
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.
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.
Azonafide conjugates ability to discriminate both normal and pathological conditions accurately responds to one of the main challenge related to the medical research and practice. Having been successfully committed to the development of innovative therapeutic molecules, Oncolinx is positioning at the centre of the ADCs scene, which represents now the cutting edge of cancer treatments and one of the most advanced stages of the healthcare biotechnology sector. Over the past decade pharmaceutical companies have started to commercialize ADCs. With nearly 65 active clinical trials, ADCs are gaining acceptance across the globe as they offer superior pharmacological efficiency along with minimized side effects. Since the early 2000’s two ADCs have been approved (Kadcyla and Adcetris) and only one addresses the unmet need in breast cancer. The Global Antibody Drug Conjugate Market & Pipeline Insight 2020 report shows that ADCs market increased at a CAGR of approximately 87.2% during 2011-2014 and is expected to grow at a CAGR of 20% during the period 2015-2020. Although many potential new ADCs are proposed every year only a few of these have been validated for clinical application, conferring the attempt to penetrate the reference market a high innovative and disruptive potential. In addition, the potential of combination therapy with checkpoint inhibitors prove Oncolinx has a unique approach to shrinking tumours and preventing recurrence through immune activation. Oncolinx’s solid technology, whose proof of concept has already been extensively demonstrated with in vitro and preliminary in vivo studies, has definitely all the prerequisites to provide evidence for high analytical value, appropriate sensitivity and specificity, and clinical validity. Azonafide conjugates will lead to better health outcomes while contributing to the sustainability of the health care system. This will be reflected not only in reducing the amount of money spent on needless treatments, but also in the opportunity to deliver better cancer care through a cost-effective breakthrough technology. Moreover, as investigated during the feasibility study, new performance-based reimbursement systems are now in place in Europe to encourage the adoption of effective and cost-saving therapeutic solutions, which is directly relevant to OncoLinx’s chemo-product future uptake. With the increasing costs for anticancer therapeutics, and an extremely fragmented reimbursement system in Europe, people may have to choose between more successful expensive treatments and less effective, affordable approaches. ADCs platform will solve this dilemma since it is based on a highly efficient linker technology allowing for the synthesis of the conjugate compound in fewer and cost-effective steps than comparable solutions. Such economic and performance advantages will ease the Azonafide-ADC therapeutic adoption in both, public and private sectors all across Europe. However, given the hurdles in some EU reimbursement national systems, OncoLinx will initially target the higher-income states, including Austria, France, Germany, The Netherlands and Sweden. These countries spend, on average, more on health given their GDP (Gross Domestic Product) per capita, allowing pioneering and innovative treatments – including targeted therapies and personalized medicine – to be available for patients in these countries
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.
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.