2019-06-011 - AONs2CureCancer - Splicing-modifying antisense oligonucleotides to treat lung cancer

AONs2CureCancer

2019-06-011

AON Therapeutics presents first in class alternative splicing modifying oligonucleotides to treat lung adenocarcinoma by targeting Notch-pathway regulator gene NUMB. When intranasally administered, the two lead AONs reduce tumor growth in a genetic mouse model (KrasG12V), an orthotopic mouse model (human A549) and two Patient Derived Xenografts (PDX, p53 and Kras mut).

Health and safety

Advances have improved the understanding of the LUAD pathology. Multiple identified signalling pathways and specific driver mutations lead to malignant transformation and LUAD progression. While for LUADs with a known driver mutation substantial clinical benefits can be achieved, no known drivers are detected in most patients, who are still empirically treated with standard cytotoxic chemotherapy and immunotherapy. Thus, our AONs, targeting a novel alteration observed in most LUAD cases and other cancer types, as reported to date by different cancer genome projects, could have huge social and economic impact if proven to be effective over standard treatment. The challenge we face is to improve patients’ treatment options, life quality and expectancy, and reducing productivity losses and health-care related costs due to premature death and morbidity through the use of novel compounds targeting AS-related diseases.

Lung cancers are amongst the most common tumours in the world representing 2.1 M cases in 2018. LUAD, a form of non-small cell lung cancer (NSCLC), is by far the most common subtype. About 70% of these patients get diagnosed when the cancer has already spread to lymph nodes or distant organs. About 50% of this subgroup, display a known driver mutation for which targeted first-line therapy exist or is eligible for immunotherapy. However, for the other 50%, only classical chemotherapy is available. The problem is the lack of sufficiently effective first-line treatment options for this patient population. Indeed, its estimated 5-year survival rate is 27%, meaning that roughly 500,000 patients worldwide are predicted to die within 5 years. Next to the emotional burden for patients and family, the economic burden including healthcare cost, productivity loss and informal care is enormous (only in Europe already €199 B in 2018). We propose to target alternative splicing (AS) of the NUMB gene. AS is a process that leads to different protein variants from a single gene by differential selection of exonic sequences. Increased NUMB exon 9 inclusion encoding a pro-proliferative isoform, is observed in the vast majority of LUAD tumours, more prevalent than any driver mutation. Its degree of inclusion correlates with worse disease prognosis. Public sequencing data show increased NUMB exon 9 inclusion also in many other cancer types. Thus, targeting NUMB exon 9 inclusion could provide a new, improved treatment option for LUAD patients without any actionable driver mutation. It could also benefit patients with known driver mutations without existing targeted treatment and, if proven to provide an improvement, for those with existing targeted treatment as well. Thus, its targeting could represent a paradigm shift in cancer treatment potentially reaching, and providing benefit to the full LUAD population and beyond. Our solution is novel proprietary AS modifying AON, being short, synthetic, chemically modified single-stranded RNA that are highly specific for the NUMB gene. Our novel therapeutics correct NUMB exon 9 pathological inclusion, significantly inhibiting cell proliferation and reducing tumour growth in four different LUAD mouse models.

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1) licensing CRG’s IPR to a pharmaceutical company at some stage of clinical development, although given the reality of drug development as pharma usually enters in such deal after positive clinical proof-of-concept (successful Phase II trial), this option (and with the lack of funding possibilities to reach such stage as an academic research institute) is least anticipated. 2) the creation of the spin-off company with a license to develop CRG’s IPR with or without an upfront payment; 3) the licensing of a product of the spin-off company, or sale of the spin-off company, to a larger pharmaceutical company which will then complete clinical development and commercialize the product.

The standard first-line treatment option for advanced LUAD patients without any actionable oncogenic driver mutation is platinum-doublet chemotherapy with immunotherapy. Its limitations are, that, despite the emergence of immunotherapy being a major breakthrough for cancer treatment, this patient population with a programmed death-ligand 1 (PD-L1) tumor proportion score of <50% 1) has still low treatment response rates (<20%), 2) develop treatment resistance and 3) suffer hazardous side effects leading eventually to poor survival rates. The same is true for existing targeted therapy against the genetic driver mutations ALK/ROS1, EGFR and BRAF. Developing novel therapeutic approaches that are more effective, do not generate resistance, are less toxic and are generally applicable to a broad range of lung cancer patients, remains an urgent unmet need. The high heterogeneity of molecular abnormalities driving lung cancers greatly contributes to the limited effects of current treatments.

Our flagship AON product will enter the non-small cell lung cancer (NSCLC) therapy market, which is segmented geographically due to the various regulatory regimesand IP geographies.The global oncology market is projected to reach€489B in 2028. The global NSCLC market size is expected to reach €37.7 billion by 2029, growing at a Compound Annual Growth Rate (CAGR) of 7.2% in the 8 main markets (NSCLC Global Drug Forecast and Market Analysis to 2029 –Global Data 2022 Update).The North American NSCLC market is the largest, and was valued at €9.6B in 2019. This market is projected to reach €14.8B in 2029, at a CAGR of 4.4%. The European NSCLC market is expected to reach €7.4Bin 2029. Some of the factors driving the market are increases in lung cancer prevalence and rising demand for safer cancer treatments.

- 2M euro to complete preclinical phase (2025-2026); - 5M euro for conducting Phase 1 (2027).

Investors

1. Lead optimization and preclinical candidate selection (2025) 2. Preclinical (2026-2027) 3. Phase 1 (2028-2029)

Our AONs could be the first splicing modifiying therapy in the oncology field.

For any therapeutic to reach the market, the possible main limitations are safety and efficacy. However, we have strong believe that those limitations will be overcome. Our in vivo results confirm its efficacy and safety through different locally delivery methods. In addition, the AONs target indirectly, a validated cancer pathophysiological pathway (Notch) by splicing correction with very high specificity and consequently, likely less or no off target effects in contrast to other Notch pathway modulators such as gamma-secretase inhibitors. The recent approval by the FDA and EMA of SPINRAZA® (nursinersen), the first effective treatment for spinal muscular atrophy, further underlines their potential representing a proof of concept of the remarkable tissue penetration, stability, specificity (safety) and efficacy of AONs as splicing modifying reagents whose therapeutic potential is only started to be explored.

- Lead optimization (chemistry, formulation and administration method), - Definition of safety and efficacy profile in vivo of the optimized lead compound, - Spin-off creation (first technology transfer point), - Establishing GMP-like manufacturing conditions, - Carry out regulatory pre-clinical studies to enable IND-filing, - Carry out Phase I/II clinical studies to establish safety and proof-of-concept efficacy in LUAD human patients, At this stage the spin-off company would be able to find a pharmaceutical company partner to complete the clinical development (second technology transfer point) and, if the results of such trial are positive, start commercializing the product.

Patents: WO2019180046A1; PCT/EP2019/056889 - Mar 29th, 2019 - Status: Filed

We are currently not directly looking for funding from investors since the project is covered by the EIC Transition until preclinical tox up to a certain extent. We prefer to engage with investors once robust data on the lead compound and formulation and benchmarking against standard of care are available.

-patent family WO 2019/180046. - additional patents protecting the technology of novel nanocarriers combined with new chemistries/administration pathways. - know-how on novel applications/indications of our current AONs. - know-how on future to be designed AONs to novel identified targets.

AONs target an actionable cancer alteration and distinguishable by a PCR (as a potential companion diagnostic). Increased NUMB exon 9 inclusion is more prevalent than any known driver mutation in in lung cancer. 98% of the patients have higher levels of NUMB exon 9 inclusion than healthy tissue. Patients with exon inclusion levels higher than 50% (42% of all lung adenocarcinoma patients) die significantly sooner. AONs exhibit high specificity. Thus, potential off-target effects are reduced. Other companies are currently using splicing-modifying AONs to treat Spinal Muscular Atrophy and Duchenne Muscular Atrophy. Therefore, regulatory pathway for AON is already defined. Lower likelihood of resistance: AONs can remain effective despite point mutations in their target sequence, and these are also likely to affect the binding of the factors antagonized by the AONs.