Aprea AB

– Putting Defective p53 Back into Shape

Aprea is a Swedish biotech company focusing on discovery and development of novel anticancer compounds targeting the tumor suppressor protein p53. APR-246 has been developed based on results from researchers at Karolinska Institutet, Stockholm, Sweden. The main owner of Aprea is KDev Investments AB, part of Karolinska Development AB (publ).The other main owners are Östersjöstiftelsen, Praktikerinvest and KD Co-Investment Fund KB.

Aprea develops target-specific drugs for the treatment of cancer by restoration of p53 function. We have a unique portfolio of molecules that via p53-dependent pathways induce apoptosis in cancer cells. Mutant p53 is an attractive target for novel cancer therapy and a number of oncology indications demonstrate a high degree of p53 mutations. Patients with ovarian cancer, small cell lung cancer, non-small cell lung cancer, colorectal cancer and head and neck cancer all demonstrate high degree of p53 mutations and receive platinum-based therapy as part of the standard treatment regimen, which enables a range of potential product label opportunities.

Cancers develop and spread due to the malfunction of the cells’ normal growth control mechanisms. One of the best-known cancer genes is p53 that can trigger the cellular suicide program to eliminate cancer cells. In about half of all tumors, p53 is mutated and no longer functions normally. This allows cancer cell survival and rapid tumor growth. The p53 status of a tumor has a strong impact on sensitivity to commonly used anti-cancer drugs and radiotherapy. Thus, p53 is important both as clinical marker and as a novel therapeutic target. In contrast to other tumor suppressor genes, p53 is typically inactivated by single missense mutations, which is accompanied by loss of the remaining wild type allele. As a rule, mutant p53 proteins are deficient for specific DNA binding, suggesting that DNA binding and transcriptional regulation of target genes are critical functions for p53-mediated tumor suppression.

The fact that p53 is mutated in around 50% of human tumors, that mutant p53 is usually expressed at high levels, and that mutant p53-expressing tumors respond poorly to conventional therapy makes mutant p53 an attractive target for novel targeted cancer therapies.

Our candidate drug, APR-246 (also known as PRIMA-1MET), is a p53-reactivating small molecule with promising clinical and preclinical results. APR-246 has been shown to induce apoptosis and cell death in cancer cells with mutant or otherwise non-functional p53 and has strong synergistic anticancer effects in combination with several conventional chemotherapeutic drugs. APR-246 activates the function of p53 and triggers programmed cell death in tumor cells. This function appears to be a unique characteristic of APR-246. APR-246 has a documented anticancer potential in a range of tumor types both as mono-therapy and in combination with conventional chemotherapies.

Clinical results from our first Phase I/II trial of APR-246 were published in the Journal of Clinical Oncology in 2012 demonstrating its safety. The trial successfully demonstrated that APR-246 was well tolerated as a single agent. Although this was primarily a safety trial, the data also indicated that APR-246 had an anti-tumor effect. This resonates well with our preclinical results, in which APR-246 has been shown to induce cell death in many cancer cell lines with varying p53 status. Aprea has also demonstrated that cells from platinum resistant cell lines treated with APR-246 can be re-sensitized to platinum based agents. Our results indicate that APR-246 may be an attractive combination product with standard of care platinum-based therapies.

APR-246’s lead indication is ovarian cancer where there is a high unmet medical need, in particular in the recurrent setting. Although more than 70% of patients respond to standard first line therapy of carboplatin and taxanes, 75% of these patients will relapse within 30 months. Unfortunately, present therapies for recurrent ovarian cancer patients have little impact on survival and there is therefore a high unmet medical need for novel therapies. Our first-to-patient strategy is based on developing APR-246 for the treatment of platinum sensitive recurrent p53 mutated ovarian cancer patients in combination with the standard of care platinum-based therapy. A clinical proof-of-concept study is ongoing in which the efficacy and safety of APR-246 will be demonstrated in recurrent high-grade serous ovarian cancer patients, which demonstrate very high (96%) degree of p53 mutations.

APR-246 may synergize with any agent that relies on p53-dependent apoptosis when it is administered to mutant p53 tumor cells. Its effect on mutated p53 cells provides a significant market opportunity for APR-246, since p53 mutations occur in more than half of all tumors. By establishing a proof-of-concept for APR-246 in a well-defined patient population with a high degree of p53 mutations (HGSOC), we aim to pave the way for a future expansion of the usage of APR-246. Label extensions to other indications are part of our commercialization strategy.

APR-246’s unique mechanism provides a significant market opportunity to expand the usage to any condition treated with drugs benefiting from p53-dependent apoptosis. Moreover, new analytical methods pave the way for patient selection through a personalized medicine’s approach.

Our development strategy is supported by a strong asset portfolio. We have developed a proprietary class of novel molecules, known as quinuclidinones. APR-246 converts to the active compound MQ, in physiological conditions. This makes APR-246 a pro-drug of MQ and we have therefore developed a solid portfolio strategy that protects it both up- and downstream, together with a novel formulation and oral second-generation drugs. APR-246 is patented for broad medical use in cancer therapy. The competetive position for APR-246 is expected to be strengthened by further regulatory data protection preventing access to our proprietary data and market exclusivity through orphan drug protection for the treatment of ovarian cancer.

Aprea2Combining cisplatin and APR-246 produces a strong synergistic anticancer effect on primary cancer cells from an ovarian cancer patient.







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