Development plan and Pipeline
APR-246 - The key project
APR-246 (also called PRIMA-1MET) belongs to a new chemical class of small molecules which has shown to induce apoptosis with a p53 dependent mechanism of action. Aprea has conducted a Phase I/II dose-escalating safety study with APR-246 in patients with refractory hematological malignancies or prostate cancer. The results show that the compound is safe at predicted therapeutic plasma levels. The open labeled, dose-escalating study included 22 patients at seven clinics in Sweden. The study was designed to reveal the highest feasible dose of APR-246 (primary endpoint) after 2 hours iv-infusions for up to four consecutive days.
Additional preclinical studies and a continuation of the clinical study are ongoing to support the design of a clinical Phase II proof of concept study.
The competitive advantages of APR-246, as compared to conventional cytostatics, are:
- Induces apoptosis in p53 dysfunctional chemo-resistant cancer cells – offering the possibility to provide effective therapy even to patients who are resistant to conventional chemotherapy
- Demonstrated cancer cell specificity in primary cells from patients, i.e. higher potency in suppressing growth of cancer cells over normal cells, compared to conventional cytostatics
- Synergistic or additive effects with different types of conventional chemotherapy observed in various cell lines and primary cells from patients
- High therapeutic index, based on preclinical as well as clinical data
- Promising therapy for combination treatment without adding to the burden of serious side effects associated with current chemotherapy regimens
Due to its unique pharmacological properties and mechanism of action, APR-246 has the potential to be active in a broad range of cancer indications.
Aprea has been granted orphan drug designation in the EU for APR-246, for the treatment of acute myeloid leukemia (AML).
Project pipeline
- A Phase I/II dose-escalation safety study with APR-246 has been conducted at seven sites in Sweden. This was an open label, non-comparative, dose-escalating study of APR-246 infusions in patients with refractory hematologic malignancies or prostate carcinoma. A robust formulation of APR-246 has been developed for the study. The IMP is a solution for infusion, which shows good stability properties. The Phase I/II safety study and the ongoing clinical trial is planned to be followed by a Phase II proof of concept study. Additional preclinical studies to support the design of this study are ongoing.
- The development of APR-246 is planned to be followed by other CDs selected from the same chemical scaffold, including compounds for oral administration.
- In addition, Aprea owns patent rights for a new drug target, WRAP53. The novel gene WRAP53 has been shown to be involved in cancer cell survival. Knockdown of WRAP53 specifically kills cancer cells, whereas normal cells are less sensitive to WRAP53 depletion. Interesting recent data show a correlation between WRAP53 protein expression in head and neck cancer cells and survival of patients. The WRAP53 gene has moreover been shown to produce a natural p53 antisense transcript that is required for p53 induction upon DNA damage.
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Market overview
Some 10 million cases of cancer are diagnosed each year worldwide, leading to about 6 million deaths. The world market for anti-cancer drugs is expected to increase considerably. Sales of 70 billion USD were achieved in 2009. Despite major scientific breakthroughs and large investments in R&D in the Pharma sector, cancer is an area with very large unmet medical needs. Further advances towards improved therapy are thus urgently needed.
There are more than 170 oncology products (for treatment of solid tumors as well as hematological malignancies) in development today, representing more activity than in any other therapeutic area. The majority of those projects aim at finding a niche in treatment regimens for patient subgroups after conventional therapies have failed.
About 150 clinical trials exploiting the p53 pathway have been conducted (BioSeeker Group 2010). The first p53-related product to be approved (in China) was Gendicine®, a p53 gene delivery viral vector product. Other competitors include the MDM2 antagonists, currently in early clinical trials. APR-246 is unique in the ability to reactivate dysfunctional wild type and mutant p53, offering a potential therapy for treatment of drug resistant patient groups.
Strong patent portfolio
Aprea AB has filed applications for six patent families including quinuclidinone derivatives, and has more than 70 granted patents. This patent portfolio provides the company with comprehensive protection of its commercial opportunities.
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