E!11435 Targeted alpha therapy in the treatment of ovarian cancer.

The aim of this project was to develop a new drug which can be an addition to established therapy for metastatic cancer. The method is particularly planned for treatment of very small tumors that are difficult or impossible to detect in the abdominal cavity. It is empirically known that such tumor growth exists, which is why adjuvant cancer therapy is given to eliminate such socalled micro-metastases. The basic idea is to use a new class of radioactive compounds, alpha emitters, which have a very short irradiation range. The principle is that the radioactive nuclide is conjugated with a targeting molecule, e.g. an antibody. After injection, the antibody binds to the cancer cells, which are therefore irradiated selectively. Alpha emitters are more suitable for the treatment of small tumors than other radioactive compounds since the short emitting range (<0.1 mm) ensures that the irradiation energy is concentrated towards the micro-metastases where the antibodies have attached, and not distributed into other tissues. This project will test another antibody than previously studied. Animal studies show that the new one has the same characteristics as the previous antibody. First, we aim to conduct a small study in patients, which will later be followed by the major study in about 200 women who have had surgery of their ovarian cancer and who apparently are free from tumors after chemotherapy. ACHIEVEMENTS We wished to conduct a clinical first-in-man study to investigate pharmacokinetics, bio-distribution, safety and toxicity. Under the project period, it was however a need to change the carrier of the radionuclide, the monoclonal antibody. The manufacturer of the planned antibody, a small American bitech company, was acquired by a large pharmaceutical corporation, and this larger one had no interest in continuing the research collaboration from the past. In addition, they decided to halt or terminate their own development of the antibody. This replacement of the antibody in our combined product caused significant delays in the project. Therefore, the aim of commercialising the results have not yet been met. However, the project partners have agreed to continue the collaboration on the development and commercialisation also after the conclusion of the Eurostars-financed part of the project. What we have achieved though, is the conduct and completion of several publishable pre-clinical trials with the new antibody (trastuzumab) conjugated to our radionuclide (211-astatine). Furthermore, we have successfully completed a very complex application for an extended manufacturing license for this conjugated drug product. Manufacturing of radioactive study drugs are strictly regulated and a huge infrastructure of qualified professionals and quality management systems and procedures are required to obtain such a license. During the Eurostars project we, through our Swedish partner, have indeed achieved such an approval from the Swedish Medicines Agency. We have also developed complex documentation related to obtaining a clinical trial approval for the planned phase 1 study in patients. In addition to the comprehensive study protocol, a complete investigational medicinal product dossier (IMPD) for the study drug has been developed. The IMPD is a collection of complete data on manufacturing (pharmaceutical quality and controls), non-clinical efficacy and toxicity, and relevant clinical recommendation based on presumed tolerability in humans. This clinical trial application with the IMPD is now ready for submitting to the authorities. Due to the implementation of the new European system (CTIS) for application of clinical trials we have acquired very useful and complex knowledge, experience and competency related to this work package. This new system requires a transition to a more centralised procedure in Europe and combines the application to competent authorities and ethics committees in one common application filing. This has required that new procedures and forms have been developed and applied. Likewise, new and updated coding systems for clinical data (CDISC) has been implemented, again strengthening our experience and competency base following the project. In terms of commercialising, the collaboration has led the project partners to establish a joint venture company, Aprit Biotech AB, which is our common tool for exploiting the results commercially. A preliminary business plan together with an investor pitching slide set has been developed. It is emphasised that the collaboration between the partners has been exceptionally good during the entire project period, and will be an extraordinary good example for how the private-public R&D collaboration can be facilitated and encouraged through public financing such as Eurostars grants.

OUTCOMES As partner, we have increased our competency level and experience base significantly through our work in the project; this mainly relates to deep knowledge into a highly innovative and relevant medical field (targeted alpha therapy, radionuclide medicine) in general, and very specifically competency in the following complex areas: manufacturing license requirements for radioactive investigational medicinal products, the new pan-European clinical trial application system (CTIS) and the new CDISC formats for clinical trial data capturing and reporting. Further, our joint ownership of the Aprit Biotech AB company for commercialising results is of significant value to us. IMPACT In terms of societal impacts, we will have to await the outcome of the clinical phase 1 trial to report any such impact.

The proposal builds directly on previous experience at our academic partner, the TAT (Targeted Alpha Treatment) research group at Sahlgrenska Academy, University of Gothenburg. In this particular project, we will employ the radionuclide astatine-211 which is produced by the PET and cyclotron unit at Rigshospitalet, Copenhagen. Partnering with US pharma company Morphotek or another provider, will now enable this consortium to access a targeting antibody, which is specifically targeted towards receptors that are overexpressed in ovarian cancer. The main pillar (WP5) in this Eurostars proposal is a First-in-Patients clinical trial in order to study bio-distribution and toxicity of the new conjugate (211At-MAb) in humans. We will conduct a small phase 1 study in female patients in complete clinical remission after second-line chemotherapy for recurrent ovarian carcinoma. This study will include 3 patients in each of 3 activity (doses) levels. Pharmacokinetic analyses will enable us to describe bio-distribution, i.e. whether or to which level doses are absorbed to various organs, whether adequate doses will reach the tumor cells. Also the PK of possible degradation products will be determined. Furthermore, possible side effects will be explored together with any dose-limiting toxicity. Embedded herein is also a complete regulatory affairs research work package (WP2). Regulatory intelligence is required to design the optimal clinical development path for our drug, and is an essential component of the business plan. Specifically, obtaining and maintaining the orphan designation status in the EU and the US is critical, as are periodic scientific advice meetings with the relevant agencies.