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Imaging NM: A Nanoparticulate Precision Medicine Approach to Target Cancer

Periodic Reporting for period 3 - INTACT (Imaging NM: A Nanoparticulate Precision Medicine Approach to Target Cancer)

Reporting period: 2019-11-01 to 2020-06-30

Cristal Therapeutics (CT) develops the next generation of nanomedicines to treat cancer. Cancer remains one the leading causes of death worldwide, and current treatment options are insufficient, in part due to the tumour heterogeneity in between patients. CT has developed state-of-the-art nanoparticles (CriPec®) to passively target a drug of choice for increased retention in the tumour site(s). The superior therapeutic performance of this approach has already been demonstrated preclinically for CT’s lead product CriPec® docetaxel and a promising clinical phase I trial has been finalised providing a significantly improved pharmacokinetic and safety profile. CT already observed therapeutic activity in patients and substantially reduced adverse events such as neutropenia and alopecia. In INTACT, CT will perform a phase II clinical trial in ovarian cancer to evaluate the therapeutic efficacy and safety of CriPec® docetaxel. Furthermore, CriPec® docetaxel will be decorated with a PET tracer (89Zr) which enables oncologists to visualize CriPec® biodistribution in patients in real-time.

The 89Zr labelling approach has the potential to turn CriPec® nanomedicines into personalized medicines whereby only those patients that benefit from enhanced tumour targeting will be treated. This personalisation would allow for increased efficacy in pre-selected patients, avoids exposing patients to inappropriate drugs and adverse effects.

CT will use INTACT to close the gap from lab to market and will validate the CriPec® nanomedicine platform and boost product development for other diseases through licensing deals. Success in INTACT will truly launch Cristal Therapeutics’ business.
Since the beginning of INTACT, significant progress has been made. Desferal (Df)-CriPec® docetaxel labelled with 89Zr and 91Zr (91Zr for analysis and characterisation as radioactive 89Zr cannot be analysed at Cristal Therapeutics) has been successfully manufactured at small scale in very close collaboration between CT and VUMC. The 91Zr-Df-CriPec® docetaxel was shown to have equal pharmaceutical characteristics to non-labelled CriPec® docetaxel and was compliant with the target SPECs set at the beginning of the project. In other words, the conjugation of Zr to the surface of CriPec® does not affect the characteristics of the CriPec® docetaxel particles.

In vivo and ex vivo quantification of 89Zr-Df-CriPec® docetaxel in healthy and tumour bearing SCID mice was performed. In both healthy and tumour bearing mice, the PK profile was comparable to that of CriPec® docetaxel, thus that 89Zr labelling did not affect the biological profile (i.e. so-called bioequivalence). Accumulation of 89Zr-Df-CriPec® docetaxel in tissue could successfully be measured via PET scan, including enhanced tumour accumulation thus providing the preclinical proof of concept.

Based on all promising formulation development and preclinical evaluations, Df-CriPec® docetaxel has successfully been manufactured under GMP conditions at clinical scale compliant with all predetermined SPECs.
For the phase I clinical protocol and all correlated documents were compiled and submitted to the regulatory authorities. The phase I study (Piccolo) received approval and 7 patients were included in the clinical evaluation including PET/CT imaging. Proof of principle of the non-invasive imaging approach has been clearly achieved with long circulation, imaging up to 168 hours after injection and non-invasive quantitative accumulation of 89Zr-Df-CriPec® being observed in in a large fraction of tumours. Meanwhile, several evaluable tumours did not show uptake, which again proves the heterogeneity within or amongst patients and illustrating the need for patient stratification.

At this time, the CINOVA phase II trial has been completed confirming the improved safety profile of CriPec® docetaxel but unfortunately, despite promising early signals, the efficacy endpoint was not met in this patient population. Along with the project preparations were made for the confirmatory phase III trial in metastatic castration resistant prostate cancer including advice from regulatory agencies in Europe and the US. Cristal Therapeutics extensively approached many potential industry partners to license the programme ahead of the start of the phase III trial. However, due to the lack of efficacy data from the phase II CINOVA trial it has not yet been possible to close a deal.
In parallel to INTACT, Cristal Therapeutics has successfully developed and applied for patent protection on a new technology to enable the labelling of the surface of CriPec® particles via metal-free click chemistry called CliCr®. This novel class of reagents has proven superiority to other proprietary compounds available and means Cristal Therapeutics now has complete freedom to operate with 89Zr-Df-CriPec® docetaxel and will not have to rely on licensing IP from third parties as had previously been the case. This so-called CliCr® technology has broad applications for the CriPec® platform and beyond and will be commercially exploited to further the growth of Cristal Therapeutics.

Cristal Therapeutics has achieved proof of principle the non-invasive imaging approach in the ongoing PICCOLO phase I trial. The phase II CINOVA trial confirms the improved safety profile as seen in the NAPOLY phase I trial. Whilst the efficacy benefit of CriPec® docetaxel in CINOVA is not shown; current findings boost the CriPec® platform for the increased tumour delivery of drugs, and the 89Zr labelling as a tool for non-invasively monitoring the (pre)clinical biodistribution of CriPec® nanomedicines.

Worldwide BD efforts have been stepped up to find a partner to license CriPec® docetaxel and finance the development through phase III and to commercialisation. This has involved active outreach to potential parties at many international events as well as via various other channels.

Once approved for the market, CriPec® docetaxel can offer patients a significantly improved therapeutic performance over conventional docetaxel leading to improved health outcomes. The improved side-effect profile would enable an improved quality of life for patients. Based on the substantially reduced neutropenia one can expect reduced healthcare costs associated with managing the side-effects of chemotherapy. Adverse effects of conventional cancer therapies cost up to €3,000 per patient per month.
The non-invasive imaging approach used to validate EPR-mediated tumour targeting of CriPec® nanomedicines can also be expanded to apply as a companion diagnostic to future CriPec® products further expanding the economic and social impact.

The clinical validation as generated by CriPec® docetaxel has already helped CT to successfully approach pharmaceutical companies to market its proprietary technologies. The CriPec® platform can be used to turn drugs into personalized medicine and speed up drug development in clinical trials by reducing toxicity. The clinical progress of CriPec® docetaxel and 89Zr-Df-CriPec® docetaxel increase in the interest in the CriPec® and CliCr® platforms demonstrated by the signing of several new collaborations with pharma companies during the project, and ongoing interactions with many more.