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Imaging NM: A Nanoparticulate Precision Medicine Approach to Target Cancer

Periodic Reporting for period 2 - INTACT (Imaging NM: A Nanoparticulate Precision Medicine Approach to Target Cancer)

Reporting period: 2018-08-01 to 2019-10-31

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 between patients. CT has developed state-of-the-art nanoparticles (CriPec®) to target a drug of choice more selectively to 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 1 trial has been finalised providing a significantly improved pharmacokinetic and safety profile. CT already observed therapeutic activity in patients and much reduced adverse events such as neutropenia and alopecia. In INTACT, CT will perform a phase 2 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) (referred to as 89Zr CriPec® docetaxel in the original DoA and since referred to as 89Zr-Df-CriPec® docetaxel), 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 assures maximum efficacy in selected patients, avoids exposing patients to inappropriate drugs and adverse effects, and allows patients with limited tumour targeting to receive other more appropriate treatment.

CT will use INTACT to close the gap from lab to market and facilitate a licensing deal for CriPec® docetaxel, projected to generate revenues exceeding >€100M in 2024. More importantly, INTACT will validate the CriPec® nanomedicine platform, boost product development for other diseases through licensing deals, and provide a growth of 10FTE by 2022. 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 at clinical scale compliant with all predetermined SPECs ready for phase 1 and phase 2 trials. For both the phase 1 study and the first phase 2 study (in ovarian cancer, named CINOVA), the clinical protocols and all correlated documents were compiled and submitted to the regulatory authorities. The phase 1 study (Piccolo) has received approval and first patients are now already included in the clinical evaluation including PET/CT imaging. In the CINOVA trial, a first patient treatment is scheduled for 2nd half 2018, and all operational actions to facilitate this are currently ongoing according to schedule.
As INTACT continues to progress Cristal Therapeutics will validate the non-invasive imaging approach in the ongoing PICCOLO phase 1 trial. This will then be incorporated into the soon to start phase 2 CINOVA trial where Cristal Therapeutics will demonstrate the efficacy of CriPec® docetaxel and the correlation between the non-invasively imaged tumour accumulation and the efficacy. This will validate simultaneously CriPec® docetaxel as an anti-cancer product, the CriPec® platform for the increased tumour delivery of drugs, and the 89Zr-Df-CriPec® docetaxel non-invasive imaging approach as a tool for predicting patients most likely to respond to CriPec® products. Following successful completion of the phase 2 programme, CriPec® docetaxel will undergo a phase 3 trial that will enable its registration for the market.

Once approved for the market, CriPec® docetaxel will offer patients a significantly improved therapeutic performance. Chemotherapeutic toxicity is a much feared burden for cancer patients and selection through patient stratification will greatly impact quality of care. In line with this, CT projects significant healthcare savings as enhanced targeting allows for more effective dosing: reduced drug use and reduced adverse effects can save €2,900 per month per patient.

CriPec® docetaxel is expected to provide benefits over existing treatments leading to improved health outcomes. The improved side-effect profile in particular will lead to improved quality of life for patients and reduce 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 use of the 89Zr-Df-CriPec® docetaxel non-invasive imaging for patient selection will allow selection of those patients who are most likely to respond to CriPec® docetaxel therapy. This will lead to further cost savings improved health outcomes as only patients who will benefit are exposed to the drug. This technology can also be expanded to apply to future CriPec® products further expanding the economic and social impact.

Commercial success of CriPec® docetaxel will allow CT to successfully market its proprietary technology to pharmaceutical companies that develop novel medicines. The CriPec® platform can be used to turn any drug into personalized medicine and speed up drug development in clinical trials by reducing toxicity. The clinical progress of CriPec® docetaxel has already lead to an increase in the interest in the CriPec® platform demonstrated by the signing of three new collaborations with pharma companies during the reporting period.
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