PROJECT / TARGET FEASIBILITY PRECLINICAL PHASE I PHASE II PHASE IIB PHASE III
NZ-2HOF NZ-DTX NZ-DOX NZ-IO NZ-Ferring NZ-Belina
We want to treat the prostate cancer locally
Our most advanced project – Liproca® Depot for prostate cancer – makes it possible to inject a well-tested anti-hormonal drug, 2-hydroxyflutamide, directly into the tumor region. Here the active substance is released slowly and has an effect for approx. six months. It is estimated that the tissue concentration can be increased up to 40,000 times compared to oral treatment. So far three clinical trials have been conducted with 57 patients with promising results concerning tolerance and safety as well as effect on tumor tissue. Currently a Phase IIb clinical trial is being conducted at urology clinics in Canada and Finland, aiming to identify the highest tolerable dose and to demonstrate that Liproca Depot prevents the progression of early stage prostate cancer
The company has clinical data that indicate that Liproca® Depot has an enhanced effect at higher doses, without the hormonal side effects that are common with tablet treatment. So far, three clinical trials have been conducted, using Liproca Depot in 57 patients with promising results in relation to both tolerance and safety, as well as in terms of effect on tumor tissue, prostate volume and the PSA biomarker. The LPC-003 trial was presented by Professor Teuvo Tammela at the European Association of Urology (EAU) in Munich in 2016.
The respected Journal of Urology, published by the American Urological Association, has decided to publish a scientific article presenting the results of two clinical trials on prostate cancer using Liproca Depot (NanoZolid® combined with 2-hydroxy-flutamide). The two trials have different set-ups and follow-up periods, but both show positive results for the PSA cancer marker, as well as reduced prostate volume without any hormonal side effects. The principal investigator in both trials, LPC-002 and LPC-003, was Professor Teuvo Tammela, from the Tampere University Hospital in Finland. Additional urologists in Sweden and Finland, together with several renowned researchers in the field of radiology and cancer, participated in the trial. In summary, the two Phase II trials with a total of 57 patients show that a higher dose of Liproca Depot has stronger effects on PSA and prostate volume, a so-called dose-effect relationship.
The Phase IIb trial, LPC-004, is treating patients with non-aggressive prostate cancer and is being conducted at urology clinics in Canada and Finland. Professor Teuvo Tammela is the principal investigator in the trial. A world-leading urologist in research on patients under active surveillance, Professor Laurence Klotz at the University Hospital in Toronto, is participating in the trial. The urologists participating in the study has expressed great interest in this new type of local treatment for prostate cancer. During the trial, the amount of medication will be increased by up to 200 percent compared with LPC-003, and the patients will be monitored for six months to evaluate the optimal dose and its effect on different cancer markers. Depending on the inclusion rate, the results of the trial are expected to be compiled during the summer of 2018.
An industrial manufacturing process for future commercialization is ensured with Recipharm for Liproca Depot, as well as for calcium sulfate hemihydrate, LIDDS’s drug carrier. The agreement that gives Recipharm exclusive production rights was signed in December 2015. The drug batch for the Phase IIb trial LPC-004 is GMP manufactured by Recipharm and approved for clinical trials.
About prostate cancer
Cancer of the prostate is one of the most common forms of cancer and approximately one million men are diagnosed each year.
By 2030, it is estimated that one in five men will be affected. The total market for prostate cancer is valued at SEK 46 billion. The market potential of Liproca Depot is significant as Liproca Depot could be an appropriate treatment for a large proportion of patients with diagnosed local prostate cancer.
The type of treatment being offered to a patient with prostate cancer is determined by the stage and extent of the cancer, as well as by the patient’s general state of health and age. The alternatives include surgery, radiotherapy or pharmacological treatment. Despite technological surgical developments, surgery with removal of the prostate is still associated with side effects such as impotence and incontinence. Radiotherapy entails risks of fecal and urinary incontinence, as well as impotence. Hormonal treatment produces side effects such as hot flushes, decreased libido, impotence, fatigue and cognitive fatigue. After longer treatment, osteoporosis and cardiovascular disease also occur.
Patients who do not have an aggressive form of cancer receive no treatment at all, but are followed up with regular monitoring, called Active Surveillance. For these patients, Liproca Depot may cause tumor regression and prevent continued cancer growth without any of the adverse hormonal side effects caused by systemic therapy or possibly halt or stop the cancer progression avoiding a prostatectomy or radiation with related side effects.
Lung cancer and Solid tumors
Based on the NanoZolid® technology, LIDDS has successfully developed a new drug candidate in combination with docetaxel, one of the most commonly used drugs for cytostatic treatment of breast, prostate, head, neck, stomach and lung cancer. A placebo-controlled preclinical trial of NanoZolid in combination with docetaxel showed clear effects in the local treatment of lung cancer cell tumors, without causing the severe side effects in laboratory animals seen in systemic treatments. LIDDS is planning a Phase I trial in humans to be started in 2018.
With NanoZolid, LIDDS has successfully developed a new drug candidate with docetaxel, a cytotoxic substance that is used for the treatment of many different types of cancer. In drug release studies where docetaxel has been integrated into the technology patented by LIDDS, a clear depot effect is seen in vitro. This allows for a controlled release with a high and lasting drug concentration for the local treatment of tumors. Cytotoxic drugs often cause severe side effects, which limit the dosage and effect as the entire body is subjected to the treatment. Docetaxel is one of the most commonly used drugs for cytostatic treatment of breast, prostate, head, neck, stomach and lung cancer. Docetaxel has a global turnover of approximately USD 1 billion, why the market potential is significant.A placebo-controlled, preclinical trial of NanoZolid in combination with docetaxel shows clear effects in the local treatment of lung cancer cell tumors, without causing the severe side effects in laboratory animals that systemic treatment inflicts. The research results bearing the title: “Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel” has been published in the prestigious scientific journal European Journal of Pharmaceutics and Biopharmaceutics. The lead author of the scientific article is Dr. Marie Jeansson at the Department of Immunology, Genetics and Pathology (IGP) at Uppsala University. Researchers at Uppsala University and Uppsala University Hospital who contributed to the project are co-authors of the article.The promising findings constitute an important step in the continued pharmaceutical development of NanoZolid with docetaxel for the treatment of lung cancer or other types of tumors.
LIDDS is planning a Phase I trial in humans, the first in man study can be initiated in 2018.
The NanoZolid®-technology works well for drug development in the treatment of diseases where there is a need for local, long-lasting effects and for minimizing side effects from potent drugs that are otherwise given in the form of an injection or tablets.
Immunotherapy – A major opportunity
Immuno-oncology is based on the principle of activating the body’s own immune system to attack cancer cells. However, with systemic immunotherapy the entire body is affected and serious side effects are common. With the NanoZolid® technology local injections can produce an improved pharmaceutical effect, as well as a controlled release of the drug directly into the tumor region, with reduced systemic impact and side-effects. Nor does the patient need to be subjected to frequent injections, which is the case today. LIDDS has several immune-modulating substances in feasability phase.
Many of the larger pharmaceutical companies have begun preclinical or clinical trials for immune-modulating drug candidates, and several products have already received market approval. With systemic immunotherapy, the entire body is affected, and serious side effects are common, especially with combination treatments.The NanoZolid technology has advantages as it can produce an improved pharmaceutical effect, as well as a controlled release of the drug directly into the tumor region, with reduced systemic impact and an improved side-effects profile. With the NanoZolid technology, the patient does not need to be subjected to frequent injections, which is the case today.
LIDDS has begun research into integrating antibody-based immunotherapies with the NanoZolid technology. The results are so promising that a formal partnership has been established with the Department of Immunology, Genetics and Pathology (IGP) at Uppsala University. Immune-modulating molecules can be formulated with NanoZolid and thus allowing administration of antibodies into tumors, in order to activate the body’s immune response in the tumour itself. This collaboration aims to contribute to the development of new cancer drugs based on the NanoZolid platform.
Immuno-oncology is an intense research area globally and LIDDS wants to be able to offer licences for the NanoZolid technology to pharmaceutical companies at an early stage. The goal is to incorporate drug molecules into NanoZolid that activate the immune system. The locally activated immune cells are then transported via the blood to all parts of the body, where the tumor cells are attacked.
NanoZolid® with cutting edge STING agonist becomes a key project for LIDDS in immuno-oncology field
Single intratumoral injections of a NanoZolid formulated STING agonist has been proven to achieve significant effects on tumor growth reduction and overall survival. These positive effects of the NanoZolid formulation with STING puts LIDDS in an exciting position in the immuno-oncology field having a technology to avoid frequent injections. The findings are now included in a patent application.
The NanoZolid technology has in aggressive tumor models shown to enable a controlled release of a STING agonist intratumorally. With the NanoZolid drug delivery technology, a single injection of a NanoZolid formulated STING agonist (NZ-STING) could replace required multiple injections and thereby provide a safer, more convenient and potentially more effective treatment. The NZ-STING efficacy has been demonstrated in several preclinical animal studies where a single injection has shown effects on tumor growth and overall survival. In addition, this marks the successful formulation of a compound class outside traditional small molecules highlighting the versatility of the NanoZolid technology.
The STING (Stimulator of Interferon Genes) pathway is one of the most promising novel target pathways in immuno-oncology, I/O. The STING pathway was evolved to detect foreign DNA as a result of infections and thereby mount an immune response. The scientific rationale for activating the STING pathways in tumours, is that activation of the STING pathway could induce an innate immune response and direct tumour killing T-cells to the treated tumour. This in turn would turn immunologically ‘cold’ tumours into ‘hot’ tumours, a prerequisite an anti-tumour immune-response. A STING activating drug could potentiate the effect and increase the response rate of existing immunotherapies, in particular checkpoint inhibitors such as Keytruda and Opdivo. STING activation is also associated with the so called “abscopal effect”, whereby a direct local effect is transmitted to distal tumors and metastases.
STING agonists are being aggressively pursued by leading Big Pharma companies and deals with potential values up to 2 billion USD have been made despite the early stages of this therapeutic area. This highlights the competitiveness of the field and hopes for this new target.
However, due to the potent immune stimulatory effects of current STING activators, their use is restricted to direct intratumoral injections to avoid systemic side effects. Using current methodologies, these require weekly injections, putting a burden on the patients and the healthcare system.
A locally delivered immunotherapy such as a STING agonist has the potential to act either as a monotherapy or in combination with systemic immunotherapies e.g. checkpoint inhibitors. Successful combination treatments could significantly increase the response rates and efficacy rates of current immunotherapies. As immuno-oncology is the fastest growing area in oncology, reaching a market size over 100 billion USD by 2022, these specific results should be of great interest to pharmaceutical companies developing STING agonists.
The promise of STING agonists and the rapid development of the field was highlighted in a recent issue of Chemical & Engineering News (February 26, 2018).
Controlled release drug development
A research agreement with Ferring signed in the summer of 2017 concerns a product development project where NanoZolid® will be used to formulate an innovative, controlled release drug with controlled release over a prolonged period.
LIDDS offers pharma companies access to NanoZolid® for their drug development projects through licensing agreements. An exclusive development and option agreement was signed in the spring of 2017 with Belina Pharma, in which NanoZolid will be used to develop a new innovative product that can improve traditional breast cancer treatment.