PROJECT / TARGET FEASIBILITY PRECLINICAL PHASE I PHASE II PHASE IIB PHASE III
2017 - 2019 NZ-DTX NZ-STING NZ-IO-TLR9 NZ-IO-003-004 NZ-DOX
Local Treatment for Prostate Cancer
LIDDS most advanced project is Liproca® Depot for the treatment of prostate cancer. Liproca® Depot makes it possible to inject a well-tested anti-hormonal drug, 2-hydroxyflutamide, directly into the tumor region where Liproca® Depot forms a solid depot and releases the active substance slowly over a period of up to six months. It is estimated that the tissue concentration can be increased up to 40,000 times compared to oral treatment.
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.
Three clinical trials with 57 patients have already been conducted with promising results for tolerability and safety as well as effect on tumor tissue, prostate volume and the PSA biomarker. Clinical data indicates that Liproca® Depot has an enhanced effect at higher doses, without the hormonal side effects that are common with tablet treatment.
The American Urological Association’s Journal of Urology published a scientific article presenting the results of two clinical trials on prostate cancer using Liproca® Depot NanoZolid® combined with 2-hydroxy-flutamide at https://www.ncbi.nlm.nih.gov/pubmed/28736321. The two trials had different set-ups and follow-up periods, but both demonstrated 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 participated in the trial, together with several renowned researchers in the field of radiology and cancer. The LPC-003 trial was presented by Professor Teuvo Tammela at the European Association of Urology (EAU) in Munich in 2016.
About prostate cancer
Cancer of the prostate is one of the most common forms of cancer and approximately one million men are diagnosed with the disease every year.
It is estimated that by 2030 one in five men will be affected by prostate cancer. The total global market for prostate cancer is valued at USD 5 billion and the market potential of Liproca® Depot is significant as it can be an appropriate treatment for a large proportion of patients diagnosed with local prostate cancer.
The type of treatment being offered to patients 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 therapy with related side effects.
Preliminary results from Phase IIb Liproca® Depot dose-finding study show a strong maximum PSA decrease and sustained PSA reduction effect
Study confirms Liproca® Depot’s potential as drug treatment for men with prostate cancer who currently are under ‘Active Surveillance’ and receiving no treatment
UPPSALA, SWEDEN. LIDDS AB (publ) – LIDDS has today announced preliminary data from the LPC-004 study that aimed to determine the tolerability of Liproca® Depot and the Prostate-Specific Antigen (PSA) effect at month 5 on patients in part II of the study.
The PSA reduction for part II patients was in line with the expected pattern for Liproca® Depot’s sustained release and maximum PSA reduction (PSA nadir) occurred during months 2-4. The patients in part II showed a strong PSA decrease and a continued PSA reduction at month 5 as well as over the full study period of six months, confirming the NanoZolid® technology’s sustained release profile.
67 % of patients receiving 16 ml dose were determined as responders. A responder is defined as a patient experiencing a PSA decrease of 15% or more. 90% of patients who received a 16 ml injection experienced a PSA decrease during their Liproca® Depot treatment.
The positive preliminary results show Liproca® Depot’s ability to reduce PSA levels over a period of six months, proving the NanoZolid® technology ́s suitability for local cancer treatment. The study also confirms the technology’s favorable toxicity and tolerability profile.
All patients in the study were under Active Surveillance with low or intermediate risk of cancer progression and these patients currently receive no treatment.
– Patients under Active Surveillance have a risk of cancer progression which places additional stress on them. Liproca® Depot could provide an option for physicians to address an unmet medical need, says Anders Bjartell, Professor and Senior Consultant at the Department of Urology, Skåne University Hospital, and LIDDS Board Member.
– Liproca® Depot was well tolerated without the hormonal side effects associated with anti-androgen therapies and a majority of patients in the study were positive to receiving a second injection. Administering Liproca® Depot is similar to performing a prostate biopsy, says Professor Laurence Klotz, a world leading expert and one of the study investigators and Professor at the University of Toronto Division of Urology.
– These results validate the continued clinical development of Liproca® Depot. LIDDS has already signed a license agreement for China with the pharmaceutical company Jiangxi Puheng which plans to conduct and finance a Phase III study. LIDDS will now continue the commercial activities in order to sign further licensing agreements in other major markets, says Monica Wallter, CEO, LIDDS.
Professor Klotz will present the Phase IIb study results in detail at the 11th European Multidisciplinary Congress on Urological Cancers (EMUC19) in Vienna, Austria, on November 16, 2019. A paper reporting the results of the Phase IIb study will be submitted to leading scientific journals for publication.
For more background information about the Phase IIb Liproca® Depot clinical trial, please see enclosed file.
About prostate cancer and the market:
Of the 1.2 million men diagnosed with prostate cancer globally each year, about 420,000 are assessed as intermediate risk and placed on ‘Active Surveillance’ where they are monitored regularly. There is no standard drug treatment for these cancer patients and many treating doctors see an unmet need.
According to market research firm GlobalData, the global market for prostate cancer drugs is expected to grow to USD 8.3 billion annually by 2023. Liproca® Depot’s target group is an untapped market potentially exceeding USD 3 billion per year.
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 injections or tablets.
With NanoZolid®, LIDDS has developed a new drug candidate with doxorubicin, a cytotoxic substance that is used for the treatment of many different types of cancer. In drug release studies 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 limits the dosage and effect as the entire body is subjected to the treatment.
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. Docetaxel has a global turnover of approximately USD 1 billion and the market potential is significant.
Cytotoxic drugs often cause severe side effects, limiting the dosage and effect as the entire body is subjected to the treatment. NanoZolid® technology offers a local and long-lasting treatment with reduced side effects from potent cytotoxic drugs that are otherwise given systemically in the form of injections or tablets.
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 as seen in systemic treatments. The research results were published in the prestigious scientific journal European Journal of Pharmaceutics and Biopharmaceutics as “Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with
In drug release studies where docetaxel has been integrated into NanoZolid®, 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.
The first part of the Phase I study (NZ-DTX-001) will enroll patients for dose escalation after which patients will be treated intratumorally at a fixed dose to confirm tolerability. The primary objective is to study tolerability of NanoZolid®-docetaxel, and a secondary objective is to assess efficacy on tumor regression.
NZ-DTX is a key project for LIDDS as most types of cancer tumors can benefit from the intratumoral delivery of cytotoxic drugs. The cancers of greatest interest to LIDDS are lung, head & neck, prostate and breast cancer, but other tumors may also benefit from treatment using NanoZolid® loaded with cytotoxic drugs.
An intratumorally sustained release of cytotoxic drugs can result in substantial tumor regression and facilitate subsequent curative surgery or radiation therapy and may prevent the tumor from metastasizing during the diagnostic lag period. Depending on the cancer indication, intratumoral treatment can also be combined with systemic drugs.
Around four million people are diagnosed with solid-tumor cancers each year and a very large number undergo diagnostic biopsies. LIDDS’ aim is that a significant proportion of patients undergoing diagnostic biopsies will be offered an injection of NanoZolid® combined with docetaxel.
Our objective is that NanoZolid combined with docetaxel will be regularly used to treat solid tumors, including at the tumor biopsy phase, to decrease the tumor size and improve surgery and radiation therapy outcomes. This will also benefit cancer patients that often have to wait many weeks before their treatment plan is decided.
LIDDS’ docetaxel strategy is to prove tolerability and tumor regression for a number of different types of cancer. LIDDS has combined NanoZolid® with docetaxel as it is indicated for a large number of common types of cancer.
NanoZolid® proven effect with STING agonist
STING (Stimulator of Interferon Genes) is a promising novel target pathway in immuno-oncology. The scientific rationale for activating the STING pathway in tumors is that it could induce an innate immune response and direct tumor-killing T-cells to the treated tumor. This in turn would turn immunologically ‘cold’ tumors into ‘hot’ tumors, a prerequisite an anti-tumor immune response.
A pre-clinical study has demonstrated that NanoZolid® has the potential to reduce the burden on cancer patients and healthcare systems by producing a long-lasting effect in a range of different tumors with one injection of a NanoZolid®-formulated STING agonist.
Confirming the results of previous studies, the pre-clinical study showed statistically significant effects on tumor growth reduction and overall survival.
Due to the potent immune stimulatory effects of STING agonists, their use is restricted to direct intratumoral injections to avoid severe systemic side effects. As weekly or even more frequent injections are required with current STING drug products, a significant burden is placed on patients and the healthcare system, limiting the types of tumors that can be treated.
A single injection of a NanoZolid® formulated STING agonist can replace multiple injections and provide a safer, more convenient and potentially more effective treatment for cancer patients.
This marks the successful formulation of a compound class outside traditional small molecules highlighting the versatility of the NanoZolid® technology.
STING is one of the fastest growing areas of cancer immunotherapy and is being pursued by pharmaceutical companies around the world, including Novartis, BMS, GSK and Merck and the market for oncology immunotherapies is expected to grow to more than USD 100 billion by 2022.
A STING activating drug can potentiate the effect and increase the response rate of existing immunotherapies, particularly checkpoint inhibitors such as Keytruda and Opdivo. The NanoZolid® STING formulation could be a significant part in bringing this new treatment to patients.
Immunotherapy – improved impact, reduced side effects and fewer injections
Immunooncology 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 pharmacological effect, as well as a controlled release of the drug directly into the tumor region resulting in reduced systemic impact and side- effects.
The advent of immunotherapy in recent years has shown the potential to revolutionize the treatment of cancer. Tumor induced immune suppression and the ability to avoid immune destruction are hallmarks of cancer. Unleashing antitumor T cell responses via immune checkpoint blockade has led to remarkable responses in previously untreatable cancer types.
As of 2019, seven immune checkpoint inhibitors targeting CTLA4, PD-1 and PD-L1 have been approved for various types of cancer. However, the response rates vary between cancer types and patients. Therefore, ways of improving the outcomes of immunotherapy in the form of combination treatments are actively being sought. One promising strategy to increase the efficacy and response to immune checkpoint blockade is through local immune stimulation, thereby promoting an intratumoral inflammation, and facilitating antitumoral T cell responses.
A treatment based on NanoZolid would leverage the possibility of simultaneously delivering one or more agents with sustained release to the tumor to provide a truly innovative and efficacious product. In addition, the slow release profile avoids the need for repeated injections providing a safer and more convenient treatment option to the benefit of patients and healthcare providers.
NanoZolid®-TLR9 for improving the response to cancer immunotherapies
TLR9 (Toll-like receptor 9) is one of the most promising targets for increasing the response and reversing the resistance to current cancer immunotherapies. Clinical data have shown that intratumoral delivery of TLR9 agonists in combination with immune checkpoint inhibitors can effectively treat solid cancers. The NanoZolid® technology can provide sustained intratumoral release of the injected TLR9 agonist, minimize the need for repeated injections, and allow for a safer treatment of deep-lying tumors.
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TLRs are expressed on various immune cells, including dendritic cells, and upon activation they initiate the body’s immune response. TLR9 activation can lead to an immunologically active or inflamed tumor environment which then recruits the cytotoxic T cells necessary for an antitumor response in immunotherapy. Thus, TLR9 agonists can convert immunologically “cold” tumors to immunologically “hot” tumors and make them susceptible to treatment with checkpoint inhibitors.
LIDDS has performed preclinical studies with promising results using a TLR9 agonist formulated with NanoZolid®. A single injection of NanoZolid®-formulated TLR9 agonist resulted in an increase of the antitumoral immune response and reduced tumor growth.
To increase antitumoral efficacy and avoid severe systemic side effects, TLR9 agonists are predominantly given as intratumoral injections. However, the need for repeated intratumoral injections when using standard formulated TLR9 agonists poses a risk for the patients and increases the costs for the healthcare systems. Using a NanoZolid®-formulated TLR9 agonist requires only a single injection, which results in continuous TLR9 activation at an optimal intratumoral concentration over an extended period of time and leads to more effective antitumoral effects.
There is significant commercial potential in the area of immunostimulating agents and the market for TLR agonists is expected to be worth hundreds of millions of dollars over the coming years.
The most relevant target cancers for the TLR9 project are head and neck cancer, melanoma, prostate cancer and lymphomas. These cancers are diagnosed in around 2 million patients each year.
Toll-like receptors have been studied for many years and the emerging clinical data suggest that their time has come as important anticancer agents when used in combination with immune checkpoint inhibitors and with the optimal delivery.