LiPlaCis
LiPlaCis®
Since its clinical approval in 1978, cisplatin has remained a cornerstone of cancer treatment, renowned for its powerful ability to combat a wide range of cancers. However, its significant drawback is its inability to differentiate between healthy and cancerous cells, leading to severe toxicity and harmful side effects for patients.
LiPlaCis® is a liposomal formulation of cisplatin, enabling precise delivery of this well-established chemotherapy agent directly to tumor sites.
What is a liposome? A liposome is a small, spherical vesicle made from lipid molecules, which closely resemble the structure of a cell membrane. This similarity makes liposomes excellent carriers for delivering drugs within the human body.
The LiPlaCis® liposomes are uniquely designed to be degraded by secretory phospholipase A2 (sPLA2)—an enzyme that is over-expressed in several types of tumors. This targeted degradation ensures that the cisplatin encapsulated inside the liposome is released specifically in the cancer cells expressing the enzyme, while healthy cells remain unaffected because they do not express sPLA2.
This precision targeting allows LiPlaCis® to direct the cisplatin to cancer cells, minimizing the risk of harming healthy tissues. As a result, LiPlaCis® has the potential to provide improved efficacy and safety compared to conventional cisplatin therapy, offering greater tolerability and fewer side effects for patients.
In-Depth History of Liposomes & LiPlaCis
Liposomes were first described by British hematologist Alec Douglas Bangham in 1961 (published in 1964) at the Babraham Institute in Cambridge. These drug-delivery vehicles can be formulated with a wide variety of natural, synthetic, and modified lipid species to effectively deliver drugs and contrast agents. Currently, more than 15 liposomal drug formulations are available on the market for various indications, including cancer, fungal infections, macular degeneration, pain management, and vaccines.
The technology behind LiPlaCis® was developed through a collaborative research effort between researchers at the Danish Technical University (DTU) and the Department of Pharmacology at the University of Copenhagen. This collaboration led to a jointly developed lipid composition that allows for liposomal drug release via lipases. Specifically, the phospholipase sPLA2 can disrupt the liposome, releasing its contents directly to the target tissue. This technology demonstrated remarkable qualities when loaded with cisplatin, resulting in a stable formulation that exhibited lower toxicity and higher potency than free cisplatin in tumor-bearing mice.
Previous attempts to develop a liposomal formulation with cisplatin aimed at reducing systemic toxicity and improving tumor delivery were challenging. For instance, liposomal formulations used for delivering doxorubicin, such as Caelyx® and Doxil®, failed when applied to cisplatin (notably SPI77 and SPI077). The Doxil formulation could not release sufficient cisplatin to the tumor, leading Johnson & Johnson to abandon its development.
In contrast, Regulon Inc. developed Lipoplatin, which showed promising clinical results regarding both efficacy and toxicity. However, recent updates on their developments appear to be lacking (Regulon Lipoplatin Technology).
Similarities can be drawn between Lipoplatin and LiPlaCis, particularly regarding the extensive costs associated with clinical trials proving superiority when comparing formulations with free cisplatin. The development of a response predictor could have potentially altered Lipoplatin’s trajectory toward success. This context is crucial for Oncology Venture’s (now Allarity Therapeutics Inc.) licensing of LiPlaCis®, as the team had previously developed a robust platinum response predictor. With an effective response predictor, demonstrating efficacy improvements can be achieved with significantly fewer patients and at a reduced cost.
LiPlaCis Clinical Trials
LiPlaCis® entered its first phase 1 clinical trial in the Netherlands, where it was administered intravenously every three weeks, starting at a dose of 10 mg of cisplatin per patient. Early in the trial, infusion reactions similar to those observed with other liposomal formulations were noted, including tachycardia, flushing, dyspnea, and low blood pressure. A new procedure was developed that successfully addressed these infusion reaction issues.
However, the study faced an unfortunate setback when the sponsor, LiPlasome Pharma, went bankrupt after the initial phases. This led to a negative publication by the investigators, which was done without the involvement or knowledge of the Contract Research Organization (CRO) or the sponsor shortly after the study's termination on the study and its implications, you can refer to sources that discuss the challenges faced during early clinical trials of liposomal formulations.
New financing led to a fresh start, allowing for the thorough collection and monitoring of all clinical study data by a professional contract research organization (CRO). The investigators were able to agree on the conclusions, resulting in a Clinical Study Report (CSR) that presented findings significantly different from a previous publication in the Annals of Oncology that followed the abrupt termination of the study. In this phase 1 trial, positive responses were observed in patients with various types of cancer, including skin cancer, head and neck cancer, esophageal cancer, and breast cancer. Contrary to earlier reports, the CSR indicated minimal toxicity issues, with any toxicity primarily linked to higher dosages of the liposomal infusion.
A DRP® focused phase 2 clinical trial in heavily treated breast cancer patients was published in 2023. Heavily pretreated late-stage breast cancer patients of any subtype represent a huge treatment challenge. Cisplatin may work in selected patients but is often disqualified because of toxicity. The cisplatin-DRP® was used to select metastatic breast cancer patients with response likelihood scores from diagnostic or later biopsies. Patients were treated until progression or unacceptable toxicity.
Metastatic breast cancer patients had received a median of 7 previous treatment lines. A DRP® score ≥80% (DRP80+) discriminated well between responders and non-responders to liposomal cisplatin. All 4 partial remissions in the study were in the DRP80+ group, and other key efficacy endpoints were in favor of the DRP80+ vs the lower scores (DRP80-). LiPlaCis® was generally well tolerated, with a mean of 4.4 treatment cycles administered per patient. Only 1 SAE (pyelonephritis) was reported and considered related to treatment. One patient died whilst on treatment, but due to disease progression. From a total of 164 treatment cycles, 18 of the patients reported 1 grade 4 and 41 grade 3 AEs considered possibly related to treatment.
LiPlaCis® shows efficacy in heavily pretreated mBC patients, especially when using the DRP method as a companion diagnostic. Further, this is the first clinical study to prospectively validate DRP as a method to identify responders to chemotherapy cisplatin. Read more information on the clinical trial and the scientific arcticle for the phase 2 clinical trial.