iCIP™ – Precision LiPlaCis® & DRP® with Breakthrough designation option

CHOSA’s clinical phase II product consists of LiPlaCis® and its Drug Response Predictor – DRP®.

In essence, iCIP™ combines the identification of patients that will benefit from cisplatin treatment with the ability to treat them with higher efficacy and less toxicity. We have strong phase 2b data in metastatic breast cancer, demonstrating that patients selected by DRP® responded better to treatment; have longer progression-free survival; and maybe even an overall longer total survival than those patients who were identified as unlikely to respond well to the treatment.

If the currently obtained phase 2b data can be repeated in the next pivotal study CHOSA believes if these data can be repeated that clinical evidence can be demonstrated that iCIP has a substantial improvement on at least one clinically significant endpoint over available therapy which could lead to a Breakthrough designation.

The LiPlaCis, and its DRP History

Liposomes – background

Liposomes were first described by the British haematologist Alec Douglas Bangham in 1961 (published 1964), at the Babraham Institutein Cambridge. Liposomes are drug-delivery vehicles that can be formulated with a wide variety of natural, synthetic, and modified lipid species to deliver drugs and contrast agents. More than 15 liposomal drug formulations are on the market for indications such as cancer, fungal infections, macular degeneration, pain management, and vaccines.

The technology behind LiPlaCis was developed in a research collaboration between researchers at the Danish Technical University DTU and The Department of Pharmacology Copenhagen University of Copenhagen. A jointly developed lipid composition allowed liposomal drug release by lipases, specifically the phospholipase sPLA2 was able to disrupt the liposome and release the liposomal content to the tissue (see reference). This technology showed unusual qualities when loaded with cisplatin. The product was stable and LiPlaCis was invented, it showed lower toxicity and higher potency than free cisplatin in tumor-bearing mice.

Previous attempts to develop a liposomal product with cisplatin to reduce systemic toxicity and to better deliver cisplatin to tumors had been very challenging e.g., the liposomes used for delivery of doxorubicin (Caelyx® and Doxil ®) failed with cisplatin (SPI77 and SPI077) the Doxil formulation was not able to release sufficient cisplatin to the tumor and the pharmaceutical company Johnson and Johnson abandoned the development.

The company Regulon Inc. developed Lipoplatin which appeared quite successful clinically both regarding efficacy and toxicity. However, in our search, recent updates from their developments are missing (http://regulon.com/lipoplatin/technology.php.).

We see similarities with LiPlaCis, the extensive costs of proving superiority when comparing with free cisplatin can be prohibitive and perhaps a response predictor could have changed the Lipoplatin story to success. The story is an important background for Oncology Venture’s (now Allarity Therapeutics Inc.) licensing of LiPlaCis as the Oncology Venture team had developed a strong platin predictor. With an effective response predictor, the efficacy improvements can be demonstrated with much fewer patients and at much lower costs.

A recent update on liposomes in cancer therapy Link and in Functionalized liposomes for targeted breast cancer drug delivery Link which includes a more comprehensive sPLA2 description.

LiPlaCis clinical development

LiPlaCis entered its first phase 1 in Holland. LiPlaCis was administered intravenously once every 3 weeks starting at a dose of 10 mg cisplatin per patient. Early on there were infusion reactions similar to what has been observed with other liposomes i.e., tachycardia, flushing, dyspnea, and low blood pressure. A new procedure solved all the infusion reaction problems. Unfortunately, the study was terminated prematurely as the sponsor LiPlasome Pharma went bankrupt after the initial phases leading to a rather negative publication by the investigators without the help or knowledge of the CRO or sponsor shortly after.
New financing led to a new start and all clinical study data were thoroughly collected by a professional CRO and monitored. Fortunately, the investigators agreed to the conclusions and could sign a clinical study report (CSR) which was with a significantly different conclusion than what was published in the Annals of Oncology right after the abrupt closing.

In contrast to the publication, the CSR reported very few toxicity problems and toxicity primarily linked to higher liposomal infusion dosage.

The Clinical Study Report conclusion:

The MTD was not reached in the present study with only one DLT reported at the lowest dose level.
LiPlaCis, administered IV, every 3 weeks in an infusion volume of 500 ml, is well tolerated up to the studied dose of 120 mg.
The recommended infusion duration is ≥ 120 minutes.
The most frequently observed LiPlaCis-related AEs were mild to moderate nausea, vomiting, fatigue and anorexia.
There was no apparent relationship between dose group and incidence of LiPlaCis-related AEs.
There were no deaths on the study and there were no LiPlaCis-related Grade 4 AEs.
Renal toxicity has to be monitored closely in future studies with LiPlaCis, especially at doses of ≥ 120 mg.
In general, no trends could be detected at any dose level with respect to cumulative changes over time for the laboratory parameters, vital signs and other physical examination parameters evaluated.

A new proposal of administering LiPlaCis in a split dose, now based on the body surface of the patient (rather than a fixed dose per patient) on day 1 and 8, every 3 weeks was approved, and a new combined phase 1/phase 2 trial was initiated at Danish sites.
Finalization of the dose-finding was done at the Phase 1 Unit at the University Hospital Rigshospitalet, Copenhagen. The Phase 2 part studying the LiPlaCis effect in DRP-selected (see later) metastatic breast cancer patients was recruiting patients from 9 out of 10 oncology sites in Denmark.

In the phase 1 part responses were seen in a patient with skin cancer, a patient with head and neck cancer, a patient with esophageal cancer, and in a breast cancer patient.

DRP – first time ever biomarker for cisplatin

Multiple molecular mechanisms for cisplatin resistance June 2022 https://encyclopedia.pub/entry/24414

DRP enters the scene in the phase 2 development in metastatic breast cancer – Key persons

The DRP opportunity led to Oncology Venture in-licensing LiPlaCis in 2016.
At this time point the cisplatin Drug Response Prediction (DRP) technology – a multi-gene test of the individual patient’s tumor tissue – was developed by Medical Prognosis Institute (MPI) in Copenhagen. MPI initially a private company was founded by Professor Steen Knudsen from The Danish Technical University. As a specialist in systems biology and molecular biology, Professor Knudsen was taking cell line data further than anybody else had done at that time. Basically, hypothesizing that human cancer cells grown in laboratories as cancer cell lines die or resist anticancer drugs with the same biology as do cancers in real life.

Similar research was done by one of the founders of CHOSA: MD, DMSc, adjunct professor in clinical oncology Peter Buhl Jensen in collaboration with MD, DMSc, pathologist, Maxwell Sehested at the University Hospital, Rigshospitalet. Working on drug sensitivity in cancer cell lines they discovered that patterns in sensitivity and resistance directly matched a drug’s mechanism of action. In this way, new mechanisms of action were found and later confirmed clinically. One such of their discoveries lead to approval by the FDA and EMA and now used globally in oncology and hematology departments is the use of dexrazoxane (Totect® and Savene®) to shield against damage after unintended leakage outside the vein of a drug type called anthracyclines.

From 2010 Steen Knudsen and Peter Buhl Jensen worked together in MPI to advance the DRP technology to clinical utility. In 2015 Peter Buhl Jensen and his wife and business partner (Bsc, Nursing, and Diploma in Health Care Administration) Ulla Hald Buhl together with Steen Knudsen and others founded Oncology Venture to further the clinical development and acquire active cancer products that could benefit from the DRP in the way that the DRP could help select the patients that would benefit from a particular product. At the same time, one could avoid treatments in vain in patients who only had very limited likelihood of benefit. During the collaboration, the team demonstrated successful prediction of 5FU efficacy in adjuvant colorectal cancer together with the clinical corporation group of gastro-intestinal experts, the PETACC group, and 5FU efficacy in metastatic colorectal cancer together with the Sahlgrenska (Sweden) group. These studies were led by MD PhD Ida Kappel Buhl (daughter of Peter Buhl Jensen) who started her research career in Oncology Venture as a medical student and later obtained a PhD from the University of Copenhagen (opponents from US-NCI Dr. Beverly Teicher and Dr. Morten Mau Sorensen University of Copenhagen).

Cisplatin efficacy in lung cancer was predicted successfully and published together with a lung cancer expert group at the University Hospital, Rigshospitalet (Denmark). This study was also led by Ida Kappel Buhl.

A biomarker for epirubicin and doxorubicin response in breast cancer was developed, validated and published together with The Danish Breast Cancer Cooperative Group (DBCG). The development and validation of biomarkers for fulvestrant and aromatase inhibitors in estrogen positive receptor-positive (ER+) breast cancer was also done together with breast cancer experts in the DBCG.

These studies were led by MD, PhD student Anna Sofie Kappel Buhl (daughter of Peter Buhl Jensen) and MD, PhD student Troels Dreier Christensen; they both started their research careers at Oncology Venture.

Prospective phase 2 of LiPlaCis in metastatic breast cancer

Following the in licensing of LiPlaCis in 2016 Oncology Venture finalized the phase 1 dose finding study and started the phase 2 study in metastatic breast cancer.

The metastatic breast cancer indication was chosen as cisplatin is active in breast cancer but is in competition with many other active products and often not used due its toxicity which we believe we can mitigate with the DRP and the liposomal formulation.

Also, there is a tradition in metastatic breast cancer to treat with single agents giving the opportunity to test single agent LiPlaCis activity without the interference of a combination drug. By use of the cisplatin/LiPlaCis DRP to select the LiPlaCis responders, the LiPlaCis product would advance to become the best choice for the patient. When Oncology Venture was led by the current CHOSA management which in addition to Ulla and Peter included serial entrepreneur, Cand Oecon, MBA Claus Frisenberg Pedersen, the company advanced LiPlaCis to a FDA 505(b2) status, and the DRP to a European CE mark and a FDA IDE.
LiPlaCis and its DRP was at that timepoint the companies lead project competing with 6 other products in-licensed by Oncology Venture. All product developments were guided by specific drug DRPs. As part of a strategic decision to move the company to the US in 2019 a new management took over in Oncology Venture and the company moved its listing from Sweden to US Nasdaq under the name Allarity Therapeutics Inc. The new team focused on some of the other projects and the previous management engaged in buyout discussions with Allarity.

In April 2022 CHOSA Oncology in-licensed LiPlaCis and its DRP from Allarity. CHOSA was founded by the previous management in Oncology Venture together with MSc. Knut Smerud, MSc. Neil Goldsmith and MSc. Andy Gardiner. Knut Smerud is the owner of the CRO company Smerud International that conducted the LiPlaCis studies and the cisplatin/LiPlaCis DRP screening. Neil and Andy are serial biotech entrepreneurs who have previously worked together with Ulla and Peter in a collaboration (TopoTarget) that led to two cancer drug approvals by the FDA and one by EMA. At the end of 2022 CHOSA entered into a reverse merger agreement with the Swedish listed company RhoVac AB who’s cancer vaccine study failed in the summer of 2022 and the project was abandoned. This was the companies only project and RhoVac bought CHOSA in a deal that gave CHOSA shareholders the majority shareholding.

In February 2023 RhoVac changed its name to CHOSA Oncology AB.