Cholangiocarcinoma (CCA)
About CCA
Cholangiocarcinoma (CCA) is a rare type of biliary tract cancer. However, it is the second most common primary liver malignancy and represents approximately 15% of all primary liver tumors and 3% of gastrointestinal cancers.1
CCA may occur in normal livers or as the result of diseases associated with chronic inflammation in the liver, including chronic infection with hepatobiliary flukes, primary sclerosing cholangitis, biliary tract cysts, gallstones, and some toxins. Cirrhosis, chronic hepatitis B and C infection, obesity, diabetes mellitus and alcohol-related liver disease are also emerging as risk factors for CCA.
Patients with CCA typically do not have symptoms until late in the course of the disease. As such, patients typically present after CCA is well advanced. CCA is highly aggressive and is often refractory to chemotherapy, which contributes to poor prognosis and high mortality, representing ~2%2 of all cancer-related deaths worldwide annually. Importantly, the incidence of CCA has been rising in the past few decades worldwide, representing a global health problem. Nine thousand new patients are diagnosed every year in the US, and 10,000 in EU5.3
Unmet Needs
There are limited therapeutic options for this aggressive disease. Surgery is a potential curative option, but unfortunately, most patients are diagnosed with metastatic or locally advanced disease at presentation, and only ∼30% are eligible for resection.3 The current first-line treatment for unresectable tumors is chemotherapy, and second-line targeted treatments exist for patients having specific mutations, but benefits on survival remain limited.
GNS561 in CCA
To address the significant unmet need in patients diagnosed with CCA, we are currently developing GNS561, which GENFIT in-licensed from Genoscience Pharma in 2021. GNS561 is a Palmitoyl Protein Thioesterase-1 (PPT-1) inhibitor that blocks cancer cell proliferation by inhibiting late-stage autophagy4, a tumor cell survival mechanism. Some types of cancer treatment, such as inhibitors of the MAP kinase pathway or immunotherapy/checkpoint inhibitors, may result in an increase in autophagy.
Accordingly, GENFIT has conducted experiments with GNS561 and a MEK inhibitor in CCA cell lines, and these studies demonstrated a synergistic effect of the combination, especially with certain mutations such as KRAS. As such, the administration of GNS561 with such medications may result in increased tumor cell death and provide a potential new treatment option for patients with CCA. In particular, this could be a very important treatment option for patients with KRAS mutated CCA for whom there are no approved targeted therapies and for whom the prognosis is dismal.
Development Stage
A Phase 1b/2a trial has been initiated to evaluate the safety, tolerability and efficacy of GNS561 combined with trametinib, a MEK inhibitor, in patients with KRAS mutated cholangiocarcinoma (CCA).
Phase 1b aims to determine the recommended doses of GNS561 and trametinib to be administered in Phase 2a based upon safety, tolerability, and early biomarker data. Phase 2a will support further evaluation of efficacy and safety with the optimal doses of GNS561 and trametinib.
Given the high unmet need in CCA and the Orphan Drug Designation obtained from the FDA for GNS561, it is expected that the program may qualify for some of the expedited regulatory pathways provided by health authorities.
Urea Cycle Disorders & Organic Acidemias (UCD/OA)
About UCD and OA
Inborn errors of metabolism (IEM) causing hyperammonemic crises (HAC) comprise a group of hereditary disorders in which a gene defect results in a clinically significant block of the urea cycle responsible for the metabolic clearance of ammonia from the body.
Among them, Urea Cycle Disorders (UCDs) and Organic Acidemias (OA), are two groups of metabolic diseases in which a deficiency in one of the six enzymes involved in the urea cycle prevents the proper elimination of ammonia in urine, resulting in accumulation of ammonia in the blood. If untreated, this may result in HAC, which is characterized by cerebral edema, hyperventilation or hypoventilation, hypothermia, seizures, and coma.
Patients are usually diagnosed after birth via newborn screening tests, but the clinical presentation of patients with HAC caused by IEM may start as early as the first days of life and as late as adulthood.
While these conditions are ultra-rare with 1,900 acute hyperammonemic crises in the US and EU5 per year,5 mortality is very high as 75% of patients will die after 5 years, and survivors will often have severe brain injuries.
Unmet Needs
The treatment of HAC typically involves prompt management of the elevated ammonia levels in the blood. This may involve hospitalization, administration of medications such as sodium benzoate and phenylacetate, and intravenous fluids to help remove excess ammonia from the bloodstream. In severe cases, renal replacement therapy may be necessary.
In clinical practice, pediatric patients presenting with HAC require immediate referral to highly specialized tertiary centers experienced and equipped to treat HAC. As many as 45%6 of UCD patients remain untreated.
VS-01-HAC in UCD/OA
We are developing VS-01-HAC, a potential first-line lifesaving treatment for acute HAC associated with IEMs.
VS-01 is an innovative, investigational drug candidate based on a proprietary scavenging liposomal technology, administered directly into the peritoneal cavity following drainage of ascites.
The peritoneal route of administration of VS-01 could optimize both ammonia clearance and implementation time, thus allowing for the timely initiation of efficient ammonia clearance while minimizing the need to transport the patient to another center.
An in vivo feasibility study showed that ammonia extracted from blood was significantly (p < 0.0006) higher following single intraperitoneal injection of VS-01 compared to the control solution at all timepoints during the dwell time and led to a significant decrease in blood ammonia.7
Our non-clinical and FIH clinical data showed that ammonia clearance in the peritoneal fluid increased proportionally with the volume of fluid infused and ranged between 5 and 95 mL/min following treatment with 0.3L and 3L VS-01, respectively. These values are in the same range as those reported in UCD patients treated with different extra corporal dialysis modalities.7
VS-01-HAC has been granted Rare Pediatric Disease designation (RPD) by the FDA for this indication and is also potentially eligible for a Priority Review Voucher upon approval.
Following completion of the non-clinical feasibility study, we plan to develop formulation optimization for specific pediatric implementation and conduct IND-enabling nonclinical studies.
1 Sarcognato S, Sacchi D, Fassan M, Fabris L, Cadamuro M, Zanus G, Cataldo I, Capelli P, Baciorri F, Cacciatore M, Guido M. Cholangiocarcinoma. Pathologica. 2021 Jun;113(3):158-169. doi: 10.32074/1591-951X-252. PMID: 34294934; PMCID: PMC8299326
2 Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, Cardinale V, Carpino G, Andersen JB, Braconi C, Calvisi DF, Perugorria MJ, Fabris L, Boulter L, Macias RIR, Gaudio E, Alvaro D, Gradilone SA, Strazzabosco M, Marzioni M, Coulouarn C, Fouassier L, Raggi C, Invernizzi P, Mertens JC, Moncsek A, Rizvi S, Heimbach J, Koerkamp BG, Bruix J, Forner A, Bridgewater J, Valle JW, Gores GJ. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557-588. doi: 10.1038/s41575-020-0310-z. Epub 2020 Jun 30. PMID: 32606456; PMCID: PMC7447603
3 IQVIA market research
4 Including HE as a therapeutic area closely associated with ACLF
5 As assessed by Child-Pugh score
6 The EASL-CLIF Consortium is a network of more than a hundred of European University Hospitals which carry out clinical investigations of the EASL-CLIF Chair aimed at performing large observational, pathophysiological and therapeutic studies to increase our understanding of Chronic Liver Failure and to improve the management of patients with cirrhosis
7 Uschner, F. E., Schulz, M., Tyc, O., Ferstl, P., Stoffers, P., Erasmus, H-P., Masseli, J., Peiffer, K-H., Finkelmeier, F., Pathil, A., Bojunga, J., Biguenet, S., Zeuzem, S., Kabbaj, M., & Trebicka, J. (2021). Safety and Preliminary Efficacy and Pharmacokinetics of Intraperitoneal VS-01 Infusions in Patients with Decompensated Liver Cirrhosis: a First-In-Human, Open-Label, Phase 1b Clinical Trial. Hepatology, 74(Suppl. 1), 139A. [208].