PTX-100 shows encouraging efficacy signals and safety in area of high unmet clinical need
Clinical stage oncology company, Prescient Therapeutics, has a diverse stable of emerging and later stage assets across CAR-T and targeted cell therapies. The company has recently had significant developments with their targeted cell therapy PTX-100 – licensed from Yale and co-invented by the Moffitt Cancer Centre – which is producing stellar data and has the potential to leap into clinical development very soon.
After demonstrating a favourable safety profile during a phase 1b dose escalation trial that is now being expanded, first in class targeted therapy PTX-100 is showing promising signs that it could be effective against two types of cancer that oncologists have been struggling to treat for years. The Ras pathway inhibitor was tested up to a dose of 2,000 mg/m2 in four patients with peripheral T-cell lymphoma (PTCL), and three patients with cutaneous T-cell lymphoma (CTCL). There were no serious adverse events related to PTX-100.
A quick background on T-cells
T-cells are a type of white blood cell that develop from stem cells in the bone marrow, and form a crucial part of the immune system because of their role of coordinating multiple aspects of adaptive immunity throughout life – including the body’s fight against pathogens, allergens and tumours. The thymus gland, an organ that is part of the lymphatic system, is responsible for producing T-cells.
There are various different types (subsets) of T-cells, and the role they play largely depends on their anatomical location as well as their developmental stage. An important part of the underlying mechanics of T-cells that result in sustained ‘adaptive immunity’ is the functionality of both naïve cells and memory cells.
All T-cells express receptors that have the potential to recognise antigens. In early life (infancy and early childhood), most T-cells are naïve cells, which means the genetic code inbuilt into them that dictates their actions has not yet had a chance to be activated by going through the process of recognising a matching antigen that will trigger its attacking protocol. Once this happens, there is an opportunity for the thymus to produce a memory cell, where the immune response that it has just practised becomes a capability that is able to be deployed faster and stronger when the same antigen is once again detected in the body.
Over time, as the body is exposed to a large variety of antigens and enters adulthood, the immune system becomes dominant with memory cells instead of naïve cells.
The genetic code of T-cells is incredibly complex, and sometimes abnormalities can occur that turn them from one of the body’s greatest defensive weapons into an insidious enemy.
Cutaneous T-cell lymphoma (CTCL)
In the case of CTCL, cutaneous T-cells experience a mutation that causes them to attack the skin. It’s a rare form of non-Hodgkin’s lymphoma, and only around 3,000 new cases are diagnosed every year in the United States. Mycosis fungoides is the most common subtype of CTCL, and accounts for approximately 50% of all cases of CTCL. It can also rarely be hereditary.
CTCL is somewhat treatable, but it is not curable – and is certainly not without its burdens on the patients or healthcare system. The estimated cost of treatment in the average patients lifetime is US$73,389 in the US, and can include therapies such as chemotherapy, radiotherapy, stem cell transplants and a whole array of pharmaceuticals. There is well documented evidence of a significantly reduced quality of life that is a product of not just the skin abnormalities (rashes, tumours, swellings, plaques and papules), but other debilitating health problems such as diabetes and kidney failure.
The clinical outcomes for CTCL are highly dependent on the progression of the disease (stage 1-4). In stages 1A-2A, studies have shown the 5-year disease-specific survival rate to be between 89 and 98%. However, in later stage progression (stages 2B-4), the same studies have shown the 5-year disease-specific survival rate to be between 18 and 67%.
Peripheral T-cell lymphoma (PTCL)
PTCL is also a rare type of non-Hodgkin’s lymphoma, but it arises in the lymphoid tissues outside of the bone marrow – such as lymph nodes, spleen, gastrointestinal tract and skin. Most PTCL’s are aggressive (fast-growing) lymphomas, and there is a high chance of patients relapsing. There are around 5,600 cases per year in the US, and the disease has an average 5-year survival rate of 32%.
The standard protocol for initial treatment of PTCL involves multi-drug chemotherapy regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). However, approximately 68% of PTCL patients relapse after treatment or are refractory (resistant) to conventional chemotherapy. The prognosis for these patients is quite dire, with a median overall survival rate of just 5.8 months.
Newer ‘breakthrough’ therapies are only given to PTCL patients after prior lines of therapy have failed, at which time the cancer has likely spread throughout the body. One of these therapies is called Folotyn, an injectable chemotherapy drug that stops cancer cells multiplying by preventing the cells from using folic acid to make DNA. It costs US$450,540 per patient, per year – and comes with a greater than 70% chance of a serious adverse event including anaemia, mucositis and thrombocytopenia (low platelets).
At the time of it’s approval in 2009, Folotyn was the only approved therapy for relapsed or refractory (R/R) PTCL. Perfectly characterising the desperation of the disease’s clinical landscape, which is still very much present today, the drug was given approval based on its overall response rate – not clinical benefits such as an improvement in progression free survival or overall survival (which were not demonstrated).
Overall, currently available therapies for PTCL are typically characterised by a high occurrence of serious toxicities, low response rates (less than 30%) and a short duration of responses (3-4 months).
Prescient’s PTX-100 targeted therapy
PTX-100 is a first in class compound that blocks an important cancer growth enzyme known as geranylgeranyl transferase-1 (GGT-1). This disrupts oncogenic Ras pathways by inhibiting the activation of Rho, Rac and Ral circuits in cancer cells which leads to apoptosis (death) of the cell.
RAS is a gene family that consists of 36 human genes, the discovery of which fundamentally transformed the understanding of cancer biology. While RAS genes are a normal part of the human genome, they have the ability to transform normal human cells into cancerous ones if their gene function becomes mutated. More than 30% of all human cancers, including 95% of pancreatic cancers, 45% of colorectal cancers, 35% of lung cancers and 15% of acute myeloid leukaemia – are driven by mutations of the RAS family of genes.
Mutant RAS proteins have been notoriously difficult to treat, partly because they are a defective intrinsic enzyme activity that have so far, for the most part, been virtually ‘undruggable’. PTX-100’s ability to block GGT-1 is an exciting clinical development, and is believed to be the only GGT-1 inhibitor in the world that is in clinical development. It has been granted Orphan Drug Designation by the US FDA specifically for its potential to treat PTCL.
PTX-100 trial showing promising results
Given the high unmet clinical need of PTCL, and the FDA’s determination that PTX-100 could be a safe and effective treatment for the blood cancer, it is encouraging to see that a partial response was achieved in a patient with aggressive PTCL. The response endured for over 32 months before the disease progressed. Importantly, this response was achieved in a patient that had failed five prior lines of therapy.
One of the patients with CTCL, who had failed four prior lines of therapy, had a very good partial response (VGPR) that has so far endured beyond 6 months. Visually evident reduction in skin abnormalities were recorded and described by the Principle Investigator of the study, haematologist Professor H. Miles Prince, as “impressive responses”. The patient remains on therapy. Two other patients with CTCL that failed three prior lines of therapy have experienced stable disease (SD) that have endured for 4 months so far.
Overall, in a study that was initially designed only to test safety, Prescient considers that the resulting detection of efficacy has been especially encouraging. The study is being expanded to include up to 12 additional patients with TCL.
Prescient expects to provide a read out on the PTX-100 TCL expansion cohort in the coming weeks. With the potential to leapfrog deep into clinical development, the company is particularly excited about the opportunity for PTX-100 to improve patient outcomes and generate near-term value.
Join an interactive investor briefing with CEO and Managing Director Steven Yatomi-Clakre on Thursday, 2nd March at 1pm (AEDT). Click here to register.
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