The history of drug development can be broken down into three broad phases. The first can be coined "accidental." In this phase, researchers stumbled across potential treatments (the early days of antibiotics fits nicely into this category) and, understandably, progress was slow. The second phase involved the use of screening, which involves testing a large library of chemicals against a particular target to identify how each modifies the target and – in turn – which of those tested could potentially be the most effective from a disease-modifying perspective.
The third and current phase is one of active design. In recent years, scientists' understanding of the pathways associated with various disease types (and their resulting progression) has increased dramatically and this has resulted in researchers being able to create drugs specific to the interruption of these pathways.
This latest phase really is a game changer in terms of how certain diseases are treated.One company is currently conducting a late-stage trial investigating one of the most sought-after pathways associated with this active development wave.
The company is Onconova Therapeutics Inc. (ONTX, Financial), and its target is the Ras oncogene.
Currently, Onconova is investigating the safety and efficacy of its lead development asset, a drug called rigosertib, in a target indication of myelodysplastic syndromes (MDS) after failure of a hypomethylating agent (HMA).
Myelodysplastic syndrome (MDS) is a group of diseases that affect normal blood cell production in the bone marrow. In patients with myelodysplastic syndrome, the bone marrow produces abnormal, immature blood cells called blast cells. These blast cells are considered a precursor to leukemia and, as things stand, the current standard of care is the above-mentioned hypomethylating agent.
In many cases, however, the hypomethylating agent fails, so these patients are left with potentially cancerous cells in their body and no form of preventative therapy.
The mechanism of action is based on the concept that cells communicate with one another on a regular basis, using proteins to pass messages from cell to cell. The proteins (messages) are instructions as to whether the cell should replicate, proliferate, grow, die, etc. However, the proteins are too large to enter the cell they are communicating with (and so cannot pass the message to the nucleus by themselves), so they rely on a signaling pathway to get the message from cell surface receptors to the cell's nucleus.
These signaling pathways involve various genes, one of which is Ras.
Ras is responsible for telling a cell to proliferate but, normally, it is switched on and off very quickly once activated. Mutations in Ras, or in the protein that signals it, can cause it to be constantly switched on, leading to the unchecked proliferation that's at the center of cancer cell development.
Rigosertib, then, seeks to inhibit the Ras oncogene and, in turn, stop the unchecked proliferation signaling that happens when Ras is stuck in an "on" position.
So does the drug work?
As mentioned, the drug is in phase III trials right now, but there is some phase II data that hit press in 2017 that suggests a strong degree of efficacy. Just as with the ongoing phase III, the trial looked at high-risk myelodysplastic syndrome patients that had failed hypomethylating agent therapy and, as per the results, there was a strong response in this population.
Specifically, 22% of patients achieved marrow complete response and 47% of patients in the study achieved disease stabilization. Further, in landmark analysis (a statistical analysis method used to assess progression), bone marrow response correlated with overall survival – overall survival was 3.3 months for progressors, 6.3 months for stable disease.
The important conclusion to draw from these results is that they showed treatment with rigosertib resulted in a reduction in bone marrow blast (BMBL) count, including complete bone marrow responses, confirming findings in earlier studies. Thus, the bone marrow blast response to rigosertib is a potential surrogate marker for improvement in overall survival in this patient population.
That's a big deal.
And it is one Onconova is now looking to confirm on a bigger scale.
There is now an ongoing phase III trial that serves as the next major data catalyst for the company, with the trial in question looking at approximately 225 patients below 82 years of age with myelodysplastic syndrome. The study is set up to compare the active drug with any approved or standard of care therapy (physician's choice) and will be judged against a primary endpoint of overall survival of all randomized patients and overall survival of patients scored as very high risk according to International Prognostic Scoring System (IPSS-R) standards.
The primary completion date for the study is October 2018, with estimated final completion slated for February 2019.
(Disclosure: The author has no positions in any of the stocks mentioned in this piece.)
