Turing's R&D investments began in February 2015, immediately after the launch of the new company. Highly experienced scientists were recruited to lead Drug Discovery, Pharmacology, Toxicology and Metabolism, Medicinal Chemistry, and Clinical Research.
Since then, Turing has initiated two high throughput screening campaigns, performed seven regulatory toxicology studies and had three Investigational New Drug Applications accepted by FDA. In 2015, we invested 60 percent of net revenues (income minus business expenses) in R&D.
With a focus on serious and neglected diseases, the company identified research opportunities in more than 10 conditions.
With the acquisition of DARAPRIM, toxoplasmosis was selected as a primary area of focus for two reasons. First, there has been no significant innovation from the pharmaceutical industry in this area for 50+ years. But, most important, existing therapies are not ideal for all patients and there is considerable need for advancement.
Toxoplasmosis Research Goals
The ideal medicine for toxoplasmosis might have three virtues. First, it would be highly specific against the parasite with limited effect on human physiology. Second, it would be simply dosed in all populations, including infants and children. Most important, it would clear Toxoplasma gondii (active and latent) from its human host. These three principles influenced Turing's research goals.
Turing set out to discover and develop medicines that could be dosed orally and could cross the blood-brain barrier, since toxoplasmosis is often a disease of the brain and eyes.
Working with academic collaborators, the R&D team focused on three protein families essential to the parasite's viability. Dihydrofolate reductase (DHFR) inhibitors are obvious, since existing medicines, including pyrimethamine, are directed at this target.
Knowledge of the structural biology, however, is incomplete. DHFR has a rich set of crystal structures available for microbial species, including T. gondii. But very little modern computer-assisted drug design (CADD) methodologies have been applied to T. gondii DHFR (TgDHFR). Using CADD, Turing formulated the hypothesis that a more selective and potent drug could be realized.
The company's medicinal chemists were able to build clear Structure-Activity Relationships for pyrimethamine binding to both human and TgDHFR.
This allowed visualization of how an existing drug binds with its target to inhibit activity, and what structural changes might facilitate higher selectivity and potency for T. gondii.
Millions of molecules were designed and screened in silico. Turing scientists selected a subset of compounds that displayed diverse pharmacophoric elements and most promise in silico, based on pre-specified criteria.
Collaborating with laboratories in the US, Asia and Europe, they synthesized these and developed a set of in vitro functional assays to determine potency and selectivity for TgDHFR.
In pursuing compounds with high selectivity, Turing hoped to achieve a limited effect on the human equivalent of this enzyme. With pyrimethamine, the relative selectivity for parasite to human DHFR is about 16:1.
In late December 2015, the first round of screening delivered several promising leads, some with the potential to improve the selectivity favoring T. gondii near 100:1 with 10-fold greater potency.
Since then, hundreds of analogs have been produced based on traditional medicinal chemistry. Turing's more mature lead candidates have even stronger selectivity profiles with excellent drug-like properties. While these data are very encouraging, much more work is required to determine if these compounds have clinical value.
In parallel with these medicinal chemistry efforts, Turing built preclinical models to better understand if the lead candidates might translate into clinically relevant therapies.
These include parasite growth inhibition assays and pharmacological studies in mouse models of toxoplasmosis. Turing is privileged to work with academic experts and is pioneering an effort to make these models available at industrial scale.
Simultaneously, Turing continues to research other therapeutic approaches and biochemical pathways relevant to toxoplasmosis. The company remains focused on its most ambitious goal – finding a medicine that treats both the acute and chronic stages of toxoplasmosis to limit disease reactivation.
Toxoplasmosis: Other Approaches
While there is certainly need for novel molecules, Turing recognizes that existing therapies might be further developed. Scientific programs are underway to explore alternative formulations of pyrimethamine intended to better meet the specific needs of distinct patient populations.
Turing is also building knowledge on how toxoplasmosis is treated in the US and in other countries where incidence is far higher. In some areas of Brazil, for example, ocular toxoplasmosis is remarkably common.
The lack of industry innovation in toxoplasmosis in the decades following the introduction of existing therapies has resulted in an absence of pharmacologic advancement.
Turing is working to address this gap and add scientific knowledge about toxoplasmosis therapy. These efforts include health economics (true cost of treatment), disease biology and other areas of research.
Turing aims to share these data, in detail, with the scientific community in due course.