Turing Pharmaceuticals Claims “Several” Anti-Toxoplasmosis Candidates in Preclinical Development
In a press release yesterday, Turing Pharmaceuticals—the sole US seller of Daraprim (pyrimethamine)—announced its development of “several” NMEs for the potential treatment of toxoplasmosis. All of these molecules, like pyrimethamine, preferentially target the essential enzyme DHFR in the toxoplasmosis-producing parasite (T. gondii)—as opposed to that in humans.* However, Turing claims that its NMEs are much more selective for the parasitic enzyme than pyrimethamine.
Moreover, the company said it has advanced these NMEs into preclinical testing. The company did not explicitly say if testing has reached the animal stage, but that would generally be the reasonably inferred meaning of the statement.** The head of Turing’s R&D, Eliseo Salinas, reported that clinical (ie, human) testing would begin in the 2nd half of 2017—which seems like a huge overpromise, IMO. But I guess we’ll see.
Notably Turing published information on the structure of one of its DHFR-targeting NMEs in ACS Medicinal Chemistry Letters on September 17th (subscription required, which I don’t have). The molecule, labeled TRC-19 (which is curiously not listed in Turing’s pipeline), is reportedly a potent inhibitor of DHFR (IC50 = 9 nM, vs 230 nM with pyrimethamine) and is preferentially selective for the T. gondii enzyme (89-fold vs 20-fold with pyrimethamine).
An examination of the article’s authors reveals the lead to be Matthew E. Welsch, PhD, who evidently left Turing in 2015 and founded the New York-based Atoms 2 Applications, “a pharmaceutical research consulting company, specializing in computer-aided drug design and the development of preclinical discovery programs.” Welsch’s bio at the A2A company website completely fails to mention his time at Turing, and he’s apparently scrubbed that relevant employment history from his LinkedIn profile as well. (Also FWIW and according to LinkedIn, Turing’s former business development executive Edward Painter is the current CFO of A2A.)
The other article authors, save one (Stephen B. Thomas, PhD***), are from WuXi AppTec, either in Shanghai and Plainsborough, NJ. WuXi is a pharma R&D service provider, which appears to have done much of the heavy lifting outside of the computer-generated (ie, in silico) design of TRC-19 done by Welsch (or I assume it was done by Welsch).
The press release continued,
Turing’s research team [although, is it really more WuXi’s research team?] also reported the first-ever crystallographic data of a novel inhibitor bound to T. gondii DHFR. These data have been deposited in the Protein Data Bank and are publicly available. Turing plans to submit additional manuscripts detailing drug discovery and development efforts for publication in peer-reviewed journals in the near future.
By using a number of reasonable search terms, I searched the Protein Data Bank and did not find the DHFR inhibitor to which Turing’s press release alludes. That’s not to say it’s not there; I just couldn’t find it. So if it’s publicly accessible, it’s not easily publicly accessible.
How Turing’s R&D program is really faring—specifically with respect to its funding and staffing—is almost impossible to know, outside of this press release and a recent Forbes interview with Turing’s R&D head. Trying to read beyond and between the usual puerile detritus of Martin Shkreli’s Twitter feed, there is this cryptic message from yesterday:
https://twitter.com/MartinShkreli/status/778718227308216321
Taken in context with Shkreli’s recent, not-so-veiled tweeted threats against Turing CEO Ron Tilles, it suggests that there’s a serious leadership struggle within Turing. Shkreli’s latest tweet hints that this presumed struggle may relate to Turing’s R&D budget.
DHFR = dihydrofolate reductase; NME = new molecular entity.
* Nevertheless, humans must generally take a folate supplement (eg, leucovorin) when taking pyrimethamine.
** The press release further stated that it had “subsequently optimized and tested the selected drug candidates in relevant disease models.” Again, however, the company did not explicitly state animal disease models.
*** Thomas, who appears to have come out of the same Columbia University lab as Welsch, is apparently still employed by Turing. However, Thomas, in addition to his employment at Turing, also appears to be an “investor” at Rare Disease Therapeutics. Both Welsch and Thomas acquired their PhDs in 2015, according to the lab website.
A native East Tennessean, Barbara Martin is a formerly practicing, board-certified neurologist who received her BS (psychology, summa cum laude) and MD from Duke University before completing her postgraduate training (internship, residency, fellowship) at the Hospital of the University of Pennsylvania in Philadelphia. She has worked in academia, private practice, medical publishing, drug market research, and continuing medical education (CME). For the last 3 years, she has worked in a freelance capacity as a medical writer, analyst, and consultant. Follow Dr. Barbara Martin on Google + and Twitter.
