NEW YORK (GenomeWeb) – At a recent conference, personalized medicine newcomer Pairnomix shared the first case report demonstrating its exhaustive methodology to functionally study and determine treatments for patients with novel or poorly understood genetic mutations.
Launched about a year ago, the firm set out with a unique approach to personalized medicine — in essence, the company engineers an entire drug testing pipeline for each patient that it serves, from the most basic functional genetics studies of a patients mutation to in vitro screens of potentially active compounds.
Genome sequencing is increasingly identifying mutational causes for rare diseases, but even patients with a positive genetic finding can be left with a result that means little for them in terms of understanding the biological nature of their disorder or finding a treatment for it.
That's where Pairnomix has positioned itself, aiming to take the next logical research steps that an academic group or drug developer might in the context of more common diseases, but on a single-patient basis.
While this meticulousness makes sense as a concept, the approach raises questions about whether and how often it can impact patient outcomes in a manner worth the huge costs involved to an individual or family.
Though the company hasn't disclosed prices for its services, CEO Matt Fox has said that just to build cell lines and do its first characterization steps can cost $75,000 to $100,000 in some cases.
Now, with its first-ever case study — shared at the annual meeting of the American Epilepsy Society — the firm has begun to shed light on some open questions about its approach, demonstrating that it was able to conduct accurate and informative drug screening, with results that reflected a patient's response to a newly administered therapy.
"There are three main considerations for a company like Pairnomix," Fox said in an interview. "First, can we characterize a patient properly?; second, can we do a drug screen properly?; and finally, does it matter to the patient?"
"One of the key questions of us for this year has been to get a case study out there showing that this is working," he said.
At the meeting, Pairnomix reported on its efforts for the family of a 10-year-old girl with a history of early infantile epileptic encephalopathy and developmental delay. At the start of the company's investigations, the young girl suffered from seizures that were uncontrolled by medications.
Her physician is a leader in the epilepsy field — one of several that the company has partnered with for its first pro bono cases to demonstrate how its methods might benefit patients and families.
Nex-gen sequencing had identified a de novo pathogenic mutation in the SCN8A gene, which became the basis of Pairnomix's efforts.
Interestingly, Fox said, although the R1872Q mutation in question was novel, it has also been investigated by an academic group at the University of Michigan, led by professor Miriam Meisler.
"She did a characterization study, which is effectively very similar to the first half of what our work is. But in the academic setting, they never actually performed a drug screen, which is the next step," Fox said.
"But it was great for us because we would be either confirming or not confirming work that had been done in a very reputable academic center, and we were very happy to see that we reflected what was seen in their work," he added.
More specifically, the company was able to develop an in vitro model of the patient's mutation, which reflected Meisler's findings and confirmed a suspected gain-of-function phenotype in the Nav1.6 sodium channel with resulting neuronal hyper-excitability.
The company then set out to perform a high-throughput drug screen using its library of more than 1,300 approved compounds representing multiple drug classes.
In a first pass, the firm identified 90 drugs that significantly inhibited the gain-of-function phenotype conferred by the patient's mutation. They then retested these, plus 24 commonly prescribed antiepileptic drugs. According to the study authors, the vast majority of the 90 hit compounds showed strong inhibition in this second test, while the AEDs mostly showed poor inhibition in comparison.
Finally, Pairnomix took three drugs with favorable safety profiles from among the 90 hits — carvedilol, amitriptyline hydrochloride, and nilvadipine — as well as carbamazepine, one of the AEDs that did show stronger inhibition, and tested them further using electrophysiological assays.
All four drugs inhibited sodium influx both in cells containing wild-type channels and in cells containing mutated Nav1.6 channels, the investigators reported.
Most important in terms of the clinical utility of the approach, when carbamazepine was administered to the patient it helped to control her seizures, the company reported at the meeting.
In this case, the doctor didn't prescribe the drug based on Pairnomix's report. He decided to try it while the company was still performing its research, so it's more of a tangential demonstration of how the company's methods could impact patient care.
"It wasn’t because of the screen, but that's one of the hits that our screen came up with," Fox said.
Another important caveat to the results is the fact that not all families that seek out Pairnomix's services may have a physician as comfortable with the research processes involved or as potentially willing to act based on the results.
Pairnomix actually consulted with the physician in this particular case before choosing the final four drugs to subject to electrophysiological characterization, Fox said.
"We took a grouping, and asked which of these would you actually try, which could you possibly feel comfortable actually prescribing?"
Though the doctor hasn't yet tried any of the other treatments that the studies yielded, one of the other top hits that the group confirmed with electrochemical analysis, amitriptyline hydrochloride, "is an SNRI that neurologists have a lot of experience with, and it showed a stronger inhibition level and a more conservative dosage level," Fox said. Because the physician is a thought leader in the field, there may be more of a chance that he would consider trying that, or one of the other treatments.
Other families that seek out Pairnomix's services might have a harder time finding a doctor even willing to consider the results of the company's work.
"We call ourselves a personalized genetic research company, so we don't give out information about things like dosage or try to influence physician decision-making directly," Fox stressed.
However, Fox said, the firm is dedicated to making sure it only takes on patients for whom it thinks it can deliver a meaningful result. For example, Pairnomix isn't taking any clients with genetic results that are considered variants of unknown significance, at least not right now.
Though he did not provide details on how the company has been ramping up operations this year, Fox said that it has several other cases underway.
Pairnomix is also part of a team — with Harvard Medical School, the University of Utah, Boston Children’s Hospital, and Recursion Pharmaceuticals — that has pledged a commitment under the Precision Medicine Initiative to apply genomic medicine, bioinformatics, and drug screening techniques to quickly identify a precision treatment strategy for patients with six genetic disorders within 12 months of diagnosis.