At the end of last week, Agios Pharmaceuticals Inc (NASDAQ:AGIO) announced its intentions to present data from its PKR activator trial at the upcoming Congress of the European Hematology Association. The data refers to both preclinical and clinical data for the drugs in question, and its implications will likely prove the near term driver in the company’s market capitalization. With this in mind, here’s a look at the science behind the trials, and what to keep an eye on when data hits markets.
So, first, a look at the drug. As mentioned, it’s part of a family of drugs called pyruvate kinase activators (PKR activators), and as its name suggests, it targets an enzyme called pyruvate kinase (PK). PK is responsible for one of the key stages (not overly important to differentiate, but for those interested, it’s the final stage) in the conversion of glucose into lactic acid. This conversion (as a whole process) prevents the cell from getting destroyed as a response to glucose buildup.
PK is coded for, and produced by, a gene called PKLR. In some people, a mutation of the PKLR gene causes the creation of deficient PK enzymes, and in turn, an inefficiency in their ability (or complete inability) to convert glucose to lactic acid.
This can lead to a whole host of issues, including a patient’s inability to fight off viral infections, gall stones, ulcers, jaundice (in babies) and more.
The problem presents itself as a blood based disorder, so blood transfusion (in which active and working PK enzymes are transferred to a patient) is the current SOC, but its only a maintenance therapy, not a cure or a long term option. Further, in most cases, a complete blood transfusion is required. This is especially true in newborns, and is very dangerous.
With its two PKA candidates, AG-348 and AG-519, Agios is hoping to offer up a long term treatment option for PK deficiency. The drugs work to activate the deficient PK enzymes, and stimulate the production of functional PK, negating the need for transfusion.
It’s still early days. AG-348 is the more advanced of the two candidates from a clinical perspective, currently in phase II trials. AG-519 is in a phase I as of the first quarter of this year. Unlike the rest of the company’s pipeline (which is being developed in collaboration with Celgene Corporation (NASDAQ:CELG)), these two PKA candidates are all Agios. Whether Celgene will take them under its wing is unclear, but the potential for such a collaboration rests heavily on the data that the company is about to present. This is one of the reasons it could have such an impact on Agios’ market capitalization near term.
So, what are we looking for in the data?
Let’s look at AG-519 first. This is the phase I, and the trial is purely a safety and tolerability study. The trial is set up in two parts. The first is a single ascending dose study – 50 or so patients (circa half of the 114 enrolled) get a single dose of the drug and the other half get placebo. Agios will measure the rate of AEs, and compare these to placebo. The second arm is the same, but with patients receiving multiple doses across a 14-day period. What we are looking for here is pretty simple. Essentially, there should be no difference between the rate of response (adverse) in the active arm and the placebo arm both the SAD and the MAD elements of the studies.
Moving on to AG-348, this one’s a phase II, but it also has a primary endpoint of safety. The difference here is that secondary measures will look at efficacy, and since a couple of safety studies (in healthy volunteers) have already completed, markets will likely be focusing more on the secondary outcome measures than the primary. Specifically, change from baseline in ATP, 2,3 – diphosphoglycerate and hemoglobin. If we see a marked increase in any of these three aforementioned focal points, it would suggest efficacy for the drug (albeit at an early stage) and so long as tolerability comes in line with the healthy volunteer studies, should pave the way for a phase III. This is where a company like Celgene could factor in to the equation. If Agios can justify a pivotal, Celgene might be willing to fund it by way of milestones.
So there we go. June 11 is the day to watch for 348, and June 12 for 519. For those looking for a sneak peek, abstracts are available here.