Ionis, fresh from its approval of Spinraza with Biogen, says it is seeking to get its heart drug volanesorsen in front of the FDA as soon as possible, as it also looks to work on a new alternative med with Biogen after dropping development of IONIS-DMPK-2.5-R.
Speaking to FierceBiotech from this year’s J.P. Morgan event in San Francisco, Ionis’ CEO Dr. Stanley Crooke wouldn’t give an exact timeline, but said the biotech is “gearing up to file the NDA in a very short time after we get our latest phase 3 results.”
He said that Ionis has been getting the NDA ready “for some time; … we’ll get it to the FDA as soon as possible.”
Just before Christmas, the biotech reported that volanesorsen showed positive efficacy data from a phase 3 trial in patients with severe hypertriglyceridemia after the antisense treatment bested placebo in terms of reducing triglycerides, hitting its primary endpoint.
After 13 weeks of treatment, 82% of patients in the volanesorsen arm had triglyceride levels of 500 mg/dl or less. Only 14% of subjects in the placebo cohort hit this level. Having a high level of triglycerides, a type of fat in the blood, can increase the risk of heart disease.
The drug’s first intended indication, Crooke said, will be for familial chylomicronemia syndrome (FCS), a rare genetic disorder in which patients cannot clear lipid particles called chylomicrons and therefore have extremely high levels of triglycerides, which can increase the risk of pancreatitis and death.
Crooke said that its FCS study is now “derisked” as a result of the positives coming from the phase 3: Data from a study in FCS patients will be unblinded in the first quarter.
Crooke said the hypertriglyceridemia test produced a “remarkable performance,” but there have been lingering safety concerns. There were severe platelet events in another drug, the GSK-partnered IONIS-TTRRx, posted last May, with the biotech saying similar issues related to declines in platelets may affect volanesorsen, information that hit its share price.
But in its latest phase 3 for volanesorsen Ionis said that “there were no serious platelet events in the study.”
Crooke said: “We didn’t expect, given what we learned from the events in the FCS patients, we didn’t expect severe platelet declines in this patient population because what we learned after the fact from natural history studies, which we hadn’t before known—I wish we had—was that people with FCS have very sizable and varied sizes of platelet count, just as a part of the disease.
“This is because they have these superhigh triglyceride levels, we think, that are driving this formation, and so that waxes and wanes. So, we think the severe platelet events that we have observed in FCS was a part of the disease process and our drug, well its lowers triglycerides, so that triglyceride rise will be keeping that platelet level high. So, in that sense, the lack of severe platelet decline events in the study is further evidence—I can’t say unequivocally that we’ve proved that—but it’s further evidence for the hypothesis that this was an FCS-related event.”
Crooke said he’s confident he has a good drug in volanesorsen and is, he believes, the only drug that works in these patient populations. “I think it’s also worth noting that we produced statistically significant reductions in pancreatitis in this small, short study, which was an incredible bonus from our point of view, even though this didn’t seem to gain the attention of Wall Street,” he said.
This also comes a week after it announced a major deal with Novartis, which paid $75 million upfront, a $100 million equity stake, and potentially around $1 billion in biobucks, for an exclusive worldwide option and collab pact to work on and sell AKCEA-APO(a)-LRx and AKCEA-APOCIII-LRx, two other Ionis drugs in the clinic for cardiovascular diseases.
Crooke said he doesn’t need to do this deal for cash, Ionis has a market cap of more than $6 billion, and that the pact is predominately about speeding up work on its other heart meds and getting them to market, and using the sales and marketing strength of Novartis, which has major experience in selling CV drugs.
Crooke said the deal, which had been in the pipe for a while, comes as Ionis “doesn’t want to build a major sales force, so we want to leverage our partner’s resources to get our outcomes studies done, and then sell.”
Ionis has another deal in place with Biogen, a collab that became highly fruitful for the pair as, just a few weeks’ ago, they announced the FDA approved their SMA med Spinraza (nusinersen), beating out rival AveXis, and becoming the first companies to sell a specific drug for the rare, genetic condition which severely reduces the life expectancy and quality of lives of very young children.
But after this was announced, the two quietly announced last week during an R&D update that one of its other collab drugs will be discontinued.
The med, IONIS-DMPK-2.5-R, has now been chopped due to inadequate potency in muscle in phase 1/2 in patients with myotonic dystrophy type 1.
Crooke confirmed the drug had been dropped, and explained: “We have drugs that are in preclinical studies that are anywhere from 5- 10 times more potent [than IONIS-DMPK-2.5-R]. Now, if we did not have such drugs already, and I should add we’re not yet ready to make a decision on one of those yet as we want to refine them and we have more work to do on that, but if we didn’t have a clear path to something more potent, we probably would have moved forward on ‘25R, but since we have this path to a more meaningful, more potent drug, as well as being more convenient and more tolerated, it made sense to do this [stop work on the med].”
He said that in the study it completed for ‘25R, there was “evidence of target engagement,” which Crooke said was “reasonable,” adding that everything they did in that study was a first, making it a series of “very, very challenging clinical experiments.”
“I feel from this that we could reduce target in muscle, but it required more drug than we had hoped.”
He said there were positive trends, though not highly statistically significant, and that they “learned a lot from this study.” He added: “I think moving onto the new path with more potent drugs was in the end however the best decision.”