Dive Brief:
- Ionis and its Akcea subsidiary reported positive Phase 3 results for lead product candidate volanesorsen (formerly ISIS-APOCIIIRx) to treat patients with familial chylomicronemia syndrome, a rare metabolic disorder. But lingering safety concerns caused the biotech’s shares to fall by about 8% on March 6.
- Investigators reported a 77% drop in triglycerides among the 33 patients taking the drug, in contrast to an 18% decline among patients on placebo.
- Yet, five volanesorsen-treated patients discontinued in the trial due to injection site reactions, five stopped participation because of declining platelet counts and three patients developed Grade 4 thrombocytopenia, a serious platelet event, that ended after dosing was halted. This led some analysts to voice concerns that the APPROACH study’s discontinuation rate was higher than anticipated.
Dive Insight:
The APPROACH trial’s positive result “represents an important milestone towards our first regulatory submissions for volanesorsen in the U.S., Europe and Canada in 2017,” said Louis O’Dea, CMO of Ionis’ subsidiary Akcea Therapeutics. “We seek to bring this new treatment as expeditiously as possible to FCS patients who have a high unmet need with potentially life-threatening consequences.”
After describing the reasons behind patient discontinuations in latest Phase 3 trial, Ionis stressed that in the entire volanesorsen clinical program, 232 individuals have been treated with the drug, including 66 FCS patients—some for more than two years.
However, safety is an issue that has dogged the drug’s various trials – to the point where Ionis Chairman and CEO Stan Crooke on Feb. 28 opened a fourth-quarter 2016 earnings by discussing it.
In May 2016, Ionis’ shares fell 40% after the company reported that its drug IONIS-TTRRx had triggered thrombocytopenia in patients with TTR amyloid cardiomyopathy. This prompted the FDA to put the program on a clinical hold and partner GlaxoSmithKline dropped plans for a late-stage study over safety concerns. Moreover, Ionis said similar issues related to platelet declines could occur with volanesorsen, prompting concerns about a possible class effect.
During the recent earnings call, Crooke said IONIS-TTRRx "is on schedule for Phase 3 data in the second quarter and we took important steps to understand and resolve the serious platelet events that were observed in two of our Phase 3 studies," he said.
He stressed there is a better understanding now of “the unique characteristics of the patients with severely elevated triglycerides and the patients in the TTR amyloidosis study that contributed to these serious platelet events.”
"Both volanesorsen and IONIS-TTRRx studies are continuing on track and we published edits showing that these serious platelet events were not a class effect of our 2-prime methoxyethyl and antisense drugs," Crooke said.
Despite the new late-stage data showing volanesorsen’s efficacy, some analysts balked at the 15% discontinuation rate for patients due to platelet declines. "Along with injection site reactions leading to additional 15% dropouts [for a total discontinuation rate of about 30%], we continue to see limited commercial potential aside from potential regulatory risks," Jefferies analysts said in a March 6 note to investors. They also noted that the number of patients in the APPROACH study with Grades 1 to 3 thrombocytopenia was undisclosed.
Moreover, Jefferies analysts said they see limited commercial potential from a drug targeting an estimated 3,000 to 5,000 FCS patients worldwide. If volanesorsen were to launch in 2018, "we estimate sales of $4M/$20M/$41M/$62M in 2018-2021," the analysts said, noting that Ionis expects to build a 75- to 100-person commercial team in the U.S., EU & Canada for the drug.
Another key component of planned regulatory filings for volanesorsen was the Phase 3 COMPASS study. In December 2016, Akcea and Ionis reported that COMPASS met its primary endpoint, lowering triglyceride levels by 71% in 75 patients with severe hypertriglyceridemia and by 73% for seven patients with FCS, besting the trial’s placebo-treated cohort.