Long-term Use of Daclizumab Safe, With Caveats

Deborah Brauser

December 07, 2017

PARIS — Despite recent warnings and a European safety review regarding the use of daclizumab (Zinbryta, Biogen/AbbVie) in patients with multiple sclerosis (MS), new research suggests that it is has a relatively satisfactory "risk-benefit profile." Still, investigators urge caution in patients with elevated liver enzymes.

The long-term open-label extension study known as EXTEND included more than 1500 patients with remitting MS, all of whom had previously completed the phase 3 DECIDE randomized controlled trial.

Interim results from up to 6 years of treatment showed that 92% of the participants, all of whom self-administered once-monthly subcutaneous injections of 150 mg daclizumab β, experienced some type of adverse event (AE). Among these patients, 82% of the AEs were mild or moderate while 18% were considered severe.

Common AEs included nasopharyngitis, upper respiratory tract infection, and headache. AEs of special interest (AESIs) included infections of any type (67%), cutaneous AEs (42%, but only 3% of participants had serious versions), and hepatic AEs (19%). Less than 1% had malignancies or autoimmune hemolytic events, and there were no reports of progressive multifocal leukoencephalopathy.

There were 9 cases of drug-induced liver injury and 7 cases of toxic hepatitis.

Still, "most AEs were mild/moderate in severity and the incidence of AESIs remained stable over time. And the most common hepatic AEs were laboratory abnormalities, such as elevations of serum transaminases," said Stanley Cohan, MD, PhD, Providence MS Center at the Providence Brain and Spine Institute in Portland, Oregon.

"Overall, these safety data…provide evidence to support daclizumab β's long-term benefit-risk profile," added Dr Cohan.

He reported the findings at the 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting.

Warnings, Restrictions

Although daclizumab was first authorized for use in the European Union in 2016, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) launched a safety review in June 2017 after a patient who had received the drug during an observational, dose-finding study died of fulminant liver failure. There were also four other case reports of serious liver injury.

The committee recommended further restrictions in October, suggesting that physicians prescribe the drug only to patients with relapsing forms of MS who had an inadequate response to at least two disease-modifying therapies (DMTs).

The US Food and Drug Administration (FDA) approved the drug in May 2016 but has also cautioned that it should be used only in those who have not responded to one or two prior therapies. Daclizumab carries a boxed warning in the United States stating that the drug can cause severe, potentially fatal liver injury.

Both organizations have recommended liver function monitoring in patients receiving this agent.

"Clearly, the drug has a solid efficacy profile for patients with relapsing disease. I don't think that's in question at all. And it's shown efficacy against other DMTs," Dr Cohan told Medscape Medical News.

"The problem is there have been adverse events. Those fall into a number of categories, but the ones that seem to be most important are cutaneous and hepatic, aside from MS relapses, and infections," he said.

Dr Cohan noted that the earlier patient death occurred during the 6-month washout period after resumption of the medication. "That patient had elevated liver enzymes, and following the resumed third dose of daclizumab, developed hepatic failure. The autopsy was consistent with the diagnosis of autoimmune hepatitis."

A second death "occurred as a result of acute fulminate hepatic necrosis. It's not really clear what this is due to, but it evolved very quickly," he said. This patient had mildly elevated liver enzymes about 6 weeks before taking daclizumab. Although those levels were no longer elevated at time of the first or third doses, the patient reported not feeling well 21 days after the third injection; hepatic dysfunction was diagnosed about 4 days after that. Fulminate hepatic deterioration occurred soon after, followed by a transplant, and then death at day 31.

"The autopsy, and I'm not a hepatologist or pathologist, reports fulminate infiltration with inflammatory cells with necrosis. That doesn't necessarily qualify it as autoimmune hepatitis, nevertheless hepatic dysfunction obviously is a concern," said Dr Cohan.

"And that's why it's been dictated that every patient not have hepatic disease before starting the drug; extreme caution should be exercised if a patient is on a concurrent medication that also has hepatic risk associated with it; and patients need to be monitored every single month before they get their next dose," he added.

Any patient whose hepatic enzymes or bilirubin levels alone or together exceed normal "should be taken off medication and observed. If the enzymes do not resolve, do not put the patient back onto medication."

Long-term Safety Analysis

The ongoing EXTEND trial was created to assess long-term safety and efficacy of daclizumab β in patients with remitting MS.

At the meeting, Dr Cohan presented safety outcomes from EXTEND for data collected as of September 9, 2016. All of the study participants received at least one dose of daclizumab while in the DECIDE trial or received interferon β-1a in DECIDE and then switched to daclizumab in EXTEND.

The total safety population included 1516 participants and represented 4637 person-years and a median range of 34 doses each.

There were 308 serious AEs reported, excluding MS relapse; 781 treatment-related AEs of any type; and 327 AEs that led to drug discontinuation.

Two patients died during the study, but both deaths were judged to not be related to treatment. One was from a traumatic subdural hematoma and the other was from aspiration pneumonia, septicemia, bed sores, and cardiorespiratory arrest.

The following AEs occurred in more than 10% of the study participants:

  • MS relapse (35%);

  • Nasopharyngitis (25%);

  • Upper respiratory tract infection (19%);

  • Headache (16%);

  • Urinary tract infection (12%);

  • Back pain (11%); and

  • Pharyngitis and pyrexia (10% for each).

Serious infections were reported by 5% of the participants, the most common being pneumonia (n = 14). There were three cases of serious opportunistic infection, which were all pulmonary tuberculosis occurrences. No cases of herpes-related complications were found.

Only 1% of the patients discontinued treatment because of infection, while 6% discontinued treatment because of cutaneous AEs. The most common cutaneous AEs were rash (9%) and eczema (6%).

"A large number of these patients already had prior history of eczema or psoriasis. Then, given the medication, the disease reactivated," said Dr Cohan.

There were no reports of Stevens-Johnson syndrome or toxic epidermal necrolysis.

Hepatic AEs led to drug discontinuation in 7% of the study population, and 1% of the total group had any serious version of this type of AE. Hepatic AEs by system organ class included the following:

  • Laboratory abnormalities (17%);

  • Hepatobiliary disorders (3%); and

  • Hemangiomas of the liver (<1%).

Finally, there were three cases of autoimmune hemolytic anemia, "two of which were considered possibly related to…treatment," said Dr Cohan. All resolved with standard treatment and discontinuation of daclizumab.

During the postpresentation question-and-answer period, session chair Mark S. Freedman, MD, professor of neurology at the University of Ottawa and senior scientist at the Ottawa Hospital Research Institute, Ontario, Canada, asked whether the hepatic abnormalities occurred upfront or "accumulated with longer exposure."

"The answer is: They can occur any time during therapy or up to 4 to 6 months after therapy is discontinued or completed; and the occurrences do not increase over time," answered Dr Cohan.

He later told Medscape Medical News that he agrees with the recent warnings issued by the PRAC. "I think they're appropriate until we have a better understanding of certain risks. And those were the FDA's recommendations even before the [PRAC's] report came out."

Postmarketing Vigilance "Key"

Dr Freedman told Medscape Medical News that the presentation "is what it is," but he's a bit wary of any safety data from an extension study.

"We need it, but it doesn't tell us necessarily what's going to happen when the drug is opened up in the marketplace," said Dr Freedman.

"The study patients are always highly selected in order for the data to be informative but also so there aren't any confounding problems. That's not the real world, where patients have other things going on and take other medications," he said. "So postmarketing vigilance is absolutely key."

He noted that the past reports of liver failure after receipt of daclizumab are still concerning.

"Where does this drug fit in our regimen? It's an immunomodulator, so maybe it goes somewhere between the first-line therapies and the anti-trafficking drugs. But there are so many choices today, and many of us don't know where to place this one," he said.

"You add the cons of 'do you want to take the risk of destroying someone's liver on this?' Granted, it's rare but it's a devastating consequence. And there so many other options now."

The study was funded by Biogen and AbbVie Inc. Dr Cohan has been on advisory boards for Biogen, Genzyme, Mallinckrodt, and Novartis; has been on speaker bureaus for Biogen, Acorda, Genentech, Genzyme, and Novartis; and has received research support from Biogen, Genentech, Genzyme, Mallinckrodt, MedDay, Novartis, Opexa, and Roche. Dr Freeman has consulted before for Biogen.

7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017. Parallel session 10, oral presentation 206. Presented October 27, 2017.

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