Author Topic: (Abst.) Efficacy & safety of daclizumab & its potential role in MS treatment  (Read 553 times)

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Offline agate

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From Ther-a-peutic Advances in Neurological Disorders, January 9, 2014:

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The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis

Ron Milo

Department of Neurology, Barzilai Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, 2 Hahistadrut St, Ashkelon 78278, Israel
rmilo@barzi.health.gov.il


Daclizumab is a humanized monoclonal antibody of the immunoglobulin G1 (IgG1) isotype that binds to the α-subunit (CD25) of the high-affinity interleukin-2 (IL-2) receptor expressed on activated T cells and CD4+CD25+FoxP3+ regulatory T cells. Based on the assumption that it would block the activation and expansion of autoreactive T cells that are central to the immune pathogenesis of multiple sclerosis (MS), daclizumab was tested in several small open-label clinical trials in MS and demonstrated a profound inhibition of inflammatory disease activity. Surprisingly, accompanying mechanistic studies revealed that the most important biological effect of daclizumab was rather a dramatic expansion and activation of immunoregulatory CD56bright natural-killer (NK) cells that correlated with treatment response, while there was no or only minor effect on peripheral T-cell activation and function. These CD56bright NK cells were able to gain access to the central nervous system in MS and kill autologous activated T cells.

Additional and relatively large phase IIb clinical trials showed that daclizumab, as add-on or monotherapy in relapsing–remitting (RR) MS, was highly effective in reducing relapse rate, disability progression, and the number and volume of gadolinium-enhancing, T1 and T2 lesions on brain magnetic resonance imaging (MRI), and reproduced the expansion of CD56bright NK cells as a biomarker for daclizumab activity.

Daclizumab is generally very well tolerated and has shown a favorable adverse event (AE) profile in transplant recipients.

However, several potentially serious and newly emerging AEs (mainly infections, skin reactions, elevated liver function tests and autoimmune phenomena in several body organs) may require strict safety monitoring programs in future clinical practice and place daclizumab together with other new and highly effective MS drugs as a second-line therapy.

Ongoing phase III clinical trials in RRMS are expected to provide definite information on the efficacy and safety of daclizumab and to determine its place in the fast-growing armamentarium of MS therapies.

The abstract can be seen here.
« Last Edit: April 29, 2015, 09:47:57 am by agate »
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Offline agate

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Re: More on daclizumab
« Reply #1 on: May 07, 2014, 08:20:50 am »
From the MS International Federation Research News, May 7, 2014:

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Daclizumab high-yield process in relapsing-remitting multiple sclerosis


This study (SELECTION) is the extension of the SELECT trial, the first randomised, double-blind, placebo-controlled trial of daclizumab high-yield process (HYP) given as monotherapy for relapsing-remitting multiple sclerosis.

Daclizumab is a humanised monoclonal antibody and the primary analysis showed that its administration for 52 weeks reduced disease activity.

The primary aim of the SELECTION extension study was to assess the safety and immunogenicity of extended treatment with daclizumab HYP. The secondary aim was to assess the durability of the daclizumab HYP treatment effect on disease activity. SELECTION is a multicentre, randomised, double-blind, 52-week extension trial in patients with relapsing-remitting multiple sclerosis who completed the SELECT study. Patients who received placebo in SELECT were randomly assigned (1:1) to receive 150 mg or 300 mg subcutaneous daclizumab HYP every four weeks for 52 weeks (treatment initiation group); those who had received daclizumab HYP were randomly assigned (1:1) to continue their present dose with (washout and re-initiation group) or without (continuous treatment group) a washout period of 20 weeks.

Bronchitis was the only serious infection reported: infections resolved with standard treatment. Alanine aminotransferase or aspartate aminotransferase concentrations of more than five times the upper limit of normal occurred in 11 patients (two per cent).

Except for a case of severe autoimmune hepatitis (one patient died), in which a contributory role of daclizumab HYP could not be excluded, and for some serious cutaneous events in six patients (urticaria, eczema, pityriasis rubra pilari, dermatitis), the drug was well tolerated and safe. Reductions in clinical and radiological disease activity in patients were maintained in the second year of treatment with daclizumab HYP. Disease activity at the end of the washout period was similar to the pre-treatment period, without evidence of increase above baseline levels. Re-initiation of treatment effectively restored the pharmacodynamic effects and reduced disease activity.

Authors: Giovannoni G, Gold R.

Source: Lancet Neurol. 2014 May;13(5):472-81. doi: 10.1016/S1474-4422(14)70039-0

The abstract for this study can be seen here.
« Last Edit: May 07, 2014, 08:23:17 am by agate »
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Offline agate

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From MS Discovery Forum Research Roundup, July 9, 2014, by Carol Cruzon Martin:

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Daclizumab Phase 3 Findings

In positive results that merit a chat with regulatory agencies about the timeline for filing for regulatory approval, a large-scale, phase 3 trial suggested that daclizumab high-yield process (DAC HYP), an experimental immune-modulating therapy injected every 4 weeks, reduced relapses and disease activity significantly more than did a weekly injection of interferon β-1a (Avonex, Biogen Idec) in people with relapsing MS over 2 to 3 years.

The preliminary results from the DECIDE study were announced in a June 16, 2014, press release by Biogen Idec and AbbVie. The companies say they will present more detailed results at a future medical conference. They report a consistent safety profile with previous studies, including a slight increase in serious infections and one death, which they consider unrelated to the treatment. The drug’s effectiveness may be telling researchers something interesting about MS, because the drug seems to increase natural killer cells, which also have an antiviral response, wrote Gavin Giovannoni, MBBCh, Ph.D., from Barts and the London School of Medicine and Dentistry, in a blog post about a phase 2 extension study of daclizumab he and his co-authors published March 19, 2014, in The Lancet Neurology.

“A rigorous safety monitoring program will need to be implemented should daclizumab HYP be prescribed in clinical practice,” wrote the authors of an accompanying commentary on the extension study.

Originally approved in 1997 for quelling rejection of transplanted kidneys, daclizumab also exposed another type of innate lymphoid cell (LTi) as a wrongdoer and potential target in MS.

This article can be seen here.
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Offline agate

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From MedPage Today, September 12, 2014:

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Novel Drug Beats Avonex for MS Efficacy; Safety Still a Worry


By John Gever, Managing Editor, MedPage Today


BOSTON -- Daclizumab HYP cut relapse rates and disability progression in multiple sclerosis patients more effectively than interferon beta-1a (Avonex) in a phase III trial, but the liver toxicity seen in earlier studies with the interleukin-2 inhibitor remained an issue, researchers said here.

In the 1,841-patient DECIDE trial, patients with relapsing-remitting disease assigned to daclizumab HYP -- the letters stand for high yield process, distinguishing the drug from an earlier formulation sold as Zenapax for preventing organ transplant rejection -- had a 45% lower annualized relapse rate compared with those receiving the interferon product (95% CI 35-5%-53.1%), reported Ludwig Kappos, MD, of University Hospital Basel in Switzerland.

Also, the risk of 6-month sustained disability progression was lower by 27% (P=0.033) in those receiving daclizumab, Kappos told attendees at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting, held jointly this year with its North American counterpart.

By every other efficacy measure included in the study, including MRI lesion counts and overall burden, daclizumab was either significantly superior or no worse than interferon beta-1a, according to the data Kappos presented.

Safety Still a Concern

But the adverse event data failed to dispel concerns that the drug is seriously hepatotoxic that emerged in earlier studies.

A separate poster presentation by the DECIDE investigators on the safety results indicated that more patients in the daclizumab arm developed alanine aminotransferase elevations to greater than five times the upper limit of normal -- 53 versus 30 in the interferon group. Elevations to more than 10 times the upper limit of normal were seen in 24 patients receiving daclizumab and 11 in the interferon group.

Also, seven of the daclizumab patients developed the combination of alanine and aspartate aminotransferase elevations above three times the upper limit of normal plus total bilirubin twice the upper limit of normal, compared with one in the interferon arm.

The risk of these abnormalities was still low -- more than 900 patients received daclizumab in the trial -- and only one daclizumab patient was determined by an independent committee to meet criteria for Hy's Law, as was one in the interferon arm.

But serious cutaneous reactions were also more frequent with daclizumab, seen in 14 patients versus one receiving interferon, although none were diagnosed as Stevens-Johnson syndrome or toxic epidermal necrolysis. Infections were also somewhat more common in the daclizumab arm.

Overall, serious adverse events excluding MS relapses totaled 141 in the daclizumab group versus 88 with interferon (P not reported). About 30% of both groups discontinued during the study -- adverse events were the most common reason given in the daclizumab group, accounting for half of all withdrawals.

Kappos pointed out that this was a 3-year trial. "For this length of study, I think this is a reasonable discontinuation rate," he said.

Jeffrey Cohen, MD, of the Cleveland Clinic, who is scientific program chair for the meeting, said the safety issues were "concerning" but would not necessarily sink the drug's chances with regulators or clinicians.

"My view is that, if it's approved, it will be a useful addition to our armamentarium," said Cohen, who was not involved with the trial. The hepatic and skin effects "will have to be sorted out [in placing] where it will be in the sequence of medications," he added, noting that he would not consider it a first-line option.

Study Details

Daclizumab binds to the high-affinity alpha subunit of the CD25 receptor for interleukin-2, providing a partial blockage of signalling in this pathway, since the cytokine can still bind to a different intermediate-affinity part of the receptor complex, Kappos explained.

The net effect is to inhibit activated T cell responses, promote proliferation of so-called CD56bright natural killer cells, and normalize inducer cell counts in lymphoid tissue, he said. This action helps to quiet immune attacks on foreign tissue (hence the organ transplant rejection indication) and also attacks on self tissues, such as in MS.

Patients from 28 countries participated in the current trial, with North and South America, Eastern and Western Europe, and India represented.

To qualify, patients had to be 18-55 years old, with scores on the Expanded Disability Status Scale of no more than 5, and at least two relapses within the past 3 years and at least one in the past 12 months.

Daclizumab was administered once monthly subcutaneous injection. Interferon was dosed weekly by intramuscular injection at 30 mcg. This was a double-blind, double-dummy trial, hence patients in each arm also received a placebo injection on the schedule of the other arm.

Patients were followed for 144 weeks with periodic MRI scans and clinical evaluations for relapses and EDSS scoring.

Key efficacy results were as follows:

Annualized relapse rate: 0.216 for daclizumab, 0.393 for interferon (P<0.0001)

Proportion relapse-free at 144 weeks: 67% for daclizumab, 51% for interferon (overall risk reduction 41%, P<0.0001)

New and newly enlarging T2 lesions at 96 weeks: 4.3 for daclizumab, 9.6 for interferon (P<0.0001)

Proportion with 6-month sustained disability at 144 weeks: 13% for daclizumab, 18% for interferon (P=0.033)

Change in MS Functional Composite score at 96 weeks, median z-score: 0.091 for daclizumab, 0.055 for interferon (P=0.0007)

Mean annualized change in brain volume, week 24-96: 0.52% for daclizumab, 0.56% for interferon (P<0.0001)
Kappos noted that, among other secondary outcomes, there was a significant benefit for daclizumab in performance on the 25-foot walk test and in the nine-hole peg test -- the latter assessing hand function, which is often neglected in MS drug studies.

Daclizumab HYP "has the potential to have a favorable benefit-risk profile as a once-monthly subcutaneous injection for relapsing MS," Kappos concluded, calling the safety issues "manageable with standard monitoring and medical interventions."

_____________________________

The study was funded by Biogen Idec.

Kappos reported relationships with Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport, CSL Behring, Neurostatus Systems, and Roche.

Cohen reported relationships with EMD Serono, Genentech, Innate Immunotherapeutics, Novartis, Vaccinex, Genzyme, Receptos, Synthon, and Teva.

The article can be seen here.
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Offline agate

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Abstract for the study cited above from the ACTRIMS/ECTRIMS conference in Boston, September 10-13, 2014:

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Primary results of DECIDE: a randomized, double-blind, double-dummy, active-controlled trial of daclizumab HYP vs. Interferon β-1a in RRMS patients   
    
L Kappos1, K Selmaj2, DL Arnold3,4, E Havrdova5, A Boyko6, M Kaufman7, H Wiendl8, J Rose9, S Greenberg10, E Demirhan11, M Sweetser11, K Riester11, J Elkins11

1University Hospital, Basel, Switzerland, 2Medical University of Lodz, Lodz, Poland, 3NeuroRx Research, Montreal, QC, Canada, 4McGill University, Montreal, QC, Canada, 5First School of Medicine, Charles University, Prague, Czech Republic, 6Moscow Multiple Sclerosis Center, Moscow, Russian Federation, 7Carolinas Medical Center, Charlotte, NC, United States, 8University of Münster, Münster, Germany, 9University of Utah Medical School, Salt Lake City, UT, United States, 10Abbvie Biotherapeutics Inc, Redwood City, CA, United States, 11Biogen Idec, Cambridge, MA, United States
 
Background:

Daclizumab high-yield process (DAC HYP) is a humanized IgG1 monoclonal antibody specific for the alpha subunit (CD25) of the human high-affinity interleukin-2 (IL-2) receptor in clinical development for relapsing forms of multiple sclerosis (MS). A previous randomized trial showed a 54% reduction in the annualized relapse rate (ARR) of DAC HYP 150mg once-monthly compared with placebo.

Objectives:

To test the hypothesis that DAC HYP 150mg is superior to IFN β-1a in reducing MS activity in patients with relapsing-remitting MS (RRMS).

Methods:

We conducted a randomized, double-blind, double-dummy, active-controlled trial comparing DAC HYP 150mg subcutaneous (SC) injection once every 4 weeks with IFN β-1a 30mcg intramuscular (IM) injection once weekly for 96 to 144 weeks. The primary endpoint was the ARR.

Secondary endpoints were the number of new T2 lesions at week 96, the proportion of subjects with sustained disability progression, the proportion of subjects relapse-free and the proportion of subjects with a ≥7.5 point decline on the Multiple Sclerosis Impact Scale-29 (MSIS-29) physical scale.

Results:

Patients (n=1841) were randomized between May 11, 2010 and April 16, 2012 across 245 study centers in 28 countries. Baseline characteristics for all subjects (DAC HYP and IFN β-1a groups) were: mean age 36.3 years, mean (median) EDSS was 2.5 (2.0), and 68% of patients were female. The mean number of relapses within the past year was 1.6. The mean number of new T2 lesions was 50.5 and the number of Gd+ lesions was 2.1. Final results will be presented.

Conclusions:

The DECIDE trial provides an assessment of the efficacy of DAC HYP in RRMS.

______________
Assigned speakers:
MD Ludwig Kappos , University Hospital Basel , Basel , CH
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Offline agate

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ZINBRYTA--once-a-month injection
« Reply #5 on: September 16, 2014, 10:06:49 am »
Sounds as if ZINBRYTA is going forward--a once-a-month shot.

For an article about it, see here.
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Offline agate

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This is mainly a repetition of the article linked in the previous post. From Medical Marketing and Media, September 15, 2014:

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AbbVie, Biogen to file MS drug next year

Deborah Weinstein

Phase-III results of the AbbVie-Biogen Idec experimental multiple sclerosis shot Zinbryta (daclizumab) indicate the drug bests Biogen's injectable Avonex (interferon beta-1a) on some measures among relapse-remitting MS patients.

The companies released the full results at the Sixth Triennial Joint Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis last week.

The clinical trial of more than 1,800 patients showed Zinbryta patients had “significantly improved key measures of multiple sclerosis disease activity,” including a 45% reduction in relapses compared to Avonex patients and fewer new brain lesions. Researchers found that 73% of Zinbryta patients were relapse-free after 96 weeks of therapy, compared to Avonex patients, of whom 59% were relapse-free within the same timeframe.

Jefferies analyst Thomas Wei wrote in a Monday research note that results put the AbbVie-Biogen Idec contender in the same efficacy space as Novartis's oral Gilenya (fingolimod) and Biogen's Tysabri shot (natalizumab), even though patients had a slightly higher relapse rate on Zinbryta than patients in Gilenya trials.

Wei also noted that Zinbryta results showed a statistically significant impact on Paced Auditory Serial Addition Test scores which measure cognitive functions that are typically affected by the disease, whereas Gilenya offered what Wei called a numerical improvement.

Side effects included higher rates of skin reactions among Zinbryta patients than among Avonex patients, which AbbVie, Biogen and Wei considered consistent with the MS population as a whole, but Leerink analyst Joseph Schwartz wrote in a Thursday research note that a key opinion leader was bothered by the reaction.

An additional MS therapy may not enhance the finances of Biogen's MS portfolio: Jefferies analyst Thomas Wei said the 50-50 split with AbbVie could have a negative earnings impact if it takes away from sales of other Biogen MS products. Jefferies's Jeffrey Holford noted in his Monday assessment that Biogen's Tecfidera is also tussling with Biogen and non-Biogen MS drugs, and writes that the twice-daily oral is gaining new prescriptions at the expense of treatments including Biogen's Avonex and Teva's Copaxone, while also fighting for prescriptions against Gilenya and Sanofi's Aubagio (teriflunomide.)

AbbVie and Biogen Idec plan to file the drug with the FDA in the first half of next year.

This part of the above article might be significant--or it might not:

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Side effects included higher rates of skin reactions among Zinbryta patients than among Avonex patients, which AbbVie, Biogen and Wei considered consistent with the MS population as a whole, but Leerink analyst Joseph Schwartz wrote in a Thursday research note that a key opinion leader was bothered by the reaction.

The article can be seen here.
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Offline agate

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The paradox of daclizumab (MS Discovery Forum)
« Reply #7 on: September 24, 2014, 08:28:49 pm »
From the MS Discovery Forum, "News Synthesis," September 24, 2014 (references  and author disclosures omitted):

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The Paradox of Daclizumab

Phase 3 results show that daclizumab reduces disease activity in relapsing-remitting multiple sclerosis by half compared with interferon, as measured by brain imaging, with skin and other side effects. The drug works in surprising ways that are revealing new details about the pathogenesis of MS.

CAROL CRUZAN MORTON

Three might be the lucky number for daclizumab, an investigational drug for relapsing-remitting multiple sclerosis (RRMS) with broad and unexpected immune effects.
 
Under the brand name Zinbryta (Biogen Idec/AbbVie), a newly patented version of the drug, called daclizumab high-yield process, or DAC HYP, recently captured headlines after researchers presented more efficacy and safety results from the phase 3 clinical trial (Kappos et al., 2014).
 
The unpublished results seem to sustain expectations that daclizumab may be as effective as the best MS drugs now approved but with lower risk (Pfender and Martin, 2014). Meanwhile, researchers have identified at least three ways the drug works to counter MS, a finding that is illuminating new details in disease pathology and may lead to novel therapeutic strategies (Bielekova, 2013; Pfender and Martin, 2014).
 
The phase 3 study, called DECIDE, is “a pivotal trial,” said Ellen  Mowry, M.D., M.C.R., a neurologist at Johns Hopkins University in Baltimore, Maryland. She cited the notable drop in disease activity as measured by relapses, MRI, and disability progression, compared to a popular older drug, interferon β-1a (Avonex, Biogen). She also noted daclizumab’s signature skin side effects as well as a small increase in serious infections.
 

Daclizumab “deserves to be approved and to be one of the options” available to people with MS and their physicians, said Ludwig Kappos, M.D., chair of neurology and head of the MS Research Group at University Hospital Basel, Switzerland, and lead investigator for DECIDE. The relative effectiveness of the drug could be “at least” at the level of fingolimod (Gilenya, Novartis) or dimethyl fumarate (Tecfidera, Biogen), Kappos speculated in an interview with MSDF. He cautioned that results of this and other drug studies cannot be compared directly, due to differences in design, selection criteria, and other details.
 
Kappos presented the DECIDE findings earlier this month at MSBoston2014, shorthand for the joint meeting of the Americas and European committees for treatment and research in multiple sclerosis (ACTRIMS-ECTRIMS), held September 10-13 in Boston. In the closing session, Mowry cited the findings as a clinical research highlight of the meeting.
 
...
 Top-level clinical findings

The double-blind phase 3 DECIDE trial pitted monthly injections of daclizumab against weekly interferon injections in people with RRMS for a minimum of 2 years. Each group received placebo injections of the other drug. A little more than 1,800 people started the 2-year DECIDE study. About two-thirds were women. On average, participants had had RRMS for about 4 years and mild disability of about 2.5 on the Expanded Disability Status Scale. About 30% dropped out for various reasons, mostly because of adverse events and lack of efficacy.
 
In the main finding, daclizumab reduced the annualized relapse rate by nearly half compared to interferon. Translated to an evidence-based medicine figure called “number needed to treat,” each patient on daclizumab had a 1-in-5.6 chance of having fewer relapses. In secondary endpoints, several brain imaging techniques also showed about half the new and enlarging lesions in the daclizumab treatment arm compared to interferon (Arnold et al., 2014).
 
Many of the top findings were reported in a press release in June. A new 6-month analysis presented at the meeting showed a slightly lowered risk of disability progression. Another new graph showed a reduction, although not statistically significant, in patient-reported physical decline (Kappos et al., 2014).
 
...
 
In response to a question from the audience, Kappos said there was no sign of secondary autoimmunity arising from daclizumab use, although “we might interpret the cutaneous events as autoimmune,” he said. “Every intervention with immune-modifying therapy has this risk, but we did not observe additional risk in these cases.” Other adverse events included a higher rate of infections (65% in daclizumab and 57% in interferon), with twice as many serious infections (4% to 2%), and elevated liver enzymes.
 
Two deaths in earlier daclizumab trials had raised concerns about secondary autoimmune disease, which is a serious side effect of another therapeutic monoclonal antibody, alemtuzumab. In a 1-year phase 2 extension study, SELECTION, a person on daclizumab died of autoimmune hepatitis. In the phase 2 study SELECT, one person died of complications of psoas abscess after recovering from a serious rash. In both cases, the experimental drug could not be ruled out as a contributing factor (Barkhof and Ciccarelli, 2014; Pfender and Martin, 2014).
 
In the phase 3 DECIDE study, there were four deaths in the interferon group and one death in the daclizumab group, none of which was considered treatment related. The death in the daclizumab group was from an MS attack in the brainstem 4 months after the patient stopped the experimental treatment and withdrew from the study. DECIDE researchers reported no cases of the life-threatening side effect, progressive multifocal leukencephalopathy, which has been associated with natalizumab, another potent therapeutic monoclonal antibody.
 
“A rigorous safety monitoring program will need to be implemented should daclizumab be prescribed in clinical practice,” advised an editorial (Barkhof and Ciccarelli, 2014) that accompanied the 1-year phase 2 SELECTION extension findings in March (Giovannoni et al., 2014). Longer-term experience with more people is needed to evaluate the risks for rare adverse events, agreed the authors of another review, who also termed daclizumab a “well tolerated therapy option in MS that is safe in the vast majority of patients” (Pfender and Martin, 2014).
 
Biogen Idec in Cambridge, Massachusetts, and AbbVie in North Chicago, Illinois, are jointly developing the drug. They plan to file marketing applications for daclizumab (Zinbryta) with regulatory authorities in the United States, Europe, and other jurisdictions during the first half of 2015, said Gilmore O’Neill, vice president for MS research and development at Biogen.
 
...

The next big thing for Biogen and other companies is “understanding how you can use biomarkers to predict how aggressive someone’s MS is going to be,” O’Neill told MSDF. “Layered on that, we’re interested in how you can predict which drug is better for which patient. We believe there are different mechanisms driving disease in different patients.”
 
Daclizumab’s unexpected actions

Daclizumab is one of a long line of drugs to be repurposed in MS. The list includes natalizumab (Tysabri, Biogen/Elan), alemtuzumab (Lemtrada, Genzyme), dimethyl fumarate (Tecfidera, Biogen), fingolimod (Gilenya, Novartis), and teriflunomide (Aubagio, Genzyme) (Schmierer, 2014).
 
The credit for developing daclizumab in all its uses goes to researchers in several labs at the U.S. National Institutes of Health (NIH). Daclizumab began 30 years ago as a promising mouse molecule for T cell leukemia for its ability to block activated inflammatory T cells (Bielekova, 2013; Pfender and Martin, 2014). By the same presumed mechanism, the humanized antibody was approved as an add-on therapy for preventing rejection of solid organ transplants and marketed as Zenapax by Hoffmann-La Roche until the company withdrew the product for commercial reasons in 2008 in the European Union and in 2009 in the United States.
 
It made perfect sense to try the drug in MS, given all the evidence that autoreactive T cells drive the disease. “It appealed to us for all the wrong reasons,” said Bibiana Bielekova, M.D., who started working on the drug as a fellow and has continued to work out the mechanisms in her own lab as an NIH investigator.
 
Bielekova sat down with MSDF at ACTRIMS-ECTRIMS to tell her 15-year story of tracking down daclizumab’s unexpected effects on the immune system and its implications for understanding MS and future therapeutics.
 
“It’s a typical story of discovery,” she said. “We think one thing. We are wrong. By being really good observers, we notice something and get it right. But we are wrong most of the time.”
 
The way it works

In 1999, Bielekova and her colleagues opened a pilot study of daclizumab in their patients for whom interferon was not working. By 6 months, contrast-enhancing MRI showed a dramatic 80% reduction in new lesions, and clinical symptoms stabilized. In an extension of the study in which interferon was withdrawn, they observed that daclizumab alone could sustain the benefits, although some people experienced a greater synergistic effect from taking both drugs together. A subsequent open-label phase 2 study showed comparable results with daclizumab as the first-line treatment.
 
In sharp contrast to the robust clinical demonstrations, the laboratory work was one negative finding after another. At first, “we were trying to prove the hypothesis that the drug was inhibiting activated T cells,” Bielekova said. “We could not demonstrate any effect on T cell functions.”
 
The original idea, still included in reviews and posters on daclizumab, was that daclizumab grabs on to part of a high-affinity receptor for the inflammatory cytokine interleukin-2 (IL-2), effectively getting in the way without turning it on. The targeted receptor piece is called CD25 and is plentiful on effector T cells. So, the reasoning went, daclizumab must bind to autoreactive T cells and block their activity.
 
It made sense to Bielekova too. After all, she and her colleagues fed IL-2 to grow T cells in culture dishes. If it worked in vitro, why wouldn’t it work in vivo? In the process of trying to prove this, Bielekova found that therapeutic levels of daclizumab in people seemed to do all the wrong things for T cells. Effector T cells could still activate, proliferate, and secrete inflammatory cytokines. Worse, regulatory T cells (Tregs), which suppress inflammation, were significantly inhibited by the drug. Yet, daclizumab obviously was working in people with a T-cell-mediated autoimmune disease. It didn’t make sense to her.
 
At the end of three frustrating years in the lab, she noticed another population of cells with an intermediate-affinity IL-2 receptor. An Internet search suggested they were a small subset of NK cells called CD56bright, previously called immunoregulatory. Interestingly, Bielekova said, they are known to increase during pregnancy and are thought to have something to do with maintaining tolerance to the foreign body that is the fetus. The rare CD56bright subset normally makes up about 5% to 10% of NK cells, which in turn represent only about 1% of lymphocytes in the blood. In daclizumab-treated patients, the tiny subset of cells expanded up to 500%.
 
Bielekova formally phenotyped those cells and then tried to figure out what they were doing. Normally, when she added therapeutic amounts of daclizumab to culture dishes of patient blood samples, the T cells could activate and produce cytokines, but they did not survive. In a key experiment, when she extracted the NK cells, the T cells could not only function in the presence of the drug, but they also survived.
 
“We demonstrated that the natural killer cells were killing autoreactive T cells,” Bielekova told MSDF. “It was difficult to publish. There was a dogma that natural killer cells should not kill autologous T cells.” Later, she and her colleagues showed that the CD56bright NK subset wielded a specialized weapon, granzyme K, not available to their other NK cousins.
 
The team also showed why and how daclizumab expands and activates the subset. It turns out that CD56bright NK cells have huge amounts of the intermediate-affinity IL-2 receptor, which is missing the CD25 component of the high-affinity receptor blocked by daclizumab. That enables the NK subset to consume the excess IL-2.
 
The NIH patented daclizumab for MS, based on the new finding that daclizumab deployed innate cells, the expanded CD56bright NK subset, as contract killers of activated T cells. “We were really excited to see that mechanism of action,” Bielekova said. “We felt it was an interesting compound that works very differently than drugs that we have. It was inducing regulation that normally happens in humans in pregnancy and other circumstances.”
 
Even more interesting was the strong correlation between the expansion of CD56bright cells in a person and the reduction of new contrast-enhancing lesions in the brain. Combined with the relative decrease in T cells, Bielekova and her colleagues found that the cell ratios in the blood could differentiate full responders from partial responders and could be a useful biomarker.
 
Three strikes and you’re in

Since then, Bielekova and her colleagues have shown two additional ways daclizumab works. One lesson came from a patient who responded well to the drug despite the lack of a CD56bright NK expansion in her blood. To solve this mystery, the investigators turned to other cells that expressed CD25: dendritic cells and monocytes.
 
After a few false starts, they realized CD25 on dendritic cells is not part of a high-affinity receptor for IL-2. Instead, the component has another job deep within the synapse dendritic cells form with T cells when activating them to fight a pathogen, in the case of infection, or to react to an antigen, in the case of autoimmune response. In a twist, CD25 on dendritic cells doesn't consume IL-2; it spoons the cytokine into the T cell.
 
“To make a long story short, dendritic cells secrete IL-2, use CD25 to hold IL-2, and feed it to T cells, like a good mother,” Bielekova said. The increased risk for serious infections in people on daclizumab in the phase 3 trial may be due to daclizumab blocking this action. “We’re still chasing the dendritic cell story,” she said.
 
In one of the wrong turns in studying how dendritic cells behaved in people, Bielekova expected that the annual flu vaccine would not activate those innate immune cells in patients treated with daclizumab. “Unfortunately,” research fellow Yen-Chih Lin, Ph.D., told her after looking at the samples, “you were wrong.”
 
But Lin pointed out another unknown group of cells that expanded in controls after vaccination but decreased in people on daclizumab. They look like T cells and can produce cytokines, but they are part of the innate immune system and can respond early. They turned out to be lymphoid tissue inducer (LTi) cells.
 
“In the fetus, they’re important for making lymph nodes,” Bielekova told MSDF. “It’s not clear what [LTi cells] do in adulthood. In animal models, it’s been shown they can still mediate formation of the lymphoid follicles in the gut. People with progressive MS are known to have lymphoid follicles in the meninges. We were wondering if these cells had something to do with MS disease process.”
 
Indeed, untreated MS patients had significantly higher levels of circulating LTi cells in comparison with healthy controls, they reported. Daclizumab seemed to normalize the LTi cell numbers in the blood. “We think this is another mechanism of action,” she said. She and her team showed that LTi and CD56bright NK cells come from the same precursor cells whose fate is determined by the IL-2 signaling. With the high-affinity receptor blocked by daclizumab, the balance tips toward more of the NK subset.
 
At ACTRIMS-ECTRIMS, Lin presented a poster showing that LTi cells were also expanded in the cerebrospinal fluid of untreated people with RRMS and that daclizumab nudges the numbers and proportions of LTi and other immune cells back closer to that of people without MS (Lin et al., 2014).
 
A new treatment paradigm

“Science is not simple,” Bielekova told MSDF. “Nature always has these back loops and controls. You have to step back and see bigger pictures. IL-2 is so important in orchestrating immune response.”
 
To sum up, daclizumab may end up being a useful therapy for MS, a T-cell mediated disease, for reasons completely different than originally thought. It knocks down activated T cells, but not in the way anyone had assumed when they envisioned the possibilities for people with MS. Instead, it harnesses the innate immune system and the IL-2 signaling pathway. The emerging science has revealed new roles for innate immune cells in MS, as well as the biology of daclizumab’s chief nemesis, the cytokine IL-2.
 
“There are some earlier studies that described direct inhibitory effect on T cells, but these used non-physiologically high levels of daclizumab,” Bielekova clarified in an email. “Using concentrations of daclizumab achievable in-vivo, we have shown absolutely no direct inhibitory effect on T cell proliferation or cytokine secretion. Daclizumab does inhibit high affinity IL-2 signaling in activated T cells, but this does not lead to their functional inhibition. Instead, it enhances their survival. There is a direct effect on Treg cells. Because these cells are dependent on high affinity IL-2 signaling for their survival and function, we and multiple other groups have shown that they are directly inhibited by daclizumab therapy. Both inhibition of Tregs and enhanced survival of effector T cells should have detrimental consequences for MS disease process, if current paradigms are right. And as you have heard, instead, MS disease process gets better on daclizumab therapy.”

____________________
 
Additional reporting from Dan Keller.
 

The article is available here.
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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A concise summary from the Rocky Mountain MS Center News, October 10, 2014:

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Emerging Therapies: Results from phase 3 trial of Daclizumab (DAC HYP)

Many of the studies presented [at ACTRIMS/ECTRIMS in Boston] related to research on disease modifying treatments. Daclizumab (DAC HYP) is a monoclonal antibody that has been studied in MS since 1999. It was developed about 30 years ago as a potential treatment for T-cell leukemia and is currently used to prevent rejection in organ transplantation. 

Monoclonal antibodies are similar to the antibodies produced by our immune systems. Antibodies fight diseases by attaching to specific foreign proteins to inactivate them. For example, if you are exposed to a virus, your immune system will produce antibodies to that virus so your body can quickly neutralize it and you won’t get sick. A monoclonal antibody is produced in the lab and works by binding to a specific protein involved in a disease process to deplete or inactivate it. Daclizumab targets the immune attack in MS.

Because we already have some partially effective therapies for MS, in the Phase 3 trial daclizumab was compared with an existing therapy rather than a placebo. The fact that this drug was tested against another drug, and not a placebo, is significant because this demonstrates how effective the drug is compared to existing treatments, rather than how it compares to no treatment.

More than 1,800 participants with relapsing-remitting MS received either DAC HYP injected under the skin once every four weeks, or Avonex injected weekly, for 92 to 144   weeks. The annual relapse rate was reduced by 45% in the DAC HYP group compared with Avonex. MRI disease activity was reduced by 54%. The reduction of disability progression was not statistically significant. Serious infections, skin-related adverse events, and liver enzyme abnormalities were increased in the DAC HYP group. Biogen Idec and AbbVie plan to file for marketing approval in 2015.
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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From the MS International Federation, December 9, 2015:

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New drug tested for relapsing-remitting MS

Results show daclizumab to be effective in reducing relapse rate and new lesions in relapsing-remitting MS


Last month, The New England Journal of Medicine published the results from a clinical trial on relapsing-remitting MS, called DECIDE.

This 96 week trial tested a new monoclonal antibody drug, called daclizumab, in 1,841 people. Monoclonal antibodies recognise and attach to specific proteins produced by cells. They work in different ways depending on the protein they are targeting.

Daclizumab is injected under the skin every four weeks. During the trial the researchers compared the effectiveness of daclizumab to Interferon beta-1a injected once a week.

Among people with relapsing–remitting MS, daclizumab appeared more effective than interferon beta-1a with regard to the number of relapses and the number of new lesions (assessed by MRI). The drug was safe, although the rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab than with interferon beta-1a.

Overall, daclizumab seems to be an effective drug in reducing the relapse rate and the number of new lesions in people with relapsing-remitting MS. Its frequency of administration, which is just once every four weeks, can guarantee a good compliance to the treatment and a good quality of life. However, daclizumab did not seem to significantly lower the risk of disability progression, which still remains a big challenge in MS.

MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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From PubMed, February 4, 2016:

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Neurology. 2016 Feb 3.

Cutaneous adverse events in multiple sclerosis patients treated with daclizumab.

Cortese I1, Ohayon J1, Fenton K1, Lee CC1, Raffeld M1, Cowen EW1, DiGiovanna JJ1, Bielekova B2.

Author information

1From the Neuroimmunology Clinic (I.C., J.O.) and the Neuroimmunological Diseases Unit (B.B.), National Institute of Neurological Disorders and Stroke, and the Laboratory of Pathology (C.-C.L., M.R.) and the Dermatology Branch (E.W.C., J.J.D.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda; and Department of Neurology (K.F.), Johns Hopkins School of Medicine, Baltimore, MD.
2From the Neuroimmunology Clinic (I.C., J.O.) and the Neuroimmunological Diseases Unit (B.B.), National Institute of Neurological Disorders and Stroke, and the Laboratory of Pathology (C.-C.L., M.R.) and the Dermatology Branch (E.W.C., J.J.D.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda; and Department of Neurology (K.F.), Johns Hopkins School of Medicine, Baltimore, MD. bibi.bielekova@nih.gov.

OBJECTIVE:

To analyze the spectrum and mechanisms of cutaneous adverse events (AEs) in patients with multiple sclerosis treated with daclizumab high-yield process (DAC-HYP).

METHODS:

A total of 31 participants in an institutional review board-approved open-label phase I study of DAC-HYP (NCT01143441) were prospectively evaluated over 42 months for development of cutaneous AEs. Participants provided written informed consent. Fifteen participants were naive to anti-CD25 therapy (cohort B), while 16 had received daclizumab (Zenapax; Hoffmann-La Roche) IV for 4-9 years (mean 5.8 years) prior to enrollment (cohort A). Immunohistochemistry was performed on pretreatment and posttreatment skin biopsies of normal-appearing skin (cohort B only) and on lesional biopsies in participants presenting with rash (both cohorts).

RESULTS:

Cutaneous AEs occurred in 77% of patients, the majority presenting with patches of eczema requiring no treatment. Moderate to severe rash developed in 6 participants (19%) and required discontinuation of DAC-HYP in 4 (13%). More severe rashes presented psoriasiform phenotype, but lesional biopsies lacked features of either psoriasis or drug hypersensitivity eruptions. Instead, irrespective of clinical severity, lesional biopsies showed nonspecific features of eczematous dermatitis, but with prominent CD56+ lymphocytic infiltrates.

Pretreatment and posttreatment biopsies of normal-appearing skin demonstrated no histopathologic changes.

CONCLUSIONS:

Observed cutaneous AEs are likely related to the immunomodulatory effects DAC-HYP exerts on innate lymphoid cells, including natural killer cells. Vigilance and timely management of skin reactions may prevent treatment discontinuation in participants with severe rash.

The abstract can be seen here.
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.