| By John Gever, Senior Editor, MedPage Today Published: December 30, 2011 |
As part of the Year in Review series, MedPage Today reporters are revisiting major news stories and following up with an analysis of the impact of the original report, as well as subsequent news on the topic. Here’s what’s happened with the investigational multiple sclerosis drug laquinimod since we published the first 2011 piece on its safety and efficacy.
The investigational oral drug laquinimod has stirred interest in the multiple sclerosis community like few other agents have. Not only can it be taken as a daily pill instead of by injection, but clinical trials are suggesting it is better than existing MS drugs at slowing disability progression and that it may be suitable as an add-on to current treatments.
But the enthusiasm has been somewhat dampened by a mystery surrounding its mechanism of action. Studies in animals and humans indicated that laquinimod alters immune cell activity to reduce the destruction of nerve fibers’ myelin sheaths. How it does so, though, has been unclear.
And people get nervous when they don’t know how a new drug works, if only because it thwarts prediction of potential adverse effects.
However, announcements of results from two major phase III trials earlier this year have now been followed by a report that claims to uncover the key to laquinimod’s mechanism of action.
The Backstory
Laquinimod is a derivative of roquinimex, an immunomodulatory drug first developed in the 1980s that drew substantial attention as a potential MS treatment.
Although early clinical studies indicated that roquinimex (also known as linomide) was well-tolerated, serious cardiovascular effects turned up when the drug went into larger trials. Phase III studies were halted in 1997 when two deaths and eight nonfatal myocardial infarctions occurred in two trials involving a total of about 1,200 patients.
But the initially promising results meant that the drug’s quinoline-carboxamide structure could perhaps be tweaked to reduce the side effects while preserving the desired immunomodulatory properties.
Laquinimod came along shortly after roquinimex’s demise, with a 2002 report that it blocked an animal model of autoimmune neuritis.
Interest in the drug was piqued earlier this year with presentations of results from the phase III ALLEGRO and BRAVO trials.
ALLEGRO was reported in April at the American Academy of Neurology’s annual meeting in Honolulu, while results from BRAVO came out at the October joint meeting of the European and Americas Committees for Research and Treatment in MS in Amsterdam.
The overall picture painted by the two studies was consistent — laquinimod’s efficacy was relatively modest by traditional measures of relapse rates, but was very strong in terms of disability progression.
BRAVO was especially convincing in the latter regard, because it tested beta-interferon as well as laquinimod in the placebo-controlled trial.
The study design did not include a direct head-to-head comparison of the two drugs, but reductions in disability progression relative to placebo were substantially larger with laquinimod than with interferon (40.6% versus 28.3% for six-month progression).
In addition, brain atrophy was significantly slowed with laquinimod in BRAVO, whereas loss of brain volume was the same in the interferon and placebo groups.
And unlike the only currently approved oral drug for MS, fingolimod (Gilenya), laquinimod did not appear to have an immunosuppressive effect.
Independent neurologists told MedPage Today that these points made laquinimod look extremely promising, especially since the lack of immunosuppression suggested that the drug could be combined with other disease-modifying agents. The add-on approach is considered far too dangerous with current products.
The Mechanism Unveiled
In presenting the ALLEGRO results in Honololu, Giancarlo Comi, MD, of the University Vita-Salute San Raffaele in Milan, Italy, said the drug alters T-cell populations to emphasize a regulatory Th2 response instead of the attack-focused Th1. It also appears to prompt a neuroprotective response from microglia and astrocytes within the central nervous system, he said.
Still, the account lacked an explanation of how laquinimod exerts these effects. But that apparently was not because Comi didn’t know.
A few weeks ago, researchers from Germany and Italy — including Comi — and from Teva Pharmaceuticals, which is developing laquinimod, published a paper in the American Journal of Pathology that filled in the details.
The key, according to the researchers, is brain-derived neurotrophic factor (BDNF).
Led by Jan Thöne, MD, of Ruhr-University Bochum in Germany, the group measured BDNF in blood collected from MS patients participating in Teva’s clinical trials.
BDNF levels increased dramatically with laquinimod treatment, with respect to baseline and also compared with study participants assigned to placebo, the researchers found.
A similar effect — also previously unnoticed — was documented in the standard mouse model of MS called experimental autoimmune encephalitis, in which an immune reaction to myelin is artificially induced.
The researchers noted that previous research had shown that BDNF enhances survival of damaged neurons and can promote a certain degree of neuroregeneration.
Meanwhile, in vitro experiments by the group pointed to monocytes as the laquinimod’s specific cellular target, “skew[ing] the phagocyte population toward a regulatory phenotype, which in turn mediates immune modulation in vivo,” Thöne and colleagues wrote.
They noted that monocytes do not appear to be targeted by other MS drugs.
“Our data indicate a multifaceted mechanisms of action of laquinimod, including immunomodulatory and neuroprotective mechanisms of action that should be further tested in human specimens,” they added.
Whether these twin actions are indeed independent is the next question, Thöne and colleagues suggested. “We hypothesize that the increase of BDNF might also be involved in [laquinimod’s] effects on monocytes and subsequent increase of IL-10,” they wrote.
The clinical trials and the mechanism study were funded by Teva.
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