By David N. Leff

Debates are not the monopoly of political candidates.

A professor of neurology at Stanford University is challenging his opposite numbers at the NIH on Oct. 31 to debate the contradictory outcomes and implications of two parallel Phase II clinical trials. Both of their studies tested an experimental drug called APL - altered peptide ligand - on patients with relapsing-remitting multiple sclerosis (MS). And both were abruptly halted last year by a safety monitoring board, consisting of independent neurologists, epidemiologists and physicians, hired by San Diego-based Neurocrine Biosciences Inc. and its partner, Novartis AG, of Basel, Switzerland. (See BioWorld Today, July 21, 1999, p. 1.)

Two back-to-back articles in the October issue of Nature Medicine report the design and bittersweet results of the two trials. Stanford neurologist Lawrence Steinman is senior author of the paper titled: "Induction of a non-encephalogenic type 2 T helper cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized Phase II trial."

That study enrolled 144 MS patients at 14 research centers in the U.S., Canada and Europe.

Steinman is the inventor of altered peptide ligand and co-founder of Neurocrine, to which the university has licensed his patent.

"Ten years ago," he told BioWorld Today, "in addition to our work on APL, we identified in the brains of MS patients a T-cell receptor [TCR] that recognized a fragment of the myelin sheath protein, which is degraded in their neurons. In order to trick their immune systems into producing beneficial, anti-inflammatory T_H2 cells rather than damaging T_H1 cells, we deleted 16 amino acid moieties from the portion of the myelin sheath that that TCR is targeting. So at the exact point of contact between the TCR and this truncated decoy myelin molecule, the receptor signals in a new manner: Instead of leading to autoimmunity, as in MS, with the production of proinflammatory cytokines such as gamma interferon or tumor necrosis factor, it's secreting regulatory chemicals like interneukin-5 and IL-13. Those cytokines, Steinman pointed out, "turn down the harmful output of gamma interferon and TNF-alpha, but do lead to some allergic phenomena."

Why Safety Monitoring Board Stepped In

Steinman continued: "One of the essential positive aspects of the trials was the very allergic side effects that we saw - the very reason that the trials were halted. This gets to the issue that with APLs we aimed to shift the immune system's T cells from T_H1 autoimmunity to T_H2 anti-allergy immunity. We actually saw those allergic phenomena in our MS patients, which is why the trial was stopped.

"Those allergic reactions were very similar to what has been reported for the FDA-approved MS drug, Copaxone, produced by Teva Marion Partners," Steinman went on. "It actually has a higher incidence of the very same allergic reactions that our trial encountered.

"But in our Phase II clinical study, those allergic side effects were not associated with neurologic worsening. That's a hint of efficacy, because at the APL dose where we had the fewest side effects - and the most patients to evaluate - we actually saw on brain scans an improvement in neuronal inflammation."

Steinman's message to neurologists: "Dealing with a non-life-threatening disease such as MS, we are going to have to become accustomed to special side effects of therapies. One of those," he added, "is that we're either going to come to accept the effects of causing a shift to T_H2 - or learn to treat allergic phenomena better."

"The safety board," he recalled, "was worried that life-threatening anaphylaxis could occur - which it did not. I thought at the time that they their apprehensions were unwarranted because when all the data were presented to me back in July of '99, I pointed out to the board that Copaxone has about the same safety profile. However, they chose to halt the trial. In retrospect it looks to me that it may have been premature."

NINDS' Pilot Study Had Harsher Results

Nature Medicine's companion paper on this subject, from NINDS - the National Institute of Neurological Disorders and Stroke, bears the title: "Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: Results of a phase II clinical trial with an altered peptide ligand." Its senior author is Roland Martin, section chief of the institute's neuroimmunology lab.

His trial assayed the APL therapy in 24 MS patients. After studying their relapsing-remitting disease patterns for six months, the team injected 50 milligrams of APL weekly for up to nine months. Two of eight treated subjects showed an increase in inflammatory brain lesions that was linked to the APL treatment.

One patient developed an allergic hypersensitivity reaction, and three others discontinued dosing due to side effects not directly blamed on the therapy. After the first seven patients showed adverse side effects, the dosage was dropped from 50 to 5 mg, but when the eighth individual experienced an increase in MS brain lesions apparently related to the APL, that trial was halted in mid-course.

"While the adverse effects in both studies were disappointing," Martin observed, "the increase in brain lesions in some patients proves that MPB [myelin basic protein] can induce an immune response in MS, and is therefore a good target for immunotherapy."

He also made the point that "lower doses of this altered peptide ligand therapy are better than higher doses."

"Our Stanford trial is over," Steinman said, "but based on the encouraging results - and the understanding that we may have to put up with allergy, or else devise some countermeasures - another Phase II trial will be done, focusing mainly on the lower APL dosages. Neurocrine will carry it ahead either on its own, with a partner, or with NIH funding. To organize the trial and get a backer, we're talking about sometime next year.

"Neurocrine gave NINDS the drug," Steinman recounted, "and they were doing their Phase II study as a sort of pilot, without placebo or double-blind controls. And most of their experience was at the 50-mg dose - the one we acknowledged, too, as responsible for most of the allergic reactions.

"So that the debatable issue comes up: Were these adverse reactions just a statistical fluke that they saw in somewhere between one and three patients - and could associate in a reasonably convincing way with APL - or were they doing something different?"