Disclosure of top-line data on Biogen Idec Inc.'s anti-LINGO-1 monoclonal antibody (MAb), BIIB033, in acute optic neuritis (AON) so captivated the analyst community that they might have been mistaken for scrutinizing a grand slam emerging from a pivotal trial. Instead, the data came from a phase II trial, dubbed RENEW, and offered evidence only of "proof of biology," showing a positive trend but not statistical significance in improving recovery of optic nerve latency – the study's primary endpoint. Secondary endpoints were missed altogether.

In the end, analysts were split on the findings and the market wavered on the stock (MASDAQ:BIIB), which popped to a 52-week high of $375 early but slumped as the notes poured it, ending the day at $350.25, down $2.99.

At a minimum, the data offered a tantalizing first peek into the challenging but promising therapeutic approach to promote myelin repair and improve functional recovery – first in AON and, ultimately, in multiple sclerosis (MS).

AON damages the optic nerve, causing loss of the myelin sheath and axonal injury, with the potential for permanent loss of vision. The condition is considered a good clinical model to measure the hypothesized mechanisms of action of anti-LINGO-1, remyelination and neuroprotection, according to Diego Cadavid, Biogen's senior medical director.

The randomized, double-blind, placebo-controlled RENEW trial was designed to evaluate anti-LINGO-1's ability to enable repair of an optic nerve lesion through axonal remyelination after the onset of a first episode of AON. The study enrolled 82 patients across 33 sites in Europe, Canada and Australia, with patients receiving six intravenous infusions of 100 mg/kg anti-LINGO-1 or placebo every four weeks.

RENEW examined the effects on remyelination by measuring the latency of nerve conduction between the retina and the visual cortex in the brain using full field visual evoked potential, or FF-VEP. Demonstration of improvement in recovery of optic nerve latency, or the time for a signal to travel from the retina to the visual cortex, over 24 weeks provided evidence of biological repair to the visual system, Cadavid explained, even if the results – a 34 percent improvement (p = 0.0504) in the recovery of optic nerve latency compared to placebo – were not statistically significant. The analysis of the intent-to-treat population included patients in both arms who did not complete the study.

However, top-line data showed no effect on change in thickness of the retinal layers (RNFL) – optic nerve neurons and axons – and visual function, as measured by spectral domain optical coherence tomography (SD-OCT) and low contrast letter acuity, respectively.

The treatment was generally well tolerated, with the overall incidence and severity of adverse events (AE) comparable across treatment arms. Treatment-related anti-LINGO-1 serious AEs included two patients with hypersensitivity reactions that occurred around the time of infusion and one patient with an asymptomatic elevation in liver transaminases, which resolved after drug discontinuation.

No deaths occurred during the trial, and no immunogenicity was observed. Biogen said analysis of the RENEW data is continuing, and the company plans to present full results later this year at an undisclosed medical meeting.

The phase II development program to assess the potential of the anti-LINGO-1 candidate in demyelinating diseases also includes the ongoing SYNERGY trial in relapsing MS. The randomized, double-blind, placebo-controlled, dose-range-finding study is fully enrolled and expected to report data next year.

'First program that's actually giving clinical readout'

Despite the missed endpoints, Biogen broke new ground with RENEW by providing the first evidence of activity in humans, according to Cadavid, who oversees the anti-LINGO-1 program at Cambridge, Mass.-based Biogen.

"The field of demyelination, in general, has been thinking about how to repair the myelin for a long time," he told BioWorld Today. "Until now, all the evidence we had was coming from animals – mostly rodents. It's very important to have evidence coming from humans, and this is the first."

Cadavid was more introspective about the prospects for translating that evidence into a therapeutic compound. Although the RENEW data suggest it's possible to repair a recent injury to myelin if the axons survive, repairing the retina is nevertheless "an incredibly complex" undertaking, he admitted.

Measuring the extent of recovery also is a challenge, but the RENEW data suggest the task is not impossible.

"How can we measure myelin?" Cadavid asked. "It's sitting in the brain, and we cannot open the skull and take out pieces. What we used, visual evoked potential, is a very established methodology that has been used for about 40 years to support the diagnosis of MS and optic neuritis. We know that, following a lesion in the optic nerve, there is very limited recovery of latency. The primary question asked in RENEW is whether, if we gave this drug, we could improve that recovery. Our interpretation of the data is that recovery did [occur]."

Pursuing the demyelinating thesis in MS could be even more daunting, but Biogen certainly has the chops to achieve that goal, with five approved drugs targeting the indication and two more in pivotal studies. In general, however, those target inflammatory injury or symptomatic treatment, Cadavid said, while the anti-LINGO-1 program is seeking actually to repair axons that are damaged but not destroyed.

"It's a really different space in MS, and this is the first program that's actually giving a clinical readout," he pointed out. "It's encouraging for the field and for the patients, but we have a long way to go."

FINDINGS REPRESENT 'A GREAT STEP FORWARD'

Andrew Blight, chief scientific officer at Acorda Therapeutics Inc., agreed, tipping his hat to Biogen's accomplishment. Acorda has its own remyelinating MAb, rHIgM22, in development in MS in partnership with the Mayo Clinic. Data from a phase I study are expected to report early this year.

The mechanism of action for Acorda's compound differs from BIIB033, with rHIgM22 designed to stimulate oligodendrocytes, the cells that make myelin, to repair areas of demyelination while anti-LINGO-1 blocks their inhibition. Still, the Biogen findings represent "a great step forward," Blight told BioWorld Today.

The RENEW data offer the first clinical validation of the premise that the central nervous system can be affected by a remyelinating compound, he added. Although Biogen has "a long way to go" to demonstrate clinically meaningful effect, "the field, in general, should be happy to see that there certainly does seem to be biological activity of an antibody-based remyelinating therapy," Blight said.

Some analysts took the same tack, giving Biogen the benefit of the doubt despite questions in the early look.

"In our opinion, the fact there is remyelination suggests that over time anti-LINGO has the ability to be neuron-protective," Deutsche Bank analyst Robyn Karnauskas wrote in an email. "In addition, company comments suggest we should not rule out this possibility either."

Checks with physicians about anti-LINGO-1 "suggest they are intrigued and believe that secondary endpoints are challenging as many are not validated/have variability," Karnauskas added. "Big picture, we also think positive LINGO data open the door for a remyelination franchise. Multiple mechanisms of action should improve efficacy and there are many targets being evaluated."

Wells Fargo Securities analysts also polled key opinion leaders (KOLs), reporting that "our consultants found the results overall to be encouraging, but far from completely clear/conclusive based on what was reported," according to analyst Ronald Hsu, noting that KOLs indicated the findings on the study's primary endpoint "suggested this was a legitimate signal of potential remyelination."

On secondary endpoints, "our consultants noted that retinal nerve fiber layer thickness measurements could be confounded by inflammation from the optic neuritis depending on where the insult is geographically in the eye, and that retinal ganglial cell layer may provide a better read," he added.

Like the market, most analysts – and respondents to a quick informal poll by Evercore ISI analyst Mark Schoenebaum – seemed to take a wait-and-see approach, using adjectives like "interesting," "encouraging," "generally positive," "underwhelming" and "still unclear," while speculating whether the early findings would be proven down the road in AON and, more importantly, in MS.

Jefferies LLC analyst Thomas Wei wrote in a flash note that "it still remains to be seen whether the drug can show neuroprotective qualities, which we view as more meaningful to the likely success in the MS trials."

He added, however, that "the duration of this AON trial may have been too short to accurately assess this. In fact, it is possible that even the phase II trial in MS (22 months) might not paint a fully accurate description." Wei said the Street may need to wait for the full AON dataset "to show at what point potential remyelination occurred in the trial and any subsequent signals of improvement in the RNFL."

He characterized anti-LINGO-1 "as a high-risk/high-reward program" for Biogen.

Be that as it may, Biogen fully intends to pursue the asset, Cadavid maintained. Despite the progress in treating MS, patients continue to ask whether there's a therapy to help them recover functionality that's been lost, he said. For now, physicians can only shake their heads.

"But we are making progress," Cadavid emphasized. "It's a challenging and complex problem, but this study provides us with welcoming news, and we are hoping for success down the road."