The Q&A – Five key questions about Biogen Idec's new Alzheimer's disease data

The success of aducanumab has massive implications for Biogen Idec, other companies working on competing programmes, and the Alzheimer’s disease (AD) space more generally. Thus, it is with delight and some relief that the latest dollop of interim Phase Ib data, presented at a conference late last week, suggest the anti-beta-amyloid mAb is performing about as well as expected in early human testing.

Nevertheless, there are still plenty more hurdles for aducanumab to avoid, including some notable ones that have felled similar predecessors, so with the start of Phase III testing fast approaching, these are the five most pressing questions about the programme.

Expectations for Biogen Idec’s aducanumab (until recently known as BIIB037) have soared since December when an initial look at data from the Phase Ib trial gave investors a lot more – and perhaps too much, according to some – confidence that the product could succeed where other mAbs like Johnson & Johnson’s bapineuzumab and Eli Lilly’s solanezumab have failed.

And succeed it must in order to justify the Street’s current valuation for Biogen Idec, which is currently brushing up against its all-time high market cap at just over $111 billion, with UBS analyst Matthew Roden estimating that investors may be assigning up to $17.6 billion of this value to aducanumab. (See ViewPoints: With billions already baked in, positive BIIB037 readout this month is a must for Biogen Idec.)

While noting that he is optimistic about the company’s prospects, Roden was one of several analysts who suggest there is reason for caution even in the face of exciting early results. “We think it's premature to say the AD code is cracked, or that BIIB037 is the only asset that can be successful,” he said.

So what important questions have been answered at this point on account of the interim results from the Phase Ib PRIME trial in 166 patients with prodromal or mild AD, and what concerns are still lingering?

1. How do aducanumab’s efficacy data stack up?

The answer appears to be “extremely well”, according to just about every analyst who weighed in on the new Phase Ib results, though it should be noted the patient numbers involved are still quite small at this point.

Echoing other analysts, Cowen’s Eric Schmidt called aducanumab efficacy “impressive” and supportive of his belief that the agent is a “best-in-class beta-amyloid mAb with massive commercial potential.” Specifically, he pointed to the strength and linearity of aducanumab’s ability to generate statistically significant time- and dose-dependent reductions in cognitive decline as measured on both the MMSE test (76 percent and 81 percent in 3 milligrams per kilogram and 10 milligrams per kilogram dose groups) and CDR-SB test (71 percent at 10 milligrams per kilogram).

What’s more, aducanumab looks to be more effective in slowing the rate of cognitive decline relative to competitors like Eli Lilly’s solanezumab, which generated a 20-percent to 30-percent difference against placebo, as well as Roche’s crenezumab, which generated a range of 25 percent to 40 percent.

“The more drug patients took, the less their cognition declined, and the longer they took it, the bigger the difference between treated and control patients. These changes in cognition decline were associated with significant dose and time dependent changes in the accumulation of amyloid plaque in the brain using imaging techniques,” added Bernstein analyst Geoff Porges.

2. Is aducanumab safe enough?

This is likely “the $64 000-question” facing Biogen Idec at the moment as Porges noted the company is far from out of the woods in demonstrating that aducanumab can be given safely. The most notable issue is the fact it – like other mAbs like bapineuzumab, which was shelved in 2012 – seems to up the risk of amyloid-related imaging abnormalities-oedema (ARIA-E), particularly at the upper 10 milligrams per kilogram dose. Porges noted that this could mean aducanumab may have a relatively narrow therapeutic window, making finding the right dose with enough efficacy more tricky.

The issue is most pronounced in patients who were carriers of the ApoE4 high risk gene, in whom “the rate of ARIA-E increased from 5 percent to 43 percent to 55 percent in the 1 milligram per kilogram , 6 milligrams per kilogram and 10 milligrams per kilogram arms. Thus, “Biogen are now faced with a relatively narrow therapeutic window for future development, whereas the drug's effect, and benefit, appears to steadily increase with dose,” Porges said.

3. What will the Phase III programme look like?

The possibility that aducanumab is hampered by a narrow therapeutic will be an important consideration for Biogen Idec as it sits down and decides on questions like what doses to test and endpoints to use in a Phase III programme slated to begin later this year.

In terms of dosing, the company will need to take a hard look at the Phase Ib data and figure out what level of risk patients and physicians would be willing to accept to get their hands on a drug capable of preserving the cognitive decline associated with AD. According to Evercore ISI analyst Mark Schoenebaum, the high incidence of ARIA-E seen at the high dose in ApoE4 carriers – a group that he said represents two-thirds of the AD market – would not be commercially acceptable. He said that an AD expert he spoke with said that one “critical thing will be whether the 6 milligrams per kilogram dose has a similar cognitive benefit as 10 milligrams per kilogram but with lower ARIA.”

There is some disagreement about what would be the best endpoint or endpoints to use, with MMSE and CDR-SB, along with ADAS-cog all being in consideration.

One KOL who spoke with Roden said “historically, cognition was used as a co-primary measure with functional measures. Some scales are being developed for very early patients. MMSE is the most widely used, it’s a blunt instrument used in screening, and it has a floor and ceiling effect. It's better for mild to moderate AD. It is also generally (but not completely) consistent with ADAS-cog.”

Schoenebaum suggested that MMSE was actually more difficult to get a positive result on because it is less sensitive than ADAS-cog, and though the former does not have the same track record for use as the latter, he said there is a case to be made that the FDA should have an open mind about accepting MMSE.

4. What does the competitive landscape look like?

Far from saddened to learn of the success of aducanumab, companies like Roche (and its Genentech unit) and Eli Lilly are likely to be pleased to see the data lending further support to the use of anti-beta-amyloid mAbs to treat AD.

In fact, while the results from PRIME may increase the chances of success for Biogen Idec’s programme in Phase III testing, Roden noted that Biogen Idec may simultaneously have provided a roadmap for its competitors to use for improving their odds of success by incorporating similar patient selection and PET screening components to future study designs.

Credit Suisse analyst Ravi Mehrotra said in a note to clients that Eli Lilly likely represents the biggest competition for Biogen Idec. There are some important mechanistic differences between the two different products though, as solanezumab targets soluble beta-amyloid while aducanumab preferentially binds to forms of the peptide that has already aggregated into parenchymal plaques, which may mean the Eli Lilly programme could cause less ARIA-E while also capable of generating lower efficacy.

As for Roche, Mehrotra said in a note to clients that he believes the future of the company’s anti-beta-amyloid agents are “uncertain” at the moment. A Phase III trial of gantenerumab in prodromal AD patients was discontinued for futility in late 2014 while another in mild AD patients is slated to readout in mid-2018.

Other companies with programmes in clinical testing include large pharma players like AstraZeneca, Merck & Co. and Pfizer, along with small biotechs such as Accera and Forma.

5. What might aducanumab achieve in sales?

Oftentimes drug candidates in Phase I testing won’t be included in sell side models but that is not the case with aducanumab, which is already garnering multi-billion dollar projections even after accounting for risk adjustments – with estimates likely to rise even further in the coming weeks as the Street accounts for Friday’s data announcement.

In notes issued prior to the new data, Bernstein analyst Tim Anderson told clients that he was estimating peak sales for aducanumab to achieve $4 billion to $5 billion on a non-risk-adjusted basis, while others such as Goldman Sachs’ Akinori Ueda are even more bullish, estimating the figure $8.4 billion.

Schoenebaum conducted a survey immediately following the presentation in which 100 buysiders put aducanumab’s probability of success in Phase III testing at 60 percent while pegging its peak sales potential once approved at a mean of $9.5 billion around 2022. In fact, almost half (46 percent) of those responding are bullish enough on the programme’s prospects that they suggest Biogen Idec should buy Eisai, with which it is developing its AD programmes under a 2014 partnership. (See Spotlight On: Eisai’s future growth increasingly levered to controversial beta-amyloid hypothesis.)

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