Biogen teases with lupus ahead of aducanumab's big Alzheimer’s reveal

Biogen’s clinical-stage pipeline carries little weight, and encouraging data in lupus is unlikely to change that.

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A look at Biogen’s pipeline lays bare the challenge that confronts the company’s management. It is full of high-risk neurological projects, to which the financial community has largely declined to assign any value.

Aducanumab carries the most weight – according to the sellside’s numbers, at least – though current estimates for the Alzheimer’s asset could soon be ripped up. Presentation of phase III data from two trials at a medical conference tomorrow promises to be a huge event, not only for the Alzheimer’s field but also for Biogen, which desperately needs to defend its commitment to some very challenging disease areas.

The table below shows that of 16 phase III and II assets, only aducanumab is attracting numbers of any notable size. Predicting the success of experimental neurological treatments is notoriously hard, which is why only a couple of these projects have been assigned any value.

Mind the gap: Biogen's unproven pipeline
Product Project 2024e WW sales ($m) Today's NPV ($m)
    Phase III      
Aducanumab Alzheimer's disease antibody  1,110 4,484
BIIB111 (NSR-REP1) Choroideraemia gene therapy  55 197
BIIB093 Large hemispheric infarction (ischaemic stroke) 33 175
Tofersen SOD-1-Amyotrophic lateral sclerosis 15 60
BAN2410 Alzheimer's disease antibody  - -
    Phase II      
BIIB078 ALS 45 284
Opicinumab MS  38 217
BIIB112 (NSR-RPGR) X-linked retinitis pigmentosa 38 183
BIIB092 Progressive supranuclear palsy/Alzheimer's  10 42
BIIB104 Cognitive impairment associated with schizophrenia  - -
Dapirolizumab Lupus antibody  - -
Natalizumab Epilepsy  - -
TMS-007 Stroke (option to buy from TMS) - -
BIIB054  Parkinson's disease antibody  - -
BIIB059 Lupus antibody  - -
BIIB074 Trigeminal neuralgia/small fibre neuropathy - -
    Phase I       
Nine assets Various - -
 
Total for projects in R&D 1,344 5,641
Total for marketed products 9,031 40,818
Total for Biogen 10,375 46,459
Biogen market cap   52,454
Source: EvaluatePharma.

It is notable that BIIB059, on which phase II data was released yesterday, is apparently devoid of value. Few agents have shown utility in lupus, and BIIB059 is handicapped further due to a novel mechanism of action that has yet to establish its relevance in the disease.

The antibody binds BDCA2, a receptor found on plasmacytoid dendritic cells; these immune cells produce large amounts of type I interferon, a key driver of lupus. Plasmacytoid dendritic cells have been shown to accumulate in the skin, and it is hoped BIIB059 will have a particularly marked impact on the rashes seen in many lupus patients.

Yesterday’s data, from a trial called Lilac, appear to support the hypothesis, though little information was released and virtually nothing said on safety. The trial enrolled 264 patients from distinct lupus populations into two separate cohorts.

The first concerned patients with various forms of lupus skin disease, including cutaneous lupus and discoid lupus, who reported significantly stronger responses than placebo patients on a skin activity score called CLASI-A. Three doses were tested but worryingly the middle one performing most convincingly.

The other group included subjects with systemic lupus erythematosus, and these patients just about registered a statistically significant improvement in joint pain over placebo. Biogen has yet to announce further plans for BIIB059, and it seems unlikely that the sellside will change its view on the asset just yet.

Phase II Lilac data (NCT02847598)
  BIIB059 50mg BIIB059 150mg BIIB059 450mg Placebo
CLASI-A score at week 16 (CLE patients) 40.9% (p=0.008) 48% (p=0.001) 42.5% (p=0.001) 14.50%
Change from baseline in total active joint count at week 24 (SLE patients) - - -3.4 versus placebo (p=0.037) -
CLASI-A; cutaneous lupus erythematosus disease area and severity index activity, CLE; cutaneous lupus erythematosus, SLE; systemic lupus erythematosus. Source: Biogen press release.

Of course the big readout for Biogen is aducanumab. Data from two trials, Emerge and Engage, will be unveiled at the Clinical Trials on Alzheimer’s Disease (CTAD) annual congress in California tomorrow. These studies failed a futility analysis earlier in the year but Biogen published a new analysis of the data in October that purported to find a benefit in patients given a high dose of the antibody and who were tracked for longer (Shock revelation sees Biogen erase its aducanumab losses, October 22, 2019).

So far the company has provided very little information on those new datasets. Given the $15bn boost to Biogen’s market cap that the reversal bestowed, tomorrow’s presentation is crucial.

Essentially, the company needs to explain exactly why this new analysis can be trusted. More specific questions concern why aducanumab seemed to work better in Emerge than Engage, and whether different distributions of patients with a genetic predisposition to Alzheimer’s played any role.

Physicians and investors will be very keen to see actual numbers – so far Biogen has only revealed percentage changes on the dementia rating scale CDR-SB – to give an idea of the absolute benefit. And then all of this must be framed within a closer look at aducanumab’s safety profile: the brain swelling condition Aria-E was seen in 35% of patients.

The worst-case scenario for Biogen is a very marginal benefit with a heavy toxicity burden. The FDA would surely require another trial in this situation, to confirm the findings.

Physicians are another major group that needs convincing, and the signs here are not encouraging. Critical editorials have been written in both the Lancet and Nature, with the authors taking exception to the use of post-hoc analyses and doubting the validity of any efficacy signal.

Biogen will have its work cut out tomorrow. With little else to fall back on, another aducanumab disappointment could have far-reaching repercussions for the company.

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