Safety scare knocks Novartis

Heightened Beovu safety concerns could turn into a big problem for Novartis, while rival Regeneron will make the most of any uncertainty.

Trial Results

On a day when the markets were already trading down on jitters about coronavirus, the American Society of Retina Specialists added to the gloom for Novartis investors. A note to eye doctors warning about worrying side effects seen with the Swiss pharma giant’s new macular degeneration treatment, Beovu, helped wipe $15bn from the company’s market cap yesterday. Today, the shares were down a futher 4% in late trading. 

Beovu is seen as one of Novartis’s most important sales growth drivers: the $1.4bn in sales forecast for 2024 will make it the company’s sixth biggest product that year, according to EvaluatePharma. But much depends on Novartis’s ability to grab share from entrenched competitor Eylea, sold by Regeneron, an effort that could be severely hampered by safety concerns.

Most worrying was the medical body’s alert about several cases of a dangerous form of eye inflammation called vasculitis; although this was seen in Beovu’s clinical programme, these occurrences appear to confirm that this is a real issue for the product. Retinal vasculitis can lead to blindness and although only 14 cases were reported to the ASRS, 11 were classified as occlusive retinal vasculitis. This happens when the smaller retinal vessels become blocked, and is of even greater concern.

The database of Advera Health Analytics, which specialises in compiling and curating US adverse event reports, shows that vasculitis has been seen with all three anti-VEGF eye products. They count two for Beovu, 17 for Eylea and 46 for Lucentis, although it is not immediately clear which specific forms of vasculitis these figures refer to.

Advera gets its data from FAERS, the FDA’s adverse event reporting system, and must be read in the context of vastly greater use of Eylea and Lucentis, which have been on the market for much longer.

However Advera calculates that these drugs' reporting odds ratios, a disproportionality measure for adverse events, currently sits at 6.02 for Beovu, 0.50 for Eylea and 1.10 for Lucentis. This means that vasculitis has a higher relative occurrence in FAERS compared to the other drugs. 

Defending an empire: the current outlook for antineovascularisation
Product Company 2020e sales ($bn) 2022e sales ($bn) 2024e sales ($bn)
Eylea Regeneron*  4.58 4.31 4.17
Eylea Bayer 2.80 2.77 2.52
Beovu Novartis 0.31 0.91 1.44
Lucentis Novartis 2.06 1.60 1.12
Lucentis Roche* 1.69 1.30 0.99
  Total market (incl others) 12.06 11.59 12.19
*Books US sales only. Source: EvaluatePharma.  

Novartis will be hoping that what looks to be a vasculitis signal turns out to be a function of heightened physician alertness when using a new drug. But Beovu is also associated with higher rates of intraocular inflammation – this was seen in 4% of patients, compared with 2% with Eylea – and is contraindicated in patients with active intraocular inflammation. Moreover, the label notes a 1% rate of retinal artery occlusion.

Throw in another, potentially more serious side-effect and physicians will be struggling to find reasons to reach for the Novartis product. Beovu’s USP was a less frequent dosing schedule, but this naturally becomes irrelevant with worse safety.

Exactly why Beovu might be associated with these inflammatory issues is unknown: as an antibody fragment the molecule is much smaller than Eylea and Lucentis, and autoantibodies are seen much more frequently in patients treated with Beovu. But to persuade physicians and patients that the product is worth trying, Novartis needs to quickly work out how to identify people at risk.

Regeneron meanwhile got a 6% boost to its stock price yesterday, as one of the big clouds on Eylea’s horizon started to look a lot less threatening. The company still has the looming prospect of Lucentis biosimilars to contend with, but for now Novartis’s setback will provide a great help as it tries to convince physicians to stick with what they know.

This article has been updated with additional data from Advera Health. 

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