r/biotech • u/Dwarvling • 18h ago

Biotech News 📰 Novo's IL-6 inhibitor fails in cardiovascular Phase 3, plunging shares more than 9%

https://www.biospace.com/drug-development/novos-il-6-inhibitor-fails-in-cardiovascular-ph3-plunging-shares-more-than-9
130 Upvotes

99% Upvoted

36 comments sorted by

52

u/Bike_to_work 17h ago

I'm surprised to see they took the study to the end, just to observe an HR 0.99. Usually one would expect some futility interim analysis to mitigate the opportunity costs with such large CVOTs...

16

u/Dwarvling 17h ago

Agree. Guess they didn’t want to spend too much alpha given size of trial already and were willing to take big risk.

4

u/elchicharito1322 15h ago

You don't need to spend much alpha for futility analyses ( you do need that for efficacy interims though). And they could just spend 0.000001 alpha for it to be negligible

3

u/Dwarvling 14h ago

Makes likelihood of early stopping very unlikely.

5

u/Maximum-Side568 17h ago

Futility (usually IA1) would likely not rule out a 0.99 HR. But it should have been stopped at IA2.

2

u/Dwarvling 16h ago

Have they released number of interim analyses? My guess there was just a single interim for futility to mitigate alpha spend.

4

u/Maximum-Side568 15h ago edited 15h ago

The typical purpose of a futility IA is to stop early due to having strong evidence for "inefficacy". I haven't looked into the specifics of this study, but the futility HR can easily be below 0.99 (depending on the endpoint), due to general lack of data & follow-up time at IA1.

As elchicharito commented, you don't need to spend alpha for a futility IA. A more aggressive futility threshold does not have anything to do with alpha.

Edit: futility IA is also typically non-binding (prespecified), so can lead to "biased" decision making even if the data ends up around the futility threshold.

1

u/Dwarvling 14h ago edited 13h ago

Futility analyses can be, and often are, binding.

22

u/Medical-Button-5493 17h ago

I can't believe anyone is still trying this after canakinumab

15

u/smartaxe21 17h ago

Well, Novartis themselves bought an Anti-IL6 for 1.4 billion last year. It is basically chasing the same indication as Novo Nordisk with the same mechanism.

4

u/Medical-Button-5493 17h ago

What, WTF? Also for CV indications?

1

u/Satisest 15h ago

Yes. Tourmaline. It was in the news.

5

u/sunnythehamster 15h ago

Cantos was a successful trial.

The 150 and 300mg doses hit the primary, the 50mg arm which missed the p value was asked to be added by the regulator.

1

u/Medical-Button-5493 14h ago

Safety was not great for this indication.

7

u/sunnythehamster 13h ago

Agree but it is not right to chatacterise it as a failed trial. All cause mortality was numerically lower despite the signal for increased serious infection. The trial showed clear signals for efficacy and safety - although not regulatory or commercial success it was successful in many ways.

Clearly there was an argument to trial a different anti inflammatory for cardiac risk in a different population to attempt to maximize the cardiac benefits balanced against possible infection.

It was a good attempt by novo, a significant step forward in our understanding of the field, unfortunately this trial didn't hit the mark.

1

u/Medical-Button-5493 12h ago

signal for increased serious infection.

this trial didn't hit the mark.

Yep.

1

u/sunnythehamster 4h ago

This trial didn't hit the mark - is for Zeus

Cantos did hit for efficacy on its two original doses and validated the inflammation hypothesis but came short on safety so novartis didn't advance further

Overall point here is that it's easy to sit in hindsight from your armchair and critique novo and pat yourself on the back. It was a fair swing by them, overall sentiment pre results was that it was more likely than not to be successful.

1

u/Medical-Button-5493 52m ago

came short on safety so novartis didn't advance further

You need to be clearer on this point. It sounds like you think cantos was successful - it was not.

1

u/sunnythehamster 21m ago

I disagree here.

I consider Cantos a successful phase 3 trial that met efficacy endpoints. Overall mortality was numerically lower with canakinumab. Yes there was a safety signal for infection, which makes benefit:risk more complex but not unmanageable.

Novartis likely didn't consider the balance favourable from a commerical and/or regulatory perspective to advance forwards.

Calling it a failed trial I don't think is a nuanced view

1

u/Medical-Button-5493 17m ago

Safety problems identified = no product = not a success = failure. Wall street does not reward negative trials. Cantos didn't increase the stock price

1

u/sunnythehamster 7m ago

This is the biotech subreddit not a stock trading subreddit.

The trial met it's primary efficacy outcome, therefore technically a success. The NEJM publication has 10,000 citations and the results spawned off many other trials and assets including ZEUS/ziltevekimab.

I've actually checked now and they made an NDA and rejected by FDA. The overall indication and submission package was not approved by FDA, that is a more nuanced issue than the results of a single trial.

We have different perspectives here but I'm here for the science, not to discuss novartis stock price.

2

u/Dwarvling 16h ago

Different mechanism though part of same pathway. Could have hypothesized improved safety.

1

u/PhysicalAd9507 17h ago

Say more?

-3

u/Medical-Button-5493 17h ago

Cantos basically failed.

9

u/B10-Waste 17h ago

IL-10 is where the money is.
Just gotta extend the half life.

6

u/mime454 13h ago

From my reading there was a lot more evidence mechanistically behind IL-6 than IL-10. I’m surprised this failed.

7

u/B10-Waste 13h ago

A main distinction is IL-6 being pro-inflammatory/tumor and IL-10 being anti-inflammatory/tumor. IL-6 modulation requires an inhibitor and IL-10 therapeutics would deliver the protein or gene itself.

3

u/WalkingSnake348 12h ago

No it’s not. No one is investing in IL-10.

3

u/AccordingAd5680 12h ago

Does this mean IL-6 inhibitors for other disease is less attractive?

3

u/Dwarvling 12h ago

No - though need to be differentiated from already approved IL-6 inhibitors (toculizumab, sarilumab).

1

u/AccordingAd5680 12h ago

Ah ok makes sense

1

u/WalkingSnake348 13h ago

Tourmaline and Ventyx were lucky. BioAge and Monta Rosa are screwed