Ionis feels the pain as the US FDA finally bares its teeth

A complete response letter for Waylivra has taken investors by surprise, and increases the pressure on Ionis before an FDA decision on Tegsedi.

Even in ultra-rare diseases with substantial need, the supposedly amenable US regulator has its red lines. Ionis learned this the hard way yesterday when it received a complete response letter for Waylivra, sending its shares crashing this morning.

This outcome was always possible given the safety worries and questions about clinical data that have plagued the antisense therapy’s regulatory journey; investors presumably believed that unmet need would be enough to carry Waylivra, which treats an ultra-rare lipid disorder, over the finishing line. It now looks uncertain whether the project will ever make it that far, and an even bigger concern is whether this means anything for the FDA’s ongoing review of Tegsedi.

The US agency is due to deliver its verdict on the amyloidosis treatment in October; EU regulators gave a green light back earlier this year. Both Tegsedi and Waylivra have been associated with declines in platelet count – one patient died of an intracranial haemorrhage in Tegsedi’s pivotal Neuro-TTR trial. 

Both are also the product of Ionis’s antisense platform, and the company set up Akcea effectively as a subsidiary, to serve as the commercial arm of the business. Despite Akcea being listed separately on the stock market, Ionis retains a 75% stake in it (Ionis gives a lesson in financial engineering, 16 March 2018).

Valuing the assets, before the CRL Ionis and Akcea
Ionis key products NPV ($bn)
Waylivra 2.91
Spinraza 2.07
Tegsedi 1.67
BAY 2306001 0.11
Total incl. others 7.01
Market cap at open Aug 28  6.50
Akcea key products NPV ($bn)
Tegsedi 1.60
Waylivra 0.55
Total incl. others 2.19
Market cap at open Aug 28  2.09
Source: EvaluatePharma.   

In hindsight, another read of the documents released for Waylivra’s advisory committee hearing back in May makes it hard to see why this setback was not more widely anticipated. True, the FDA rarely goes against a panel decision, but the outcome was far from unequivocal: panel members voted 12 to 8 in favour of Waylivra reaching the market. 

Familial chylomicronemia syndrome, which Waylivra seeks to treat, is a very serious disorder that causes extremely high triglyceride levels and leaves patients exposed to fatal pancreatitis and organ damage. While acknowledging that Waylivra markedly lowers triglycerides, FDA reviewers flagged several concerns about the data. 

Serious bleeding

The main issue, and the one likely to be holding up approval, is the potential for Waylivra to cause serious bleeding – several cases of severe thrombocytopenia were observed in the study. Reviewers even suggested that a risk-mitigation plan might not be sufficient to ensure safe use of the drug, and questioned the feasibility of any monitoring scheme for a lifelong therapy. The fact that the proposed dosing regimen, designed to mitigate bleeding risk, was not thoroughly tested throughout the clinical programme also raised flags. 

Adding to all this was a high rate of patient discontinuations, which many panel members noted could have compromised both the safety and efficacy data. And the fact that Waylivra showed no difference to placebo on secondary endpoints such as abdominal pain or acute pancreatitis.

Other than expressing “extreme disappointment” with the decision, no details of the complete response letter were revealed. Investors apparently fear that the project is dead – shares of Ionis opened down 13%, while the more exposed Akcea plunged 43%.

What this means for Tegsedi is another question. European approval is a positive sign, though bleeding risk was always going to be a big issue for this project as well. 

The sellside brushed off concerns about read-through this morning, pointing to a much stronger set of supporting data, though of course this is the same sellside that predicted regulatory success for Waylivra. 

At the very least the Waylivra halt makes Tegsedi look like a riskier bet. The US regulator has already delayed its decision once, and another setback would be a huge blow. 

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