Can Kalvista make HAE after Pharvaris’s misstep?

A clinical hold for Pharvaris raises questions about the group’s approach, and could leave the door open for its acute rival.

There are already a surprising number of options for hereditary angioedema (HAE), given its rare disease status. But this has not stopped other players trying to get a piece of a market that was worth over $2bn last year.

One of these groups was dealt a blow yesterday, however, with Pharvaris disclosing an FDA clinical hold for PHA121, the active ingredient in its two contenders. No reasons for the hold were given, but some sellside analysts took the news as a good sign for the company’s rival Kalvista.

Oral option

Both Pharvaris and Kalvista are developing oral projects for the prophylactic and acute treatment of HAE. In the acute market, the companies hope to provide a more convenient option than current therapies like Pharming’s Ruconest, which is given intravenously, and Takeda’s subcutaneous Firazyr.

On the prophylaxis side, Biocryst’s oral Orladeyo is already available, but this is less efficacious than market leader, Takeda’s subcutaneously injected Takhzyro. However, Orladeyo’s launch has been stronger than expected, indicating an appetite for oral therapies, particularly if they can show better efficacy than Biocryst’s drug.

This is where Pharvaris and Kalvista hope to come in. The companies are taking different approaches: Pharvaris’s PHA121 is a bradykinin B2 receptor antagonist, while Kalvista is focused on inhibiting kallikrein.

Stifel and Leerink analysts speculated that the hold on PHA121, which was based on “non-clinical data”, might be related to its mechanism: the analysts noted that there are cardiovascular toxicity worries with the similarly-acting Firazyr, based on preclinical data. This could be a particular concern with a chronically dosed prophylactic therapy.

Without knowing the reasons behind the hold, it is too soon to write off PHA121. It is also worth noting that Kalvista’s prophylactic project, KVD824, was placed on clinical hold last year, but that this was resolved a few months later.

Still, Kalvista’s lead in the oral HAE space looks to have been boosted by Pharvaris’s misstep – next year, the former group expects phase 2 data with KVD824 and pivotal results with sebetralstat, its acute contender.

Kalvista’s stock climbed 10% yesterday, while Pharvaris sank 34%.

Shrinking market?

However, even if Kalvista manages to get its projects approved, there are questions about how big they can become, particularly in acute HAE.

Takhzyro has been shown to reduce HAE attacks by nearly 90%, and since its launch in 2018 the acute market has shrunk dramatically. However, this decline is mainly due to the genericisation of Firazyr, according to Stifel.

Although a cheap acute option could also be bad news for any new entrants, the analysts noted that demand for other acute products remains high, as shown by growing sales of another on-demand option, Ruconest.

“Most/all HAE patients need some form of acute treatment,” they concluded.

Still, there are other prophylactic contenders coming that could also put a squeeze on Kalvista and Pharvaris. While the recommended dosing schedule for Takhzyro is every two weeks, others are working on monthly or even longer-lasting options.

The hereditary angioedema pipeline
Project Company Description Setting Trial details
Phase 3
Garadacimab CSL Once-monthly SC anti-factor XIIa MAb Prophylaxis Vanguard toplined positive Aug 2022 
Sebetralstat (KVD900) Kalvista Pharmaceuticals Oral plasma kallikrein inhibitor Acute Konfident data due H2 2023
Donidalorsen (IONIS-PKK-LRx) Ionis Pharmaceuticals Once-monthly/every 2 months SC prekallikrein antisense Prophylaxis Oasis-HAE data due 2024
Phase 2
KVD824 Kalvista Pharmaceuticals Oral plasma kallikrein inhibitor Prophylaxis Komplete data due mid-2023
PHVS416 (softgel capsule containing PHA121) Pharvaris Oral bradykinin B2 receptor antagonist Acute & prophylaxis Rapide-1 in acute & Chapter-1 in prophylaxis on US clinical hold; studies continue OUS; data had been due Q4 2022 & Q1 2023 respectively
Phase 1/2
NTLA-2002 Intellia Therapeutics One-time in vivo Crispr KLKB1 gene knockout Prophylaxis NCT05120830 interim data due H2 2022
BMN 331 Biomarin Pharmaceutical AAV5-based Serping1 gene therapy Prophylaxis Haermony-1
Phase 1
PHVS719 (extended-release tablet containing PHA121) Pharvaris Oral bradykinin B2 receptor antagonist Prophylaxis PHA121 on clinical hold
STAR-0215 Astria Therapeutics ≥Every 3mo anti-plasma kallikrein MAb Prophylaxis NCT05477160 in healthy volunteers, preliminary data due YE 2022
Source: Evaluate Pharma & clinicaltrials.gov.

The most advanced of these, CSL’s once-monthly garadacimab, posted a top-line win in the pivotal Vanguard trial this month, and details will be crucial. In phase 2 garadacimab reduced HAE attacks by as much as 99%, so if the phase 3 data come close to this it could be a strong contender.

Also in phase 3 is Ionis’s antisense project donidalorsen, dosed monthly and every two months.

And earlier in development there are a couple of once-and-done approaches: Intellia’s in vivo Crispr editing project NTLA-2002 and Biomarin’s gene therapy. If these progress, it will be interesting to see how their risk-benefit trade-off is viewed by regulators given that HAE is a well-served disease.

Kalvista investors will no doubt be keeping an eye on how these rival projects shape up. As for Pharvaris, more clues about that group’s future in HAE should come with the FDA’s formal clinical hold letter, due in around a month.

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