CSL Behring Nears Market With Easier-To-Administer HAE Prophylactic

CSL Behring’s long-acting subcutaneous C1 inhibitor formulation, CSL830, has confirmed its efficacy for the prevention of hereditary angioedema (HAE) attacks, and is expected to be introduced this year, giving it initial traction in what could become a crowded sector.

The results of the CSL Behring-sponsored Phase III COMPACT (clinical study for optimal management of preventing angioedema with low volume subcutaneous C1-inhibitor replacement therapy) trial showed that twice-weekly, self-administered subcutaneous injections of CSL830 were associated with a significant reduction in the frequency of acute HAI attacks, compared with placebo, with only mild and transient adverse effects.

“More than 50% of patients had no moderate-to-severe attacks while they were receiving CSL830,” noted UK clinical researcher Hilary Longhurst and colleagues in a paper presenting the final COMPACT results, published in this week’s New England Journal of Medicine (March 23, p 1,131).

CSL Behring has considerable experience in the HAE market, having marketed an intravenous formulation of C1-esterase inhibitor, Berinert, for the treatment of HAI for a number of years. A US BLA was submitted for the subcutaneous version, CSL830, in Aug. 2016, and analysts at Morningstar expect the new product to be approved and launched in 2017. They value the market at around $1.4bn, and expect CSL830’s commercial role to be focused on defending CSL’s 20% share of the HAE market.

CSL’s products are likely to come under pressure from Shire PLC’s subcutaneous formulation of its plasma-derived intravenous HAE product, Cinryze (C1 esterase inhibitor (human)) that is in Phase III studies, and Shire’s monoclonal antibody product, lanadelumab, also in Phase III. Lanadelumab was acquired by Shire via its $5.9bn purchase of Dyax Corp. in late 2015, and can also be given by subcutaneous injection; Phase III data for SHP643 are expected around the second quarter of this year. (Also see "Shire's Wellhoefer On Genetic Disease R&D And Expanding Access To Medicines" - Scrip, 27 Feb, 2017.)

Cinryze intravenous is currently marketed in the US for the prevention of HAE attacks with a twice weekly infusion, and in Europe for the prevention and treatment of HAE attacks. A subcutaneous therapy, the bradykinin antagonist, Firazyr (icatibant), is also marketed by Shire for the treatment of HAE attacks.

Also active in the sector is the tiny Dutch biotech Pharming NV that markets an intravenous recombinant human C1 inhibitor, Ruconest (conestat alfa) in the US, EU and other countries for the treatment of HAE attacks. Ruconest was also recently evaluated in both a once and twice weekly dosing in a Phase II double-blind placebo-controlled study for HAE prophylaxis and met all clinical and statistical endpoints; the company is exploring further clinical and regulatory strategies to develop the product further.

Selected investigational products in development for HAE include the following:

Selected HAE Products In Development

Source: Biomedtracker.

Company	Project	Mode Of Action	Stage Of Development
CSL Behring	CSL830 subcutaneous	C1 esterase inhibitor	BLA submitted
Shire	Cinryze subcutaneous	C1 esterase inhibitor	Phase III
Shire	lanadelumab (SHP643, DX-2930)	kallikrein binding MAb	Phase III
BioCryst Pharmaceuticals Inc.	BCX7353	oral plasma kallikrein inhibitor	Phase II
Ionis Pharmaceuticals Inc.	ISIS-PKKRx	antisense prekallikrein	Phase I
KalVista Pharmaceuticals Inc.	KVD818	kallikrein inhibitor	Phase I
Shire	SHP623	recombinant C1-esterase inhibitor	Phase I

COMPACT’s Results In Detail

The COMPACT researchers evaluated 79 patients from 10 countries who were treated with either 40 IU or 60 IU of CSL830 per kg body weight, or placebo, twice-weekly for 16 weeks, and then crossed over to the other treatments.

Both doses of CSL830 significantly reduced the rate of HAI attacks compared with placebo, the primary endpoint. Response rates, calculated as a greater than 50% reduction vs placebo in the number of attacks, were 76% (95% CI, 62 to 87) in the 40 IU group and 90% (95% CI 77 to 96) in the 60 IU group. The average severity of attacks was lower in the CSL830 group than in placebo treated patients; 13 CSL830 treated patients had 52 severe attacks, compared with 64 placebo-treated patients who had 252 severe attacks.

The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40 IU group, and from 3.89 uses per month in the placebo group to 0.32 uses per month in the 60 IU group, said Longhurst et al. Mild and transient local site reactions were the most common adverse events that occurred in similar proportions in treated and placebo patients.

Regular intravenous C1 inhibitor replacement therapy has been marketed for many years, and reduces the frequency and severity of HAE attacks, but intravenous access is difficult to maintain, and there are risks associated with indwelling venous catheters, the researchers remark. They note an open label extension trial is ongoing to explore the reasons for the variability in patient responses, and whether dose adjustments can improve treatment responses.

HAE is a rare genetic life-threatening condition that occurs in around 1 in 10,000 to one in 50,000 people that is caused by the lack of, or malfunctioning, C1-esterase inhibitor. Fluid accumulates in the body causing swelling episodes, known as angioedema. HAE attacks can cause swelling of the face and throat leading to asphyxiation and death, and also extreme pain, diarrhea and vomiting as the intestinal wall swells.

This story was updated on March 24, 2017 to reflect the fact that Salix Pharmaceuticals Ltd is no longer Pharming’s US partner. Pharming has bought back the US rights to Ruconest from Valeant/Salix (which included all indications and uses for Ruconest, including prophylaxis).