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NEW ORLEANS -- Although still technically an orphan disease, hereditary angioedema (HAE) remains a popular focus for drug developers despite a half-dozen products already approved in the U.S.

That was on full display at the American College of Allergy, Asthma and Immunology's annual meeting here, with phase II studies on two investigational agents featured in oral presentations. Both target elements of the so-called kallikrein pathway that produces HAE attack symptoms: one an oligonucleotide intended to knock down a precursor molecule and serve to prevent attacks, the other a direct kallikrein inhibitor for treating acute symptoms.

HAE, you may recall, is a chronic condition that manifests as unpredictable acute attacks typically lasting many hours. Severe facial swelling and gastrointestinal symptoms are common features. Although the condition arises from genetic defects related to complement activation and might be properly considered a rheumatologic disorder, it's usually treated by allergists because the symptoms are often mistaken at first for anaphylactic reactions.

In addition, because it's frightening and often disfiguring and disabling, finding effective treatments is a high priority for patients and clinicians. It's a rare disease, with fewer than 10,000 people in the U.S. affected, yet the pharma industry has battled for space in the tiny market. Six products are now available both for prophylaxis or attack treatment, mainly delivered by infusion or injection, though with one oral medication.

But developers still see opportunities for improvements.

Antisense Oligonucleotide

Danny Cohn, MD, of Amsterdam University Medical Center in the Netherlands, reported (in a prerecorded video) on the antisense agent, called PKK-LRx. Its target is prekallikrein, a molecule that sits between the action of the C1 inhibitor on factor XIIa and kallikrein -- midway in the longer pathway connecting factor XII and bradykinin activation, which triggers the acute attack symptoms. By inhibiting prekallikrein expression, the hope is that PKK-LRx will shut down this cascade and prevent attacks from occurring.

In the , 20 patients were assigned to receive subcutaneous injections of PKK-LRx (n=14) or placebo (n=6) every 4 weeks for 16 weeks. Participants had had at least two HAE attacks in the 8 weeks prior to randomization; the study's primary outcome measure was the monthly rate of HAE attacks during the treatment period.

Participants had long histories of HAE: most began having attacks in childhood or adolescence and their mean age when enrolled was about 40. Histories obtained during screening indicated that they had been having roughly two attacks per month in the past year.

PKK-LRx had its intended pharmacologic effect, with prekallikrein levels in plasma suppressed by about 60% from baseline after the first two doses and staying down through the rest of the study. Levels remained at baseline levels in the placebo group.

In terms of clinical efficacy, the agent hit a home run. Of the 14 patients randomized to the drug, only one patient had any attacks after the third study week. That patient suffered two attacks following the second dose, including one rated as severe during week 12. Six participants in the active-drug group had no attacks after the first dose.

Meanwhile, five of six patients in the placebo group experienced multiple attacks -- as many as 17. The other placebo participant had a single moderate attack during week 12.

Statistically, the mean monthly attack rates were 0.23 with PKK-LRx versus 2.21 for placebo, for a 90% reduction (95% CI 76%-96%), Cohn said. That included eight attacks occurring in the 2 weeks following the first dose. When looking only at week 5 onward, attack rates were 0.07 versus 2.06 per month for PKK-LRx and placebo, respectively -- a reduction of 97%.

Safety findings were unremarkable and probably meaningless given the small number of participants. Most participants experienced adverse events but these appeared to be related mainly to the disease rather than treatment: those rated as "drug-related" in blinded reviews were markedly more common with placebo than with PKK-LRx (66.7% vs 28.6% of patients), according to Cohn.

Based on these data, a phase III trial is "in preparation," he said.

Oral Kallikrein Inhibitor

Called KVD900, this agent is positioned by its developer, Massachusetts-based KalVista Pharmaceuticals, as an "on-demand" oral treatment for acute attacks. The only oral drug for HAE currently approved is for prophylaxis, and certainly the convenience of a pill that patients can keep in their medicine cabinets in case of attacks -- which do still occur, if less frequently, for patients receiving preventive therapy -- is an obvious attraction.

The reported here by Jonathan Bernstein, MD, of the University of Cincinnati in Ohio, had two components: an initial pharmacokinetic analysis involving 42 patients, and then a randomized cross-over comparison of the active drug versus placebo with 68 participants.

During the efficacy phase, the main endpoints were based on the Patient Global Impression of Change (PGI-C), which participants filled out every 30 minutes for the first 4 hours after self-dosing, then hourly for the next 8 hours, and then every 3 hours up to hour 24. PGI-C has seven possible ratings, ranging from "much worse" to "much better."

Efficacy was analyzed as the time needed to reach either of the following:

• A: Ratings of "a little better," "better," or "much better" at two consecutive points
• B: Ratings of "better" or "much better" at any one point

Both of these were examined during the first 12 hours after dosing and within 24 hours.

The cross-over phase was designed with two groups of 34 patients each, which would run until each participant had experienced two attacks. One group was given placebo for the first attack and KVD900 for the second; the other group started with the active drug and then had placebo for their second attack. As it happened, investigators stopped the study when 53 patients had experienced two attacks, such that the efficacy analysis came from 28 in the first group and 25 from the second.

Findings from the pharmacokinetic portion confirmed KVD900's rapid absorption and availability, with peak blood levels reached in 45 minutes and remaining near it for 4 hours.

In the efficacy analysis, the drug clearly outperformed placebo. Mean time to reach endpoint A within 12 hours was 1.6 hours for KVD900 versus 9.0 hours for placebo; for endpoint B within 12 hours, the mean was 5.0 hours for the drug and not reached for placebo. Results were nearly identical when examined over the full 24 hours. All comparisons had P values below 0.01, mostly well below.

Bernstein also presented a responder analysis: 83% of the active drug group met endpoint A in 12 hours compared with 51% of those using placebo; the gap narrowed somewhat when analyzed over 24 hours but still remained statistically significant.

KalVista hasn't announced plans for phase III testing.