Eighteen months after picking up Dyax Corp. for $5.9 billion in cash, Shire plc appears to have a winner with lanadelumab, originally known as DX-2930. The plasma kallikrein inhibitor, which Shire first designated as SHP-643, met its primary and secondary endpoints with highly statistical significance, compared to placebo, in the phase III HELP study in patients 12 and older with hereditary angioedema (HAE).

Dublin-based Shire expects to file a biologics license application (BLA) with the FDA by early 2018 for the prophylactic treatment, which has both orphan drug and breakthrough therapy designation from the agency and orphan drug designation from the EMA in HAE.

"It was actually just less than two years ago when we held a similar investor call to announce our acquisition of Dyax," Shire CEO Flemming Ornskov said at the outset of the company's conference call with analysts. "Since then our goal has been abundantly clear: To bring a potentially transformative product to the hereditary angioedema patient community and further expand and extend our leadership position in this very important therapeutic area."

The top-line findings from the phase III trial represent "a big step" toward realizing that goal, he added, noting, "I'm more convinced than ever that lanadelumab has the potential to truly change the treatment paradigm in hereditary angioedema and dramatically expand the hereditary angioedema market."

The global, multicenter, double-blind, parallel group HELP trial enrolled approximately 125 HAE patients across sites in North America, Europe and the Middle East to evaluate the efficacy and safety of subcutaneously administered lanadelumab over 26 weeks. Patients were randomized into four arms to receive subcutaneous injections of lanadelumab dosed at 300 mg every two weeks, 150 mg every four weeks, 300 mg every four weeks or placebo. To maintain the blinded protocol, participants received placebo injections on weeks when they were not scheduled to receive the study drug.

The primary efficacy endpoint was the number of investigator-confirmed angioedema attacks observed in each lanadelumab treatment arm compared to placebo during the treatment period. Secondary endpoints included the number of HAE attacks per week that required acute therapy use for each treatment arm compared to placebo and the number of moderate or severe HAE attacks per week for each treatment arm vs. placebo, according to Cortellis Clinical Trials Intelligence.

Lanadelumab is designed to prevent angioedema attacks in patients with HAE, a genetic disease characterized by recurrent swelling of extremities, gastrointestinal tract and upper airways that is thought to affect about one in 10,000 to one in 50,000 people worldwide.

Top-line data showed the 300-mg dose administered once every two weeks resulted in a reduction in mean HAE attack frequency of 87 percent compared to placebo (p <0.001), and results were consistent regardless of baseline attack rate. For each of the three lanadelumab regimens, whether administered biweekly or monthly, a higher proportion of patients compared to placebo were attack-free throughout the 26-week study period.

Lanadelumab was generally well-tolerated, with no treatment-related serious adverse events (AEs) or deaths reported during the study period. The most common AE was injection site pain (29.3 percent placebo vs. 42.9 percent combined lanadelumab arms).

Shire said patients enrolled in HELP represented the full HAE disease spectrum, including 52 percent of patients who experienced three or more attacks per month at baseline, 65 percent of patients who reported a history of laryngeal attacks and 56 percent who were on long-term prophylaxis. Ninety percent of patients completed the study, and 96 percent of those chose to roll over into the ongoing long-term HELP study extension.

'This is a market we know extremely well'

At the time of its acquisition, Dyax was set to move DX-2930 into the phase III program. The company's shareholders are in line for an additional $646 million if and when lanadelumab is approved by the FDA. (See BioWorld Today, Nov. 3, 2015.)

The deal also gave Shire ownership of the marketed Dyax product Kalbitor (ecallantide), approved to treat acute attacks of HAE, padding Shire's own HAE portfolio, which included Firazyr (icatibant) and Cinryze (C1 esterase inhibitor). That aspect of the acquisition, which came in the midst of Shire's contested $32 billion all-stock offer for Baxalta Inc., attracted some antitrust concerns. (See BioWorld Today, Nov. 30, 2015.)

In the end, Shire kept all three products, with Kalbitor most often used as a rescue medicine when attacks occur and Cinryze used as prophylactic therapy, according to Howard Mayer, Shire's head of global clinical development.

But lanadelumab's mechanism of action is fundamentally different from those products and from those in development to treat HAE, Mayer said. The fully human monoclonal antibody was engineered to move rapidly to the active site of plasma kallikrein, preventing the production of bradykinin – the key mediator of enhanced vascular permeability and inflammation, which results directly in an HAE attack.

"Based on the phase III pivotal clinical trial, we believe this unique mechanism of action, coupled with the long half-life, is what allows lanadelumab to be effective at reducing the frequency and severity of HAE attacks," Mayer explained. "As a trained physician who has been developing drugs for over 20 years across numerous disease areas, I can tell you it is not every day that we see the kind of efficacy, safety and convenience features that we have generated in the phase III HELP study."

HELP, he added, was the largest double-blind prevention trial ever conducted in HAE.

Although Shire is completing a full analysis of the data, the company now turns most of its attention to regulatory filings and potential commercialization. The breakthrough therapy designation positions lanadelumab for priority review, Mayer said, with a potential U.S. launch before year-end 2018.

"We clearly envision this as a global opportunity," he added. "And the next priority region will be Europe," where filings are expected in the first half of 2018.

Officials were coy on pricing, with Ornskov suggesting that lanadelumab might not be a one-size-fits-all drug from that standpoint. With three products already in the space, "the good news is this is a market we know extremely well," he said. "We will have an opportunity both in the U.S. and internationally to truly play to as many met and unmet needs as we can" with the HAE portfolio.

Cowen and Co. analyst Ken Cacciatore declared that lanadelumab will likely "transform the HAE treatment paradigm," calling the drug a "$2[-billion] long-duration asset that will convert, grow and extend Shire's leading HAE franchise."

Jefferies Group LLC analyst David Steinberg agreed, writing in a flash note that "the impressive phase III lanadelumab results in hereditary angioedema prophylaxis therapy lead us to believe the drug will be 'best in class' for years to come."

And BTIG analyst Timothy Chiang suggested the number of patients who receive prophylaxis treatment could double within three years from lanadelumab's approval and launch, based on a twice-monthly dosing schedule compared to daily Cinryze.

Lanadelumab also is likely to keep competitors at bay, analysts suggested. Although CSL-830 (Haegarda) from competitor CSL Behring demonstrated an 84 percent reduction in attacks at the highest dose, lanadelumab "appears to have a far superior clinical profile as it is dosed once every two weeks and, potentially once a month, given that the once-monthly dosing regimen appears very viable (73-76 percent reduction in attacks during the study), relative to CSL-830's twice a week dosing," Cacciatore wrote. In other words, CSL-830 will require four to eight times more injections throughout the course of a year, "which is clearly inferior," he said.

Moreover, the injection volume of CSL-830 – Which is under FDA review – is approximately 10 mL compared to 1 mL to 2 mL for lanadelumab, leading to increased dosing times and incidence in injection site reactions, Cacciatore suggested.

Despite the "solid all-around" data from Shire, Jefferies analyst Maury Raycroft sought to make the case that BCX-7353, the kallikrein inhibitor in phase II development at Biocryst Pharmaceuticals Inc., still offered the potential for "slotting in to the treatment paradigm," but he conceded the competitive landscape is "increasingly challenging."

As for the economics, Shire's existing HAE portfolio represented roughly $1.3 billion in 2016 sales, Cacciatore pointed out. Although lanadelumab will likely capture most current first-line prophylaxis sales, "it could nearly double, to potentially treble, Cinryze's utilization," he wrote, putting the drug on pace to reach $1.5 billion to $2 billion in sales. At that rate, "long duration product revenues would more than offset any lost/cannibalized Cinryze sales," Cacciatore noted.

On Thursday, Shire's shares (NASDAQ:SHPG) gained $7.83, or 4.3 percent, to close at $190.

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