Dyax Kalbitor Is Third To Market For HAE, But First For All Acute Attacks

Overcoming an FDA advisory committee that expressed doubts about efficacy and potential hypersensitivity reactions and a "complete response" letter asking for a Risk Evaluation and Mitigation Strategy, Dyax won approval for Kalbitor (ecallantide) Nov. 27 to treat acute attacks of hereditary angioedema in patients 16 and older.

Ecallantide (also known as DX-88) is the third drug approved by FDA for HAE, an orphan condition, in the past 14 months, but the first to win an indication for treatment of acute attacks at all sites in which they manifest.

HAE is a rare, potentially life-threatening genetic disease; attacks occur without warning and can cause pain and swelling in the face, hands, feet, abdomen and larynx. Laryngeal attacks are the most dangerous as they can cause death by closing the patient's airway. An estimated 7,000 U.S. patients have the disease and have, on average, more than 20 attacks a year.

ViroPharma's Cinryze (C1 esterase inhibitor) was approved for prophylactic use in October 2008, while CSL Behring's Berinert - also a C1 inhibitor - was approved Oct. 9 for treatment of attacks affecting the face and abdominal area (¹ (Also see "Berinert Claims Another Part Of The HAE Orphan Market, But May Leave Room" - Pink Sheet, 19 Oct, 2009.)). Both drugs are administered intravenously.

Ecallantide, a plasma kallikrein inhibitor, is administered as a subcutaneous injection. It received a narrow 6-5 vote for approval by FDA's Pulmonary-Allergy Drugs Advisory Committee this past February (² (Also see "Dyax’s Acute HAE Candidate Faces Efficacy And Risk Hurdles At Panel Review" - Pink Sheet, 3 Feb, 2009.)). The panel expressed concerns about hypersensitivity reactions, which occurred more frequently in treatment groups than in placebo groups during pivotal trials, especially since as a subcutaneous injectable, it might be self-administered without a clinician present.

At the advisory committee, it was reported that eight cases of anaphylaxis occurred during the two pivotal trials - EDEMA-3 and EDEMA-4 - and the panel also questioned whether efficacy data from the studies was robust enough to support approval. Ultimately, the committee voted in favor of approval because of the lack of an approved therapy for acute attacks.

Cambridge, Mass.-based Dyax received a "complete response" letter in March for the BLA, requesting a REMS to address the previously raised safety concerns (³ (Also see "Dyax Receives “Complete Response” For HAE Drug; REMS Will Be Required" - Pink Sheet, 30 Mar, 2009.)). Company officials expressed confidence that much of the groundwork for the REMS was already laid in the BLA, which included an "elements to assure safe use" program, and were relieved that FDA did not require any additional trials for the drug. Dyax resubmitted its application during the summer.

FDA's final label includes a "black box" warning on anaphylaxis, and lists the occurrence as 10 cases from the pivotal trials, or an incidence rate of 3.9 percent in patients treated with the drug. Labeling also instructs, in the warning and the indication, that ecallantide should only be administered by a health care professional with adequate medical support to manage HAE and anaphylaxis.

The REMS focuses on the risk of anaphylaxis and the importance of distinguishing between a hypersensitivity reaction and HAE attack symptoms. The approved REMS does not feature an "elements to assure safe use" program; the plan entails a Medication Guide and communication plan with a "Dear Healthcare Professional" letter explaining the risk of anaphylaxis and potential overlap in symptoms. The initial audience for the communication plan will be health care providers likely to prescribe ecallantide, such as allergists, immunologists and emergency medicine doctors.

Competitor Has Limited Label

Between the re-filing and approval of ecallantide, Berinert became the first drug approved in the U.S. for treatment of HAE attacks, but with an incomplete label that does not include treatment for potentially lethal laryngeal attacks.

As a result, FDA has approved one C1 esterase inhibitor for prophylaxis, one C1 inhibitor for treatment of some attacks, and now a kallikrein inhibitor for treatment of any and all types of HAE attacks. Under FDA orphan drug rules, that appears to leave the door open for approval of compounds other than C1 inhibitors in prophylaxis, for C1 inhibitors for treatment of laryngeal, hand and feet attacks, as well as for drugs with another mechanism of action for any or all acute attacks.

ViroPharma, which has seven years of orphan exclusivity for Cinryze as a prophylactic treatment, continues to seek approval in the acute setting. An sBLA for that indication received a "complete response" letter from FDA this past June (⁴ (Also see "ViroPharma Gets Good News And Bad News On Cinryze From FDA" - Pink Sheet, 4 Jun, 2009.)).

Other companies are also hoping to enter the HAE market. Shire is seeking approval for Firazyr (icatibant), a bradykinin inhibitor, while Pharming intends to file Rhucin , a recombinant C1 inhibitor, for the disease as well. Cinryze, Berinert and Firazyr all are approved in Europe to treat HAE.

Dyax CEO Gustav Christensen said his company has no intention of seeking approval for prophylaxis of HAE, meaning that setting may be left to ViroPharma, the only company that specifically studied its drug for prevention of HAE attacks.

"Kalbitor is a small protein, and as such, it has a short half-life," Christensen said in an interview. "The benefit of that is that it's useful for acute treatment [because] you don't want it circulating any longer than you have to. So we will not pursue a prophylactic [indication]; our product does not lend itself to that."

He added that Dyax expects the majority of HAE patients will be treated in the acute setting.

Investors And Analysts Bullish On Ecallantide

Investors and industry analysts both expressed significant enthusiasm for ecallantide's prospects following the approval. Dyax's stock price increased 21 percent in trading on Dec. 2, the day after approval, to $4.23 per share.

Analysts largely agree that Kalbitor will enjoy market advantages over Berinert and that the REMS required by FDA will not be too onerous for Dyax. Christensen called the REMS "fairly typical" for a recombinant protein or protein drug.

"While CSL's Berinert was also approved earlier this quarter for acute HAE attacks, we believe Kalbitor has distinct advantages (approval in all HAE attack locations and sub-q dosing) that will allow it to capture a majority of the acute HAE market," wrote UBS Investment Research analyst Jeff Elliott in a Dec. 2 note.

He predicted ecallantide will be priced similar to Berinert, about $5,000 per dose, and forecast sales of $37.4 million in 2010, $73.4 million in 2011 and $116.6 million in 2012 for the Dyax product.

Brian Skorney of Think Equity noted that Berinert has its own safety issues, "a perception amongst physicians that the use of pooled plasma elevates the risk of transmissible disease." In his Dec. 2 note, Skorney projected peak-year sales of $104 million for ecallantide, but asserted that neither drug would enjoy a big advantage over the other.

Looking at the approval from ViroPharma's perspective, Joel Sendek, Lazard Capital, called ecallantide's REMS requirement "strict" and said the drug would pose little threat to Cinryze in the prophylactic setting.

Dyax Getting Started On Commercial Plans

Christensen said Dyax plans to launch ecallantide during the first quarter of 2010 and is putting together both a marketing group and a medical affairs organization to help promote the product. The company hopes to have its entire team in place within two weeks, he added.

As the third approval for the rare disorder, Dyax should have an easier time hitting the market - especially as it has a broader label than the only other acute therapy (Berinert). ViroPharma and later CSL Behring have done much of the legwork in preparing the market for treatment, raising awareness and mobilizing prescribers (⁵ (Also see "Cinryze Launch Plans Bear Hallmarks Of Successful Orphan Strategies" - Pink Sheet, 1 Dec, 2008.)).

Outside of North America, Dyax hopes to get ecallantide approved in Europe and then find a commercial partner to market it. Christensen said a Marketing Authorization Application likely would be filed with the European Medicines Agency during the first half of 2010.

"We are aligning all the necessary activities to do the filing in Europe," he said. "We assume that [while] doing that, we will probably sign a partnership sometime during that process. We are engaged in conversations for both European partnerships as well as partnerships with larger companies, which would be ex-North America."

- Joseph Haas ( ⁶ [email protected] )