Is Europe's HAE Market Big Enough To Sustain All The Competitors?
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As more companies of all sizes embrace rare diseases – lured in part by supposed lower regulatory and reimbursement hurdles – some niche markets are beginning to look rather busy. Hereditary angiodema (HAE) is one example: this genetic disorder, characterized by swelling due to fluid leakage from blood vessels, affects just one in 10,000 to 50,000 people. Yet there already are four competitors on the European market, with two more expected soon. If this leads to lower prices, it may start to erode one of the key economic arguments behind rare diseases R&D – and jeopardize the ability of smaller companies to compete.
HAE PlayersApproved products in Europe:
Future entrants?
The European Commission’s March 3 approval of a new, self-administrable version of Shire PLC’s HAE treatment Firazyr (icatibant) to treat acute forms of the disease is the latest new entry into this niche therapy area. In October 2010, the European Medicines Agency approved Dutch biotech Pharming Group NV’s Ruconest (conestat alfa), a recombinant human C-1 inhibitor derived from the milk of transgenic rabbits. HAE is associated with a deficiency in the C-1 inhibitor protein, which is involved in inflammation and clotting; hence most of the treatments aim to replace that protein. Ruconest will be marketed for HAE attacks by Swedish Orphan BioVitrum International (SOBI) per an April 2010 deal Both Shire and Pharming hope to supercede CSL Behring's plasma-derived C-1 inhibitor Berinert P, which has been available across most of Europe since 1985 for acute HAE, although Italy and Luxembourg authorized the drug only in 2010. Meanwhile Sanquin Blood Supply's C-1 inhibitor Cetor, for acute forms of HAE, has been available in four European countries since 1997. But U.S. players ViroPharma Inc. and Dyax Corp. are knocking on the door in Europe too: in March 2010, the European Medicines Agency accepted a marketing application authorization for ViroPharma's highly purified C-1 inhibitor Cinryze for both prophylaxis and acute treatment and in July 2010, EMA validated Dyax's MAA for DX-88 (ecallantide) for treatment of acute HAE attacks. Ecallantide has been marketed in the U.S. since 2010 as Kalbitor, and is the only acute HAE product to enjoy U.S. patent protection, according to Dyax. As the HAE market gets more crowded, the players likely can no longer rely so heavily on unmet need as a driver of sales. They will be forced to prove their product's supposed advantage over the rivals – just as in other more mainstream therapy areas. Onus On Shire To Prove Firazyr's Benefits The added convenience of Shire's newly approved version of Firazyr could give the product a big advantage over the competition for treating acute forms of HAE. All of the alternative treatments have to be injected by a health care professional. One direct benefit of self-administration means that patients can be treated immediately during an attack. An attack is characterized by swelling episodes, typically in the upper respiratory tract and intestine. Attacks that affect the larynx or tongue are particularly dangerous, often leading to death by suffocation if untreated. Despite what Deutsche Bank analyst David Steinberg calls a "modest" launch to date – Firazyr in its original form was approved in 2008 by Jerini, which Shire acquired the same year – the label expansion means the asset "may prove to be the most underappreciated opportunity in Shire's portfolio this year." Shire management likewise now expects the product to flourish. In addition to convenience benefits, Shire points to potential cost savings generated by reduced hospitalization of HAE patients. Firazyr still hasn't been approved in the U.S., however; Jerini first submitted the drug for approval in 2007, and Shire submitted a response Feb. 28, 2011, to FDA's last "not approvable" letter on the product (Also see "Shire Finally Able To Move Firazyr Forward" - Pink Sheet, 1 Dec, 2010.). The U.S. market is dominated by Cinryze, with sales of $175 million in 2010, according to EvaluatePharma. Cinryze was approved in the U.S. in 2008. Kalbitor, approved in the U.S. in December 2009, achieved modest sales of $9 million in 2010, according to EvaluatePharma. That's about the same as Firazyr's worldwide (ex-U.S) sales – including the EU and Russia. Firazyr does, however, have other advantages over the current EU incumbents, Berinert P and Cetor, in that it's not a blood plasma-derived product. That means there's no danger of transporting blood-borne pathogens – a point Shire is sure to seize upon, even though the risk of infection is very low. Firazyr is further differentiated in not being another C-1 inhibitor protein; instead, its active ingredient, icatibant, is a specific agonist of bradykinin B2, a vasoactive peptide produced as a result of C-1 inhibitor deficiency, and a key mediator of edema formation. Hitting this downstream peptide makes the treatment more targeted, according to Shire. Incumbents Have Familiarity Advantage However, Shire is a late starter in the HAE field in Europe. And that matters in an medical area where patient relationships and networks are particularly important, given the rarity of the disorder. CSL Behring’s first C1-inhibitor, a plasma-derived intravenous therapy, was licensed in Germany in 1979 and a pasteurized version was then introduced in 1985, which was later named Berinert P. (As the product was initially marketed before the establishment of an earlier version of EMA in 1995, Berinert P was not eligible for the centralized product review procedure; since then, however, Behring has used the mutual recognition procedure to gain approval in 24 European countries). CSL Behring's Global Product Manager for Berinert – the “P” has been dropped in some countries – Hanno Waldhauser says that based on the company's very recent market research, Berinert is seen as the first-choice product for acute treatment. “There is still very limited experience with Firazyr and Ruconest, so the comfort level of physicians and patients with these products is still lower,” he opined. That may change, however, as the newer treatments become better established in Europe. Sanquin Blood Supply – a not-for-profit foundation, responsible for blood supply in the Netherlands – has been selling its HAE drug even longer. It introduced its first product in 1972, a human-plasma-derived C1-inhibitor, in powder form for solution for intravenous injection. The more highly purified Cetor, now the company's lead product, was launched in March 1997. The product initially was available only in the Netherlands, due to the organization's focus then purely on national blood supplies, but Sanquin has since launched Cetor in Belgium, France, Finland and Luxembourg via the mutual recognition procedure. (The drug is called Cebitor in some of these countries.) Ruconest: Safety And Supply Advantages? Pharming and partner SOBI are hoping that Ruconest will get a look in thanks mainly to safety and supply advantages. The company claims that its technique of using the milk of transgenic rabbits as a product platform to create human proteins is cheaper than more conventional production methods. “Rabbits help us make complex proteins in an economically viable way, which cannot be produced in cells lines,” said CEO Sijmen de Vries. Rabbits have the advantage of being versatile and fast breeding, while at the same time possessing no pathogens for humans, he said. “We also have a virtually unlimited supply, where as people who deal in blood products have a very limited supply,” he added. It's not clear what advantage Ruconest will offer over self-administrable Firazyr however, which also is not a blood-derived product. And for now, Pharming doesn't appear to be turning its claimed production cost advantage into a more competitive price: the drug costs about £1,560 ($2,500) per dose, roughly the same as Berinert P and Firazyr, which costs £1,395 per dose. The number of doses required depends on the severity and frequency of attack. Ruconest has secured reimbursement in Germany, Scandinavia and the U.K. Under the U.S. trade name Rhucin, the product could see FDA action this year (Also see "The Return Of Big Pharma? 2011 Novel Approvals Could Show Payoff Of Licensing And Acquisition Strategies" - Pink Sheet, 28 Feb, 2011.). ViroPharma: Hedging Bets In Europe Via Sanquin Deal Assuming their respective HAE products are approved in Europe – which Edison analyst John Savin expects will happen by mid-to-late 2011 – ViroPharma and Dyax may have some room to use price as a means of gaining advantage for their drugs among Europe's cost-conscious health care systems. But ViroPharma has further hedged its bets in Europe. In January 2010 it signed a deal with Sanquin granting it the rights, if Cinryze isn't approved, to market Cetor in European countries other than those where Sanquin already sells the drug. The bet looks well-judged: EMA on March 18 granted Cinryze a positive opinion – including, importantly, a recommendation for a self-administration option for appropriately trained patients – but it warned that this may not be translated into a full approval by the European Commission, given that Sanquin already markets what the agency considers to be essentially the same product in some countries (Also see "EU's Advisory Panel Clears BMS/Pfizer's Apixaban; Turns Down Vectibix Extension" - Pink Sheet, 18 Mar, 2011.). Indeed, under an existing agreement between the two companies, Cinryze is actually produced from U.S. source plasma at Sanquin’s plant in Amsterdam, The Netherlands and is processed by Sanquin Blood Supply Foundation. Dyax Ties Up With Rare Diseases Specialist Sigma-Tau Dyax also is using a local partner to help break into the European market: in June 2010 it signed a deal with Portuguese company Defiante Farmaceutica S.A., a subsidiary of Italian drug manufacturer Sigma-Tau Group, to develop and commercialize subcutaneous DX-88, a recombinant kallikrein inhibitor, for HAE and potentially other indications in Europe, Russia, the Middle East and North Africa. Sigma Tau knows rare diseases well: the company has spent the last decade or more turning itself from an Italian regional partner into a global rare diseases specialist. Dyax's product inhibits an enzyme, human plasma kallikrein, that plays a key role in the biochemical processes that lead to HAE-related swelling (notably, it prevents the formation of bradykinin). But Dyax claims that its route of administration – via subcutaneous injection – gives it the edge over intravenously-administered drugs like Berinert, because vein deterioration can result from frequent injections. HAE patients can rrequire from six to 20 injections per year). In the U.S., Dyax maintains that Kalbitor is the only acute HAE drug approved for all attack locations –Berinert's approved use in the U.S. is limited to facial and abdominal incidents. In Europe, however, Firazyr, Ruconest and Berinert P all have multiple body-location indications. And although Kalbitor has no self-administration label – nor is the company seeking one – Dyax will ship the product to patients’ homes so that they can take it to a health care professional to administer in the event of an attack. Competitor "Noise" May Not Stretch The HAE Market Enough: Looking Beyond Waldhauser, product manager for Berinert, argues that increased competition in HAE needn't all be bad news. He claims that the added "noise" around the new product approvals has created more awareness about HAE, leading to increased diagnosis and changes in treatment patterns. Moreover, as patients become more vocal about treatment, it is likely that more attacks will be treated per patient, Waldhauser concludes. This is all good news for HAE patients. But as intense competition forces aggressive product differentiation to win a viable slice of a small, if expanding, market, the dynamics of the HAE market raise a question mark over assumptions by both small biotechs like Pharming, and mid-sized in-licensors like SOBI. And that is whether rare diseases any longer offer a chance of commercial sustainability. Small wonder, then, that most of the HAE players already are looking to expand their treatments into new indications. Pharming is trialing Ruconest as a preventive treatment for kidney transplant rejection. As well as seeking to expand Kalbitor's label into the pediatric population – since HAE generally starts to manifest itself as a result of hormonal changes during puberty – Dyax is studying Kalbitor in drug-induced angioedema, which sometimes afflicts patients who are taking ACE-inhibitors. |