Cerdelga Becomes First Oral First-Line Therapy For Gaucher Disease

Sanofi’s Genzyme unit obtains U.S. approval for eliglustat as an oral, first-line therapy for adults with Type 1 Gaucher disease. The new product will augment its market-leading Cerezyme, and the company says it will price Cerdelga at par so that patient/physician choice will not be based upon price.

With FDA’s approval of Cerdelga, market leader Sanofi is bringing a second brand into the already competitive Gaucher disease space, but while it offers a convenience advantage over the firm’s existing enzyme replacement therapy Cerezyme, Sanofi is not opting push the price.

Cleared Aug. 19 for adults who suffer Type 1 Gaucher disease, Cerdelga (eliglustat) is not the first oral therapy for the disease but will be the first with a broad indication. Actelion Pharmaceuticals Ltd.’s Zavesca (miglustat), approved by FDA in 2003, is the only other oral therapy for Gaucher, but is limited to patients who can’t receive enzyme replacement therapies such as Cerezyme and has worse side effects than Cerdelga.

Cerezyme’s main competitor is Shire PLC’s Vpriv (velaglucerase), approved in 2010. At the time of approval, Shire decided to price its drug at a 15% discount to Cerezyme, which then cost $200,000 a year. Cerezyme now costs $300,000 a year and Sanofi/Genzyme execs said Aug. 20 that they are inclined to price Cerdelga at par with Cerezyme.

Noting that Cerezyme has been on the market for 20 years as of this past May, Simone Azevedo, VP of Genzyme Corp.’s Gaucher portfolio, said the approval of Cerdelga reflects Sanofi/Genzyme’s “commitment to the Gaucher community” (Also see "CEO Shifts, Life Cycle Management On Agenda at Morgan Stanley" - Pink Sheet, 16 Sep, 2013.).

“Part of the request that we receive from Gaucher patients is for an oral therapy that would work as well as Cerezyme,” she said in an interview. The intravenous Cerezyme (imiglucerase) was approved in 1994 as long-term enzyme replacement therapy for Type 1 Gaucher disease.

“That was our biggest driver to move ahead with Cerdelga – not to create internal competition but to offer a choice to patients and physicians in how they prefer to manage their disease and be treated. We had great results with Cerdelga [in the clinic] and now the option and the power of choice is out there for patients who either are on Cerezyme or other [enzyme replacement] therapy or even patients who have never received treatment before.”

Cerdelga, a novel glucosylceramide analog, is a capsule that most eligible patients will take twice-daily, Azevedo explained. Adult Type 1 patients make up between 60% and 70% of the total Gaucher patient population, she said, and within that group some will not qualify for Cerdelga therapy based on how they metabolize the drug. Meanwhile, some patients may metabolize it well enough to need only a single daily dose.

Type 1 adult patients will have their suitability for Cerdelga therapy determined by a companion diagnostic that will measure how they metabolize the drug. Patients who metabolize the drug rapidly may not be able to achieve sufficient concentration for a therapeutic effect. FDA calls for testing to identify patients who are CYP2D6 extensive metabolizers, intermediate metabolizers or poor metabolizers.

But despite the convenience advantages, the company plans to price it at par with Cerezyme so that patients and physicians can make the best therapeutic decision for themselves without price being a major consideration, Azevedo said. Pricing has not yet been finalized, she said.

Fitting Into The Treatment Landscape

One of the assets that drove Sanofi’s 2011 purchase of Genzyme, Cerdelga will treat the rare lysosomal storage disorder by a different mechanism than Cerezyme or Vpriv (Also see "Differentiation Will Be Key Challenge For Shire's Gaucher Disease Drug Vpriv" - Pink Sheet, 8 Mar, 2010.).

While Cerezyme and Vpriv are intravenously infused enzyme replacement therapies that address the patient’s deficiency fat-dissolving enzyme glucocerebrosidase, Cerdelga addresses the disease by inhibiting the enzyme glucosylceramide synthase, which builds up in the cells of people with Gaucher and reduces production of glucocerebrosidase.

Cerezyme is the top seller in Gaucher, with sales of $757 million projected for full-year 2014, according to Societe Generale analyst Stephen McGarry. Besides Sanofi/Genzyme and Shire, Pfizer Inc. and Israeli partner Protalix BioTherapeutics Inc. have a recombinant enzyme replacement therapy derived from carrot cells called Elelyso (taliglucerase).

Elelyso and Actelion’s oral drug Zavesca have made only a small dent in the Gaucher market, while Vpriv has provided the main competition for Sanofi. Shire’s product is projected to earn $356 million in global sales this year, McGarry said in an Aug. 20 note.

McGarry said the approval will be bad news for Shire, while Zavesca, with 2013 sales of CHF 96 million ($105 million), has never become a major factor due to its limited labeling and severe gastrointestinal side effects. He predicts peak sales of $938 million for Cerdelga.

“Cerdelga could gain traction relatively quickly, especially in a pediatric setting where patients have the inconvenience and stigma of hospital visits on a regular basis for intravenous infusions of Cerezyme or Vpriv,” the analyst wrote. “For Sanofi forecasts, pricing will be the key swing factor, as the profitability of Cerdelga – due to its significantly lower manufacturing costs vs. Cerezyme – could be significantly higher than currently forecast.”

Plans To Extend Into Pediatric Population

The current FDA indication only calls for treatment in adult patients, but Azevedo said Genzyme’s post-marketing program will include studying the drug in children. The European Medicines Agency is requiring such a study, and is expected to make a decision on Cerdelga before year-end. Sanofi/Genzyme intend to include U.S. under-18 patients in that study as well because they want to make the drug available to that population.

The FDA approval was based on data from two successful Phase III studies, as well as a Phase II trial. In each trial, patients were permitted to continue Cerdelga therapy under an extension portion, which continue to generate additional data. In the Phase III ENGAGE study involving 40 treatment-naïve patients, the molecule met its primary endpoint of improvement in spleen size compared to placebo after nine months of treatment (mean decrease from baseline of 28%, absolute difference of 30%), while also meeting secondary endpoints for improved platelet levels, improved hemoglobin levels and liver volume decrease.

The other Phase III trial gives the company evidence of non-inferiority to Cerezyme. In ENCORE, which included 160 patients who had been on enzyme replacement therapy for at least three years, Cerdelga met the standard for non-inferiority to Cerezyme based on a composite endpoint of spleen volume, hemoglobin levels, platelet counts and liver volume. Eighty-four percent of patients receiving Cerdelga remained stable after one year of treatment compared with 94% of those who received Cerezyme, according to the company.

With success in obtaining regulatory approval for an oral therapy in a lysosomal storage disorder, Sanofi/Genzyme will look to replicate that space in other indications, Azevedo said. The company currently has Genz-682452 in Phase I as a substrate reducer in Fabry disease. Sanofi/Genzyme already offer the market-leading enzyme replacement therapy for Fabry, Fabrazyme (agalsidase beta).

Coming off a disappointing 2013, Sanofi is gearing up for several launches in the near future, including the next-generation basal insulin Toujeo, Lemtrada (alemtuzumab) for multiple sclerosis and the PCSK9 inhibitor Praluent (alirocumab) (Also see "On The Offense: Sanofi Suits Up For A Game Change" - Pink Sheet, 11 Aug, 2014.). During its July 31 earnings call, CEO Christopher Viehbacher noted that the French pharma has spent €700 million in preparation for these launches (Also see "Sanofi Investing €700 Million Ahead Of Launches" - Pink Sheet, 31 Jul, 2014.).