1. Pfizer's drug Elelyso received FDA approval in 2012 for the treatment of type 1 Gaucher disease, joining two other enzyme replacement therapies on the market. 2. Elelyso was shown in clinical trials to effectively reduce spleen and liver volumes and improve blood counts in patients with type 1 Gaucher disease. 3. As an orphan drug for a rare disease, Elelyso faces competition from other treatments but aims to have advantages in lower production costs and reduced risk of viral transmission compared to therapies produced in mammalian cells.

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Pfizer Claims Success for Their New FDA Approved Drug, Elelyso for
Treatment of Type 1 Gaucher Disease Despite Market Competition for
an Orphan Indication
Shiva Bolourchi
December 2013
On May 1, 2012 Protalix and Pfizer’s orphan drug, Elelyso, received FDA approval
for the treatment of the most common lysosmal storage disorder (LSD), Gaucher Type I
disease.10
In this automosal recessive disease an enzyme called glucocerebrosidase is absent or
has low activity, causing the build up of a fatty acid molecule, glucocerebroside (a.k.a.
glucosylceramide), within macrophages (Gaucher cells) in the spleen, liver and bone
marrow. 9,3
The symptoms are enlarged spleen and liver, thrombocytopenia (low platelet
count), and anemia. The prevalence of Type I Gaucher disesase is 1:40,000 in the general
population and 1:500 among the Ashkenazi Jews (1 in 10 are carriers), accounting for
more than 90% of all cases of Gaucher disease. 9
In the United States only 6,000 patients
are reported to have Gaucher Type 1 diseaese.9
A minority of Gaucher types II and III
patients show neurological decline due to glucocerebrosidase accumulation in the central
nervous system (CNS). While the prevalence of Gaucher disease is not as high as other
diseases, untreated it could lead to life-threatening multi-organ dysfunction. 9, 3, 1
The low prevalence of Gaucher Disease defines treatment methods as orphan drugs.
FDA Office of Orphan Products Development (OOPD) provides orphan drug status to
compounds that are intended for treatment diagnosis or prevention of diseases that effect
less that 200,000 people in the US or effect more than 200,000 people but are not
expected to recover the cost of development and marketing.2
The incentives for orphan
drug development include higher clinical success rate and shorter clinical trials, premium
pricing, lower sales force, enhanced patent protection and marketing rights (10 years),
reduced taxes from federal government, clinical research financial subsidies, and
government run enterprises to do research and development. 2,4
Gaucher Diease Treatments –Competition in an Orphan Drug Space:
Gaucher Type I disease can be treated by enzyme replacement therapy (ERT) to
compensate for the underlying enzyme deficiency of glucocerebrosidase [Figure 1,
right].9
Despite the small number of patients globally, several ERTs are now on the
market. One of the key business drivers for companies to develop treatment for this
orphan indication is that Gaucher treatment is an approximately 1.1 billion dollar market,
so capturing even a portion of the market is attractive business.3,7,2
In 1991 the first approved ERT for Gaucher disease was Genzyme’s Ceredase
(alglucerase), glucocerebrosidase isolated from human placenta. As the 90’s saw the
advancements in recombinant DNA technology for generating protein therapeutics,
Genzyme replaced this product in 1994 with a recombinant glucocerebrosidase product
called Cerezyme (imiglucerase) generated in Chinese Hamster Ovary (CHO) cell line. 9,7

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The use of purified proteins from well-characterized cell lines, certified to lack any viral
contamination, are considered significantly less risky than use of human tissue that could
contain a range of viruses and pathogens.
While Cerezyme was on the market for about seventeen years, Shire Human Genetics
Therapies developed VPRIV (velaglucerase alfa), a recombinant glucocerebrosidase with
the natural amino acid sequence (compared to one amino acid variation from Cerezyme)
and a production method based on gene activation technology in human fibroblast cell
line (compared to recombinant DNA technology in CHO cell line by Genzyme).7,9
Shire
HGT’s VPRIV was approved in 2010, during a time when there was a supply shortage
for Cerezyme because of viral contamination in Genzyme’s biorectors at the Allston
Landing, MA manufacturing facility that had led to the temporary facility shut down
since June 2009. The drug supply shortage was exacerbated with several other product
issues that resulted in rejection of the manufactured batches throughout 2011.5
The
situation has created more opportunity for Protalix and Pfizer’s drug, Elelyso, which
received FDA approval in May 2012 despite two other drugs on the market. However,
since Shire’s VPRIV had obtained market exclusivity in Europe, Pfizer did not receive
market authorization in Europe. 5
Elelyso differs from its former drug competitors because it is a hydrolytic lysosmal
glucocerbroside-specific enzyme expressed in genetically modified carrot plant root cells.
The plant based ERT differs from human glucocerebrosidase by two and seven amino
acids at the N- and C- terminals, respectively.9
The marketing pitch for Elelyso by
Pfizer/Protalix is the following claimed advantages:
§ Use of plant cell does not carry the potential risk of viral transmission compared
to mammalian cells.7
§ Plant cell growth is simpler and does not require complex cell culture media that
mammalian cells need. Moreover, this simple cell culture media makes the
subsequent purification process efficient. As a result the total production cost is
lower. 7
§ The uptake of enzyme by the target cells (macrophages) requires specific
glycosylation of the enzyme molecule, which is in turn defined by the cell line
and cell culture process. While both Genzyme and Shire have to use a specific
compound during cell culture process to generate the required glycan structure,
the plant cell naturally makes a glycan structure that allows macrophage uptake
without needing the addition of specific compounds to the cell culture process.
This decreases both the complexity and the cost of the cell culture process. 7
§ The developers of Elelyso, Protalix, a pharmecuetical company based in Israel,
will be able to market Elelyso directly to Austrian Jews, the most high-risk
population for Gaucher disease. 7
To avoid future shortage issues, Pfizer is building multiple manufacturing facilities.
And finally, competing on price, Elelyso will be priced lower than the two other
competitors, down at 150,000 dollars per patient per year compared to 170,000 dollars for
Shire’s VPRIV and 200,000 dollars for Genzyme’s Cerezyme.7
Elelyso would launch in

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fiscal year 2013 with analyst projected US market share of 64 million dollars,
approximately 10% of the total market.7
Figure 1. Origin of Gaucher Disease and Associated Treatment Approaches. Gaucher disease is
caused by the lack of glucocerebrosidase, which the enzyme replacement therapies address. Alternatively,
the accumulation of glycocerebroside can be prevented by inhibiting glucosylceremaide synthase, which is
addressed by Eliglustat Tartarate.
Clinical Studies as the Basis for Approval of Elelyoso:
Typically clinical trials for new molecules include a Phase I dose escalation safety
study, a Phase II dose-response study, and a Phase III safety and efficacy study.
However, in orphan drugs where there are very low number of patients and the natural
history heterogeneous, Phase I and Phase II trials are combined to obtain safety and
initial dose response, with the use of extention studies to accumulate further bioactivity
and safety data. Then Phase III trial statistically confirms efficacy and adds more safety
data needed for product approval [Figure 2].2,8,6

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Figure 2: Differences in Clinical Trial Stages for Orphan Drug Approval versus Typical Non-
orphan Drug Approval.
The clinical basis for Elelyso approval was the collective data on a total of 56 patients
with Type I Gaucher disease enrolled in two clinical trials. Study 1 was a 9 month multi-
center, double blind, parallel-dose trial (30 Unit/kg and 60 Units/kg) that evaluated the
initial safety and efficacy of Elelyso in 31 adult patients (ages 19-74, mean age 36) naïve
to ERT. Patients were selected by Gaucher disease symptoms of enlarged spleen (> 8
fold) and thrombocytopenia (< 120,000/mm3
). Elelyso was effective in decreasing spleen
volume by 29% in patients receiving 30 Units/kg dose and 40% in patients receiving 60
Units/kg dose. 9
The selected dose of 60 Units/kg for Elelyso in this study was based on
the best improvements of spleen and liver volume, blood platelet counts and hemoglobin
levels. Study 2 assessed the safety and efficacy of Elelyso in 25 Type 1 Gaucher patients
who switched treatments from imiglucerase (Genzyme’s Cerezyme) to Elelyso. This
study was conducted as a multi-enter open-label, single-arm trial with patients who had
been treated with imiglucerase for at least two years before switching to Elelyso. The
results of this study demonstrated that Elelyso maintained spleen and liver volumes,
blood platelet counts, and hemoglobin levels over the 9 months of evaluation. 9,1,3,10
The adverse effects of Elelyso treatment were typical for ERTs, with the most
common side effects of infusion reactions and allergic reactions. Greater than 10 percent
of patients treated with Elelyso showed other side effects: upper respiratory tract
infection, common cold-like symptoms, joint pain, influenza, headache, extremity pain,
back pain, and urinary tract infections. 1,3,9
Post-marketing Commitments:
Since orphan drug clinical studies have smaller number of patients in their clinical
studies before approval, often post marketing clinical studies have to be conducted to
monitor safety and immunogenicity of the drug. For example, typical pharmacovigilance
studies under FDA section 505(k)(3) are not sufficient to address the risk of Elelyso on
newborns, pregnant women and infants.9
Therefore Protalix is required to collect detailed
clinical data on newborns and infants whose mothers were treated with Elelyso during
lactation. Furthermore, Protalix is required to complete the ongoing 12 month
randomized double blinded parallel-dose group in treatment-naïve pediatric (ages 2-14)

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patients. However, because of orphan drug designation, Protalix is exempt from
conducting other required Pediatric studies under the Pediatric Research Equity Act (21
U.S.C. 355c). Other commitments include developing validated assays that can detect
antibodies against plant specific sugars in Elelyso in patient serum.9
Future Advances and Competition:
Another approach to treatment of Gaucher type 1 disease is Substrate Reduction
Therapy (SRT). Successful oral SRTs could pose a large threat to intravenous ERT
because oral drugs are more convenient for patients and are cheaper. The mechanism of
action of such drugs are completely different from the other three intravenously injected
ERTs. SRT small molecule drugs reduce the production of the substrate glucocerbraside
by partially inhibiting the enzyme, glucosylceramide synthase, as shown in figure 1.11
Interestingly, Actelion Pharmecueticals has had an SRT oral drug, Zavesca
(miglustat), on the market since 2003. However, Zavesca is used only for the treatment
of adult patients with only mild to moderate Type 1 Gaucher disease for whom ERT is
not a therapeutic option. 12
ERT is not an option for patients who have pretreatment
constraints such as allergy, hypersensitivity, or poor venous access for injections.
Zavesca also has adverse side effects such as peripheral neuropathy and tremors not seen
in ERT treated patients.12
Currently Genzyme is also developing an oral drug for Gaucher Type I as a
convenient treatment alternative that should be cheaper and have less side effects.
Genzyme has completed a Phase III study that met primary endpoints for Eliglustat
Tartrate. The potential approval of Eliglustat Tartrate by the FDA or EMA in 2013 may
pose a serious threat to all intravenous drugs depending on its safety and efficacy profile
and its ability to treat both adults and children.13
While ERTs work for treating the somatic symptoms, the current therapies are not
able to cross the blood brain barrier to treat the CNS manifestations of the disease. 9
Future small molecule drugs that can penetrate the CNS could expand the indication to
Gaucher Type II and III, and transform the business benefit.
Sources:
1. "Elelyso Injection." Official FDA Information, Side Effects and Uses. N.p., n.d. Web. 15
Dec. 2012. <http://www.drugs.com/pro/elelyso-injection.html>
2. "For Industry." Developing Products for Rare Diseases & Conditions. FDA, 13 Dec.
2012. Web. 13 Dec. 2012.
<http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/default
.htm>.
3. "Gaucher Elelyso (taliglucerase Alfa) for Injection Safety Info." Gaucher. Pfizer, 2012.
Web. 4 Dec. 2012. <
http://www.elelyso.com>
4. Kephart, Craig L. "Orphan Drugs: Small Markets, Big Opportunity." Specialty Pharmacy
Times. N.p., 20 Feb. 2012. Web. 4 Dec. 2012.

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<http://specialty.pharmacytimes.com/publications/specialty-pharmacy-
times/2012/February-2012/Orphan-Drugs-Small-Markets-Big-Opportunity>.
5. Petrochko, Cole. "New Gaucher Drug Goes to Market During Shortage." MedPage
Today. N.p., 3 Sept. 2009. Web. 4 Dec. 2012.
6. Silverman, Ed. "Rare Opportunities: Orphan Drugs & Big Bucks." Pharmalot Rare
Opportunities Orphan Drugs Big Bucks Comments. N.p., 23 Aug. 2012. Web. 10 Dec.
2012. <
http://www.pharmalot.com/2012/08/rare-opportunities-orphan-drugs-big-bucks>
7. Shilpa, Siddhi, and Yang Ning. "Protalix Biotherapeutics: Eyes On Elelyso Sales And
Advancing Pipeline - Seeking Alpha." (2012): n. pag. Protalix Biotherapeutics: Eyes On
Elelyso Sales And Advancing Pipeline - Seeking Alpha. Sealking Alpha, 1 Oct. 2012.
Web. 4 Dec. 2012. <Shilpa, Siddhi, and Yang Ning. "Protalix Biotherapeutics: Eyes On
Elelyso Sales And Advancing Pipeline - Seeking Alpha." (2012): n. pag. Protalix
Biotherapeutics: Eyes On Elelyso Sales And Advancing Pipeline - Seeking Alpha.
Sealking Alpha, 1 Oct. 2012. Web. 4 Dec. 2012.>
8. "The Portal for Rare Diseases and Orphan Drugs." Orphanet: About Orphan Drugs
Clinical Trails. N.p., 14 Dec. 2012. Web. 15 Dec. 2012.
<http://www.orpha.net/consor/cgi-bin/Education_AboutOrphanDrugs.php?lng=EN>.
9. United States. Food and Drug Administration. CENTER FOR DRUG EVALUATION
AND RESEARCH. FDA Summary of Approval for Elelyso. By Julie G. Beitz. FDA.gov,
1 May 2012. Web. 4 Dec. 2012.
<http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022458Orig1s000SumR.pdf>
.
10. Yo, Stephanie. "FDA Approves New Orphan Drug to Treat a Form of Gaucher Disease."
(n.d.): n. pag. Food and Drug Administration, 1 May 2012. Web. 4 Dec.
2012.<http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302549.ht
m>.
11. "How Can GD1 Be Treated?" How Can GD1 Be Treated? Acetlion, n.d. Web. 15 Dec.
2012. <http://www1.actelion.com/en/patients/diseases/type-1-gaucher-disease/how-can-
gd1-be-treated.page>.
12. "ZAVESCA (miglustat) Capsule: Drug Label." Daily Med. Actelion Pharmaceuticals US,
Inc, 20 Nov. 2010. Web. 15 Dec. 2012.
13. "Genzyme Phase 3 Study of Oral Compound Eliglustat Tartrate for Gaucher Disease
Meets Primary Endpoint." Genzyme Phase 3 Study of Oral Compound Eliglustat Tartrate
for Gaucher Disease Meets Primary Endpoint. Business Wire, 2 Oct. 2012. Web. 15 Dec.
2012. <http://www.businesswire.com/news/home/20121001006987/en/Genzyme-Phase-
3-Study-Oral-Compound-Eliglustat>.

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Follow Up August 20, 2014:
Sanofi’s Genezyme took 15 years to develop an oral pill for Gaucher disease,
Cerdelga, that got FDA approval on August 19, 2014. Cerdelga will now compete and
likely win over the three intravenous infusions of Genzyme’s own Cerezyme, Shire’s
Vpriv, and Pfizer’s Elelyso. While Actelion also made a Gaucher oral pill, Zavesca, it
can only be taken by pateints who cannot use enzyme replacement infusions, thus leaving
Cerdelga to grab the majority of the market. Cerdelga is expected to go on market within
a month and prices are expected to be set close to that of Cerezyme ($300,000 per patient
per year). Sanofi claims that the 10,000 Gaucher patients around the world, 6,000 of
whom reside in the US, prefer taking an oral pill twice a day over intravenous injections.
Analysts expect that in 2020, Cerdelga will bring in $749 million in sales just from the
pool of 6,000 US patients. Although information about Sanofi’s costs of developing the
drug are not available, the total profits made from this market is expected to exceed far
beyond Cerezyme which profited only from a portion of the $913 million market for
intravenous infusions with Shire’s Vprive and Pfizer’s Elelyso. Genezyme, the first
company to develop treatment option for Gaucher disease is looking forward to being at
the top of the market once more with Cerdelga’s approval.
Resources:
http://www.fiercebiotech.com/story/sanofi-wins-fdas-blessing-oral-gaucher-drug/2014-
08-19
http://www.fiercepharma.com/story/price-could-be-key-sanofis-new-gaucher-pill-it-sets-
out-against-iv-rivals/2014-08-20