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With Phase 3 data expected from Amicus Therapeutics (FOLD), we wanted to take the time to do a thorough analysis of the trial and what to expect. Jason Chew has covered Amicus since early 2012, so their story should be familiar for our readers. Now, we would like to review some insightful points revealed during their recent third quarter conference call and frame the current trial in more detail.

During after-hours last week, Amicus filed an S-3 establishing a new $145 million registration statement. This shelf replaces their previous shelf from 2009. Amicus currently has over $100 million in cash and no debt, so we do not foresee a raise before their Phase III trial topline results. With positive data in hand, Amicus should be able to tap the equity markets during the first or second quarter.

Upcoming Catalysts

AT2220 final cohort Phase 2 Study 010 co‐administration data in Q4 for Pompe's disease

Amigal Phase 3 Study 011 top-line data readout in Q4 for Fabry disease

Completion of additional AT3375 IND‐enabling studies in Q4 for Parkinson's disease

Presentation of Phase 3 Study 011 results at the Lysosomal Disease Network WORLD Symposium Orlando, Florida - February 12-15, 2013.

Amigal Phase 3 Study 011 - 12‐month data H1'13

Amigal+ERT Phase 3 Study 012 - 18-month GFR data in 2H'14

Amigal, Fabry and GSK

Amigal, also known as migalastat HCL, is a synthetic compound designed to stabilize the enzyme alpha-alactosidase A (alpha-Gal A). Reduced or absent levels of the enzyme lead to the build-up of globotriaosylceramide (GL-3), resulting in the symptoms of Fabry disease, including pain, kidney failure, and increased risk of heart disorders and stroke. Fabry disease is currently treated with enzyme replacement therapy (ERT), via Sanofi/Genzyme's Fabrazyme and Shire's Replagal.

Amicus originally signed a $440M biobucks ex-US deal with Shire in 2007 for Amigal, Plicera, and AT2220. However, Plicera failed in Phase 2 testing during 2009, which then lead to Shire's termination of the deal in October 2009. Amicus was later given new life in late-2010 when they partnered with GlaxoSmithKline (NYSE: GSK) for $60M upfront plus significant equity buys required from GSK. They would have only been due to tiered double-digit royalties on global sales of migalastat and biobucks for milestones/sales.

In July 2012, Amicus and GSK expanded their deal over Amigal in Fabry disease, where Amicus retrieved full US rights (profits) to Amigal, which is a significant valuation boost over the previous royalty structure. Although speculation, the timing of this deal restructuring came at a time when Amicus and GSK could have had some knowledge of the 6-month blinded data. See BioWorld's "Amicus, GSK Extend Their Fabry Disease Collaboration".

Current Phase III studies

Currently, Amicus and global partner, GlaxoSmithKline, are conducting 2 Phase III studies using Amigal: Study 011 of Amigal versus placebo in 67 patients with Fabry disease and Study 012 to compare the safety and efficacy of Amigal plus enzyme replacement therapy for the treatment of Fabry disease. They intend to use Study 011 for approval in the US and Study 012 for worldwide regulatory applications. Study 012 is randomizing patients at 1.5:1 for drug and placebo; currently 57 patients have enrolled in that study (24 males and 33 females). Final enrollment is expected by the end of this year with data not expected for roughly 18 months. The primary endpoint is renal function assessed by glomerular filtration rate (GFR) at 18 months. For the rest of the article we will be focusing upon Study 011.

Study 011 is a randomized, placebo-controlled study of Amigal in 67 patients (24 males/43 females) with Fabry Disease and Amigal-responsive GLA mutations. This trial specifically enrolled patients ERT-naïve or had not received ERT for at least 6 months prior to study entry 2) genetic mutations amenable to chaperone monotherapy and 3) GL-3 levels at least 4-times the upper limit of normal at baseline. CEO John Crowley noted at Lazard on 11/15 that roughly 2/3 of men and 1/3 of women who were screened would have qualified for the trial based on the 4-time ULN threshold of GL-3. Amicus has been quite open about the screening and makeup of the trial, see their PR and detailed poster (PDF). Out of 180 patients, 75% were considered to have amenable mutations and were potentially eligible for the Phase 3 study.

We should note that the primary endpoints between the original Fabryzyme study and Amicus' are slightly different. Amicus and the FDA agreed upon the design of Study 011, including the primary endpoint under a more accurate histological scoring methodology. The primary endpoint for Amicus' Study 011 defines a patient as a responder if they show greater than 50% reduction in GL-3 from baseline. Genzyme's study used a slightly stricter primary endpoint; it required achieving a score of zero on a scale of 0-3 measuring the level of GL-3 in the kidney vasculature (none, mild, moderate, severe). Study 011 secondary endpoints include eGFR, 24-hour urine protein, and urine GL-3 levels. The FDA is in agreement that Amicus would be eligible to seek accelerated approval for Amigal with Study 011.

During the call, the company highlighted that the 6-month primary treatment period was completed in June of this year in 63 out of 67 patients (6% drop out rate) and all 63 patients went into the six month follow-up period. They then continued on Amigal or were switched from placebo to migalastat if they had been in that arm. The trial was double-blind up until the 6-month time period. Currently, 51 (80%) of patients have completed the 6-month follow-up period and received their 12 month biopsies, a secondary endpoint. Additionally, of those 51 patients, 49 (96%) enrolled in the ongoing voluntary extension studies. They are currently waiting for the remaining 12 patients to complete the 12-month biopsy, which is expected to happen in December. (Study 011 enrollment was completed on December 19th, 2011, and has a 12-month blinded treatment period.) At that time, Amicus will unveil the results of the primary endpoint, reduction of kidney GL-3 levels by histological assessment.

Admittedly, it is somewhat strange that they have not released the 6-month blinded data, while patients in both arms know they are on Amigal. However, the reasoning behind it does make sense. The idea is that if the 6-month data are unblinded, knowledge of results will affect participants in the 6-month extension study. Remember placebo patients are allowed to switch over to the Amigal 6-month extension study. Technically, they don't know if the drug works or not; patients are not told the results of the 6-month data. Hence unblinding at 6 months would interfere with analysis of 12-month efficacy results. This should allay some concerns about data integrity.

To date, Amigal has had a favorable safety profile and strong signs of efficacy in those Fabry patients with Amigal-responsive GLA mutations. They recently announced some very encouraging long-term extension study data on patients treated with Amigal. Notably, median treatment duration on Amigal was 5.2 years (4.7 to 6.4 years) in 17 subjects who completed Study 205. Amicus also provided a slide highlighting how patients with amenable mutations vs. non-amenable respond to Amigal, see below. In 4/5 (80%) patients with amenable mutations (on the left), Amigal showed a greater than 50% reduction in GL-3, including 67% (2/3) in females.

(Click to enlarge)

As a reference for the placebo arm, we can look at the data from Genzyme's Fabrazyme. "The primary efficacy endpoint of GL-3 inclusions in renal interstitial capillary endothelial cells, was assessed by light microscopy and was graded on an inclusion severity score ranging from 0 (normal or near normal) to 3 (severe inclusions). A GL-3 inclusion score of 0 was achieved in 20 of 29 (69%) patients treated with Fabrazyme compared to 0 of 29 treated with placebo (p<0.001). Similar reductions in GL-3 inclusions were observed in the capillary endothelium of the heart and skin (Table 4)." See FDA review documents for Fabrazyme here.

Placebo arms patients are very unlikely to achieve a response in Amicus' Phase III study. Amigal's efficacy data will be scrutinized by all versus Fabrazyme; specifically on GL-3 inclusion score. We believe Amigal's will be in the range of 40-80%. Amigal's side effect profile is very tame versus an ERT like Fabrazyme. Management has already stated that safety has not been a worry. We are confident the trial will be statistically significant, the million dollar question is whether it will be clinically meaningful.

The major trial risks are two-fold: how do heterozygote females respond and are there amenable mutation assays highly predictive of response? Based on the trial design, it only requires 9 patients to achieve 50% reduction for statistical significance, but this is likely not be looked upon favorably for future commercial potential. We based this on previous Phase 2 data in patients with eligible mutations. Even when patients did not have eligible mutations, we still see some activity, but nowhere near as much. We suspect the percentage of reductions will be around 40% at the low-end and 70% at the high-end. Somewhere in between would be a success.

Predictive "biomarkers" of a positive study?

We think there are several possible indicators of a successful outcome to Study 011 that fuel our bullishness. First, Amicus and GSK expanded their Amigal collaboration, which subsequently occurred after the blinded 6-month data had been collected. Given the placebo arm likely had 0% responders, the study drug arm would be apparent to any. Additionally, management has given subtle hints about how the trial has gone via the long-term Phase extension results, low dropout rates in Phase 3 and very high continuation rate into the Phase 3 extension study. Patients must be experiencing some level of clinical benefit to justify remaining in the study so long.

Market Opportunity on Approval

At their sales peak, Fabrazyme sales were close to $500 million. The past few years, Genzyme's manufacturing difficulties and supply constraints created a real stir amongst the Fabry community due to the shortages. Their manufacturing woes seem to have passed for Sanofi/Genzyme's Fabryzyme with good quarterly sales numbers of $112.8 million worldwide and projections for doubled production of Fabryzyme by year-end. Patients will still face the possibility of another manufacturing hiccup to interrupt their supply of Fabryzyme. Amicus will should be helped by Shire's Replagal being pulled from FDA review and closing down their treatment IND in the US.

With the approval of Amigal, Amicus be able to begin taking market share from Fabrazyme. This is based on convenience (oral vs bi-monthly 4-5 hour infusion sessions), pharmaeconomics, and side effect profile. Clearly, Amigal's clinical profile will need to be in the same ballpark as Fabrazyme. Amicus might also be able to tap into symptomatic heterozygous females better than Genzyme. Most insurers have required that female patients show documented Fabry disease carrier status with significant manifestations before they will cover Fabrazyme. Amicus has a real opportunity in not only getting male Fabry patients, but in reaching female Fabry patients who are underserved by ERT. We have seen estimates of US patients with Fabry disease around 2000 to 2500 patients with a significant number of females underdiagnosed.

Conservatively, if Amicus is able to get 500 patients on Amigal, this could represent potential revenues of $75 million per year. This is based on a 1-year treatment cost of $150K, which is conservative for newly launched rare-disease drugs. Amicus will be able to use much of the Fabry community that Genzyme helped establish and target main treatment clinics for Fabry. If Amicus is able to achieve the desired efficacy in female Fabry patients, there could be substantial upside to the monotherapy regiment. Amicus Study 012 could open up significantly more revenue if it can demonstrate a meaningful benefit to ERT vs ERT alone.

Conclusion

Holding a long position in Amicus through pivotal data readouts requires ample confidence in management, the drug, and a bit of luck. With what we have seen from our investigations, we believe the Phase 3 trial will be positive. Amicus currently has ample cash (~$106M as of 9/30/12, EOY'12>$90M) to get into middle-2013. We suspect the AT-2220 data will come before the Phase 3 data. Not too often do we see opportunities that present themselves with such compelling conditional information before the data is known. We plan to capitalize on it.

Source: Bullish On Amicus Therapeutics