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Triplet Therapy & Q2-2017 Results = ESPR Spike!

11:07 EDT 8 Aug 2017 | Biotech Watcher

On Tuesday morning, August 8, 2017, Esperion Therapeutics (ESPR) releasedits Q2-2017 results and held aconference call with presentation slides.

The clear focus was on the results from the Triplet Therapy trial. The Triplet Therapy consists of the fixed-dose combination levels (180 mg bempedoic acid (BA) + 10 mg ezetimibe) plus 20 mg atorvastatin (Lipitor). The positive results fueled a strong jump in ESPR’s valuation on large volumes.

Financial Summary

Basic Facts for Quarter Ending June 30, 2017
(in Thousands except Share Price & Market Cap)

Q2-2017
Q1-2017
Q4-2016
Q3-2016
Q2-2016
  R&D Expense
38,248
35,860
24,881
13,498
9,698
  SG&A Expenses
5,412
5,029
4,404
4,214
4,633
Total Operating Expenses
43,660
40,889
29,285
17,712
14,331
Operating Income (Loss)
(43,660)
(40,889)
(29,285)
(17,712)
(14,331)
Net Income (Loss)
(43,337)
(40,541)
(28,956)
(17,402)
(14,035)
Comprehensive Income (loss)
-
(40,597)
-
(17,498)
(13,932)
Basic & diluted earnings (loss) per share
(1.92)
(1.80)
(1.29)
(0.77)
(0.62)
Avg. Shares Outstanding
Basic & Diluted
22,591
22,591
22,563
22,563
22,554
22,554
22,550
22,550
22,541
22,541
Recent Price (per share)
       45.17
(8/7/17)
       33.31
(5/19/17)
       31.28
(3/6/17)
       9.40
(11/3/16)
       10.87
(8/2/16)
Market Capitalization
1.0B
752M
705M
212M
245M
Cash & Equivalents
20,373
19,867
38,165
47,140
48,768
Short-term Investments
160,715*
162,017
162,017
162,961
158,410
Long-term Investments

25,920
30,906
49,646
67,637
  *We will parse between short-term and long-term investments with the publication of the 10-Q

Esperion VP of Finance affirmed that there were enough funds to last through top-line results for the Phase 3 trials required for regulatory filings in the U.S. and European Union. Esperion should end the year with $125M to $135M in cash and securities, while burning about $125M to $135M.

Triplet Therapy Results

The triplet consists of the fixed dose combination (180 mg BA + 10 mg ezetimibe) + 20 mg atorvastatin (Lipitor). Atorvastatin is the top prescribed generic statin, and this compelled Esperion management to pursue BA therapies, starting with Triplet Therapy.


Placebo
(N=20)
Combo + Statins
(N=43)
LDL-C Change from Baseline
-3%
-64%
(p < 0.001)
% Achieving LDL-C Reduction ≥ 50%
0%
95%
(p < 0.001)
% Achieving LDL-C < 70 mg/dL
0%
90%
(p < 0.001)
hsCRP Reduction from Baseline
-3%
-48%
(p < 0.001)
Safety Profile


Serious Adverse Events (SAEs)
0
0
Total Related AEs
2
(10%)
8
(18.6%)
Discontinuation due to AEs
1
(5%)
3
(7%)
Any Lab Abnormalities? (i.e. ALT/AST, CK)
0
0
Any Potential Muscle AEs
6
(30%)
7
(16.3%)
Related Potential Muscle AEs
2
(10%)
2
(4.7%)
Discontinuation due to Potential Muscle AEs
1
(5%)
2
(2.3%)

Effective LDL-Reduction

While no one is surprised that Triplet Therapy beat placebo, the results still constitute a stellar win. Triplet Therapy achieved a 64% absolute reduction: patients were baselined at 154 mg/dL of LDL and had a mean ending of 56 mg/dL.  

Based on historical data, ezetimibe (Zetia) + atorvastatin would only have a reduction to 71 mg/dL. This implies that BA created an additional relative reduction of 21% or 15 mg/dL.

Since this was only a historical comparison, Esperion cannot be conclusive. Multiple replications should create a strong argument.

Nevertheless, these are unprecedented results. Almost every patient on triplet therapy experienced very meaningful reductions in bad cholesterol (LDL). Furthermore, the onset of action was faster than previously seen with each drug: most of the LDL reduction was achieved within 3 weeks. CEO Tim Mayleben speculated that it was due to the “complementary nature” of the three drugs.

Reduction in Other Markers

Triplet Therapy patients experienced a robust reduction in hsCRP, a cardiac inflammation marker. HsCRP appears to relate to major cardiovascular events.

CEO Mayleben also said there was significant reductions in most of the atherogenic particles. We look forward to viewing the full results in a poster presentation or publication.

Safety

The tabular summary of results shows a clean safety profile for BA, especially concerning muscle AEs. Muscle AEs are the main dose-limiting feature for statins. Pairing the FDC with the lowest dosage of atorvastatin produced good safety results.

Additional BA Combination Markets

Mayleben said that the staff has been considering a number of studies in which BA is added to other treatments.  For example, the good results from this trial implicate the possible creation of a “doublet” pill, consisting of BA + atorvastatin.  

In terms of the market ecosystem: statins are the standard of care, and then generics are usually considered the next option. Ezetimibe is a popular non-statin generic. With this in mind, BA is being positioned for flexibility with physicians and payers.  

BA can be used with a statin, ezetimibe, or (hopefully) even a PCSK9 inhibitor (PCSK9i). Its mix of pricing, efficacy, safety & tolerability should drive this.

As for pairing BA with a PCSK9i, Esperion recently announced a Phase II trial launch. Management readily acknowledged that the treatment market for BA + PCSK9i is very small. It’s for patients with severe LDL reduction needs that must avoid using a statin. Management feels an obligation to serving these strong needs.

Partnering Thoughts

CEO Mayleben clearly affirmed that consummating a partnership by early 2018 is “a top priority”. This leaves enough time for the partner to assist with commercialization in 2020. Esperion also feels no time pressure. It has the resources to finish the current set of Phase III trials needed for regulatory filings in the U.S. and Europe.
There are two main groups of physicians that will prescribe BA: cardiologists and primary care physicians. The cardiologists will be the leading edge. This group has a history of using new drugs and devices. Esperion can develop a specialty sales force that targets cardiologists.

The primary care physicians drive the bulk of cardiac drug prescriptions. They are also relatively conservative with respect to using new treatments. A major partner with an established sales force may help drive sales into the primary care physician market.

Mayleben has been pleased with the ongoing discussions with potential partners. We suspect that the Triplet Therapy results will only spur the process forward.

Milestones

Esperion Therapeutics - Clinical Milestones
ETC – 1002 - Bempedoic acid
Bempedoic acid is an inhibitor of ATP citrate lyase (ACL). ACL is the primary enzyme responsible for the synthesis of cytosolic Acetyl-CoA in many tissues. The product, Acetyl-CoA, in animals serves several important biosynthetic pathways, including the metabolic formation of fat and cholesterol synthesis. Bempedoic acid inhibits cholesterol synthesis in the liver, decreases intracellular cholesterol and up-regulates LDL-receptors, resulting in increased Low Density Lipoprotein-Cholesterol (LDL-C) clearance and reduced plasma levels of LDL-C.
CLEAR Program – Establish LDL-Cholesterol Lowering via ETC-1002
CLEAR HARMONY - ETC - 1002-040– 2,233 pts.
A global Phase III randomized, multicenter, double-blind, placebo-controlled study evaluating 180 mg of bempedoic acid versus placebo in 2,233 patients with hyperlipidemia at high cardiovascular disease risk and whose LDL-C is not adequately controlled with maximally tolerated lipid-modifying therapy. The study finished enrolling patients from approximately 100 sites in the U.S., Canada and the European Union.

The primary objective is to assess safety and tolerability of patients treated with bempedoic acid for 52 weeks. Secondary objectives include assessing the effects of bempedoic acid on lipid and cardiometabolic risk markers, including LDL-C and hsCRP.
Top-line Results
Q2-2018
Open-Label, Extension Study (1002-050) Results -1,400 Pts
Q4-2019
Phase III efficacy and safety study of bempedoic acid in Patients with Hyperlipidemia and Statin Intolerance.
Top-line Results
Q2-2018
Phase III efficacy and safety study of bempedoic acid in Hypercholesterolemic Patients with ASCVDand/or HeFH. These are high cholesterol patients who are at risk for a cardio event and are not “Adequately Controlled with Current Lipid-Modifying Therapy” – this includes statin intolerant patients.
Top-line Results
Q3-2018
Phase III efficacy and safety study in Hypercholesterolemicpatients that are already taking ezetimibe. Subjects have elevated LDL-C not Adequately Controlled with Current Lipid Modifying Therapy
Top-line Results
Q2-2018
Study Completion
2H-2018
Establish Cardiovascular Risk Reduction (Outcomes)
A Phase III trial of outcomes in statin intolerant patients. Esperion management requires a set number of patients to experience a MACE event (CD death, heart attack, stroke, hospitalization for angina, coronary artery bypass). 1,437 events triggers the evaluation of the primary endpoint. Esperion will provide yearly updates in February.
Anticipated Top-line Results
1H-2022
Regulatory Submission
2H-2022
Fixed Dose Combination (FDC) Program
It’s a fixed dose tablet of 180 mg bempedoic acid + 10 mg ezetimibe (BA+EZ).  The aim is to support approval of a low-cost, oral, statin alternative in the United States and Europe. The US FDA has given the go-ahead for Esperion to use the 505(b)2 abbreviated pathway for approval. Although the pathway only provides 3 to 5 years of protection, the company has patents on the treatment.
Phase III Bridging (Safety & Efficacy) study – 350 Pts
Launch
Q4-2017
Phase III Bridging (Safety & Efficacy) study – 350 Pts
Top-line Results
Q4-2018
Additional Phase II Exploratory Studies
Esperion will conduct additional exploratory studies of bempedoic acid in combination with other drugs, aiming to broaden the label.
Dual combination Therapy – Daily 180 mg BA and monthly PCSK9i (Repatha)
50 Pts in placebo-controlled trial.
Top-line Results
Q1-2018
Ex-USA Partnership
The extent of the (hoped for) partnership is unknown. There are several Big Pharma candidates that sorely need to reload or jumpstart its cardiovascular pipeline. While a partnership can be consummated in the near term, Esperion can afford to wait.
Announce Partnership
TBA
Regulatory Filings
Submissions for FDA / EMA Approval
New Drug Application (FDA) / Monotherapy
Indication: LDL-C lowering
Q1-2019
Monotherapy Marketing Authorization Application (EMA) / Monotherapy
Indication: LDL-C lowering
Q2-2019
New Drug Application (FDA) - Fixed-dose Combination Agent - BA+EZ (FDC)
Indication:  LDL-C Lowering
Q1-2019
Monotherapy Marketing Authorization Application (EMA) - FDC
Indication:  LDL-C Lowering
Q2-2019
Commercial Approvals – United States (FDA) & European Union (EU)
Monotherapy & FDC
1H-2020
New Drug Application (FDA) / Marketing Authorization Application (EMA) 
IndicationCardiovascular Risk Reduction
Q3-2022

Our Thoughts

It’s amazing what has changed in 12 months.

ESPR has vaulted from $10.87 to reaching over $53.
The FDA has confirmed LDL-reduction as an approvable endpoint.
The CETP drugs have evaporated and so the competitive ecosystem has improved
Positive Phase II Studies

It’s also amazing what hasn’t changed
Even when ESPR was depressed, the clinical trials painted a consistent, positive profile for BA
The target market, ESPR management team, and BA’s clinical characteristics remain unchanged

Upcoming Milestones

While Esperion has listed the near-term milestones, these will have minor impacts on the valuation: a clinical trial launch and the publication of an already summarized (genetic validation) study.

In the next months, the key event involves a potential partnership. CEO Mayleben expresses confidence in the ongoing discussions. We believe him…but we’re perennially cautious about the timing with Big Pharma. To create a fractured religious quote: “A year is sometimes only like a day in the eyes of Big Pharma”

(At the time this post was written, one or more BioWatch authors held a position in ESPR)

Original Article: Triplet Therapy & Q2-2017 Results = ESPR Spike!

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