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Anyone surprised that the share price is still sub $14 despite all the medical organizations that have publicly supported the results and despite the great results?
What is it that the shorts are banking on?
Surprised the price is not rising going into the ADCOM.
I will have to step away from computer with these day to day fluctuations and return Nov. 15th.
I don't get it.
Is JT tired? He is mumbling through this presentation. SMH
No energy. So Frustrating.
Although dated (from 2009) interesting quote from Dr. Kenneth Burman (chair of the AdCom) on Crestor:
Agency staff asked the advisory panel to weigh higher numbers of diabetes cases, gastrointestinal-related deaths and reports of a “confusional state” in patients who took Crestor instead of a placebo. Panelists generally agreed it was unlikely the deaths and confusion were related to Crestor.
On diabetes, panelists felt the Jupiter findings “probably represent an authentic increase” that may be common to all statins and urged further study, said panel chairman Dr. Kenneth Burman, chief of the endodrine section at Washington Hospital Center.
https://uk.reuters.com/article/astrazeneca-crestor/update-2-us-panel-backs-wider-use-of-astrazenecas-crestor-idUKN1521901920091215
Found this presentation from Dr. Connie Newman - AdCom Member
Are Statins as Effective in Women as in Men?
Update on PCSK9 Inhibitors
https://slideplayer.com/slide/10335182/
On the flip side, Dr. Connie Newman, another AdCom member, is a huge proponent of statins.
See: https://med.nyu.edu/faculty/connie-newman
Hard to discern how she will come out in terms of the scope of the label.
From her bio:
My main interests are statin safety and intolerance and the effects of statins on cardiovascular disease. I have designed, conducted, and analyzed efficacy and safety data from large cardiovascular outcomes trials of statins in various populations, including patients with diabetes, stroke or transient ischemic attack (TIA), cardiovascular disease, and chronic kidney disease.
My research has involved the following:
evaluating the effects of atorvastatin 10 mg on heart attacks and stroke in about 2,500 patients with diabetes, as part of the steering committee of the Collaborative Atorvastatin Diabetes Study (CARDS)
analyzing safety data from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine, or SEARCH, and the Study of Heart and Renal Protection, or SHARP
performing meta-analyses of safety data from trials of statins, including a meta-analysis of cancer events and deaths in 27 randomized controlled trials of various statins in about 170,000 patients and meta-analyses of safety data from early clinical trials of atorvastatin
serving as a member of the Cholesterol Treatment Trialists’ Collaboration
In addition, I was a member of the steering committee of the Biochemical Efficacy and Safety Trial of Vitamin D, or BEST-D. This randomized double-blind trial in people older than 65 years evaluated the effects of one year of vitamin D treatment at either 4,000 IU or 2,000 IU per day, compared with placebo. Outcomes measured included levels of vitamin D, parathyroid hormone, and calcium; other safety parameters; and selected cardiovascular endpoints such as arterial stiffness, blood pressure, and lipids.
I am currently chair of the task force for the Endocrine Society’s clinical practice guideline on lipid management in patients with endocrine disorders, including type 1 and type 2 diabetes.
Previously, I studied mammary gland growth and development and the role of novel pituitary factors in primate and rodent models. My earlier clinical research focused on new therapies for the treatment of pituitary tumors, including the effects of somatostatin analogues in patients with acromegaly. I have also investigated the effects of growth hormone replacement on cardiopulmonary function in growth-hormone–deficient adults.
See: https://www.ncbi.nlm.nih.gov/pubmed/26318980?otool=nynyumlib&myncbishare=nynyumlib
Statin tolerability: In defence of placebo-controlled trials.
Tobert JA1, Newman CB2.
Author information
1
Nuffield Department of Population Health, University of Oxford, UK jonathan.tobert@cantab.net.
2
Department of Medicine, Division of Endocrinology and Metabolism, New York University School of Medicine, USA.
Abstract
BACKGROUND:
Statin intolerance is a barrier to effective lipid-lowering treatment. A significant number of patients stop prescribed statins, or can take only a reduced dose, because of adverse events attributed to the statin, and are then considered statin-intolerant.
METHODS:
Examination of differences between statin and placebo in withdrawal rates due to adverse events - a good measure of tolerability - in statin cardiovascular outcome trials in patients with advanced disease and complex medical histories, who may be more vulnerable to adverse effects. The arguments commonly used to dismiss safety and tolerability data in statin clinical trials are examined.
RESULTS:
Rates of withdrawal due to adverse events in trials in patients with advanced disease and complex medical histories are consistently similar in the statin and placebo groups. We find no support for arguments that statin cardiovascular outcome trials do not translate to clinical practice.
CONCLUSIONS:
Given the absence of any signal of intolerance in clinical trials, it appears that statin intolerance in the clinic is commonly due to the nocebo effect causing patients to attribute background symptoms to the statin. Consistent with this, over 90% of patients who have stopped treatment because of an adverse event can tolerate a statin if re-challenged. Consequently, new agents, including monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, will be useful when added to statin therapy but should rarely be used as a statin substitute.
The more I research the AdCom panel the more I am starting to believe the AdCom is really about the label and how broad it should be. I think the fact that it is before the Endocrinologic Committee will end up being a blessing. Think broad label. The ADA guidelines/recommendation should be quite helpful and convincing for us.
Dr. Cecilia Low Wang is one member of the committee. She focuses on Diabetes and is particularly interested in cardiovascular disease. When you have a chance review this paper she co-authored. It is filled with many nuggets. Suffice it to say I think she will be in our corner. Especially considering she recognizes not everyone can tolerate statins. See this section below on Statins & Diabetes (https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.022194):
Statins and Diabetes Mellitus
Although there are clear benefits of statins to reduce cardiovascular events and mortality in patients with or at risk for ASCVD,183,184 statins also modestly accelerate the development of diabetes mellitus in individuals with preexisting risk factors.186–189 In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which involved participants without diabetes mellitus but with LDL cholesterol levels <3.4 mmol/L (130 mg/dL) and high-sensitivity C-reactive protein concentrations of 2.0 mg/L or higher, the hazard ratio for newly diagnosed diabetes mellitus was increased 25% in the rosuvastatin group compared to the placebo group.186 Despite the increase in the risk of new-onset diabetes mellitus, the participants previously considered to be at low cardiovascular risk had clinically important cardiovascular event reductions over a median follow-up period of only 1.9 years, with a hazard rate 44% lower with rosuvastatin in comparison with placebo for the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Almost two-thirds of participants had ≥1 major risk factor for developing diabetes mellitus: metabolic syndrome as defined by the 2005 American Heart Association/National Heart, Lung, and Blood Institute consensus criteria, impaired fasting glucose (as defined by fasting serum glucose of equal to or >100 and <126 mg/dL [5.55–7.00 mmol/L]), BMI 30 kg/m2 or higher, or HbA1c >6%.190 As expected, incident diabetes mellitus was 28% higher those with than without any major diabetes mellitus risk factor, and statins accelerated the average time to diagnosis of diabetes mellitus by 5.4 weeks. However, statin allocation reduced the risk for the primary end point both in participants with and without a major risk factor for diabetes mellitus, such that in patients with ≥1 risk factor for diabetes mellitus, in total 54 new cases of diabetes mellitus were diagnosed, whereas 93 first major cardiovascular events or deaths, or 134 total cardiovascular events or deaths were avoided.
Several meta-analyses have now been performed examining the risk of developing diabetes mellitus in statin-treated individuals, and relative risks are somewhat lower overall than that found in the index JUPITER trial.187–189 Diabetes mellitus relative risk was 13% higher with no heterogeneity across 5 trials (including HPS [Heart Protection Study],191 LIPID [Long-Term Intervention with Pravastatin in Ischemic Disease],192 ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial],193 JUPITER,186 and CORONA [Controlled Rosuvastatin Multinational Trial in Heart Failure]194) with a total of 57?593 patients, mean follow-up of 3.9 years, and 2082 incident cases of diabetes mellitus.187 Addition of WOSCOPS (West of Scotland Coronary Prevention Study)195 to the analysis introduced significant heterogeneity and attenuated risk, which no longer retained statistical significance as WOSCOPS reported a protective effect of pravastatin versus placebo on the incidence of diabetes mellitus. In a second meta-analysis, a 9% increase in risk for incident diabetes mellitus was found (odds ratio [OR], 1.09, 95% CI, 1.02–1.17), including 13 trials with 91?140 participants and development of diabetes mellitus in 4278 patients over a mean of 4 years.188 Investigators were contacted to obtain unpublished data regarding incident diabetes mellitus resulting in 7 additional trials (and both JUPITER and WOSCOPS) included as compared with the other meta-analysis. In this analysis little heterogeneity was found across trials despite the inclusion of WOSCOPS, potentially attributable to different criteria used to diagnose diabetes mellitus. Statin-associated diabetes mellitus risk may be slightly higher in women.196 A meta-regression analysis showed the highest diabetes mellitus risk was associated with older age, but not baseline BMI or LDL cholesterol level.188 One extra case of diabetes mellitus resulted from treating 225 (95% CI, 150–852) patients with statins for 4 years, whereas 5.4 vascular events were prevented. In the larger context, given that statins are used by approximately 24 million Americans, the population-attributable risk of statin-associated diabetes mellitus is not small. However, considering the many treatments for diabetes mellitus and the importance of cardiovascular event reduction, providers should not avoid using statins when indicated solely because of concern for risk of diabetes mellitus.
Potential effects, if any, of statin-induced diabetes mellitus on the development of long-term microvascular complications remain unknown, but current epidemiological data are reassuring. With recent lower lipid target goals and increasing use of statins, as well as improved screening, early detection, and multifactorial interventions, the age-adjusted percentage of adults with diabetes mellitus reporting visual impairment197 and the incidence of end-stage renal disease in adults with diabetes mellitus198 have decreased over the past few decades. Furthermore, the 10-year risk of myocardial infarction or stroke (˜25%) is markedly higher than that of blindness or renal failure (approximately 1%–2%) for patients with recent-onset diabetes mellitus impacting risk-to-benefit considerations.199
The risk of developing diabetes mellitus appears to be related to statin potency200 and dose.189 Cellular mechanisms underlying the increased incidence of diabetes mellitus remain incompletely understood. Genome-wide studies do not reveal associations between genes that regulate HMG-CoA reductase or LDL cholesterol metabolism and type 2 diabetes mellitus. Statins may interfere with ß-cell insulin secretion either by decreasing Ca2+-dependent insulin secretion or by interfering with isoprenylation of guanosine triphosphate–binding proteins.201 Statin inhibition of isoprenoid biosynthesis may lead to lower expression of insulin signaling proteins in adipocytes and to reduced glucose transporter expression or translocation.202 Fasting insulin levels may increase modestly, suggesting that insulin resistance may be increased, but euglycemic hyperinsulinemic clamp studies do not show consistent changes in insulin sensitivity.203 Other off-target effects may also be involved.
Overall, the risk of incident diabetes mellitus with statin therapy is present but largely outweighed by the actual cardiovascular benefits.204 Patients should be educated regarding the risk of incident diabetes mellitus with statins as with other risk–benefit of all therapies.132 Lifestyle modification should be encouraged to lower cardiovascular risk and that for developing diabetes mellitus.205 Patients on statins at higher risk for but without preexisting type 2 diabetes mellitus should undergo periodic screening for diabetes mellitus with fasting glucose and HbA1c, and if type 2 diabetes mellitus develops, standard of care and national guidelines should be used to manage diabetes mellitus.206,207
From the paper:
What Is on the Horizon?
A number of new approaches for glucose lowering are under development and may provide agents with dual benefit for diabetes mellitus and the diabetic heart. Additionally, drugs that are developed for cardiovascular risk reduction may also lower glycemia. In the meantime, cardiovascular outcome trials will provide useful information on cardiovascular safety of use of diabetes mellitus drugs in patients with established heart disease or at high risk for events and additional exposure, information that may reveal previously unrecognized positive or negative effects. These trials may help to better address the question of the impact of specific glucose-lowering drugs and pharmacological class agents on the diabetic heart.
Conclusions
The long-term treatment of diabetes mellitus is challenging because of diverse goals: to address metabolic derangements and to reduce risks for both micro- and macrovascular adverse outcomes. Management of hyperglycemia has resulted in substantial reductions in risks for retinopathy with associated preservation of vision, and nephropathy with prevention of end-stage renal disease when combined with aggressive blood pressure control. Progress in prevention and amelioration of these microvascular complications has conversely resulted in a shift in the major causes of long-term morbidity and mortality in diabetes mellitus, which now consists of cardiovascular risk with associated ischemic heart disease, ischemic stroke, peripheral artery disease, and congestive heart failure. Diabetes mellitus clearly exacerbates mechanisms of atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately fully modulated or addressed by focusing solely on optimal glycemic control. Fortunately, aggressive management of cardiovascular risk factors, particularly lowering of LDL cholesterol concentration and blood pressure along with glycemic management, provides substantial improvements in cardiovascular outcomes. Therefore, we prioritize recommendations for management of cardiovascular and heart failure risk to focus on the most effective therapies, as summarized in Table 1.
Multiple areas of further investigation remain. Potential cardiovascular benefits versus risks of new glucose-lowering agents and timing of (early or prolonged) glucose-targeting interventions are incompletely understood. Evidence for a more effective antiplatelet regimen than aspirin in moderate to high risk patients with diabetes mellitus without ischemic heart disease is necessary. Recommended blood pressure goals are also not fully evidence-based, and the role of new potent lipid-lowering therapies (PCSK9 inhibitors) and lipid-lowering drugs that target triglycerides and HDL cholesterol needs further study. Another unaddressed issue is the ultimate risk–benefit ratio for polypharmacy that occurs when physicians add multiple drugs to achieve an optimal level of glycemic control and cardiovascular risk management. These are pragmatic concerns wherein the use of multiple medications can result in less overall medication compliance and increased risk of drug–drug interactions. Although the overall management of diabetes mellitus has improved substantially over the past 2 decades, there is a large unmet need for cardiovascular prevention.
Sounds good. And I agree Dr. Bhatt has to be there!!
As a follow up to a post from oneragman on AdCom members. I am starting to research them.
Roster: https://www.fda.gov/advisory-committees/endocrinologic-and-metabolic-drugs-advisory-committee/endocrinologic-and-metabolic-drugs-advisory-committee-roster
As has been reported Dr. Michael Blaha has been quoted with positive comments on REDUCE-IT.
See: https://www.nbcnews.com/health/heart-health/drug-fish-oil-cuts-risk-heart-attack-stroke-study-finds-n934701
I thought it is also interesting that Elizabeth Chrischilles has done research looking at ways to reduce cardiovascular disease and suggests she is open to new approaches.
See: https://ahajournals.org/doi/10.1161/CIRCOUTCOMES.117.004188
Also from https://icts.uiowa.edu/about-us/leadership/elizabeth-chrischilles-phd (scroll down and look at publications):
4 R01 HL116311 (Carter, Barry)
08/08/13-07/31/18
NIH
Improved Cardiovascular Risk Reduction to Enhance Rural Primary Care (ICARE) Trial
Objective: To conduct a multi-center, cluster-randomized study utilizing a centralized Prevention Health & Cardiovascular Risk Service to support the efforts of rural medical offices to improve adherence to the Guideline Advantage metrics for reducing cardiovascular risk.
Role: Co-Investigator
R18 HL116259 (Carter, Barry)
04/01/14-03/31/19
NIH
MEDication Focused Outpatient Care for Underutilization of Secondary Prevention: MED-FOCUS
Objective: To conduct a multi-center, cluster-randomized study utilizing a centralized Cardiovascular Risk Service for medical offices with large geographic, racial and ethnic diversity to improve cardiovascular disease guideline adherence using the Guideline Advantage metrics.
Role: Co-Investigator
CDRN-1501-26643 (Chrischilles, Elizabeth)
09/07/15-09/07/18
Subcontract with University of Kansas Medical Center Research Institute, Inc/Patient-Centered Outcomes Research Institute
Greater Plains Collaborative Clinical Data Research Network – PCORnet Phase II
The goal of the CDRN is to create a national data infrastructure for practice-based comparative effectiveness research. The initiative enhances the clinical decision making around empirical evidence of effectiveness and patient preferences. The initiative emphasizes engaging patients, practicing clinicians, healthcare IT programs and health system leaders in the design and implementation of comparative effectiveness studies.
5R21 HS023952-01 (Chrischilles, Elizabeth)
04/01/15-03/31/18
AHRQ
Design and Testing of a Mobile Cardiovascular Risk Service with Patient Partners
Risk factors for cardiovascular disease are poorly controlled even for patients who frequently visit their physician, leading to large numbers of preventable cardiovascular events such as heart attacks and strokes.
Research from integrated healthcare systems suggests that risk factors can be controlled better and treatment strategies for cardiovascular disease can be markedly improved by using a centralized cardiovascular risk service (CVRS) managed by pharmacists. The objective of this project is to develop and test a mobile app enabled, pharmacist managed CVRS for disseminating and implementing evidence-based guidelines in practice.
Understood, thanks!
What do you view as variant perception here? FDA approval? Wider label?
Thanks for posting the article about variant perception.
This is going to be a long 6 weeks. SMH.
Haywood's investment. I would read it as very bullish. He is one of the smartest biotech investors in the world. His track record speaks for itself. He was an early investor in Sarepta (Avi), Martek, and XM Satellite Radio just to name a few. The fact that he stepped up big in Neurotrope should be read as very bullish.
one last point I think the jan 2021 call options, strike price $35, which are trading in the low $2 dollar range are a tremendous value.
I think the price of AMRN will be far north of $35 in January of 2021.
just my two cents
I've read the conference call transcript several times now and I encourage you to do so as well from the vantage point of JT's conservatism.
JT drops several gems. He said, "[w]hen we come together next quarter, we believe we will have received FDA approval of our expanded indication for Vascepa, and we look forward to sharing even more about the progress we're making to introduce a new era in cardiovascular health." Given JT's conservative nature, you do not make this comment unless you are certain FDA approval is imminent.
This brings me to my second point, I believe FDA approval is going to come sooner than people/Wall Street realize. And this is why they had to raise cash when they did. JT is no dummy. He surely could have waited until closer to the PDUFA date or even after but you don't do so if you have a good indication that approval is coming faster.
There will be no ADCOM and the FDA is not sitting on their hands here. They have had ample time to review this. In fact, I would not be surprised if label discussions have already commenced.
Again reread the transcript there are several gems in it.
As to what to make of the current share price? It is a tremendous buying opportunity for those who still have access to cash.
As for GIA vs buy-out? Let's put it this way: the opportunity for Big Pharma to steal this company has long passed. Those days are gone. We are looking at a de-risked opportunity and if BP wants Amarin they will have to come big. It's not a question I lose a lot of time on because I believe JT & Baker Brothers will not let the company be stolen. GIA and buy-out value will converge as time passes.
Don't let the current share price scare you. Hold on to you shares and reread the conference call transcript.
Just my two cents
Thanks so much for this info!
Raf respectfully I think you are focused on the wrong thing. Whether it is chronological or not is not as important as the calendar itself.
There is an Adcom on August 7th this year from CDER. Again, historically post August 7th CDER does not schedule Adcoms for the remaining weeks in August. Why? Most likely because August tends to be a popular vacation month. Scheduling is a nightmare.
So that leaves September. What do we know about September. Two things: 1) Adcoms for CDER tend to resume around the second week of September (Sept. 11th / 13th). Why? People are back from vacation / scheduling is easier. September signals back to business on Wall Street and with the federal government.
2) Our PDUFA date is September 28th.
Do you really think the FDA will schedule an ADCOM for us in September. And do you really think if we were going to have an ADCOM the first or second week of August we wouldn't know by now?
Relax. There will be no Adcom. I believe we are in for an early approval. How soon? I don't know but before September 28th.
PS: I'm sure CDER saw that front page article on heart attacks in the WSJ. CDER is gravely aware of what is at stake.
Clock is ticking. All is well.
Adcoms from CDER are what are relevant in our case. Center for Drug Evaluation and Research.
In 2016 the Adcoms on August 10th and 16th were from the Center for Devices and Radiological Health.
You will not find an Adcom from CDER post August 7th in the historical years for the remaining month of August. This is a fact.
The Adcoms from CDER tend to resume the second week of September.
Clock is ticking.
Historical AdCom Fact Bodes Well for AMRN - CDER appears to have a hiatus in scheduling after first week of August (7th) until 2nd week of September (11th)
I'm led to believe there will be no Adcom as the window seems to have closed. For one, historically the Center for Drug Evaluation and Research ("CDER") has not scheduled an Adcom after the first week of August in 2018, 2017, and 2016. You can use the link below to search.
August is a huge vacation month and this does not surprise me as post the first week of August most of Wall Street and the Federal Government takes vacation. Scheduling is a nightmare.
Based on the link you will see after the first week of August, Adcoms tend to resume for CDER around the 2nd week of September.
Also note there is already an Adcom scheduled for August 7th of this year.
Me thinks we are home free with respect to an Adcom. People take vacation in August and that will not change this year.
Just my two cents.
https://www.fda.gov/advisory-committees/advisory-committee-calendar
use this link to search and select All from the drop-down.
Potential threat to Amarin? Acasti(CaPre/krill oil)
This article appeared on Seeking Alpha today. Is Acasti a threat to Amarin?
https://seekingalpha.com/article/4271991-home-run-hitters-bat-acasti-pharma
Home-Run Hitters, At Bat With Acasti Pharma
Jun. 25, 2019 11:47 AM ET|
7 comments
|
About: Acasti Pharma Inc. (ACST)
Gene Katz
Gene Katz
Long/short equity, special situations, arbitrage, activist investor
(15 followers)
Summary
ACST’s drug, CaPre, promises to be the best-in-class Omega 3 play, used to lower triglycerides. It was recently trading at $1.01/share, with a market cap of $79M.
The biggest competitor to CaPre is Amarin's drug Vascepa. After September 2018 study results, AMRN increased from $3/share to $19.01/share recently, or a market cap of $6.29B.
The triglyceride-lowering market is large, but CaPre also potentially improves cholesterol, unlike any other Omega 3 play. If this is confirmed, CaPre becomes a game-changer.
Two of the biggest investors in ACST are arguably two of the smartest investors in biotech: Joe Edelman of Perceptive and the legendary George Haywood. Both have been accumulating.
If positive Phase III Trial results are a 30% probability (and it would appear that it's significantly higher), then the price should be $8.29/share (leading into December 2019).
Editor's note: Seeking Alpha is proud to welcome Gene Katz as a new contributor. It's easy to become a Seeking Alpha contributor and earn money for your best investment ideas. Active contributors also get free access to SA Essential. Click here to find out more »
Acasti Pharma (ACST) is a small biotech that few people in the market know about. However, two of the biggest investors in ACST, are arguably two of the smartest investors in biotech. Joe Edelman of Perceptive and the legendary George Haywood have both accumulated large positions, and seem to have increased share ownership recently. Legendary biotech investor, George Haywood, has scored home runs with Sarepta Therapeutics (SRPT) and others.
Haywood added 2.7M shares in his Dec. 31st filing, taking his total to 5.1M shares. In addition to ACST shares, Haywood and Edelman are large shareholders of Neptune (NEPT), which is one of the biggest shareholders of ACST. Why are these home-run hitters accumulating ACST? It appears that this little biotech might just be offering a realistic 30-to-1 payoff, with a fraction of the risk.
Phase II Trial Summary
This is a summary of the results, per ACST, from September 2014:
Statistically significant mean placebo-adjusted reduction of triglycerides of 36.4% at 1 gram and 38.6% at 2 gram daily doses of CaPre
Statistically significant reduction of 5.3% in non-HDL-C using 2 grams of CaPre daily (considered the most accurate risk marker for cardiovascular disease)
No increases in LDL-C (bad cholesterol) and slight increases in HDL-C (good cholesterol)
Clinically meaningful mean placebo-adjusted reduction in VLDL-C of 10.9% and 13.5% at 1 gram and 2 gram daily doses CaPre, respectively (VLDL-C is considered a highly significant predictor of cardiovascular disease)
Statistically significant dose dependent improvement in Omega-3 Index (a risk factor for coronary heart disease)
CaPre shown to be safe, well tolerated and effective
If confirmed in Phase III Trial, these results would make CaPre the best-in-class Omega 3 play.
Phase III Trial Update
Management states that Phase III Trial results will be announced in December 2019. Randomization has been achieved, per management. There have been fewer than expected dropped patients from the highly subscribed trial, and per management, there have been no adverse reactions. Management has announced multiple international patents, demonstrating a readiness to go to market after the trial's announcement in December.
Initially, the approval will be for high triglycerides (greater than 500 mg/dl). This is a 4 million person market in the U.S., with another 13 million globally. The next step would be for the 50 million people in the U.S. that have mildly high triglycerides (greater than 150 mg/dl), with another 333 million people globally.
Phase III Trials may confirm that CaPre has significantly high bio-availability, allowing for the drug to be absorbed with a low-fat diet, as opposed to competing drugs, which should help CaPre succeed in the high and mildly high triglyceride market. Phase III Trials may also confirm that CaPre offers the possibility of improving cholesterol, among other benefits, making it the only Omega 3 play to offer this advantage, which again should solidify its dominant position in the high and mildly high triglyceride market.
In addition, there is a further chance that the Phase III Trial data will also confirm previous findings, of improving cholesterol and/or the lowering of diabetic sugars. The triglyceride opportunity is large on its own, but if Phase III Trial data also confirms these other medical applications, CaPre might just become one of the biggest blockbusters in the market.
Competitor
The most notable competitor to ACST's CaPre, is Amarin's (AMRN) drug Vascepa. In September 2018, Vascepa demonstrated positive results in a study regarding Cardiovascular Disease, and the stock consequently increased from $3/share to $19.01/share recently, or approximately $6.29 billion market capitalization. CaPre and Vascepa are both Omega 3 plays. CaPre is made from krill oil, whereas Vascepa is made from fish oil.
CaPre Vs. Vascepa
Advantages:
Trials have shown that CaPre not only maintains cholesterol, but in fact, from the first two clinical trials, it appears that CaPre may improve cholesterol. Vascepa does not have this capability.
Both CaPre and Vascepa have been targeted for patients with high triglycerides (greater than 500 mg/dl), but also offer viability for patients with mildly elevated triglycerides, due to the limited side effects of the medicine. This label expansion to mild elevation of triglycerides (greater than 150 mg/dl) would offer an enormous market opportunity. 50 million people in the U.S. have mildly high triglycerides (greater than 150 mg/dl), with another 333 million people globally. CaPre has the potential to dominate this mild elevation of triglycerides market, due to the minimal adverse side effects, and outright medical benefits.
CaPre has shown promise in Phase I and Phase II Trials of lowering diabetic sugars, and in fact, 40% of patients in Phase III trials have diabetes, which should offer more validity to this claim. Vascepa does not have this capability.
CaPre has significantly high bio-availability, allowing for the drug to be absorbed with a low-fat diet. Vascepa requires a high-fat diet, which has further implications on cholesterol levels.
Disadvantages:
Vascepa has first-mover advantage. While CaPre has the potential to dominate the market in mild elevation of triglycerides (greater than 150 mg/dl), per above, it will likely need further studies on cardiovascular disease, to fully challenge Vascepa, which may take several more years. That said, if Phase III Trial data is highly successful, this may lead to off-label prescriptions. Also, there might be a chance to piggy back off the outcome studies done by others in the Omega 3 space.
CaPre may cause an allergic reaction in patients that are allergic to shell fish.
The Science, As Per Haywood
Back in 2014 in an interview with Propthink, George Haywood described the science of CaPre and the specific advantages of CaPre versus Vascepa. Since that time and the completion of Phase II Trials, Haywood has become a larger and larger investor in ACST, and today, Phase III Trial results are just months away. Since I am not a scientist, let me defer to Haywood in this section alone, by summarizing Haywood's findings at the time, in these six interesting bullet points that reflect his exact thoughts:
Vascepa is stripped out fish oil. It takes fish oil, which is a healthy ingredient, healthy substance, and strips out half of what's in it. They take out the DHA, and DHA is a very healthy, helpful ingredient.
The nutritional superiority of krill oil is conferred by two ingredients that are not in fish oil: phospholipids and astaxanthin, which is the very powerful antioxidant that's in krill oil.
If you take studies out there that look at the effects of phospholipids on lipid profile (and phospholipids are extremely effective at lowering triglycerides and LDL) and you look at sort of the witch's brew - EPA, DHA, phospholipids, and astaxanthin, which is what krill oil contains - you have that one ingredient that tends to raise LDL, DHA, which Amarin decided to get rid of. But at the same time you have an abundance of phospholipids which are very effective at lowering LDL.
So net-net with krill oil, you get a lowering of LDL and a raising of HDL. And at the same time, you get a very effective lowering of triglycerides.
If you are going to rank four ingredients in descending order of effectiveness at lowering triglycerides, you would start with phospholipids number one most effective; number two DHA; number three EPA; and number four astaxanthin - common sense kind of says that if you've got a drug that consists entirely of number three on the list of effectiveness at lowering triglycerides, and I've got a combination of the most effective, the second most effective, the third most effective, I just want to take a wild guess and say, "My drugs are going to work better." And early work, sort of preliminary results, seem to back up that thesis.
The risks involved in the data here are substantially less than the risks that people in the biotech world are accustomed to when they're waiting for clinical trial results.
Other Support for the Investment Thesis
The former CEO and founder of the company who left ACST several years back, was asking for a large settlement for a dispute over his separation from the company. Just recently in May 2019, he settled his dispute, for an issuance to him of 900,000 new shares of ACST. Assuming that the former founder knows a lot about the CaPre, it would appear likely that he is expecting these shares to be worth a great deal, heading into December's Phase III trial results.
While ACST trades at $1.01/share, Haywood's average price seems to be closer to $1.40/share, but it doesn't seem to bother him and in fact, Haywood has continued to add to his position in a massive way. We have the chance to get better prices on ACST, than one of the best investors in the world.
At $1.01/share, and a $79 million market capitalization, ACST is very small, and would be an ideal acquisition for AMRN. There is enough confirming evidence that ACST poses a real risk to AMRN if the Phase III Trial is successful in December, and as a result, it would make sense for AMRN to mitigate this risk, by acquiring ACST immediately.
Financials
With only six months left before Phase III Trial results, and the boom or bust nature of what will transpire, this is not a typical financial valuation. The following financial considerations are essential:
There is no revenue at ACST. The Income Statement is not applicable in the analysis of value.
Regarding the balance sheet, it would appear that the company has enough cash to last until the end of 2019, in order to complete and announce Phase 3 Trials. Management has said this numerous times in press releases, and other than the risk of delayed results mentioned below, there is no reason to not believe management in this assertion.
If the Phase III Trial results are successful, a capital raise will lead to minimal dilution, due to the lofty price expectation. If the Phase III Trial results are unsuccessful, ACST will likely be bust, making dilution a moot point.
Valuation
Citigroup states that 50 million patients in the United States suffer from high triglycerides, and believes that AMRN will eventually have 2 million of these patients. When this occurs in the next several years, Citi values AMRN at $50/share, or approximately a 163% increase.
ACST appears to have more advantages over AMRN per above, making it potentially the best-in-class Omega 3 play. As a result, one would think that given positive Phase III Trials in December, ACST consequently could be worth as much as AMRN. A $6 billion market capitalization would value ACST at approximately $55.3/share (108.5 million fully diluted shares of ACST), from the recent close at $1.01/share. However, even if we were to discount this by 50% (due to some of the risks), ACST would be worth $27.65/share, given strong Phase III Trial results.
So what should be the expected value today? Even if positive Phase III Trial results are a 30% probability, then the price today should be $8.29/share ($27.65/share * 30%). This is based on the expectation that ACST will be worth zero, if Phase III Trial results fail.
If you agree with this logic, and believe that the market will absorb this information before the announcement of Phase III Trial results, that would be a 720% return in the next 3-6 months, based on the recent close of $1.01/share.
In addition, there is a further chance that the Phase III Trial data will also confirm previous findings, of improving cholesterol and/or the lowering of diabetic sugars. The triglyceride opportunity is large on its own, but if Phase III Trial data also confirms these other medical applications, CaPre might just become one of the biggest blockbusters in the market. For example, the cholesterol-lowering statin market is approximately $20 billion in revenue, or more than 10x larger than the triglyceride market. CaPre seems to have significantly fewer side effects than statins. If either of these other medical applications appear to be confirmed by the Phase III Trial results, then the price target may surpass AMRN's market capitalization of $6B+, valuing ACST at over $55.3/share.
Downside Risks
Although there is a lot to be excited about, and it appears that the market is greatly mispricing the value of ACST, there are downside risks that must be considered:
There is a risk that Phase III Trials get delayed, and the company runs out of cash, creating the need for a capital raise and further dilution.
If Phase III Trials of CaPre fail, ACST will likely be worth $0.
There is a risk that Phase III Trial results do not confirm that CaPre lowers cholesterol, but simply maintains it. This will limit the further upside of also taking market share from the cholesterol reducing market.
There is a risk that Phase III Trial results do not confirm that CaPre lowers diabetic sugars. This will limit the further upside of CaPre in other medical applications.
Vascepa has first-mover advantage. While CaPre has the potential to dominate the market in mild elevation of triglycerides (greater than 150 mg/dl), per above, it will likely need further studies on cardiovascular disease, to fully challenge Vascepa, which may take several more years. While the hope is that if Phase III Trial data is highly successful, this may lead to off-label prescriptions and also allow ACST to piggy back off the outcome studies done by others in the Omega 3 space, this is not a guarantee.
Others in the Omega 3 space may emerge. For instance, Matinas BioPharma (MTNB), shows promising studies, versus Vascepa, and does it in a "more traditional" fish oil, that may be easier for physicians to adapt to.
Conclusion
ACST's science has the potential of having a significant impact on the large cardiovascular industry, and the Phase III Trial results are only 6 months away. Even if positive Phase III Trial results are a 30% probability, then the price today should be $8.29/share. And if Phase III Trials demonstrate strong results, it appears that this little biotech might just be offering a realistic 30-to-1 payoff, with a fraction of the risk.
Disclosure: I am/we are long ACST. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
Heart Attacks Make a Comeback
Here is the entire article for those without a subscription:
Heart Attack at 49—America’s Biggest Killer Makes a Deadly Comeback
Younger people, women and nonsmokers are more likely to be victims of the crisis in cardiovascular health, driven by skyrocketing obesity and diabetes
By Betsy McKay
June 21, 2019 10:58 am ET
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One of America’s greatest achievements over much of the past century has been a huge decline in death rates from heart disease and strokes. Anti-smoking campaigns, medications to control blood pressure and cholesterol, and surgical advances have extended millions of lives, fundamentally reshaping the U.S. population.
Now, progress has stalled. That’s helping drive down life expectancy in the U.S. after decades in which each generation of Americans could expect to live longer than the one that came before.
The death rate for cardiovascular disease—which includes heart disease and strokes—has fallen just 4% since 2011 after dropping more than 70% over six decades, according to mortality statistics from the Centers for Disease Control and Prevention.
Particularly alarming is that the death rate is actually rising for middle-aged Americans.
Health Reversal
The reduction in heart disease had been sopromising that it was expected to fall belowcancer to become the No. 2 cause of death inthe U.S. by 2020—but that no longer seemslikely.
Source: Centers for Disease Control and Prevention
.deaths
Heart disease
Cancer
2000
’05
’10
’15
0
200,000
400,000
600,000
800,000
Heart diseasex2016x635,260 deaths
The overall cardiovascular-disease death rate is an under-recognized contributor to the recent decline in U.S. life expectancy. While that has been driven mostly by deaths from drug overdoses and suicides, improvements in cardiovascular health are no longer providing a counterbalance.
Among victims are John Singleton, the 51-year-old filmmaker behind the movie “Boyz N The Hood,” and actor Luke Perry, the 52-year-old former star of “Beverly Hills, 90210.” Both died of strokes earlier this year.
Heart disease was once on course to fall below cancer as the nation’s leading cause of death, a change public-health statisticians most recently predicted would occur by 2020. No longer, said Robert Anderson, chief of the CDC’s mortality statistics branch. “It’s highly unlikely given the current trend that there will be a crossover anytime soon,” he said.
The obesity epidemic and related rise in the prevalence of Type 2 diabetes are key culprits in the new wave of cardiovascular disease mortality, researchers and cardiologists say. Studies have linked obesity and diabetes to high blood pressure and other conditions that increase the risk of heart attacks, strokes and heart failure.
“It’s a really major driver,” said Stephen Sidney, director of research clinics at the Kaiser Permanente Northern California Division of Research, who has studied the changes in cardiovascular disease mortality rates. Obesity began rising across the U.S. population in the early 1980s, and Type 2 diabetes rates accelerated several years later. That has given both “enough time to really impact in a negative way on the population,” Dr. Sidney said.
Dr. Steven Nissen, at the Cleveland Clinic, said cardiovascular-disease patients nowadays are younger, more obese, much less likely to be smokers and include more women. PHOTO: DUSTIN FRANZ FOR THE WALL STREET JOURNAL
Nearly 40% of U.S. adults age 20 and over are obese, another 32% are overweight, and 9.4% of U.S. adults 18 and over have diabetes, according to the CDC.
The consequences of obesity are eroding the enormous gains brought about by public-health campaigns against smoking, along with medical innovations such as cholesterol-lowering statin drugs. Statins, which were introduced starting in the late 1980s, have prevented millions of Americans from developing life-threatening blockages in their blood vessels that can cause heart attacks.
“You couldn’t see the effects of the obesity epidemic when we were in the process of getting people to use statins,” said Steven Nissen, chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic. Now, he said, “we’ve got a counterforce here.”
Progress Stalls
After 60 years of steep declines, cardiovascular and heart disease death rates have been nearly stagnant since 2011.
The trend is especially bad for middle-aged Americans, who are more likely to die of cardiovascular disease now than in 2011, reversing a decadeslong improvement.
Death rate from major cardiovascular disease for people ages 45 to 64
Death rates, all ages
1,000
deaths per 100,000
225
deaths per 100,000
Cardiovascular disease*
750
200
500
175
Heart disease
250
150
0
125
1900
’20
’40
’60
’80
2000
2000
’05
’10
’15
*Includes heart disease and stroke
Source: Centers for Disease Control and Prevention
Oscar Washington Jr., just 49 years old, wasn’t feeling well when he got out of the shower one morning in April 2017 after a workout. “I think I got overheated,” the utility company vice president told his wife, Doris. He lay down on their bed.
His arm was hurting, and he started to twist and turn. Ms. Washington became worried. She wondered if he was having a heart attack. Mr. Washington’s father had passed away just four months earlier, of heart disease, and the couple was co-chairing a coming American Heart Association ball.
She gave her husband some aspirin and an ice pack. Then she helped him get dressed and drove him to the emergency room. Doctors there found him in the midst of a deadly heart attack, with blockages in a main artery on the heart and two others. Despite an emergency triple bypass operation, Mr. Washington died two weeks later of complications of his condition.
A family photo of Mr. Washington and his daughters in 2016. PHOTO: ANDREA MORALES FOR THE WALL STREET JOURNAL
Mr. Washington was an active member of his community who left behind a wife and two daughters. Hefty for his height, at 5 feet 6 inches and 250 pounds at the time of his heart attack, he had been on blood-pressure and cholesterol medications for years. But he worked out regularly and hadn’t been diagnosed with a heart condition, his wife said.
“He didn’t have any symptoms,” said Ms. Washington, a 52-year-old agriculture-agency official in Little Rock, Ark., who has managed her grief and loneliness by staying busy with work, caring for her daughters, now ages 20 and 13, and setting up a scholarship fund for Arkansas high-school students in her husband’s name.
Today’s heart-disease victim is vastly different from the classic patient doctors and the public were trained to recognize a half-century ago: a smoker, usually male, whose LDL, or “bad” cholesterol numbers were “sky high,” said Dr. Nissen. Now, the patients are younger, more obese, much less likely to be smokers and include more women, he said. Many are unaware that they are at risk.
Where Heart Disease Death Rates Are Rising
Death rates for people aged 55-64 are increasing in the south, where they are already high, and across the country, especially in rural and smaller metropolitan areas.
Percentage increase in heart disease death rates ages 55-64, 2010-15
2%
10%
Decrease/no change
50 highest increases
This section of California includes Eureka and Red Bluff, small- to medium-size metros.
These counties had high death rates to begin with in 2010, a common trait of many counties with strong increases.
These mostly rural counties in eastern Michigan and southeastern Georgia are among several areas with consistently high rates of increase among all age groups.
Heart disease deaths per 100,000 people
ages 55-64 , 2015
Percentage of counties with an increase
in heart disease death rates, 2010-15
150
250
350
30%
40%
50%
60%
70%
COUNTY TYPE
AGE GROUP
45-54
55-64
65-74
35-44
Large central metro
Large fringe metro
Medium metro
Small metro
Nonmetropolitan
Noncore (most rural)
Source: Centers for Disease Control and Prevention
“I’ve been working in a coronary-care unit for 40 years, and the patient that comes in now looks completely different from the patient when I was starting out,” he said. “It is an absolutely striking difference.”
He calculated the median BMI of patients in the unit one day recently. Obesity is defined as a BMI of 30 or above. The unit’s median was 34, he said. Several patients had BMIs over 40.
“I think obesity is the new smoking in terms of contribution to heart disease,” said Sadiya Khan, a cardiologist and assistant professor of medicine at Northwestern University Feinberg School of Medicine. “We’ve made such great progress in coming up with smoking-cessation programs. For physical activity, healthy diet and weight loss we haven’t found the right approach.”
Dr. Khan was lead author of a 2018 study in the journal JAMA Cardiology showing the lifetime risk of cardiovascular disease and deaths from it to be higher for overweight and obese adults than for people with a normal body-mass index. The researchers analyzed data from more than 190,000 participants in 10 study cohorts going back several decades.
Cardiovascular-disease death rates rose 1.5% between 2011 and 2017 for 45-to-64-year-olds, according to CDC statistics. That includes increases in the rates of deaths from strokes, hypertensive heart disease and heart failure—all diseases associated with obesity.
Julie Kubala had a heart attack in 2016 and is now working to change a lifetime of habits. PHOTO: TIM GRUBER FOR THE WALL STREET JOURNAL
Older people still account for most cardiovascular deaths, but the cardiovascular-disease mortality rate for people 75 and older—who had benefited from the treatment advances and smoking cessation—actually fell 6% in the same years.
“I have seen 30-year-olds coming in with heart attacks,” said Robert Sanchez, medical director of cardiovascular medicine at HCA West Florida’s Northside Hospital and Tampa Bay Heart Institute. Over his 28-year career, he said, he has started to see younger patients. He also has more patients in their 90s, who have survived longer due to better health care.
The past success curbing cardiovascular deaths was hard-won. Heart disease and strokes were dreaded killers in the early- and mid-20th century. Scientists and doctors were only starting to understand the risks of smoking, high cholesterol and high blood pressure on the heart, and there were few treatments to prevent heart disease or save people.
The death rate fell steadily and sharply beginning in midcentury as public-health officials waged a war on smoking and exhorted people to eat more fruits and vegetables and to exercise. Medical advances such as coronary-artery-bypass surgery, defibrillators, better blood-pressure drugs and statins also saved lives.
The progress was so great that an editorial in the journal Science in 1996 posed the question, “Heart attacks: Gone with the century?”
But heart disease is still the nation’s top killer, and strokes, the other main component of cardiovascular disease, ranked fifth in the latest data.
Growing Risk for Hearts
Obesity and diabetes—factors that contribute to cardiovascular disease—have skyrocketed in the U.S. since the 1980s, and more people have uncontrolled high blood pressure.
Percentage who are obese*
Percentage who have diabetes
People taking medication for high blood pressure*
40
%
10
%
100
%
Have it under control
8
30
75
6
20
50
4
Don’t have it under control
10
25
2
0
0
0
2000
’04
’08
’12
’16
1988-94
2000
’04
’08
’12
’16
1980
’90
2000
’10
*Data are for people age 20 and older and are for two-year surveys ending in the year shown
Sources: Centers for Disease Control and Prevention (obesity, diabetes); American Heart Association (blood pressure)
Obesity and diabetes add to common risk factors such as high blood pressure that already made heart disease and stroke widespread. About 46% of American adults have high blood pressure, or hypertension, under guidelines released in 2017 by the American College of Cardiology and the American Heart Association. Of that group, three-quarters either aren’t being treated with medications or don’t have it under control, according to a study in Circulation, an AHA journal. High blood pressure can be caused by hereditary factors, too much sodium, excess weight and other factors.
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The family of Mr. Singleton, the filmmaker, said after his death that he struggled with high blood pressure, a condition that often affects African-Americans earlier in life and more severely than people of other racial backgrounds in the U.S.
In obese people, excess weight leads to elevated blood pressure in several ways, including by increasing circulating blood volume and stiffening or narrowing blood vessels. The high blood pressure, in turn, puts strain on the heart and arteries, potentially leading to a heart attack. It can make blood vessels in the brain clog or burst, causing a stroke. It can also lead to heart failure.
People with obesity and diabetes also tend to have high triglycerides, a sign of poor metabolic health, a measure of factors such as blood sugar and blood pressure, and other metabolic abnormalities that are damaging to the heart and blood vessels. Abdominal fat produces proteins that drive inflammation, which research has shown to be linked to heart disease and stroke.
Staff at the Cleveland Clinic, which is known for its Heart and Vascular Institute. PHOTO: DUSTIN FRANZ FOR THE WALL STREET JOURNAL
Heart experts say they need new tools and approaches, because today’s cardiovascular disease patients differ from those of past decades, and they need to reach people young, before obesity and diabetes develop.
Researchers and doctors also need “more granular, more accurate, more timely” digital health-care data from multiple sources to verify and better understand the trend the mortality rates point to, said Harlan Krumholz, a Yale University cardiologist and health-care researcher. “We have to have great respect for the signal but need to be working to understand the signal,” he said.
Julie Kubala was at a movie with her husband when she developed a pounding headache and felt mild discomfort “in my breastbone.” She thought it was aftereffects of the flu that she was recovering from.
Mr. Washington, shown in 2015, had been on blood-pressure and cholesterol medications for years, but he also worked out regularly and hadn’t been diagnosed with a heart condition. PHOTO: WASHINGTON FAMILY
The next morning, the pain was still there. She and her husband went to the emergency room. She was given an electrocardiogram, which showed she was having a heart attack. Doctors found an 80% blockage in her left anterior descending artery, a major pipeline of blood to the heart, and immediately placed a stent.
Ms. Kubala, who has obesity and Type 2 diabetes, was terrified from the experience, in March 2016. Until the heart attack, she had never spent a night in the hospital. “You have no idea what to do with this body now that it has betrayed you,” said the 51-year-old, who lives in Superior, Wis. “You realize that you don’t have the time that other people have.”
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How to Cut Your Risk
She attended a cardiac-rehabilitation program, and connected with other patients on an American Heart Association support network for help dealing with the trauma and fear of mortality that patients can develop in the aftermath of a heart attack. She is exercising more and watching what she eats.
Still, she said, “the battle continues.” Her blood sugar is higher than she wants it to be. The medications she is on make it hard to exercise intensely, and she spends long hours at a clerical job at a health clinic. “I can’t lose a pound to save my life,” she said.
Ms. Kubala said she is working to change a lifetime of habits that go back to being overweight in childhood and several years of jobs in fast-food establishments. Diabetes runs in her family but no one ever talked about the disease, risk factors, or dangers of burgers, fries and soda when she was growing up, she said. “I am of a generation that was never educated in any of that,” she said.
The Washington family in Little Rock. PHOTO: ANDREA MORALES FOR THE WALL STREET JOURNAL
Write to Betsy McKay at betsy.mckay@wsj.com
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