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I would not be surprised if Amarin management is currently working with ISS and/or Glass Lewis to see if these proxy voting advisory companies would support the WHITE CARD agenda. As per the Okapi Partners website: "We provide input on document drafting as well as advice regarding communication with proxy voting advisory agencies such as ISS and Glass Lewis."
Looks like some house cleaning is continuing. Both, CFO Holder and COO McGee were hired by the former CEO Michael Perry who himself was abruptly replaced last September.
The Japanese market approval was submitted by Cosmotec on 2/15/19 and at the time shareholders were told it would take 9-months to a year to reach a regulatory approval decision. Based on this timeline, under normal circumstances it would appear that the regulatory decision could have been reached prior to the start of the pandemic.
From today's 10Q filing:
As has been a practice in the generic pharmaceutical industry, on April 27, 2021, Dr. Reddy’s filed a complaint against the Company in the United States District Court District of New Jersey (case no. 2:21-cv-10309) alleging various antitrust violations stemming from alleged anticompetitive practices related to the supply of active pharmaceutical ingredient of VASCEPA. Damages sought include recovery for alleged economic harm to Dr. Reddy’s, payors and consumers, treble damages and other costs and fees. Injunctive relief against the alleged violative activities is also being sought by Dr. Reddy’s. Amarin believes it has valid defenses and will vigorously defend against the claims. Amarin has also received a civil investigative demand from the U.S. Federal Trade Commission and a subpoena from the New York Attorney General with respect to information on the same topic. The Company believes such contact from the governments may have been prompted by a generic competitor. Amarin is cooperating with the government agencies.
Per the more recent 1/12/21 press release, 9 additional patients have been enrolled in the pivotal study of the RECELL System to treat stable vitiligo.
@yada202
a mixed shelf is a registration form that is filed with the regulatory authorities (i.e., the SEC in the US) to be able to do a public offering of various classes of securities, including common stock, preferred stock, warrants or combinations thereof.
RCEL's filing yesterday is not yet effective. The Company will have to file another form "Notice of Effectiveness" before it is allowed to sell the securities that are offered as part of the mixed shelf.
Poster Melody432 has correctly pointed out the reasons for the filing in post 6539.
VVV
A $200 million mixed shelf has been filed after market close today.
Here are brief professional bios of the two co-authors Curfman and Pencina who worked with Bhatt on the "Federal Judge Invalidates Icosapent Ethyl Patents - But Based on a Common Statistical Mistake" paper.
https://icer-review.org/people/gregory-curfman-md/
Deputy Editor | JAMA
Gregory Curfman, MD, is the Deputy Editor at the Journal of the American Medical Association (JAMA). Dr. Curfman was previously the editor in chief of Harvard Health Publications, the publishing division of Harvard Medical School, and, prior to assuming this role, had a 28-year career as an editor of the New England Journal of Medicine (NEJM), most recently as the Journal’s executive editor. He has written numerous editorials and Perspective articles for NEJM and has published widely in other medical journals. He is a member of the Faculty of Medicine at Harvard Medical School (HMS) and holds an affiliated faculty appointment in the HMS Department of Health Care Policy. He is also a member of the affiliated faculty of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School. Dr. Curfman, who received his education at Princeton University and Harvard Medical School, is a board-certified cardiologist and internist.
https://medschool.duke.edu/about-us/our-faculty/michael-pencina-phd
Michael Pencina, PhD
Vice Dean for Data Science and Information Technology
As vice dean of data science and information technology, Dr. Pencina is responsible for developing and implementing quantitative science strategies as they pertain to the education and training, and laboratory, clinical science, and data science missions of the School of Medicine. He leads the School’s IT strategic direction and investments, working in collaboration with the vice presidents and chief information officers of Duke Health and Duke University’s Office of Information Technology.
Dr. Pencina is a professor of Biostatistics and Bioinformatics at Duke University and served as director of Biostatistics at Duke Clinical Research Institute (DRCI). Dr. Pencina is an internationally recognized expert in risk prediction model development and evaluation. The methods for quantifying improvement in model performance proposed in his research have been recommended by expert panels and guideline groups. Dr. Pencina is actively involved in the design, conduct and analysis of clinical studies with particular focus on novel and efficient designs and applications of machine learning for medical decision support. He interacts regularly with investigators from academic and industry institutions as well as with the Food and Drug Administration. Dr. Pencina has co-authored over 300 manuscripts in peer-reviewed journals. He serves as deputy editor for Statistics at JAMA-Cardiology and associate editor for Statistics in Medicine.
Dr. Pencina received his PhD in Mathematics and Statistics from Boston University. He joined the Duke faculty in 2013. Prior to joining Duke, Dr. Pencina served as an associate professor in the Department of Biostatistics at Boston University and the Framingham Heart Study and as director of Statistical Consulting at the Harvard Clinical Research Institute.
Is this the Mori et al study that everybody is talking about?
Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men.
Mori TA, Burke V, Puddey IB, Watts GF, O'Neal DN, Best JD, Beilin LJ.
Am J Clin Nutr. 2000 May;71(5):1085-94.
The American Journal of Clinical Nutrition is a widely respected, peer-reviewed clinical research journal.
From their website:
Established in 1952, AJCN is the highest peer-reviewed journal in its category, with a 2017 Impact Factor of 6.549 and a standing in the top 5% of all journals included in the Journal Citation Reports from Clarivate Analytics.
https://academic.oup.com/ajcn/pages/ajcn_editor
Interesting editorial comments from Steven Nissen regarding "vulnerable plaque" related imaging research.
Members on this board will recall that Budoff's EVAPORATE trial interim analysis that was presented at the AHA meeting in November last year failed to meet its primary endpoint (which was the change in "low-attenuation plaque" [=vulnerable plaque]) because the steering committee had changed it from the original “non-calcified plaque” primary endpoint.
The editorial comments by Nissen that are now published in the Journal of the American College of Cardiology raise many questions regarding the line of research that has used various imaging techniques to detect vulnerable plaque.
A quote often attributed to Albert Einstein defines insanity as “doing the same thing over and over again and expecting different results.” That’s exactly what has happened with efforts to identify the elusive entity of “vulnerable plaque” using various coronary imaging modalities. Proponents of this concept have tried for decades to demonstrate the existence of a specific plaque phenotype that portends major adverse outcomes, such as myocardial infarction or sudden cardiac death. In many cases, an underlying motivation for identifying vulnerable plaques is the notion that interventional cardiologists could place a stent within such plaques, thereby avoiding untoward outcomes. Now, after a long series of failures, it seems abundantly clear that the entire concept of vulnerable plaque is fundamentally flawed and reflects an overly simplistic view of the pathophysiology underlying coronary events.
Unfortunately, the full editorial paper is not open access but if you do have access, it can be found here:
Source: Journal of the American College of Cardiology
Title: Vulnerable plaque and Einstein's definition of insanity
Volume:75, Issue:12, pp. 13830-1385
Publication Date: 3/31/20
ACC.20 World Congress of Cardiology Virtual
Selected abstracts are available online now:
https://www.abstractsonline.com/pp8/#!/8992/presentation/19854
1212-205 / 205 - EICOSAPENTAENOIC ACID INHIBITS OXIDATION OF VERY LARGE DENSITY LIPOPROTEINS (VLDL) IN A DOSE-DEPENDENT MANNER OVER TIME AS COMPARED TO DOCOSAHEXAENOIC ACID IN VITRO
March 28, 2020, 3:45 PM - 4:30 PM eAbstract Virtual Hall
________________________________________
Link to Presentation
eAbstract Presentation View
Authors
R. Preston Mason, Samuel C. R. Sherratt, Brigham & Women's Hospital, Harvard Medical School, Beverly, MA, USA, Elucida Research LLC, Beverly, MA, USA
Abstract
Background: Eicosapentaenoic acid (EPA) reduces oxidation of LDL in patients with hypertriglyceridemia, a benefit that may contribute to reduced cardiovascular (CV) risk. EPA may specifically inhibit oxidation of triglyceride-rich lipoproteins such as VLDL, through a free radical scavenging mechanism. We compared the dose and time-dependent effects of EPA and docosahexaenoic acid (DHA) on oxidation of VLDL at a pharmacologic dose (4 g/d).
Methods: VLDL was isolated from human plasma and incubated in the absence (vehicle) or presence of EPA or DHA over a range of concentrations that match plasma levels (1-5 µM). We also tested the combination of these fatty acids with ATM. All samples were then subjected to oxidation that was measured over eight hours.
Results: EPA inhibited VLDL oxidation in a highly dose- and time-dependent manner. At higher concentrations (>2 µM), EPA significantly inhibit LDL oxidation through 8 hr. At 5 µM, EPA inhibited LDL oxidation by 94% (p<0.001) at 8 hr. Large effect shifts were observed with relatively small concentration shifts. By contrast, DHA had limited effects on VLDL oxidation over time. Even at the highest concentration (5 µM), DHA inhibited VLDL by only 38% at 4 hr and lost activity completely by 8 hr. The antioxidant activity of EPA in VLDL was enhanced with ATM at an equimolar concentration (1 µM), whereas DHA showed no such benefit.
Conclusion: These data support concentration-dependent antioxidant effects for EPA that require pharmacologic concentrations for sustained activity over time. The antioxidant benefits with EPA in VLDL were not reproduced with DHA and enhanced with a statin. As oxidation of ApoB particles contributes to plaque instability and reduced clearance, the inhibition of this process by EPA may provide a potential mechanism of atheroprotection and warrants further investigation.
ACC.20 World Congress of Cardiology Virtual
Selected abstracts are available online now:
https://www.abstractsonline.com/pp8/#!/8992/presentation/23391
1161-128 / 128 - COST-EFFECTIVENESS OF ICOSAPENT ETHYL IN US REDUCE-IT PATIENTS
March 28, 2020, 12:30 PM - 1:15 PM eAbstract Virtual Hall
________________________________________
Link to Presentation
eAbstract Presentation View
Authors
William S. Weintraub, Deepak Bhatt, Zugui Zhang, Cheng Zhang, Dolman Sarahfaye, William E. Boden, Philippe Gabriel Steg, Michael Miller, Eliot Brinton, Jordan King, Adam Bress, Terry Jacobson, Jean Claude Tardif, Christie M. Ballantyne, Paul Kolm, MedStar Washington Hospital Center, Washington, DC, USA
Abstract
Background: The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) showed that among US patients with elevated triglyceride levels on statin therapy (n=3,146), the risk of cardiovascular disease events was reduced by 31% in those randomized to 4g of icosapent ethyl daily compared to placebo. We determined cost-effectiveness of icosapent ethyl compared to standard care in US patients.
Methods: This was a patient level cost-effectiveness analysis of US subjects using data from REDUCE-IT. Costs were based on Optum costs for those under age 65 years and Medicare for those at or over age 65. Icosapent ethyl cost was $4.16 a day, based on SSR net cost. Utility was from the literature. Quality adjusted life years (QALYS) were calculated as survival x utility. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), defined as cost per QALY gained. Where icosapent ethyl was dominant (i.e., better outcome at lower cost), the ICER was not calculated. The percent dominant was calculated at thresholds of $50,000, $100,000, and $150,000 per QALY gained. The time horizon was in-trial, the perspective was payer. The subgroups of primary vs secondary prevention were assessed.
Results: Overall, icosapent ethyl was a dominant strategy in 85.2% of simulations, and the probability of being cost-effective was, at the $50,000, $100,000, and $150,000 thresholds, shown in 99.7%, 99.7%, and 99.9% of simulations, respectively. In primary prevention, the ICER was $36,118/QALY gained, and the probability of icosapent ethyl being cost-effective was, at the $50,000, $100,000, and $150,000 thresholds, shown in 62.3%, 79.1%, and 83.5% of simulations, respectively. In secondary prevention, icosapent ethyl was dominant in 98.6% of simulations, and the probability of being cost-effective was, at the $50,000, $100,00, and $150,000 thresholds, shown in 100% of simulations.
Conclusion: In the United States, icosapent ethyl was shown to be dominant overall, cost-effective in primary prevention, and dominant in secondary prevention.
@jaspirr, see post #227412 regarding MRCs (Steven Giardino) previous efforts in this regard.
Amarin / Vascepa related upcoming presentations at the American College of Cardiology meeting in Chicago, IL (3/28/20-3/30/20)
COST-EFFECTIVENESS OF ICOSAPENT ETHYL IN US REDUCE-IT PATIENTS (3/28/20)
Authors: William S. Weintraub, Deepak Bhatt, Zugui Zhang, Cheng Zhang, Dolman Sarahfaye, William E. Boden, Philippe Gabriel Steg, Michael Miller, Eliot Brinton, Jordan King, Adam Bress, Terry Jacobson, Jean Claude Tardif, Christie M. Ballantyne, Paul Kolm, MedStar Washington Hospital Center, Washington, DC, USA
https://www.abstractsonline.com/pp8/#!/8992/presentation/23391
REDUCE-IT ELIGIBILITY AND PREVENTABLE FIRST AND TOTAL CARDIOVASCULAR EVENTS IN THE US POPULATION: AN ANALYSIS OF THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY (NHANES) (3/29/20)
Authors: Nathan D. Wong, Wenjun Fan, Peter Toth, Craig Granowitz, Sephy Philip, University of California, Irvine, Irvine, CA, USA, Amarin Corporation, Bridgewater, NJ
https://www.abstractsonline.com/pp8/#!/8992/presentation/23431
EICOSAPENTAENOIC ACID INHIBITS HIGH DENSITY LIPOPROTEIN (HDL) OXIDATION IN A SYNERGISTIC MANNER IN COMBINATION WITH ATORVASTATIN IN VITRO (3/29/20)
Authors: R. Preston Mason, Samuel C. R. Sherratt, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA, Elucida Research LLC, Beverly, MA, USA
https://www.abstractsonline.com/pp8/#!/8992/presentation/19855
Eicosapentaenoic Acid Levels in REDUCE-IT and Cardiovascular Outcomes (3/30/20)
Authors: Deepak L. Bhatt, Michael Miller, Gabriel Steg, Eliot Brinton, Terry Jacobson, Steven Ketchum, Ralph Doyle, Rebecca Juliano, Lixia Jiao, Christina Copland, Craig Granowitz, Peter Libby, Paul Ridker, Jean-Claude Tardif, Christie Ballantyne, Brigham and Women's Hospital, Boston, MA, USA, Harvard Medical School, Boston, MA, USA
https://www.abstractsonline.com/pp8/#!/8992/presentation/23924
This is part of the "Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials" session. I consider it very likely that we will see publication of the full article concurrently.
also of interest:
VASCEPA® (icosapent ethyl): Elevating the Standard of Care (3/28/20)
DESCRIPTION: There is an urgency to treat Persistent Cardiovascular Risk (P-CVR) as it remains high despite statin-based standard-of-care therapy in patients with elevated triglycerides. In this program, we will review data from a practice changing trial that provides a new therapeutic option to elevate the current standard of care. This event is not part of ACC.20/WCC, as planned by its Program Committee, and does not qualify for continuing medical education (CME), continuing nursing education (CNE) or continuing education (CE) credit. Sponsored by Amarin Pharma, Inc
https://www.abstractsonline.com/pp8/#!/8992/session/1179
ASSOCIATION OF HDL SUBCLASSES WITH BASELINE CORONARY PLAQUE BURDEN BY CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY (CCTA) FROM EVAPORATE (EFFECT OF VASCEPA ON IMPROVING CORONARY ATHEROSCLEROSIS IN PEOPLE WITH HIGH TRIGLYCERIDES TAKING STATIN THERAPY) TRIAL (3/28/20)
Authors: suvasini lakshmanan, Chandana Shekar, Suraj Dahal, Afiachukwu Onuegbu, April Kinninger, Andrew Cai, Divya Birudaraju, Lavanya Cherukuri, Ilana Golub, Vahid Rezvanizadeh, Christopher Dailing, Ferdinand Flores, Sajad Hamal, Sion K. Roy, John Nelson, Matthew J. Budoff, Lundquist Institute for Biomedical innovation, Torrance, CA, USA
ASSOCIATION OF INFLAMMATORY MARKERS WITH BASELINE CORONARY PLAQUE VOLUMES BY CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY (CCTA) FROM EVAPORATE (EFFECT OF VASCEPA ON IMPROVING CORONARY ATHEROSCLEROSIS IN PEOPLE WITH HIGH TRIGLYCERIDES TAKING STATIN THERAPY) TRIAL
Authors: Suvasini Lakshmanan, Chandana Shekar, Suraj Dahal, Afiachukwu Onuegbu, April Kinninger, Andrew Cai, Vahid Rezvanizadeh, Ilana Golub, Divya Birudaraju, Lavanya Cherukuri, Sajad Hamal, Christopher Dailing, Ferdinand Flores, Sion K. Roy, John Nelson, Matthew J. Budoff, Lundquist Institute for Biomedical innovation, Torrance, CA, USA
https://www.abstractsonline.com/pp8/#!/8992/presentation/19939
EFFECT OF MINERAL OIL ON PLASMA LIPIDA: A META-ANALYSIS (3/28/20)
Authors:Joshua Radel, Danielle Pender, Sachin Shah, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA, David Grant Medical Center, Travis Air Force Base, CA, USA
https://www.abstractsonline.com/pp8/#!/8992/presentation/23385
Canadian Review Timeline
icosapent ethyl
Last Updated: October 31, 2019
Result type: Reports
Project Number: SR0619-000
Product Line: Common Drug Review
Generic Name: icosapent ethyl
Brand Name: Vascepa
Manufacturer: HLS Therapeutics
Indications: Ischemic events in statin-treated patients
Manufacturer Requested Reimbursement Criteria1: To reduce the risk of ischemic cardiovascular events (death due to cardiovascular event, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, and unstable angina) in statin-treated patients with elevated triglycerides and other risk factors such as: established cardiovascular disease, or at high risk for cardiovascular disease.
Submission Type: New
Project Status: Active
Biosimilar: No
Companion Diagnostics: No
Fee Schedule: Schedule A
The requested reimbursement criteria are provided by the applicant and do not necessarily reflect the views of CADTH. Reimbursement criteria from CADTH will be documented in the final recommendation, if applicable.
Key Milestones
Call for patient input posted May 17, 2019
Patient group input closed July 09, 2019
Clarification:
- No patient input submission received
Submission received June 17, 2019
Submission accepted for review July 02, 2019
Review initiated July 03, 2019
Clarification:
- Submission temporarily suspended pending receipt and review of information
- Additional information has been received and the temporary suspension of the review has been lifted
Draft CADTH review report(s) sent to sponsor October 22, 2019
Comments from sponsor on draft CADTH review report(s) received October 31, 2019
CADTH review team's comments on draft CADTH review report(s) sent to sponsor November 29, 2019
Canadian Drug Expert Committee (CDEC) meeting December 11, 2019
CDEC recommendation sent to sponsor and drug plans December 23, 2019 To January 02, 2020
Source: https://cadth.ca/icosapent-ethyl
Regarding "I can honestly say that the Krill People, ACST, are liars and their lying goes back many years..."
FWIW....I did a little DD into the people behind the early research work done at Acasti/Neptune. It looks like JSS Medical Research Inc (which is listed on clinicaltrials.org as sponsor of the company’s 2 phase II trials) is a CRO that was founded by Dr. John S. Sampalis, a Professor of Surgery and Epidemiology & Biostatistics in the Faculty of Medicine of McGill University and the University of Montreal. He is the brother of Acasti/Neptune’s Dr. Tina Sampalis, (she received an MD in Oncology in Greece and then a PhD in Epidemiology and Experimental Surgery at McGill) who holds the key patents in her name, and in turn was a lead researcher (with Ruxandra Bunea as PI on one of the studies) on Acasti/Neptune’s 2003/2004 publications. Ruxandra Bunea was an Assistant Professor in the Department of Internal Medicine at McGill University at the time.
Of these three, John Sampalis has a current regular established research publication record (PubMed shows 114 citations but topically they are all over the place which suggests his coauthorship on these papers is related to his biostatistics expertise). Tina Sampalis (=Fotini Sampalis) has 14 citations involving mostly breast cancer research but nothing is cited after 2008. Ruxandra Bunea herself has only the two early Neptune Krill Oil publications for which I provide the links below.
http://archive.foundationalmedicinereview.com/publications/8/2/171.pdf
http://archive.foundationalmedicinereview.com/publications/9/4/420.pdf
ClinicalTrials.gov has the EVAPORATE trial estimated study completion date listed as September 2019. The study completion date refers to the date that the last study participant is expected to undergo his/her final study related test evaluations.
The last update posted to the site was on 2/15/19 where the study status changed from "Recruiting" to "Active, not recruiting." I take this to mean that all subjects were enrolled in the study at that time.
https://clinicaltrials.gov/ct2/show/NCT02926027
Giardino already tried that several years ago by offering his services as "Blue Note Investing."
https://angel.co/company/blue-note-investing
Product
The product is basically my brain! I'm a bit of a savant with numbers. Genetics I suppose. High IQ. My late paternal grandfather was actually a bookeeper for some notorious figures in the 60s. I digress.. Here's the thing--I have the ability to find high yield moments of investing in carefully chosen securities. Over the last few years I've achieved fantastic results: 74%, 58%, and 116% respectively (well, 116% is still in flux--we have a bit under two weeks left. And I got there with the help of buying SRPT at $13.12 on the dip, and selling today at $19.40--a rare, but highly lucrative find).
The problem is, I'm not wealthy by any means, and the meager sums I've been producing seem almost a waste of good trading: my account would have grown to just under $30k had I not withdrawn profits. Of course, if I had started with, say, $500k, instead of $5k, it would have grown to almost $3mm (yes, volume would have allowed the higher money trades... mostly).
Technology
Now what if I could find a number of wealthy investors who would be willing to risk, say, 1% of their portfolios on some 30-something from Albany, NY, who claims to know his way around the market? Obviously a high risk scenerio(?), but I would do so for no fees, only a cut of the profits. In fact, should the investments lose ground, I would consider it a negative commission. In other words, say you lost 10% in two months, and then gained 15% from there in one month. I would receive commission from just the 5%. Also, I would deduct commission quarterly only (or upon your withdrawl).
The numbers I'm thinking of are as follows: if your portfolio under my complete management grows 10%, you receive 7% and I, 3%. If it grows 20%, you receive 16% and I, 4%. If it grows 30%, you receive 25% and I, 5%, etc. Therefore the more you make, the more I make, even though the more you make the LOWER the % you are giving me (relative to your gain).
Don't forget...From Bhatt et al "REDUCE-IT USA: Results from the 3,146 Patients Randomized in the United States" recent Circulation paper
Results: A total of 3,146 USA patients (38.5% of the trial) were randomized and followed for a median of 4.9 years; 32.3% were women, 9.7% Hispanic. The primary endpoint occurred in 24.7% of placebo versus 18.2% of icosapent ethyl patients [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.59-0.80, p=0.000001]; the key secondary endpoint occurred in 16.6% versus 12.1% (HR 0.69, 95% CI 0.57-0.83, p=0.00008). All prespecified hierarchy endpoints were meaningfully and significantly reduced, including cardiovascular death (6.7% to 4.7%, HR 0.66, 95% CI 0.49-0.90, p=0.007), myocardial infarction (8.8% to 6.7%, HR 0.72, 95% CI 0.56-0.93, p=0.01), stroke (4.1% to 2.6%, HR 0.63, 95% CI 0.43-0.93, p=0.02), and all-cause mortality (9.8% to 7.2%, HR 0.70, 95% CI 0.55-0.90, p=0.004); for all-cause mortality for the USA versus non-USA patients, pinteraction=0.02. Safety and tolerability findings were consistent with the full study cohort.
Conclusions: While the non-USA subgroup showed significant reductions in the primary and key secondary endpoints, the USA subgroup demonstrated particularly robust risk reductions across a variety of composite and individual endpoints, including all-cause mortality
The Latest in Treatment Beyond Cholesterol and Statins by Deepak L Bhatt
From 2013 AdCom Transcript – Voting Comments from Wilson and Brittain:
DR. WILSON: Peter Wilson. I voted no. I won't repeat all the other comments that were said very ably by the other panelists. But I think of safety. I think of lipid changes. I think of subclinical disease. More and more, as I look at how we're developing care and guidelines moving forward, is we need guidelines that are based on trials. I'm not sure we really need any more agents being prescribed because we think they're going to work. We should really rely on what we know that works and get fairly simple messages out to clinicians.
I did have one concern because it's one that's not been mentioned up to now. I had a concern that there would be overprescribing, potentially. There already is overuse of some of the Omega-3s without proven benefit. There might have been an approval, and there still might be, depending how the FDA interprets our voting, for patients not on statins who would then be prescribed an Omega-3 in this mixed dyslipidemia group.
But the point was, we were voting especially on those on statins, and with a promise -- I would like to say that's an important promise – that there will be a trial, and it will be concluded, and a panel like this will get to review the results. So I think we've moved beyond testing lipid results. The major three trials that have focused on similar types of populations have shown that we have to have the trials in hand to guide our decisions.
DR. BRITTAIN: I'm Erica Brittain. I voted no. I agree that I'm confident about the triglyceride lowering, but there's unclear implication to the clinical benefit of that lowering. I did feel that some of the data presented were quite promising. Some of the clinical trial data were quite promising. So I'm optimistic that the outcomes trial will be positive. I certainly hope so. And I guess I was influenced partly by the fact that the product is already on the market, and that does give treating physicians some flexibility.
I am optimistic that these two experts will vote "YES" this time around.
Regarding the tweet from AF...
Exerpt from the full pub:
The statistical interaction terms for heterogeneity for the comparisons of USA and non-USA patients were not significant for most endpoints, and therefore differences in efficacy outcomes for the USA patients are best viewed as qualitative and not quantitative. Nevertheless, the data are useful and provide reassurance that the results seen in the USA are at least as strong as the results seen outside the USA and in the trial overall.
Here is the YouTube link to Dr. David Needham's presentation that you asked for and that I previously posted on this board earlier this summer:
Conclusion from Harris review article:
This short overview of the known effects of EPA in biological systems does not lead us to one definitive reason for “why REDUCE-IT was successful.” The term pleiotrophic comes to mind when considering the multitude of ways in which the body utilizes this one omega -3 fatty acid. Opportunities for future researchers to uncover and capitalize on the cardioprotective effects of EPA appear to be endless.
OT: good read regarding "meta-analysis" if anybody is interested.
Meta-Analysis in the Mirror of its Quotations: Science, Scepticism, Scorn, and Sarcasm
Franz H Messerli, MD, Sripal Bangalore, Adrian W Messerli
European Heart Journal, Volume 40, Issue 40, 21 October 2019, Pages 3290–3291, https://doi.org/10.1093/eurheartj/ehz702
Published: 21 October 2019
Link: https://academic.oup.com/eurheartj/article/40/40/3290/5594072
ISPOR Europe 2019
Health economics and outcomes research conference held 11/2/19-11/6/19 in Copenhagen, Denmark
Abstract Presentation:
DOES THE COST-EFFECTIVENESS OF ICOSAPENT ETHYL IN COMBINATION WITH STATIN THERAPY COMPARED TO STATIN ALONE DIFFER BETWEEN PRIMARY AND SECONDARY PREVENTION?
AUTHOR(S)
Ademi Z1, Zomer E2, ofori-Asenso R3, Owen A2, Liew D3
1Monash University, Melbourne, VIC, Australia, 2Monash University, Melbourne, Australia, 3Monash University, melbourne, VIC, Australia
OBJECTIVES : To assess the cost-effectiveness, from an Australian healthcare system perspective, of icosapent ethyl in combination with statin therapy compared to statin alone for prevention of cardiovascular disease (CVD).
METHODS : A Markov model profiled on data from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), supplemented with Australian contemporary population data, was designed to predict the effectiveness and costs of icosapent ethyl in combination with statins compared to statins alone over a 20-year time horizon. The model included three health states: ‘Alive without CVD’, ‘Alive with CVD’ and ‘Dead’. Disease costs and utility data were sourced from published sources. The icosapent ethyl annual costs were assumed to be AUD 1637 (USD 2907) per-person. All future costs and outcomes were discounted annually by 5%. The main outcome of interest was the incremental cost-effectiveness ratio (ICER) in terms of cost per quality adjusted life year (QALY) gained, and cost per years of life saved (YoLS).
RESULTS : Over a 20-year time horizon, compared to statin alone, icosapent ethyl in combination with statin was estimated to cost an additional AUD 13,022 (discounted) per person, but provided additional 0.338 YoLS (discounted) and 0.289 QALYs gained (discounted). This resulted in ICERs of AUD 45,036 per QALY gained and AUD 38,480 per YoLS. The ICERs for primary and secondary prevention were AUD 96,136 and AUD 35,935 per QALY gained respectively. Results were sensitive to time horizon, age related disease trends and the acquisition price of icosapent ethyl.
CONCLUSIONS : Our model suggests that compared to statin alone, icosapent ethyl in combination with statin therapy may be cost-effective in the prevention of CVD using willingness-to-pay threshold of AUD 50,000 per QALY gained. Furthermore our model demonstrates that better value for money was gained when icosapent ethyl in combination with statin therapy was used in population with existing CVD.
Source:
https://www.ispor.org/heor-resources/presentations-database/presentation/euro2019-3121/97329
Follow-up...
both of the "in press" articles that Bhatt was referring to in his talk are available online.
Residual Cardiovascular Risk in Statin-treated patients with elevated triglycerides: Now we can REDUCE-It
link:https://externalmediasite.partners.org/Mediasite/Play/11c7a8e5eb084f06ab156a77460b34bf1d
The video link offers lots of insightful comments from Dr. Bhatt's 55-min talk at the Mass General Hospital Grand Rounds (from 9/18/19).
It is a must-listen for every AMRN investor and I suggest to sticky it.
He discusses ASCENT and VITAL trials, omega-3 supplements, JELIS, CHERRY, REDUCE-IT and EVAPORATE trials, as well as the competing STRENGTH and PROMINENT trials that will read out in the future.
The following two articles are currently in press:
Bhatt, DL, Steg, PG, Miller, M, etal; J. Am Coll Cardiol, 2019: 1845-50 Total Ischemic Events by baseline TG and achieved TG at 1 year (in press)
Patel PN, Patel SM, Bhatt DL, et al. Curr Opion Cardiol, 2019: 34 (in press)
vvv
JL: Calm down...
Just to be clear,
you had asked me the question "Do you understand what a meta analysis is" (post 217070) after I first posted my comments (post 217064) regarding the newest meta-analysis review published by Hu et al. in JAHA. I stand behind these comments and have no problem if you don't agree with me.
As far as the rest of this exchange goes, I am not the one who needs to get off the high horse.
vvv
JL: "Do you understand what a "Meta Analysis is?..."
yes, I do, and contrary to your belief, I am of the opinion that meta analyses can make a valuable contribution to the advancement of a body of scientific knowledge. If done properly (i.e., no cherry picking], they allow for the combination of original sets of data from across a multitude of defined studies using standard statistical methodologies to objectively assess treatment effects.
Regarding the question of potential author bias (i.e., JoAnn Manson run the VITAL trial) and lack of quality of this latest omega-3 meta-analysis, do you honestly believe that the editorial review process at JAHA applied any less rigor in peer reviewing this particular submission than did the editorial boards of JACC and NEJM when they peer reviewed the Reduce-It clinical trial data manuscripts? I don't.
However, if you think that co-author JoAnn Manson failed to properly disclose her earlier key role in the VITAL trial, I suggest you write the JAHA editorial board about this lack of disclosure.
The main point of my original post was that it is important to recognize a biological omega-3 dose-response effect likely exists. While it will take some time to sort all of this out, the most powerful aspect of the scientific process is that it is perpetually self-correcting, i.e., the truth will always shine in the end.
I agree with you regarding the various issues commonly associated with "fish oil" dietary supplements.
vvv
This newest meta-analysis makes a case for the importance of the omega-3 dose in effecting outcomes. Why would that be considered fake news?
Yesterday's blog on Scientific American by Dyerberg emphasized the same basic point, i.e. the importance of dose-response.
This came out today...
The FDA should expand their efforts to include the MRC "gaming" type petitions.
FDA issues final guidance to address ‘gaming’ by the use of citizen petitions
September 18, 2019
Media Inquiries
Sandy Walsh
301-796-4669
“A key area of focus in the FDA’s Drug Competition Action Plan is our work to deter brand-name drug companies from ‘gaming’ the system by taking advantage of certain rules, or exploiting loopholes, to delay competition. One of the anticompetitive tactics we’ve been concerned with involves companies submitting certain types of citizen petitions in order to delay FDA action on a generic or other abbreviated application. While the FDA has rarely delayed specific drug approvals because of citizen petitions, there’s no doubt these shenanigans can burden the drug review process. Today we’ve issued a final version of a guidance for industry that addresses these concerns,” said FDA Acting Commissioner Ned Sharpless, M.D. “Also, to further dissuade companies from improperly using these petitions, the FDA will highlight in our annual report to Congress our determinations of petitions that are judged by the agency to have been submitted with the primary purpose of delaying an approval. Importantly, the guidance outlines our intention to refer these matters to the Federal Trade Commission, the agency that oversees anticompetitive business practices. We hope this increased transparency will help reduce hurdles to drug development and approval.”
Today the U.S. Food and Drug Administration issued the final guidance, Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act. It seeks to lessen the impact that FDA review of certain citizen petitions may have on any pending approval actions. The approach would help the FDA allocate resources efficiently when addressing petitions that are most likely to present an obstacle to the availability of generic drugs. If a citizen petition is received while a product application is already under review, and if the goal date for that review falls within the next 150 days, the guidance states that the FDA would expect to respond to that petition within 150 days. This policy aligns the FDA’s 150-day timeline to review and respond to these petitions described in section 505(q) with the timeline for review of the applications themselves. The FDA will continue to ensure that any scientific and regulatory issues raised in a petition are considered prior to the product approval, as citizens petitions can raise relevant concerns.
The guidance describes the FDA’s current thinking on what constitutes a 505(q) petition and some of the factors the agency will consider in determining whether a petition is submitted with the primary purpose of delaying the approval of a drug application. If the agency determines that this is the case, the FDA will consider whether the petition can be denied on that basis and may in any case note this determination in the petition response, which is posted publicly. The agency believes this will provide an additional deterrent to pursuing these tactics. By addressing challenges associated with this type of petition, the FDA aims to improve the efficiency and predictability of the drug review process and to help to drive down the costs of drug development.
# # #
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines, and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
https://www.fda.gov/news-events/fda-brief/fda-brief-fda-issues-final-guidance-address-gaming-use-citizen-petitions?utm_campaign=091819_FIB_FDA%20issues%20guidance%20on%20certain%20citizen%20petitions&utm_medium=email&utm_source=Eloqua
For many analytical test assays (based on blood, saliva, or urine samples), it is often ok to freeze the sample for prolonged periods of times until the analysis is finally performed, sometimes years after data collection.
In large clinical trials like REDUCE-IT, the blood samples from study participants are likely to be biochemically analyzed centrally at an approved core lab. It is quite conceivable that these analytical tests were only performed in recent months, i.e. after the CVOT was already published.
Thanks for catching it. You are absolutely correct.
I was simply looking at some of the statements from Tardugno that he repeatedly made in past earnings calls.
For example, here is how he explains the interim data readout OPTIMA hazard ratios on the Q4 2018 earnings call (dated 3/29/19) in response to a question by Matthew Cross of Jones Trading:
Matthew Cross
No, I think that does, appreciate that. And then, since this first interim data readout for OPTIMA is likely to be a major part of the story for 2019, could you kind of remind us of that optionality that I think you've kind of alluded to a little bit here, subsequent to this first look, and even for the second, next year before final data, in terms of what modifications you may be able to make if the lesser PFS for either arm or negatively outside of what you're anticipating, but more asking also about the potential to stop the trial earlier is a substantial enough survival benefit. I guess, this 33% specifically is shown sooner.
Michael Tardugno
Yeah. So the hazard ratio at the first interim, in order for us to be successful as 0.61. At the second interim, I believe it's 0.70. And at the third interim, that's 0.75. So if we want to talk in layman's terms, 0.75 translates to a 33% improvement, 0.70 represents a 42% improvement and 0.61 approximately 60 plus percent improvement in the way the statisticians talk about in the risk for death.
Source: https://seekingalpha.com/article/4251843-celsion-corporation-clsn-ceo-michael-tardugno-q4-2018-results-earnings-call-transcript
The correct numbers are:
HR of 0.75 = 25% risk reduction
HR of 0.70 = 30% risk reduction
HR of 0.61 = 39% risk reduction
Some reasons to remain "caveat emptor" on the stock...
- Despite the most recent change back to an excessive stock "pumping" tone, Tardugno in previous CCs repeatedly admitted it is highly unlikely that the phase 3 OPTIMA trial will be successful (i.e., show a hazard ratio of 0.61 which equals about a 64% reduction in risk of death) at the first interim analysis.
- For those not familiar with the Company, historically Tardugno used the same unwarranted pumping style leading into the previous phase 3 HEAT trial announcement before acknowledging in the end that the study outcome results were "not even close."
- Independently of the story management continues to sell, it is refreshing to be able to obtain the independent perspectives of Dr. David Needham, the inventor of the technology used in CLSN's DIGNITY / HEAT / OPTIMA studies. He correctly has been very critical of the study protocol designs that were adopted for CLSN's clinical trials. To learn more about his expert perspectives, his talk (specifically from minutes 16 through 23) at the European Foundation of Clinical Nanomedicine from a few years ago is enlightening. Here is the link:
@CalMustang,
Giardino a few years ago also tried to attract wealthy people to invest with him via his so-called "Blue Note Investing" advanced trading methodology.
https://angel.co/blue-note-investing
He is an excerpt on how he described his "Product" at the time...
Product
The product is basically my brain! I'm a bit of a savant with numbers. Genetics I suppose. High IQ. My late paternal grandfather was actually a bookeeper for some notorious figures in the 60s. I digress.. Here's the thing--I have the ability to find high yield moments of investing in carefully chosen securities. Over the last few years I've achieved fantastic results: 74%, 58%, and 116% respectively (well, 116% is still in flux--we have a bit under two weeks left. And I got there with the help of buying SRPT at $13.12 on the dip, and selling today at $19.40--a rare, but highly lucrative find).
The problem is, I'm not wealthy by any means, and the meager sums I've been producing seem almost a waste of good trading: my account would have grown to just under $30k had I not withdrawn profits. Of course, if I had started with, say, $500k, instead of $5k, it would have grown to almost $3mm (yes, volume would have allowed the higher money trades... mostly).
Technology
Now what if I could find a number of wealthy investors who would be willing to risk, say, 1% of their portfolios on some 30-something from Albany, NY, who claims to know his way around the market? Obviously a high risk scenerio(?), but I would do so for no fees, only a cut of the profits. In fact, should the investments lose ground, I would consider it a negative commission. In other words, say you lost 10% in two months, and then gained 15% from there in one month. I would receive commission from just the 5%. Also, I would deduct commission quarterly only (or upon your withdrawl).
So, you are saying this is not you?
http://www.finishedworks.com/#!contact/con8
Steven Giardino
owner/operator
Email: finishedworks@yahoo.com
Tel: (518)-xxx-xxxx
The FDA held a public meeting on "Responsible Innovation in Dietary Supplements" a few days ago. For those interested, here are links to Acting FDA Commissioner Ned Sharpless speech and some of the meeting's highlights, as summarized by an industry publication.
https://www.fda.gov/news-events/speeches-fda-officials/fda-public-meeting-responsible-innovation-dietary-supplements-05162019
https://www.nutraingredients-usa.com/Article/2019/05/20/15-highlights-from-the-FDA-s-public-meeting-on-responsible-innovation-in-dietary-supplements
OT: Here is a good example of the timeline of a recent biotech buy-out involving multiple suitors
Source: John George – Senior Reporter, Philadelphia Business Journal
https://www.bizjournals.com/philadelphia/news/2019/03/20/the-10-months-that-led-to-the-proposed-4-8b-sale.html
The groundwork for the proposed $4.8 billion sale of Philadelphia gene therapy pioneer Spark Therapeutics to Roche actually began last spring and would eventually involve three potential suitors, according to documents filed with Securities and Exchange Commission related to the proposed transaction.
Founded in 2013 when it was spun out of Children's Hospital of Philadelphia, Spark earned the distinction of being the first company to received Food and Drug Administration approval for gene therapy to treat a genetic disease. That product, Luxturna, was approved in December 2017 to treat a rare, inherited retinal disorder that leads to blindness.
What follows is a timeline, based on SEC filings, of the key events that led to the blockbuster deal for Spark.
May 2018: Spark’s management and board begin actively considering ways to optimize the company's experimental hemophilia A gene therapies, potentially de-risk its investment in those programs and raise capital and/or decrease its expenses to offset the company’s future cash needs.
May 2018 to August 2018: Spark engages in discussions Roche Holdings and two other undentified global biotechnology and pharmaceutical companies regarding a potential hemophilia A collaboration.
December 2018. Spark CEO Jeffrey Marrazzo and Roche CEO Dr. Severin Schwan meet in Teterboro, N.J., where Schwan informs Marrazzo of Roche’s interest in exploring a potential acquisition of Spark. Later in the month, Roche makes an offer to buy Spark for $70 per share. The offer is deemed insufficient by Spark’s board.
January 2019: Marrazzo sends an e-mail to Schwan suggesting that they talk after the 2019 J.P. Morgan Annual Healthcare Conference in San Francisco. Spark’s board, senior management and advisers, Centerview and Goodwin Procter, also meet at the conference. The company tells Roche its offer would need to be “well in the $80s” to be considered. Roche says it is interested in exploring further talks. Before the month ends, Spark’s newly formed transaction committee decides to contact two other potential buyers, both of which express an interest in a deal. Roche submits a new offer at $73 per share, which is again rejected by Spark’s board as inadequate.
February 2019: Spark receives a $75 per share offer from “Party C,” whose identity is not disclosed. Spark decided to allow Roche and Party C access to a “virtual data room” to conduct additional due diligence. The other unnamed potential acquisition partner, "Party A," informs Spark it is not prepared to make an offer. The company continues discussions with another company, referred to only as "Party B," that it is in advanced talks regarding a potential hemophilia A collaboration, but not an acquisition. Before the month ends, Party B submits terms for a worldwide collaboration that includes a $450 million upfront payment. Party C submits a proposal to acquire Spark for $84 per share. Roche submits a proposal to buy Spark for $91 per share. Spark establishes a bidding proposal that results in Roche Holdings submitting a “revised final proposal” of $114.50 per share in cash. Party C submits a “revised final proposal” of $105 per share.
Feb 22 2019: Following a telephonic board meeting on the same day the final proposals were submitted, Marrazzo calls Schwan to inform him Spark’s board has unanimously approved the proposed transaction with Roche — a 122 percent premium to Spark’s Feb. 22 closing price of $51.56. In the evening, a merger agreement is executed and the deal is announced before the markets open on Feb. 25.
The hashtag #NLAPortland on Twitter offers bits and pieces of information from the NLA conference