The Captain Of Amarin's Listless Ship Makes Ready For The Storm

The run-up to Amarin's (AMRN) advisory committee on October 16th has been muted by the ruling favoring generic manufacturing of Lovaza, but also by a sense amongst would-be investors that the payoff may not be worth the risk after all. And there is more risk than some would have you believe. More on that later.

There's also a sense of foreboding rooted in the FDA's silence and Adam Feuerstein's loud warnings of delay.

In my first and only article on Amarin found here, I essentially stated what I still feel today. Vascepa is a wonderful drug that will gain market share within its present indication. I also mentioned that I believed Adam Feuerstein's pessimism regarding Anchor approval suggesting a delay until the cardiovascular benefits of Vascepa can be confirmed was overblown at best. The FDA had already ushered Vascepa to success in the Marine indication because its agenda of supporting ObamaCare by keeping patients out of the hospital through preventative care trumped any misgivings it might have had. And I thought then that Anchor approval would run a similar course.

Recently, I liquidated my position in Amarin and moved my principal and profit to Cyclacel (CYCC). I did this because I listened to the Amarin presentation at Canaccord Genuity and heard several things that gave me pause suggesting that Mr. Feuerstein might be correct after all.

Silence

Let's take a measure of President John Thero's confidence index expressed at Canaccord in these remarks. It should be noted that Mr. Thero prefaced nearly every statement concerning the advisory committee meeting and Anchor's sNDA with brimming conviction in its approval.

Now from an adcomm perspective we've not yet gotten the briefing book from the FDA. That's not prevented us from having multiple mock advisory board committee meetings. We had planned for an adcomm for our Marine indication but we ended up not needing one because the FDA decided not to have an advisory board for that. Similarly, we've been planning for awhile for an advisory board meeting for the Anchor indication in the event that we would have one and the FDA has told us that they would assign that particular day. So we've been going through multiple mock advisory board meetings.

This has been done with our internal staff. This has been done with the help of a professional firm that does specialize in doing these things. And also we have lots of advisors and we've been pulling in other doctors who have a lot of experience at advisory board participation to try to challenge ourselves on questions that could be asked and haven't yet found a question that we don't believe we have very good answers to.

So we begin with a continuance of the FDA's silence on NCE with the withholding of a briefing book. And forgive me for saying so John, but your extensive preparations seem to contradict your declarations of faith. But let's give Mr. Thero the benefit of the doubt here and simply commend him on preparing well for battle. Make no mistake however, battle is exactly what Amarin is preparing for.

Hidden Bias

Now there are those of you who might believe that the FDA approval process is solely a function of scientific analysis appraising the benefits and detriments of a certain drug or device. And I'm not here to attack your position. I do however have a different one.

I believe that in addition to this objective assessment of a candidate based on its merits there are also subjective elements at play. The agenda element I spoke of earlier would be one. And, of course, there are others.

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My core theory goes something like this. Representatives of the FDA are human beings subject to all manner of temptations, frailties and unconscious motivations that each of us is subject to on a daily basis. One aspect of our human condition is an innate proclivity to think prejudicially in terms of our friends. We define our friendships essentially by what a person can or cannot do to further our own survival.

Representatives of big pharma like AstraZeneca, Novartis, Biogen, Gilead, Amgen and GlaxoSmithKline (GSK) meet with FDA representatives and surrogates hundreds of times a year. Friendships are struck. And when an outside party - defined as someone who meets with the FDA once or twice a year comes along with a competing product they're likely to meet with resistance rooted in subconscious motivations. How this plays out can be interesting.

Take for instance the recent rejection of Aveo's Tivozanib. In an article entitled, The ODAC Postmortem: Lessons Learned Part 1, Aveo, PropThink's Dr. Aafia Chaudhry suggests "four main areas that contributed to a negative panel vote. 1. Tone set by Richard Pazdur, MD, Director of Division of Oncology Drug Products, and by Mikkael Sekeres, MD, Chair of ODAC Voting Committee"

Here's Dr Chaudhry.

FDA framed the tivozinib review in the context of their concerns about the increased potential detrimental survival signal; the availability of other approved therapies in this setting; and their concerns with flaws in the study design and the unexplained 30 day safety/mortality discrepancies. Pazdur was very vocal throughout the session in reiterating these points, and the committee's questions certainly focused extensively in these areas. Sekeres opened the questions to the sponsor with a scathing criticism directed to Robert Motzer, MD (principal investigator for the AVEO pivotal study) on the poor study design. In my opinion, the position of the FDA and the ODAC Chair definitely set a negative and somewhat hostile tone for the proceedings.

Sounds frustrated, yes? Dr. Chaudhry is certainly suggesting an absence of objectivity. Of course Pfizer's Sunitinib was standard of care in the disease space that Tivozanib was attempting to enter and Aveo chose to avoid a head-to-head comparison in their pivotal trial. But it might be more helpful to understand that Pfizer representatives have developed long lasting friendships with FDA personnel.

Now, am I suggesting that FDA rejected Tivozanib on bias? No, I'm not. The trial was poorly structured and failed on merit or lack thereof. I'm simply bringing this to your attention to illustrate a point that Dr Chaudhry certainly seems to confirm as existent.

So what does this have to do with Amarin?

Well you would think that one of those many advisors President Thero spoke of earlier would have gone over his prepared remarks at Canaccord and weeded out this one regarding GlaxoSmithKline.

Now we are marketing this [Vascepa] to the very high triglycerides population right now. Most of Lovaza use is not in that population. So the only thing it's approved for - most of Lovaza use is not in that indication - most of it is off-label in the 200 to 500 category which is where we're going with Anchor.

Today, we're being very careful to not market our drug off-label. We think we're going to be getting that indication in December and the last thing we want to be doing is going into FDA conversations with them suggesting somewhere that we're marketing it for that indication already.

When we do get that indication which we're counting on, we intend to make it very clear to docs that they have a misconception over Lovaza being approved for that indication. In fact, Lovaza was studied twice for that indication and failed to get approval due to its LDL increase.

Furthermore, we're going to be working with, continuing to work with the payers to insure that they're aware of the off-label use of Lovaza and seek, at least with certain of the plans the opportunity to put further restrictions on off-label use of Lovaza.

What's that old expression? Some things are better left unsaid. I think that qualifies!

Apparently, certain business persons believe that their audience is comprised strictly of investors interested in their product and that competitors aren't paying attention. Furthermore, they must believe that noting the strategic advantages of their product over a competing brand has only one possible outcome - stirring investor interest. I believe that Mr. Thero may have stirred an undesirable amount of interest amongst a larger audience than he has bargained for.

Another FDA Agenda Amarin Continues to Ignore - Corporate Tax Avoidance

As previously mentioned, I noted the benefit of approaching this FDA with a product designed to make patients healthier and keep them out of the hospital - ObamaCare.

There is however another agenda that the FDA might be pursuing unbeknownst to corporate applicants in the drug approval process. And that is a disdain for companies that gloat over avoiding taxation by establishing their corporate centers of operation abroad.

Amarin never seems to miss a chance to remind investors of their low tax obligations afforded them by their location in Ireland. Might I suggest that the FDA has been listening to that as well.

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Consequences of Holding Through Adcomm and Approval in December

Generally speaking, I avoid binary events. There seems to be little to gain by holding through them and much to lose. Though adcomm is scheduled for October 16th, the FDA has notoriously leaked a document in advance of such proceedings that provides a tip to the direction it might take. Investors should be alert not to fall asleep thinking that their investment dollars are safe up until the scheduled day of reckoning.

Also, holding through a positive adcomm might not provide the price per share lift I anticipated months ago. Vascepa prescriptions have been rising but revenues have not kept a commensurate pace. I believe Q3 will be the exception and sales figures will speed past $100M for the quarter. This together with a positive adcomm could see prices appreciate rapidly. Then again, maybe not.

The problem for investors now is weighing that possibility against that of delay. There's no doubt Anchor will one day be approved for Vascepa, but any delay would weigh heavily on the company's prospects. It would likely force them to either accept a partnership in advance of eventual approval on uneven terms in order to make marketing expenses or sell the enterprise for a fraction of the lofty figures bantered about by longs over the past year or so.

If neither of these options were chosen, investors might have to slog through more secondary offerings or perhaps Amarin would choose to borrow more money instead. Regardless, the price of the stock would then slide and stagnate for an indeterminate period of time.

This would be the year's saddest outcome of all. Vascepa is an extraordinary product with health benefits that are equal to its low side-effect profile. Amarin should be granted FDA approval for the Anchor indication. And on every rational level, it's quite possible that it will be. It's certainly the right thing to and the best thing to do for patients.

Now, if only we lived in a world where these were the only considerations.

Always be well...

Michael Webb

Disclosure: I am long CYCC. 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. (More...)

Additional disclosure: Any information or opinion expressed herein may not be true, accurate or correct and it does not constitute any suggestion to buy, sell, hold or adopt any investment strategy for this stock or any stock that may be mentioned. Reliance upon information in this article is at the sole discretion of the reader. The sole purpose of my article is to entertain by providing information the accuracy of which is as good as the public sources it was derived from. Do not act on anything I have written. Rather, do your own due diligence and consult an investment professional before making any investment decision. Acting on what any one writer, including me has imparted to you is foolish at best. I have no better access to resources or gift of opinion formulation than you do. I sometimes make mistakes. There are a myriad of things which can happen in lieu of any forward looking statement I have made. Any stock featured or mentioned in an article I compose is subject to all manner of influences which can change its value in dramatic fashion upwards or downwards. These events can be of a wide variety not limited to news related occurances, managerial decisions, trial failures, stock manipulations and so on. I make every effort to declare positions I have in stocks I cover or mention in an article but reserve the right to move in and out of said investments at my own discretion based upon the wisdom of doing so. I implore you to do your own due diligence, invest at your own considerable risk attaining the just reward your efforts have wrought. And always be well.

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Refined And Ready To Rebound: We Like What We See At Arca Bio

ARCA Biopharma, Inc. (ABIO) is developing Gencaro (bucindolol hydrochloride), a pharmacologically unique beta blocker and mild vasodilator for the prevention of atrial fibrillation (AF) in patients with left ventricular heart failure. Below we discuss the unique properties of bucindolol compared to other beta blockers on the market for heart failure or atrial fibrillation, outline the genetically defined patient population and how the company identified these patients, analyze the existing data, make some predictions for the future, and wrap up our article with some thoughts on the market opportunity and valuation for the stock. ARCA is certainly not without risk, but at $1.39 per share we see a favorable risk / reward profile and believe the stock offers limited downside and meaningful upside over the next two to three years, with potentially enormous returns in the distant future should bucindolol succeed and be commercialized by a larger pharmaceutical partner. Accordingly, we think the stock is a 'Buy' and the shares are worth $3.00.

A New Era Of Personalized Medicine

Personalized medicine refers to the tailoring of medical treatment to the individual genetic characteristics of each patient in order to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. Preventative or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effect for those who will not.

-President's Council of Advisors on Science and Technology Priorities for Personalized Medicine 2008

ARCA is developing GencaroTM (bucindolol hydrochloride), a pharmacologically unique beta blocker and mild vasodilator for the prevention of atrial fibrillation in patients with left ventricular heart failure. Bucindolol was originally developed by Bristol-Myers Squibb for the treatment of heart failure (HF) and hypertension. It was subsequently out-licensed to Incara Pharmaceuticals Corporation. In 1995, a Phase III trial in HF was initiated in collaboration with the Department of Veterans Affairs and the National Heart, Lung, and Blood Institute. In 1999, the trial was stopped early, in part due to the demonstration of reduced mortality in completed Phase III trials of other beta blockers then in development. This created ethical issues around continuing to proceed with a sub-optimally treated placebo cohort. ARCA licensed bucindolol from Incara in 2003 with the goal of developing bucindolol as the first genetically targeted personalized cardiovascular medicine.

Based on the identification of genetic markers of responsiveness, ARCA believes it has pinpointed those patients most likely to experience clinical benefit, can potentially obtain approval with a pivotal clinical trial program of reduced size and expense. It plans to provide this genetically defined subset of patients with a treatment offering significant therapeutic advantages over available therapies.

The increasing recognition of the importance of individualized therapy in the treatment of AF was recently recognized in a joint consensus document published by the Atrial Fibrillation Competence Network and the European Heart Rhythm Association. The paper notes that new treatments for atrial fibrillation have lagged compared to those for other cardiovascular diseases such as myocardial infarction, and calls for the greater application of personalized medicine approaches for the development of new therapeutic approaches as the most promising approach. Opportunities for a personalized medicine approach include a greater research focus on how individual characteristics such as AF type and burden, cardiovascular damage, blood biomarkers, genetic predisposition, and symptomology affect risk for disease progression and stroke and the need and response to medical and surgical therapies (Kirchoff, 2013).

Source: Kirchoff, 2013

Background On Heart Failure

The American College of Cardiology defines heart failure as, "Any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood." Heart failure affects approximately 5.7 million Americans, and contributed to over 3 million hospitalizations and 250,000 deaths in 2006 (Norton, 2011).

The primary symptoms of heart failure are dyspnea (shortness of breath) and fatigue, pulmonary congestion and peripheral edema. Heart failure normally takes a progressive course, with about half of patients dying within 5 years of diagnosis (Source: U.S. CDC). The staging of Heart Failure is commonly performed according to the standards of New York Heart Association (NYHA) functional classification system. The system recognizes four stages of disease on the basis of symptomology.

Heart failure is a progressive disorder that develops in the aftermath of an initial event such as heart attack or prolonged hypertension that reduces the heart's ability to pump blood. The resulting compensatory mechanisms that are activated have the short-term effect of restoring normal blood flow, but lead to a gradual, continuous decline in cardiac function as the heart undergoes structural changes (cardiac remodeling) in response to the continuous high intracardiac pressures. The volume of the ventricle increases and the walls become thinner, with an overall loss of contractility. The ventricles lose their oval shape and become more spherical. Other deleterious effects may include reduced perfusion of the heart muscle, free radical damage, and loss of cardiac valve function due to substantial changes in the overall geometry of the heart. Most patients experience a gradual decrease in exercise capacity that is punctuated by episodes of severe symptoms requiring medical attention (decompensation).

The most common form of heart failure involves the left ventricle, which compared to the right ventricle, has the greater workload associated with pushing blood through the large vascular bed of the tissues. Left ventricular failure is further classified as systolic or diastolic, depending on whether the primary defect lies in the ability of the ventricle to relax and fill with blood, or its ability to contract and expel blood into the vasculature. Diastolic and systolic heart failure are about equally common, but despite the wealth of information available from clinical trials regarding the treatment of patients with systolic heart failure, there are no proven or approved treatments for diastolic heart failure. The remainder of this discussion will focus on systolic left ventricular heart failure, the target indication for ARCA Bio's Gencaro in patients with atrial fibrillation.

AF in Heart Failure

The mechanical pumping action of the heart is critically dependent upon coordinated and properly timed contraction of its chambers. Each beat is initiated when cells of the heart's natural pacemaker, the sinoatrial (SA) node, initiates an electrical pulse that travels across the surface of the heart. The electrical pulse travels first across the surface of the atria, causing them to contract and eject blood into the ventricles. Upon reaching the atrio-ventricular (AV) node, the pulse slows briefly to allow the atria to complete their contraction. It then continues across the surface of the ventricles via specialized conducting fibers, inducing the ventricles to contract and expel blood into the arteries. Atrial fibrillation is a rapid, unproductive beating of the atrium that occurs when the pace making signals generated by the SA node are overwhelmed by disorganized electrical impulses usually arising in the roots of the pulmonary veins. The cause of this disordered electrical activity is not fully understood.

The prevalence of AF in patients with HF is 30-40%, with higher prevalence being associated with more advanced HF (Linssen, 2011; De Ferrari, 2007). While some patients are asymptomatic, others experience severe palpitations, angina, exercise intolerance, dizziness, or fainting. The rapidly irregular contractions lead to a loss of atrial contractility. Incomplete ventricular filling leads to an increased heart rate, which may exceed 200 beats per minute. This increased heart rate leads to increased oxygen demand and accelerates the progression of heart failure. Loss of contractility and emptying of the atrial appendage increases the risk of clot formation and stroke.

A large meta-analysis of clinical trials and observational data studies found a relative mortality risk of 1.33 to 1.57 for HF patients with AF relative to those with HF only (Wasywich, 2010). Community studies examining mortality in patients with both HF and AF have found a higher risk of mortality for patients with HF who later develop AF than for those who develop AF and then HF. Among patients hospitalized for heart failure in a Netherlands study, re-hospitalization or death occurred in 50% of "AF first" patients and 78% of "HF first" patients during a 16 month follow-up (Smit, 2012). Similarly, a U.S. community study found that the relative risk of death over a 4 year observation period was 1.0 for HF patients without AF, 1.3 for patients with AF who later developed HF, and 2.2 for patients with HF who later developed AF (Chamberlain, 2011).

The truth of the matter is that development of either HF or AF is associated with higher rates of hospitalization and death than the general population, but patients with HF that go on to develop AF seem to follow a particularly more negative prognostic pathway. This has been confirmed by peer-reviewed literature, with one study suggesting a relative risk of death of 9.6 (Khan, 2008) in the months immediately following AF diagnosis.

Current Treatment Options for Heart Failure and Atrial Fibrillation

The American College of Cardiology (ACC) and the American Heart Association (AHA) regularly publish updated guidelines for the treatment of heart failure (Jessup, 2009) and atrial fibrillation. Highlights of medical therapy recommendations for systolic left ventricular HF are shown in below.

Diuretics - Many of the early symptoms of HF result from excess salt and water retention that arise as a result of the body's efforts to maintain blood pressure. These result in exacerbation of congestive symptoms, including dyspnea and edema. Diuretics and salt restriction are recommended for patients with current or prior symptoms of HF and reduced LVEF who have evidence of fluid retention. Diuretics exert their effect in the kidney by inhibiting the reabsorption of sodium, potassium, and/or chloride ions, thus increasing ion secretion and urinary volume.ACE Inhibitors (ACEis) and Angiotensin Receptor Blockers (ARBs) - Angiotensin converting enzyme (ACE) catalyzes the final step in the synthesis of Ang2. ACEis are a cornerstone of treatment for patients with systolic heart failure due to their demonstrated ability to reduce both the symptoms and progression of disease. ACE inhibitors stabilize left ventricle remodeling, improve symptoms, reduced hospitalization, and prolong life. Higher doses are more effective than lower doses, but tolerability can be an issue, in part because ACE has multiple functions in addition to its role in producing Ang II. The most important side effects are chronic cough and angioedema. Patients who cannot tolerate ACE inhibitors are commonly treated with ARBs. Each of these two drug classes block the action of Ang2, but by different mechanisms.Beta Blockers - The beta blockers, such as carvedilol, bisoprolol, and metoprolol, form a second cornerstone of systolic HF treatment. ß1 blockade prevents the stimulation of the heart's electrical system by norepinephrine in response to reduced blood pressure. Beta blockers slow the heart rate, reduce stroke volume, and reduce the force of contraction of the heart. Cardiac workload and oxygen demand are decreased, and inhibition of sympathetic stimulation of the heart's electrical system reduces the risk of arrhythmia. Blockade of ß1 receptors in the kidney inhibit the formation of Ang 2. Some beta blockers also block the a1 adrenergic receptor and thus limit blood pressure increases arising from increased sympathetic tone. Cardiac remodeling is inhibited by mechanisms that are not fully understood, and reverse remodeling is observed in some patients.

Carvedilol, bisoprolol, and metoprolol have different receptor selectivity profiles, but all have been shown to produce improved outcomes in heart failure, including reduced mortality, improved left ventricular dysfunction, and reversal of cardiac remodeling. The USCP, CIBIS-II, MERIT-HF and COPERNICUS trials demonstrated a broad array of clinical benefits including reduced mortality and hospitalization.

Treatment guidelines for AF include the use of anticoagulants in almost all patients to minimize the risk of ischemic stroke. Therapeutic strategies directed at controlling the AF itself (rhythm control) have been limited by the toxicity and limited efficacy of available agents, especially in HF. These limitations have led to the investigation of an alternative therapeutic strategy that pursues the more limited goal of preventing the large increases in heart rate that are associated with AF (rate control). The American College of Cardiology recommends the latter approach for most patients, using a beta blocker or a calcium channel antagonist as first line therapy in non-HF patients, and the use of a beta blocker as first line therapy in patients with both AF and HF (Fuster, 2011).

In spite of these guidelines, there are questions regarding the efficacy of beta blocker therapy in patients with concomitant HF and AF. A recent meta-analysis of retrospective studies concluded that beta blockers reduce mortality and hospitalization in HF patients in sinus rhythm but failed to find a statistically significant effect on either endpoint for patients in AF (Rienstra, 2013). Beta blockers provide less protection against hospitalization in patients with AF relative to those in sinus rhythm, and this difference is statistically significant.

Pharmacogenetics of Beta Blocker Response and the BEST Trial

Bucindolol is a non-selective beta blocker with activity at both the ß1 and ß2 receptor subtypes. It also has activity at the a1 receptor, which confers a mild vasodilative effect, and indirectly at the a2c receptor, which serves to reduce the release of norepinephrine from sympathetic nerve terminals (sympatholytic effect). It was originally evaluated for the treatment of HF in a genetically unselected population, and when the primary endpoint of the Phase III trial did not reach statistical significance, the original sponsor (Incara) abandoned development. A subsequent analysis by the academic researchers who ran the trial concluded that certain patients, identifiable by the genetic signature of the receptors involved in sympathetic stimulation of the heart, have greater benefit from the drug than previously realized. In 2008, ARCA Biopharma submitted an NDA for bucindolol that included the genetic information. In 2009, in a Complete Response Letter, FDA asked for additional, prospectively derived data in the genetically defined subpopulation.

Most of what is known of the clinical properties of bucindolol comes from the Beta Blocker Evaluation of Survival Trial (BEST), a large Phase III study designed to determine whether bucindolol reduced mortality in patients with moderate-to-severe HF (NHYA class III or IV and ejection fraction (EF) < 35%). Secondary endpoints included cardiovascular death, hospitalization for any reason, hospitalization for HF, myocardial infarction, quality of life, and a composite of death or heart transplantation. A total of 2,708 patients were randomized into the BEST trial.

The BEST trial was stopped early based on the recommendation of the Data Safety and Monitoring Board (DSMB). The DSMB was concerned about the ethics of continuing to treat half of the patients in the trial with placebo, given that other beta blocker trials had completed demonstrating clear efficacy and a reduction in mortality. The primary endpoint, all-cause mortality, trended lower in bucindolol treated patients relative to placebo (30% vs. 33%, p=0.10). Compared to placebo, bucindolol significantly reduced death from cardiovascular causes (25% vs. 29%, p=0.04), the composite of death or transplantation (32% vs. 35%, p=0.04) and hospital admissions for HF (35% vs. 42%, p <0.001). Bucindolol also improved patient quality of life as measured by patient and physician global assessment questionnaires.

…DNA Analysis Of BEST Patients…

Frequent polymorphisms have been identified in two of the receptors involved in sympathetic stimulation of the heart. The ß1 receptor, the principal adrenergic receptor found on cardiac myocytes, is polymorphic at position 389. Approximately 50% of the population carries two copies of the gene encoding for an arginine (ARG) at this position. Most of the remainder of the population carry one copy of the Arg at position 389 polymorph and one copy of a version having glycine (Gly) at this position. The Arg389 variant can be regarded as a more active version of the receptor. It exhibits higher constitutive signaling (e.g., signaling in the absence of bound ligand), has a higher affinity for norepinephrine, and signals more strongly in response to norepinephrine binding. In vitro, bucindolol acts as an inverse agonist, suppressing both the constitutive and the norepinephrine-stimulated signaling of the ß1 receptor.

The a2c receptor is a presynaptic receptor that helps regulate the sympathetic activation of the heart by providing feedback inhibition of norepinephrine release. Approximately 20% of the population carries a single copy of a version of the gene encoding a deletion mutant of the protein that lacks amino acids 322-325. As the 322-325 del mutant is non-functional, it cannot contribute to feedback inhibition of norepinephrine release.

The BEST trial, which was sponsored by the Department of Veterans Affairs and the National Heart, Lung, and Blood Institute, included a 1,040 patient DNA bank, which could be accessed by submission and successful peer review of a sub-study protocol. The analyses discussed here were submitted prior to the trial's ending while patients were still being enrolled.

The 47% of patients homozygous for the Arg389 version of the ß1 receptor exhibited the greatest effects on HF endpoints, with all of the endpoints nominally significant at the P < 0.05 level, and four, including the co-primary endpoint of mortality or transplant significant at the p<0.0125 level required to accommodate multiple hypothesis testing. Gly389 carriers homozygous for the wild-type (WT) version of the a2c receptor showed a trend toward efficacy, but the outcomes were generally not statistically significant. The 13% of patients with at least one copy each of the minor polymorph of the ß1 and a2c receptors trended toward no treatment effect, but the 95% confidence intervals were very wide (O'Connor 2012).

Two similar analysis examined the effect of ß1 and a2c receptor polymorphisms on bucindolol's effects on AF in patients with HF. The first of these examined the prevention of new onset AF in the 925 patients from the genetic sub-study that were not in AF at baseline. A hazard ratio of 0.26 (95% C.I. 0.12 - 0.57) was observed for treatment with bucindolol (n=235) relative to placebo (n=206) in patients homozygous for the Arg389 version of the ß1 receptor. Hazard ratios for carriers of the ß1Gly389 variant were 0.94 for patients homozygous for the wildtype a1 receptor and 1.33 for patients who were carriers of both minor alleles.

A second study examined the impact of patient genotype on outcomes for patients already in AF at study baseline (Kao, 2013). Among the 108 patients from the genetic sub-study with AF at baseline, 51 were homozygous for the Arg389 version of the ß1 receptor and 57 were Gly389 carriers. Combined mortality and hospitalization endpoints approached statistical significance for the Arg389 homozygotes but not for the Gly389 carriers (Kao, 2013).

Taken in sum, these studies provide strong support that bucindolol will have a meaningful favorable effect on both the time to onset of AF and, over longer time periods, on all-cause mortality in this patient population. The available evidence suggests a less robust effect for other beta blockers (Baudhuin, 2010; Petersen, 2011).

Regulatory Strategy

ARCA Bio plans to pursue the prevention of recurrent AF in HF patients with persistent AF post electrical cardioversion as the initial indication for Gencaro. These patients have recurrent episodes of AF that last for >7 days or longer if untreated. The episodes can be terminated by application of a direct current shock but are expected to recur in about 40-60% of patients within 3 months (Lundstrom, 1988).

GENETIC-AF is planned as a Phase IIb/3, multi-center, randomized, double-blind clinical trial comparing Gencaro to Toprol XL (metoprolol extended release) for prevention of AF in patients with heart failure and reduced left ventricular ejection fraction (HFREF). Worldwide Toprol XL sales peaked at $1.4 billion in 2009 at AstraZeneca. ARCA plans to enroll only patients with the Arg389 variant of the beta-1 cardiac receptor which the company believes responds most favorably to Gencaro. GENETIC-AF has an adaptive design, under which the company plans to initiate it as a Phase IIb study in approximately 200 patients and then, depending on the results of an interim analysis by the trial Data Safety Monitoring Board (DSMB), expand the trial to a Phase III study by enrolling an estimated additional 420 patients.

The company anticipates that patient enrollment in GENETIC-AF will begin in the first quarter of 2014. Under a collaboration with Medtronic, ARCA plans to conduct a sub-study that will include continuous monitoring of the cardiac rhythms of all 200 patients enrolled during the Phase IIb portion of GENETIC-AF. Each patient will have heart rhythm monitoring via a Medtronic device, either a previously implanted cardiac resynchronization or defibrillation device, or a previously or newly inserted Reveal® loop recorder. The collaboration sub-study will measure AF burden, defined as a patient's actual time in AF regardless of symptoms.

For the DSMB interim analysis, AF burden and the primary endpoint of the study, time to recurrence of symptomatic AF after electrical cardioversion, or death, will be reviewed by the DSMB to determine if there is sufficient potential for a statistically significant efficacy signal to be determined for all patients enrolled in the Phase IIb/III study. We anticipate DSMB review of the Phase IIb portion of the study approximately 24 to 30 months after initiation of enrollment. That puts a decision from the DSMB around the middle of 2016. This is the biggest catalyst for revaluation of the shares in our view.

Typically gaining approval of a new chemical entity requires two adequate and well controlled trials each achieving a p-value < 0.05. However, if the GENETIC-AF trial is successful and statistically significant on the primary endpoint with a p-value < 0.01, based on management discussions with the FDA, the agency should accept the application as complete given the strength of the trial and the previous prospective generic data submitted from the Phase III BEST trial. This would be enormously positive for ARCA, shaving years and potentially tens of millions in development cost prior to refilling the U.S. NDA.

We note a retrospective analysis of patients without baseline AF in the MERIT-HF trial found a relative risk of 0.61 (95% C.I. 0.39-0.94) for new onset atrial fibrillation for metoprolol XL relative to placebo in patients without AF at baseline. While the nominal relative risk is considerably larger than that determined for bucindolol in ß1 Arg389 patients, the 95% confidence intervals of these estimates overlap. It is also important to keep in mind other issues that could confound these comparisons, such as the fact that these are retrospective analyses and not randomized studies. Nevertheless, management has designed the GENETIC-AF study with superiority at p < 0.01 in mind, and in our conversations seems confident that this hurdle will be met.

We note that the specific nature of the baseline AF determination in the MERIT-HF trial is not completely clear, and the unknown proportions of patients with a history of AF is likely important, as well as whether the AF was paroxysmal or persistent. Lastly we note that the effect of ß1 389 polymorphs on the effect of metoprolol in HF patients with AF has been characterized in six separate studies. The general conclusion from these six independent studies is that Toprol XL (metoprolol CR/XL) does not seem to demonstrate any differentiation of heart failure clinical response by ß1 389 Arg/Gly genotype (White, 2003; Sehnert, 2008). This represents the key significant advantage to the design of the GENETIC-AF study in our view.

…Our Take On GENETIC-AF…

In comparing the Hazard ratio for bucindolol vs. placebo in the BEST study of ß1 389 Arg/Arg polymorphs (n=441), we find the ratio at 0.26 (95% C.I., 0.12-0.57), corresponding to a 74% risk reduction. As noted above, the Hazard ratio for Toprol XL from the MERIT-HF study compared to placebo was 0.61 (95% C.I. 0.39-0.94), corresponding to a 39% risk reduction. GENETIC-AF is 90% powered to achieve statistical significance on the primary endpoint. In a meta-analysis of Phase III HF trials covering ~12,000 randomized patients, there was a 27% average reduction in incidence of new onset AF in heart failure where new onset AF was reported (Abi Nasr I, 2007). If these data hold, bucindolol should achieve a 56% relative risk reduction when compared to Toprol XL. Given the size of the GENTIC-AF study, we expect these results to be statistically significant at p < 0.01.

Assuming clearance by the DSMB around the middle of 2016 to proceed into the Phase III portion of the study, we then anticipate another 30 months to enroll the next 420 patients and report top-line results. We note the Phase IIb portion of the study will seek enrollment at 50-60 centers around the U.S., with several (potentially another 30-50 centers) coming online following the DSMB review mid-2016, thus allowing for dramatic acceleration of enrollment leading to data around the end of 2018. If all goes well, we anticipate ARCA being in position to re-file the NDA on bucindolol during the first half of 2019, putting a regulatory decision late 2019 and potential launch in 2020.

Intellectual Property

Bucindolol's original composition of matter patent has long expired, but the use of the compound in the intended indication of atrial fibrillation is protected by U.S. Patents 8,093,286, 8,080578, and 7,678,824, each of which claim the use of a genetic test evaluating ß1 389 and/or a2c deletion polymorphism status for determining whether a patient is a suitable subject for bucindolol treatment. As the approved label will undoubtedly reflect the restrictions used to select the patients for the pivotal clinical trial(s), a generic firm seeking to market bucindolol would unquestionably be infringing. As the patents have been granted and the novelty and non-obviousness of the claims seem difficult to challenge, the protection seems reasonably firm.

For the EU market, patent EP1802775 claiming "A method for evaluating bucindolol treatment for a patient comprising obtaining sequence information regarding at least one polymorphism in an adrenergic receptor gene of the patient…wherein the patient is likely to exhibit a positive response to bucindolol if the patient is homozygous ARG389 in the beta-1 AR gene or if the patient is homozygous wild-type in the alpha-2c AR gene" has a priority date of September 14, 2004. It would likely expire on September 14, 2029 based on a 20-year patent life and an expected 5-year Supplemental Protection Certificate. Data protection (similar to Hatch-Waxman) in the EU lasts for 10 years, with a bonus of one year for a significant medical advance. Therefore, assuming approval in the EU in 2020, the data protection would end in 2030, whereas the patent protection would expire a few months earlier.

Market Analysis

Given that Gencaro would be the first genetically-targeted approved therapy for HF in the U.S. if approved in 2020, we see sizable uptake for the drug upon commercialization. If approved, all ß1 Arg-389 homozygous patients that are currently taking non-specific beta blockers for HF like Toprol XL should immediately switch to Gencaro. We can see as high as 50% market share in this sub-population. We model a price of $3,000 in the U.S. (slightly lower in the EU), which yields a peak opportunity for the drug at around $1.6 billion worldwide. We note sales of Toprol XL peaked at $1.4 million in 2009 at AstraZeneca. Our revenue model for Gencaro is shown below.

Conclusion

We are initiating coverage of ARCA Biopharma, Inc. with a Buy rating and a $3.00 price target. The company has identified a genetic signature that appears to be associated with enhanced response to bucindolol against both AF and heart failure endpoints. ARCA plans to initiate enrollment in a Phase IIb/III clinical trial program, called GENETIC-AF, in the first quarter 2014.

Gencaro was previously studied in a 2,708 patient Phase III clinical trial, called BEST, examining the efficacy for the treatment of heart failure in a non-genetically selected population. A 1,040 patient sub-study of the BEST trial prospectively collected information regarding polymorphisms in the ß1 and a2c adrenergic receptors, which are among those targeted by the drug. Although the overall trial failed to achieve its primary endpoint of reduced all-cause mortality, secondary endpoints of cardiovascular mortality and hospitalization were significantly lowered in the Gencaro arm. More importantly, analyses of the prospectively collected adrenergic receptor polymorphism data demonstrated that most of the treatment effects seen against multiple HF and AF efficacy endpoints were due to a particularly robust response among patients homozygous for the Arg-389 polymorph of the ß1 adrenergic receptor. Among patients with this genotype, Gencaro reduced the incidence of new onset AF by 74%, vs. a 1% increase in patients with one or more copies of the Gly-389 version of the gene. This finding is mutually supported by the in vitro, preclinical, and clinical data that are described in our article above.

GENETIC-AF is a double blind, Phase IIb/3 clinical trial comparing Gencaro to Toprol XL (active comparator) in patients homozygous for the ß1 Arg-389 variant. The Phase IIb portion of the trial will enroll 200 patients electrically shocked to restore normal sinus rhythm followed for 24 weeks. The co-primary endpoints of this trial will be: 1) Time to recurrent AF or all-cause mortality, and 2) Total AF burden (time spent in AF). At the end of enrollment of the first 200 patients, primary and secondary endpoints will be evaluated by the trial's Data and Safety Monitoring Board (DSMB) for evidence of an efficacy signal. If a sufficient efficacy signal is detected and acceptable safety is observed, the trial will then proceed to the Phase III portion of the trial, which will involve expansion to a total target of 620 patients.

…DSMB Review Of GENETIC-AF Seems Low-Risk…

The primary thesis and backbone of our Buy recommendation on ARCA Biopharma is the expected clearance of the DSMB to allow expansion of the 200-patient Phase IIb portion of the GENETIC-AF study to the 620-patient Phase III portion. We expect this to occur around the middle of 2016, and be a major re-valuation catalyst for the shares. We base our confidence in the approval of the DSMB to allow expansion of the GENETIC-AF study on our analysis of the prospective data from the BEST trial. We believe clearance of the DSMB review to expand the trial into the Phase III portion of the study will kick-start potential commercialization partnerships with larger pharmaceutical companies interested in bucindolol.

…Top-Line From GENETIC-AF The Ultimate Driver…

Secondary to our recommendation is the outcome of the GENETIC-AF Phase III portion of the study, which offers significantly higher risk / reward, which we anticipate will take place late 2018. We base this on the fact that top-line data from the Phase III portion of GENETIC-AF is still five years away. Nevertheless, this event represents the ultimate value-driver for the company, and one we see as high risk / high reward. Specifically, in comparing the Hazard ratio for bucindolol vs. placebo in the BEST study of ß1 389 Arg/Arg polymorphs (n=441) we find the ratio at 0.26 (95% C.I., 0.12-0.57), corresponding to a 74% risk reduction. As noted above, the Hazard ratio for Toprol XL from the MERIT-HF study compared to placebo was 0.61 (95% C.I. 0.39-0.94), corresponding to a 39% risk reduction. While the nominal relative risk reduction is considerably larger for bucindolol than Toprol XL, the 95% confidence intervals of these estimates overlap. It is also important to keep in mind other issues that could confound these comparisons, such as the fact that these are retrospective analyses and not randomized studies. Nevertheless, management has designed the GENETIC-AF study with superiority at p < 0.01 in mind, and in our conversations they seem confident that this hurdle will be met. GENETIC-AF is 90% powered to achieve statistical significance on the primary endpoint. If these data hold, bucindolol should achieve a 56% relative risk reduction when compared to Toprol XL. Given the size of the GENTIC-AF study, we expect these results to be statistically significant at p < 0.01.

Lastly we note that the effect of ß1 389 polymorphs on the effect of metoprolol in HF patients with AF has been characterized in six separate studies. The general conclusion from these six independent studies is that Toprol XL (metoprolol CR/XL) does not seem to demonstrate any differentiation of heart failure clinical response by ß1 389 Arg/Gly genotype (White, 2003; Sehnert, 2008). This represents the key significant advantage to the design of the GENETIC-AF study in our view.

Assuming clearance by the DSMB around the middle of 2016 to proceed into the Phase III portion of the study, we then anticipate another 30 months to enroll the next 420 patients and report top-line results. We note the Phase IIb portion of the study will seek enrollment at 50-60 centers around the U.S., with several (potentially another 30-50 centers) coming online following the DSMB review mid-2016, thus allowing for dramatic acceleration of enrollment leading to data around the end of 2018. If all goes well, we anticipate ARCA being in position to re-file the NDA on bucindolol during the first half of 2019, putting a regulatory decision late 2019 and potential launch in 2020.

…A Very Large Market…

Heart failure affects approximately 5.7 million Americans, and contributed to over 3 million hospitalizations and 250,000 deaths in 2006 (Norton, 2011). We estimate that approximately 3.0 million are Class II or III in severity. The prevalence of AF among these patients is 30-40%. In patients with HF, AF is associated with increased risk of stroke, all-cause mortality, and hospitalization. Most approved medical therapies for the treatment or prevention of AF are contraindicated in patients who also have HF, thus there are limited treatment options. As beta blockers are already considered one of the cornerstones of HF treatment, the development of a beta blocker with substantial anti-AF efficacy would represent a significant therapeutic advance. Currently approved beta blockers have demonstrated only modest effects on AF endpoints in clinical trials. We estimate the size of the market in Europe is similar, if not slightly larger than the U.S.

Given that Gencaro would be the first genetically-targeted approved therapy for HF in the U.S. if approved in 2020, we see sizable uptake for the drug upon commercialization. If approved, all ß1 Arg-389 homozygous patients that are currently taking non-specific beta blockers for HF like Toprol XL should immediately switch to Gencaro. We can see as high as 50% market share in this sub-population. We model a price of $3,000 in the U.S. (slightly lower in the EU), which yields a peak opportunity for the drug at around $1.6 billion worldwide. We note sales of Toprol XL peaked at $1.4 million in 2009 at AstraZeneca (AZN).

As noted above, we believe that ARCA will seek a global commercialization partner for Gencaro after the clearance by the DSMB allowing expansion of the Phase IIb study to the Phase III portion of GENETIC-AF. A drug like Gencaro, which we estimate has peak global sales at around $1.6 billion, cough fetch up to $50 million upfront and $100 million upon approval (10% of peak sales prior to commercialization). Given the stage of development, we model a 25% royalty payment from this potential big pharma partner to ARCA. We note ARCA has some minor sub-milestone payments (totaling $13 million) and sub-royalty payments (12.5% to 25%) to Indevus.

ARCA exited the second quarter ended June 30, 2013 with $20.4 million in cash and investments. Operating burn for the company is around $1 million per quarter, plus an estimated $10-12 million for GENETIC-AF from start to finish. Therefore, over the next five years, we model ARCA burning approximately $30-32 million in cash. The current cash balance is not sufficient to fund operations to Gencaro commercialization. Therefore, the company will either need to finance or sign a commercialization partnership prior to the filing of the NDA in early 2019. If the company does choose to raise cash, we suspect that $15 to $20 million is a fair target to obtain either late 2014 or in 2015. We have factored in an additional 10 million shares for dilution into our financial model.

…Conservative Target of $3.00…

Plugging all the above into our discounted cash flow model, we arrive at a conservative target of $3.00 per share. Inputs include: $1.6 billion in peak Gencaro sales in 2024 with 25% royalty payment from a large pharmaceutical partner, along with $50 million upfront, $100 million upon approval, and $100 million in back-end milestones realized between the signing of the deal and 2024. We assume an operating burn of around $32 million between now and the filing of the NDA in 2019, a financing to raise an additional $20 million in 2015, a 25% discount rate, 2% terminal growth rate, and a fully-diluted share count in 2019 of around 35 million. All this equates to a market value of approximately $125 million. We believe the current market value of only $15 million vastly under-values the company today. Thus, despite the company's past failures and risk inherent in running a large Phase IIb/III trial like GENETIC-AF, we rate the shares 'Buy.' Our target is $3 per share.

Co-Authored by John Tucker, PhD.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. 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. (More...)

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Venaxis Is Getting Ready To Take Off, All On Board?

I wrote an article recently about Venaxis (APPY), a company with tremendous growth potential that has been under the radar of most investors. That is all about to change in the coming weeks, as the company just announced that they will present at three upcoming investment conferences:

Event: Rodman & Renshaw Annual Global Investment Conference

Date: Monday, September 9, 2013

Time: 3:40 pm (Eastern Time)

Location: Millennium Broadway Hotel; New York, NY

Event: Craig-Hallum 4th Annual Alpha Select Conference

Date: Thursday, September 26, 2013

Time: 3:10 pm (Eastern Time)

Location: Flatiron Room; Convene 730 3rd Avenue; New York, NY

Event: Aegis Capital Vegas Healthcare Conference

Date: Thursday, September 26, 2013

Time: 11:30 am (Mountain Time)

Location: Wynn Las Vegas Hotel; Las Vegas, NV

A webcast of their presentation will be available for 90-days after the live presentation through the company's investor relations link: ir.venaxis.com

Venaxis is on track for obtaining FDA clearance in Q1/Q2 of 2014 of their proprietary CE Marked APPY1 test-a rapid multiplex biomarker assay for identifying patients with low risk for appendicitis. The company has recently established distributors in Europe and has on-going contracts in multiple countries within the region. In my previous article, I discussed in detail the company's product and the reason it was approved in Europe and why it's pending approval here in the U.S. The unique APPY1 test shows a high sensitivity and negative predictive value, allowing for more conservative management of patients and limiting the use of CT scans. (Please see FDA initiative to reduce CT scans in U.S.). Appendicitis affects primarily the adolescent and young adults, who are routinely sent for CT scans for abdominal pain to rule out the risk of appendicitis. Thus, the unnecessary exposure increases the patients risk for cancer (i.e. up to 2% of U.S. related cancers result from CT scans123). There are approximately 22 million emergency visits for abdominal pain in the U.S. and Europe annually, providing a large potential market for the APPY1 test.

APPY is setting up for take-off

The stock has slowly, but steadily maintained a bullish trend for the past 60 days.

It established new support at $1.40 after breaking its previous resistance a month ago (the first signal that the security is about to move higher). After trading side-ways and testing its new support level all of August, it finally broke free this Wednesday rising more than 15% over the last three days. The initial spike occurred one day prior to the company's announcement about its planned presentation(s) at the three investment conferences this month, which will likely result in another surge of buyers. The company is still not covered by the majors, but this may soon change and that "golden opportunity" to invest may also pass.

Trading volume has been very heavy over the past three days, with mostly buyers, and is three times its monthly moving average.

The 60-day chart below shows today's spike, the overall bullish trend, and signs of continued momentum. As I discussed in "Venaxsis: The Hidden Gem With a 'Feel-Good' Investment Opportunity" the initial spike a month ago was a good signal that this particular security is going to move higher.

(click to enlarge)

There are a few additional catalysts scheduled by the end of this year and first two quarters of 2014. The final pivotal-study (requested by the FDA) is on track for completion by the end of 2013, which will lead for filing of FDA approval of the proprietary APPY test in the U.S.

While the technical analysis showed signs of this move a month ago, the company's innovative product and success in Europe were equally important in predicting this surge. As I mentioned previously, it is only a matter of a time before Venaxis reaches investors' doors, and that day is coming sooner than later now. The surge in buying over the last few days is likely the result of investors learning about Venaxis, its product, and overall potential in the coming years. Another fact worth noticing is that the markets performed miserably over the last three days, barely closing with minimal gains today, all while APPY skyrocketed.

Venaxis continues to present a great long opportunity for investors. The company's one of a kind proprietary diagnostic test for appendicitis, and overall progress and execution of milestones are great signals that this is only the beginning.

1 Brenner et al., Rev on Enviromental Health, 2010; 25(1):63-67

2 Brenner et al., New England Journal of Medicine, 2007; 357:2277-84

3 Larson et al., Radiology, 2011; 259(3):793-801: 793-801

Disclosure: I have no positions in any stocks mentioned, but may initiate a long position in APPY over the next 72 hours. 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. (More...)

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Ready, Jet-Set, Go! 10 Stylish (& Affordable!) Carry-Ons

That basic black wheelie bag you never recognize at baggage claim? Leave it behind this summer! We've found the cutest (and most affordable) travel bags out there. Think polka dots, hot pink & fun prints!

By Rachel Greenberg - June 28, 2013

J.CREW

Ideal for a picnic or light hike, this duffle is a versatile addition to your travel-bag collection. Personalize it with a monogram for just $10 more.

To buy: J.Crew Canvas Overnight Bag, $36.50 at jcrew.com

target.com

Make “spotting” your suitcase at baggage claim a little bit easier with this cute polka dot patterned luggage duo.

To buy: Rockland 19-in. rolling carry-on with tote, $40 at target.com

saturday.com

Shoe lovers rejoice, this one’s for you. Keep your spare pair of soles in the separate, zip-off compartment and then stuff this duffle full with all you need for a weekend of fun.

To buy: Kate Spade Saturday Weekender Bag, $150 - $180 at saturday.com

heysusa.com

There’s nothing better than a hard case bag that’s easy on your wallet – and your biceps. Lightweight luggage at its very best, this suitcase isn’t just pretty in pink, it’s practical, too.

To buy: Heys USA 'xCase' 20-in. high-gloss wheeled carry-on, $100 at heysusa.com

horchow.com

Summer travel personified. These pastel pieces feel classic and beachy all at once. Martha’s Vineyard, here we come!

To buy: Brics 'X-Bag' travel collection, $95 - $179 each at horchow.com

deuxlux.com

Preppy meets practical in this weekender-wheelie hybrid. Carry up the stairs with the ease of a gym bag or pull it through the airport like a frequent flyer for true jetsetter style points.

To buy: Deux Lux 'Raleigh' luggage bag $185 at deuxlux.com

hideowakamatsu.com

Expand or cinch this water-repellent suitcase depending on your packing needs. The tarp shell and adjustable straps mean there’s always room for whatever souvenirs you snag along the way.

To buy: Hideo Wakamatsu tarpaulin carry-on, $179 at hideowakamatsu.com

shopbop.com

Toughen up your travel style with this rock 'n' roll weekender, which fuses sparkle and sophistication for a downtown-chic vibe.

To buy: Deux Lux 'Berlin' weekender bag, $114 at shopbop.com

dvf.com

Never one to shy away from prints or patterns, Diane von Furstenberg offers up an iconic design that’s ideal for pretty much any destination. The included garment sleeve makes it easy to pack one of her famous wrap dresses, too.

To buy: DVF 'On the Go' 24-in. suitcase, $120 at dvf.com

horchow.com

These bags look super luxe thanks to the exotic embossed design, but their faux-lizard material means easy maintenance and cleaning once you get back home.

To buy: Adrienne Vittadini embossed lizard tote, $80, and 21-in. spinner, $180 at horchow.com

Connect with Us Follow Our Pins

Yummy recipes, DIY projects, home decor, fashion and more curated by iVillage staffers.

The very dirty truth about fashion internships... DUN DUN @srslytheshow http://t.co/wfewf

On Instagram

Behind-the-scenes pics from iVillage.

View the original article here

Ready, Jet-Set, Go! 10 Stylish (& Affordable!) Carry-Ons

That basic black wheelie bag you never recognize at baggage claim? Leave it behind this summer! We've found the cutest (and most affordable) travel bags out there. Think polka dots, hot pink & fun prints!

By Rachel Greenberg - June 28, 2013

J.CREW

Ideal for a picnic or light hike, this duffle is a versatile addition to your travel-bag collection. Personalize it with a monogram for just $10 more.

To buy: J.Crew Canvas Overnight Bag, $36.50 at jcrew.com

target.com

Make “spotting” your suitcase at baggage claim a little bit easier with this cute polka dot patterned luggage duo.

To buy: Rockland 19-in. rolling carry-on with tote, $40 at target.com

saturday.com

Shoe lovers rejoice, this one’s for you. Keep your spare pair of soles in the separate, zip-off compartment and then stuff this duffle full with all you need for a weekend of fun.

To buy: Kate Spade Saturday Weekender Bag, $150 - $180 at saturday.com

heysusa.com

There’s nothing better than a hard case bag that’s easy on your wallet – and your biceps. Lightweight luggage at its very best, this suitcase isn’t just pretty in pink, it’s practical, too.

To buy: Heys USA 'xCase' 20-in. high-gloss wheeled carry-on, $100 at heysusa.com

horchow.com

Summer travel personified. These pastel pieces feel classic and beachy all at once. Martha’s Vineyard, here we come!

To buy: Brics 'X-Bag' travel collection, $95 - $179 each at horchow.com

deuxlux.com

Preppy meets practical in this weekender-wheelie hybrid. Carry up the stairs with the ease of a gym bag or pull it through the airport like a frequent flyer for true jetsetter style points.

To buy: Deux Lux 'Raleigh' luggage bag $185 at deuxlux.com

hideowakamatsu.com

Expand or cinch this water-repellent suitcase depending on your packing needs. The tarp shell and adjustable straps mean there’s always room for whatever souvenirs you snag along the way.

To buy: Hideo Wakamatsu tarpaulin carry-on, $179 at hideowakamatsu.com

shopbop.com

Toughen up your travel style with this rock 'n' roll weekender, which fuses sparkle and sophistication for a downtown-chic vibe.

To buy: Deux Lux 'Berlin' weekender bag, $114 at shopbop.com

dvf.com

Never one to shy away from prints or patterns, Diane von Furstenberg offers up an iconic design that’s ideal for pretty much any destination. The included garment sleeve makes it easy to pack one of her famous wrap dresses, too.

To buy: DVF 'On the Go' 24-in. suitcase, $120 at dvf.com

horchow.com

These bags look super luxe thanks to the exotic embossed design, but their faux-lizard material means easy maintenance and cleaning once you get back home.

To buy: Adrienne Vittadini embossed lizard tote, $80, and 21-in. spinner, $180 at horchow.com

Connect with Us Follow Our Pins

Yummy recipes, DIY projects, home decor, fashion and more curated by iVillage staffers.

The very dirty truth about fashion internships... DUN DUN @srslytheshow http://t.co/wfewf

On Instagram

Behind-the-scenes pics from iVillage.

View the original article here