A Ticket to Ride from AdComm to PDUFA
REZA is a member of The Motley Fool Blog Network -- entries represent the personal opinion of the blogger and are not formally edited.
About a week before arrival Vivus was notified by the FDA that PDUFA would be delayed for three months, which would give the FDA time to sort out the REMS program. Some believe this delay to be positive, arguing no news on a CRL is good news. Others are not as optimistic, arguing there is still a solid chance for the FDA to ask Vivus to perform more pre-approval work and therefore issue a CRL for which FDA needed more time.
My guess is that Vivus will get approved but with heavy restrictions, and Arena will be the first to market. Orexigen Therapeutics' (NASDAQ: OREX) obesity medication train is far behind the other two and no arrival time has been specified. The obesity market is so large that there is plenty of room for different tools. Lorcaserin is in a unique position that, due to its excellent safety, it can be used for a wide range of patients.
As for international travel, at least in Europe, Arena's in the lead, and I anticipate by 4Q2012 it will have its European Ticket To Ride.
Arena’s train left the AdComm station to the cheers of a 19-4 vote in favor. (The 19 votes includes one abstention, which was not allowed; the AdComm administrator asked the FDA if a new vote should be taken and the answer was no, as an 18-4-1 was a clear indication of the panel's sentiments. However, the abstaining voter admitted to not knowing abstentions aren't allowed and that the vote would have been a yes).
Either way, it was a strong endorsement. Given the positive tone of the FDA briefing documents and the urgent nature of the obesity epidemic, it's fair to expect Arena a yes vote at PDUFA, although the timing has been a subject of debate since the AdComm. Reporters like Adam Feuerstein, who published plenty of unfounded negativity about Arena prior to AdComm, are now singing their gloomy song of delays, but that call is as non-credible as their negativity prior to AdComm.
Just after admitting they made the wrong call, Jim Cramer's crew is making yet another wrong call: the need for REMS (see Dr. Lopez's discussion below). A commentator on a recent negative piece put it nicely:
"AF has been wrong all along... I don't see him improving his record on Arena, or any stock for that matter. His opinion isn't even up for consideration."
Others, including respectable doctors, maintain that due to the epidemic and urgent need for a solution, FDA is doing everything it can to approve Lorcaserin as soon as possible, and at the latest by June 27. The bottom line is we just don't know. If I had to guess I'd say Arena will receive the good news by June 27. The reasoning is that any post-marketing study will not be complicated to define and I do not believe REMS will be required.
The expert views of three physicians indicate why Arena's ride to approval may be a smooth one.
Safety Concerns about Vivus' Qnexa
Dr. Syed Sayeed, medical director of Missouri Delta Medical Center, is very interested in seeing Lorcaserin approved. He's eagerly awaiting Lorcaserin because he faces the obesity epidemic every day. Dr. Syed however, has serious concerns about Qnexa's safety. He wrote:
"Many obese patients have anxiety problems and when they're started on Phentermine it exacerbates the anxiety symptoms. Phentermine could cause severe aggression and agitation in patient with underlying bipolar disorder. Phentermine is used by physicians for short term because of addiction potential and if used for long periods it could cause dependency. If Qnexa is used for longer periods and by millions of people it could be a disaster for our nation -- it will make millions of people addicted to Phentermine and government need to open rehab for Phentermine dependency. In Europe you will find Phentermine addiction clinics for those who were abusing Phentermine. There is a higher chance of Qnexa being abused and no physician would write Qnexa and prefer to write Phentermine alone for short periods if needed".
In contrast, Dr. Syed finds Lorcaserin safe and he's keen on using it on most of his obese patients as soon as it's available.
No REMS for Lorcaserin
Vivus has to do a REMS because Qnexa has safety issues, which Lorcaserin does not have. Many experts have commented on whether REMS will be required, including Dr. Daniel P. Lope, M.D., F.A.C.O.G., an obstetrician and gynecologic surgeon in Los Angeles who is interested in Lorcaserin because endocrinology is a major field in the specialty of gynecology, and obesity is a significant problem in both obstetrics and gynecology. He made the following comments, which I reprint with permission:
“The following discussion is the basis for my opinion as to why a REMS will not be required for valvulopathy.
First of all everyone talks about valvulopathy but does everyone understand the clinical significance of this entity? If you don’t I will first discuss it and then discuss the FDA findings regarding the risk.
The FDA case definition of valvulopathy: requires documented mild or greater aortic regurgitation OR moderate or greater mitral regurgitation.
REMS will not be needed. The FDA conditions for a REMS (from the guidance in the FDA website): REMS will be required if it is necessary to ensure that the benefits of the drug outweigh the risks of the drug – that is, the seriousness of any known or potential adverse effects that may be related to the drug. There are others but these are the relevant ones for our discussion. Remember, the word is SERIOUSNESS. Here are the reasons REMS will not be required:
1. Clinical significance: Aortic regurgitation (AR): long term prognosis, especially those who are asymptomatic, has a favorable outlook and this has been well documented. It evolves in a very slow and insidious manner and has very low morbidity during a LONG asymptomatic course; this can remain for decades and usually does not progress to treatment. Only those that develop severe AR can result in left ventricular dysfunction, and eventually heart failure. This was rare with dexfenfluramine which by the way, AR was the primary lesion, not mitral regurgitation (MR). With lorcaserin it is the opposite – most common lesion was MR.
2. Mitral regurgitation (MR): isolated mild to moderate MR is without symptoms – very little overload of the heart – heart function remains normal. Even with severe MR, most remain without symptoms until there is left heart failure, pulmonary hypertension, or atrial fibrillation. There were no cases of this with lorcaserin.
3. In fact, because of the benign nature of these lesions the guidelines for followup of patients who had been on dexfenfluramine are the following:
- Physical exam with auscultation of the heart. In the absence of heart murmurs or other findings, exam is repeated in 6 months – the absence of heart findings by stethoscope predicted the absence of echocardiographic valvular regurgitation in 93% of patients, while the presence of murmur had only a positive predictive value of 19%;
- Echocardiography is only indicated in the presence of murmurs, symptoms, or difficult exam by stethoscope due to body habitus;
- If a lesion is found, depending on severity, followup is between 6-12 months because of the slow progression to more serious lesions.
So those who are suggesting that echocardiograms will be required you can see this is nonsense. Any patient who presents to doctors office should have an exam, including the heart by stethoscope. You do not need to have a REMS requiring echos because all you need what is normal practice in an office. Of course any patients on anorectic medications will especially need a heart exam in the office by the MD with a simple stethoscope.
CONCLUSION: ECHOCARDIOGRAPHY is not necessary to evaluate these patients who will be lorcaserin.
2. THERE IS NO CLINICAL SIGNAL IN ANY OF THE CLINICAL TRIALS TO WARRANT A REMS – IT IS PURELY THEORETICAL BASED ON AN ARBITRARY CUTOFF.
Every author who wrote an article suggesting the need of a REMS based on valvulopathy [e.g. Adam Freuerstein] has no clue what they are talking about. If they had spent time understanding the clinical significance and the analysis of the data in the FDA BD they would not come to that conclusion.
The following is all based on the data in the FDA BD:
- Plasma levels of lorcaserin at the clinical dose of 10 mg bid is substantially below the EC50 for activation of 5HT2A and 5HT2B based on functional receptor activation assays whereas the plasma levels of lorcaserin remain within the selective range for activation of 5HT2c. In plain English, plasma levels of lorcaserin are not high enough to activate 2a and 2b receptors but are high enough to active 2c receptors. That is, activation of 2a and 2b at therapeutic levels is unlikely.
- Functional profiling studies showed that lorcaserin had the same potency for activating 2B receptors as did the compounds known NOT to cause valvulopathy – demonstrating a low risk of lorcaserin to behave as a valvulopathogen.
- The FDA commented that the more appropriate data in determining risk for VHD was these functional profiling studies along with the receptor activation assays and the echocardiography data from the clinical trials.
- FDA’s position was that ruling out a relative risk of 1.5 for FDA-defined VHD was an ARBITRARY but reasonable endpoint. They acknowledged the difficulty in obtaining a noninferiority margin smaller than 1.5 because it would require a very large study.
- As noted above fenfluramine VHD was driven by increases in AR whereas lorcaserin was more MR than AR. I will spare you the statistical gymnastics and get to the conclusions:
Pooled phase 3 trials:
Only one patient in the phase 3 trials developed severe MR – and this was in the placebo group; no patients developed AR.
In the BLOSSOM and BLOOM DM trials patients were allowed to enroll with preexisting FDA-defined VHD. Lorcaserin did not develop worsening of their VHD over the 52 weeks as compared to placebo, which had an increase in worsening.
Now when they looked at patients at week 52 (LOCF) you get the following:
- 2.0% of patients on lorcaserin and 1.7% placebo developed moderate or severe regurgitation at week 52
- BLOOM – DM at week 52(LOCF) 1.9% of patients on lorcaserin and 1.0% placebo developed moderate regurgitation. NO PATIENTS IN BLOOM DM DEVELOPED SEVERE REGURGITATION AT ANY VALVE.
- NO patient in any phase 3 trial treated with lorcaserin required heart valve surgery or replacement. FURTHERMORE, NO patient treated with lorcaserin reported symptoms from valvular regurgitation.
- POOLED nondiabetic phase 3 trials: 0.3% on lorcaserin bid and 0.1% on lorcaserin qd and four on placebo had cardiac murmur
- BLOOM DM two (0.8%) on lorcaserin 10 bid had murmur – no increases in scores in regurgitation scores for any valve in those two patients.
CONCLUSION: The functional profiling, receptor activation assays, and the echocardiographic studies demonstrate the safety of lorcaserin and also demonstrate THE LACK OF ANY CLINICAL SIGNAL.
Any consideration for a REMS with regard to valvulopathy is purely theoretical based on a theoretical cutoff point PERIOD."
With REMS not required most people I talk to believe the FDA will meet the June 27 PDUFA date and not delay the approval of Lorcaserin.
EKG Not Necessary; Valvulopathy Non-Issue?
Dr. Murthy Andavolu, a specialist in hematology and oncology in California, was appalled by some of the Lorcaserin AdComm panel members' argument about need for EKG.
"The most insane thing I heard in the Arena AdComm was about doing EKGs for patients on Lorcaserin. What is the screening value of EKGs for valvular heart disease? I find it appalling that some physicians talked about it in the AdCom. I am a physician - a non-cardiologist physician - but I can guarantee you that EKGs have no value in patients taking this drug (or any drug) to look for valvulopathy. If they recommend an echo I can understand though not agree with it, but an EKG, for Christ's sake!!"
A cardiologist published (and this) in reaction to some of the discussion in the AdComm, claiming some of the AdComm members did not have an in-depth understanding of the subject of EKGs and valvolupathy. He further contends vallulopathy to be a "NON issue".
Another Doctor's Plea to the FDA
In a letter to the FDA on May 20 May, Dr. Steven Vig, a practicing internist in Tuscon who treats obese patients, encouraged the FDA to approve Lorcaserin as soon as possible (reprinted with permission):
"As a practicing internist in Tucson, Ariz., I would encourage the FDA to grant approval for lorcaserin (Lorqess) on or before the PDUFA date of 6 27 2012. Lorcaserin will be indicated for weight loss in patients with BMI over 30, or for patients with BMI over 27 who have co-morbidities. Arena Pharmaceuticals did a wonderful job of answering all questions in the Complete Response Letter, and the FDA Advisory Committee members voted 18 to 4 in favor of lorcaserin (with one member abstaining) on 5 10 2012.
Any concerns about breast cancer in rats were answered by the pathology review of the previous rat slides, and by additional studies on prolactin done in the last two years by Arena Pharmaceuticals. Obesity is associated with higher rates of cancer, and there is reason to believe that patients who lose weight due to lorcaserin may actually have lower rates of cancer. Average weight loss on patients who completed lorcaserin for a year was 18 pounds, and the top 25% of weight losers lost an average of 35 pounds.
Receptor studies have shown a high degree of specificity of lorcaserin for the 5HT2C receptor (the weight loss receptor), and a very low activity at the 5HT2B receptor (the valvulopathy receptor). Heart rate and blood pressure levels are not increased by lorcaserin. Pooled analysis of the Bloom, Blossom, and Bloom DM studies have not indicated an issue with cardiac valve disease due to lorcaserin. In fact, the two year data in the Bloom study showed a 2.7% chance of valvulopathy on PLACEBO, and a 2.6% chance of valvulopathy on lorcaserin. Lorcaserin at exposures of up to 50 times the human dose for a year did not induce changes in cardiac valves or the pulmonary vasculature in monkeys. I do not believe that a requirement for echocardiogram monitoring is necessary in patients who take lorcaserin.
The Bloom DM (diabetes mellitis) one year study produced a 27 point drop in the fasting glucose level on lorcaserin, along with a 0.9 point drop in the hemoglobin A1C level (compared to a 0.4 point drop on placebo). These improvements are comparable to many of the diabetes pills that we currently use!
I see overweight and diabetic patients every day. 2/3 of Americans are overweight, and 1/3 of Americans are obese. Physicians often refer to the BIG FOUR DIAGNOSES in a patient, which includes obesity, diabetes, hypertension, and hyperlipidemia. Patients who are obese have higher rates of cancer, back pain, knee pain, hip pain, fatty liver, venous insufficiency (swelling of the legs), cardiovascular disease, and sleep apnea compared to patients with normal weight. The cost to America in terms of morbidity, mortality, and work disability is enormous, and getting worse. Other than diet and exercise, current medications for weight loss are limited, and have side effects. Lorcaserin has a very benign safety profile, and I am convinced that lorcaserin will be the first medicine that most doctors will reach for when prescribing a treatment for weight loss in a patient.
Lorcaserin is a 5HT2c receptor agonist, and causes lower dopamine levels in the brain. Studies from Duke University Medical Center in 2011 showed that rats given lorcaserin used less nicotine. Studies of 5HT2c agonists in rats also showed a decreased tendency to use cocaine. Decreases in dopamine lower the tendency for excessive gambling, and for sexual addictions. 25 years of research on the 5HT2c serotonin receptor has been documented in the 2010 medical textbook “5HT2C RECEPTORS IN THE PATHOPHYSIOLOGY OF CNS DISEASE” by Giuseppe Di Giovanni.
Physicians are in desperate need of weapons for the War on Obesity. Please don’t send us back into battle unarmed. Please approve this novel agent lorcaserin (Lorqess) for weight loss as soon as possible!"
Lorcaserin's Low Potential for Abuse
The question of Schedule 4 labeling was on the minds of some investors. In a new article, Dr. Vig argues why Lorcaserin is not a controlled substance, and therefore has low potential for abuse.
I see a green light for the Arena Train to arrive at the Approval station and deliver a much needed gift to millions of obese patients and doctors who are eager to see their patients benefit from this marvelous novel agent.
I own shares in Arena because I believe Lorcaserin will be approved and it will be able to capture a large share of the enormous obesity treatment market. I like Lorcaserin's very good safety profile and its good efficacy. I also like the fact that so many doctors are highly interested in this molecule and really want it as part of their toolkit. The opinions expressed in this article are not investment or medical advice. Please do your own research. For more information about the author please visit www.rezamusic.com. The Motley Fool has no positions in the stocks mentioned above. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy. If you have questions about this post or the Fool’s blog network, click here for information.