Sequenom is one such company on the list that I found particularly interesting. 

As I approach my mid-thirties, along with many of my friends, I find myself still at the early stages of raising my own familial unit, with future children on my mind.  This is in sharp contrast to the experience of our parents, who most likely at this point were finished with that stage of their lives and had children many years older than ours.  We all have our reasons for starting our families at a time that would be considered “late” by our parents’ standards, but one of the downsides is increased (albeit still small) risk to the baby for Down Syndrome.  Amniocentesis is one of the best accepted methods to screen for this disorder, but it carries with it a risk of miscarriage and can only postiviely identify 70 to 90 percent of the cases prior to birth.  Sequenom, however, has developed a method that could trump amniocentesis at identifying Down Syndrome cases — so far with 100% accuracy in clinical trials — and do so with minimal risk using only a prenatal blood test.

Sequenom’s technology, dubbed SEQureDx(TM), targets fetal DNA circulating in the mother’s blood to examine the genetic status of the fetus.  The first application identified a fetus’ risk for RhD disease, which occurs when the blood of an expectant mother is incompatible with her unborn child.  Jaundice, anemia, brain damage, heart failure and even death can result from the incompatibility, so identifying it early is crucial to taking measures against it.  Showing that it can additionally be applied as a method for testing a fetus for Down Syndrome would be an added incentive for any potential buyers for the company.

I am encouraged by the company’s charter to make “safe, non-invasive prenatal testing available to all women, independent of age and other factors that may contribute to pregnancy complications,” and am hopeful that the knowledge gained in this kind of research could lead to an increased understanding of the kind of defects that could affect the normal development of an unborn fetus.  As parents, knowing in advance how we should be prepared for any difficulties an unborn little one might have is invaluable and gives us the opportunity to prepare for what might be.

The obvious win for any pharmaceutical company that entertains the idea of Sequenom as an acquisition is an increase in the number of parents willing to run the test.  Like many parents, I fear the risks of amniocentesis, despite the information it will give me.  If the risk is mitigated, then wouldn’t more parents do it?  Would it just become part of the standard barrage of tests that expectant mothers are put through?

They say knowledge is power.  Today, we may be having our children later, but we know a lot more about them before they are born than our parents ever did.  Gender, heartbeat, skeletal development, and soon even certain genetic diseases can be safely screened well before the baby is born and steps can be taken to prepare for or even prevent hardship for the child later in life.  But does this take any of the excitement or anticipation out of child birth?  Does knowing any of this information change the way you feel about a child growing inside your wife (or you)?  Or does knowing the information help you prepare to be a better parent?

Your thoughts, as always, are welcome.

Can you guess which agency granted approval and which agency did not?  If you’ve been following the pharmaceutical industry for the past five years or so, then you probably guessed that Bridion was approved by the European Commission (EC) and turned down by the FDA.  And you’d be right.  This isn’t the first time that the FDA has rejected a product that was approved in Europe, but the fact that all signs were pointing toward approval and the fact that the FDA rejected Bridion a mere three days after it was authorized by the EC, makes it a stand-out example of just how cautious the FDA has become.

So why was it a surprise that the FDA rejected Bridion? 

First, Bridion (or sugammadex by its generic name) is seen by many as a breakthrough drug in the anesthesia field.  Its manufacturer, Schering-Plough, states that “it was specifically designed to reverse within minutes both moderate and deep muscle relaxation induced by rocuronium or vecuronium during general anesthesia. As a result, BRIDION can give anesthesiologists greater control in managing the depth of muscle relaxation through to the end of a surgical procedure.”  The drug is able to quickly reduce paralysis induced by anesthesia, allowing doctors to take the patients off breathing tubes in less time and reduce the side effects of being “under” for a long duration, such as undetected loss of oxygen.  In clinical trials, Bridion showed an ability to reverse muscle relaxation with a median time under 3 minutes, up to 9 to 12 times faster than neostigmine with glycopyrrolate.

Second, the safety risks had not raised any eyebrows during clinical trials.  The most commonly reported adverse effect was a metallic or bitter taste.  Some patients experienced anesthetic complications, such as limb movement or coughing during surgery, or unwanted awareness during anesthesia. Other patients experienced allergic reactions, but these reactions did not appear to be any worse than the reactions caused by the most commonly used anesthesia drugs today - neostigmine and succinylcholine.  In many physicians’ views, the benefits of faster paralysis reversal far outweighed these safety risks.  In fact, the advisory committees for both the FDA and EC performed their respective benefit/risk analyses and gave their recommendations for marketing approval.

Regardless, on August 1, 2008, the FDA rejected Bridion citing concerns about “hypersensitivity and allergic reactions” to the drug.  The agency raised no concerns about the drug’s effectiveness. Meanwhile, the first post-marketing patient was treated with Bridion in Sweden last week. The physician reported that the patient experienced reversal from the muscle relaxant used during surgery in just two minutes.

Schering-Plough plans to move forward with its plan to market the product in the U.S., and perhaps the authorization will go a little smoother after the FDA allows the Europeans to be their test subjects for a little while.  Maybe the U.S. will see Bridion soon… or maybe not.  We’ll have to wait and see.

TA-CD essentially works just like vaccines that are used to fight traditional diseases (such as tetanus or the mumps). It gets the body to recognize cocaine as an invader and uses the body’s immune system to prevent the cocaine from doing what it normally does: get the user high. 

As we know, the body doesn’t normally treat cocaine as a harmful trespasser, so TA-CD pairs deactivated cocaine molecules (norcocaine) with deactivated cholera toxin molecules.  The body recognizes cholera as an enemy, and since it is paired with cocaine molecules, the body builds anti-bodies to fight both foreign substances.  The anti-bodies bind to the cocaine molecules, and the resulting bound molecules become too large to enter the user’s brain.  As a result, the patient does not feel the high associated with cocaine use.  In other words, the patient builds immunity to cocaine.

Celtic reports that it completed four Phase II trials with 161 patients prior to 2007 and a larger Phase II trial was slated for 2007.  Preliminary results from the Phase II trials showed efficacy (an increase in cocaine-free days) in a significant number of patients in the treatment group (see the article in Medical News Today for more information).

Of course, Celtic does not plan to lobby to get TA-CD introduced into the list of common childhood vaccinations just yet.  They intend to market the product to assist in the fight against cocaine addiction.  Celtic reports that 800,000 patients in the US attend in-patient programs and out-patient clinics seeking treatment for cocaine addiction, and more than 95% of all cocaine addicts who try to quit relapse.  This is a significant patient population that can benefit from this product.  Along with counseling and the support of family and friends, it will be a tool to help addicts quit. 

Further back in Celtic’s pipeline is TA-NIC, a nicotine vaccine.  If TA-CD is successful, it may pave the way for TA-NIC as well.  It’s not hard to imagine a full suite of vaccines against our pharmacological vices (marijuana, MDMA, heroin, crystal meth, etc.) on the market some day.

I’ll be looking for answers to some of the following questions in the Phase III studies: 

• How long will the vaccine last before a booster dose is needed?
• How many patients will overdose because they increase their cocaine intake in hopes of overwhelming the anti-bodies and getting their high?
• How many patients will switch to another drug (e.g. methamphetamines) to get their fix?

And if the product makes it to market, how will our society react? 

• Will addicts really submit to the vaccinations if the product promises to kill their high for, say, 10 years like a tetanus shot? That’s a big commitment for an addict - there’s no turning back.
• Will parents vaccinate their children against cocaine?
• Will employers require their employees to be vaccinated?
• How will cocaine producers innovate in order to retain their business?

This is an interesting product to keep an eye on.  Your thoughts and comments are welcome.

According to the FDA, in order to be considered a “botanical” product, a drug must have the following characteristics:

• A botanical drug product consists of vegetable materials, which may include plant materials, algae, macroscopic fungi, or combinations thereof.
• A botanical drug product may be available as (but not limited to) a solution (e.g., tea), powder, tablet, capsule, elixir, topical, or injection.
• Botanical drug products often have unique features, for example, complex mixtures, lack of a distinct active ingredient, and substantial prior human use. Fermentation products and highly purified or chemically modified botanical substances are not considered botanical drug product. (1)

Headquartered in Jamesburg, NJ, Phytomedics was launched in 1996 to focus on such botanical drug products and has partnered with the Biotech Center at Rutgers University for its research and development, allowing it to function as a private company with access to cutting-edge research facilities while keeping its costs low. Those costs are being covered by several investment firms including Inventages Venture Capital GmbH (life ventures by Nestle), Burrill & Company, Polar Investments Ltd and Biotech M.A.H. Plant Genomic Fund.

The company currently has 2 drugs in development. The first, which has already commenced its Phase III clicnical trial development, is a new, oral drug for treatment of auto-immune diseases. In its Phase II, double-blind clinical trial, PMI-001 was given to 120 patients with moderate to severe rheumatoid arthritis. The results showed significant efficacy of the drug, with rapid pain reduction in as little as 2 weeks and a halt in joint erosion in 6 months. PMI-002 is the second botanical drug under development and shows promise in the treatment of cancerous cells as well as the possible prevention of neurological and opthalamic degenerative disorders.

Other drugs are also in their pipeline, but have not yet received the same focus as their other products (it seems due to lack of funding). These products include:

• A botanical bioactive that acts as a COX-2 inhibitor but with less risk than a Vioxx, Celebrex or other synthetic chemical entity.
• A botanical appetite suppressant that could be leveraged for weight loss, and a counterpart derived from an agricultural waste processing stream that could block fat absorption.
• A plant-derived agent that could be used to limit the impact of aging on muscle cells.

It seems that these drugs, along with the proprietary methodologies the company is using to develop them, could usher in a new wave of drugs that will be prescribed by doctors in the future. As you may know if you’ve read a few of my posts, I’m very interested in keeping an excessive amount of “artifical” stuff out of my body, and the research here shows promise for drugs that may be headed in that direction. I am hopeful that companies like Wellgen and Phytomedics can provide breakthroughs in this area of research and demonstrate the safety and efficacy of these drugs because of their origins as completely natural substances.

However, until an actual product has been released and clinical trials can demonstrate the safety of the product and its interaction in the human body can be better understood, I remain cautious of drugs developed within this emerging field.

Your thoughts?

(1) See “What is a Botanical Drug?“, FDA web site.

One of the persistent challenges of the Pharmaceutical industry has been maintaining the safety and efficacy of drug products in patients over time. In other words, when a patient starts taking the drug, the patient is able to take a lower, safer dose of the product in order to treat the symptoms. However, over time, the patient becomes desensitized or builds tolerance to the drug such that he/she must take higher, less safe doses of the product in order get the desired effect. Eventually, the dosing may reach dangerous levels causing serious, or even fatal, side effects. The crux of the problem is that the pharmaceutical industry does not really have a handle on how target drug-receptors are activated or de-activated in the body in order to achieve the desired result. As a result, desensitization is viewed as an unavoidable side effect.

Last week, I attended the NYC Bio Meetup. One of the presenters was Richard G. Lanzara, President of Enhanced Pharmaceuticals (EP). EP is attempting to combat the problem described above by modulating targeted drug-receptor effects to create new drug combinations which are safer and more effective. EP’s methodology combines an agonist, which triggers a response from the receptor, with an antagonist, which produces no response from the receptor and can block the action of the agonist, in a calculated formulation in order to optimize the drug’s efficacy while curtailing desensitization. EP has shown promising research for improving products used to treat heart failure and asthma. Additionally, EP believes that drugs used to treat Parkinson’s disease, memory loss and other diseases can be enhanced to reduce patient tolerance.

EP does not yet have a website, but the technology was transferred from Bio Balance, and one can obtain more information about their philosophy and technology on the Bio Balance website. EP’s goal is to license the technology to pharmaceutical and biotech companies so that these companies can develop safer, more effective new products and enhance (and potentially extend the patent life of) their existing product lines.

In my limited research (within the first 10 pages of some Google searches), I did not find any competitors for EP nor did I find anyone refuting the ideas and technology put forth by EP/Bio Balance. However, it may be safe to assume that pharmaceutical companies, small and large, have put significant resources toward developing similar/competing technology. On the other hand, this type of technology brings the ethics vs. profit question into light for Big Pharma. While companies have an ethical duty to put forth the safest and most effective products, they may not be able to sell as much of their product if they do. If they are able to create a product that does what it is supposed to do for as long as the patient needs it without a build up of any kind of tolerance, then the patient will never need to increase dosage (such as taking two pills instead of one) and there will be less of a need for more costly variations/extensions of the same product (e.g. extra-strength” variations). Do pharmaceutical companies really want this technology? EP is betting that they do.

EP hopes to start Phase 1 clinical trials of their technology in the near future. Ideally, the clinical trial process will prove that the technology works and provide answers to some of the following questions:

• Over long periods of time, do the combination products retain their efficacy or does desensitization eventually occur? This question may or may not be answered in clinical trials depending on the amount of time it takes to build up tolerance.
• Will the formula work the same for everyone? Different people build up tolerance at different rates. A drug’s efficacy varies from person to person. Will EP’s formula work the same for everyone or will the ratio of agonist-to-antagonist need to change from person to person?
• What new side effects will appear with the agonist/antagonist combination products? While the adverse affects for agonist alone and antagonist alone may be well known, unexpected events may occur when taken together.

EP’s methodology is certainly something to watch in the coming years. If EP can demonstrate that their technology really works and drug companies buy into it, then consumers can look forward to drug products that get the job done safely every time.

Obviously, not all clinical trial participants treat their participation as a job; some are people who are donating their body in the hope of finding a cure for some disease that afflicts them, while others are health but participate for extra cash. Many, however, are like Brandon, a 30-year-old professional lab rat that spends a good part of his free time in a research facility. In the last 18 months, he earned $25,000 in a number of trials in Michigan, Indiana and Texas, likely earning more than in his previous career path: a part-time, minimum-wage job hopper. As he puts it:

“This is the longest I’ve ever done anything,” says Brandon. “I don’t plan on doing it forever, but it sure beats the heck out of working at a regular job.” (1)

Brandon’s lifestyle may not be right for me, living study after study, subjecting my body to likely safe, but still experimental chemicals (only 1 in 10,000 will suffer a fatal side effect).(2) For now, though, it seems to work for him and guinea pigs do help determine what drugs are safe to bring to market.

Or do they?

The biggest problem with these volunteers is what they do for the money they earn for each study. In a Johns Hopkins survey, 10 percent of a sample group of research volunteers admitted to participating in more than one study at a time — double-dipping, so to speak — and most likely doing so without the knowledge the researchers. (3) In most other careers, this kind of multitasking would probably be applauded, but in clinical research it is risky behavior. Treatments for the different studies may interact in unpredictable ways, skewing test results, causing harm to the volunteer and subsequently blocking the drug’s path to approval.

Federal regulations exacerbate the problem because personal information that could identify study participants are supposed to be kept confidential. This wouldn’t be as much of a problem if there were only a select few research facilities where the drugs were being tested. But that coupled with the pharmaceutical industry’s increasing reliance on subcontracted, for-profit contract research organizations (CROs) makes tracking these moonlighting individuals difficult, if not impossible. As a result, the system is set up to almost encourage participation in multiple studies. Organizations that specialize in running clinical studies take advantage of this group of guinea pigs because the most time-consuming (and therefore costly) part of any clinical trial is finding those volunteers.

What does this mean for us? It means that as the prevalence of these professional clinical trial volunteers who participate in more than one study increases, so do the risks of results being skewed. These results, once reviewed by the FDA for approval, could prevent a critical drug from reaching the market because of its reaction with an entity about which the researchers weren’t aware. A worse scenario in my mind would be a drug prone to present a patient with more side-effects, but that was effectively neutralized by a drug that was being taken by a patient in another study. Forgoing the scientific process for the sake of earning a few extra dollars could put more people at risk down the line than just these professional volunteers.

To guard yourself against any kind of adverse event that slipped through a clinical trial, follow these four steps outlined by the Jenna Stumpf as a sidebar to “Drug-Test Dummies:”

Don’t be first

Unless there’s no comparable durg available, try to stick with a medication that’s been on the market for 2 years or longer. Like a new car model, a brand-new drug may still have bugs that weren’t worked out (or even detected) in clinical trials, says Steven Scott, Pharm. D., an associate professor of clinical pharmacy at Purdue University.

Stay at One Store

If a doctor hands you a prescription and you forget to mention that you’re on other medications, you risk a drug interaction. That’s why Robert Freeman, Ph.D., a professor of pharmaceutical sciences at Texas A&M, recommends that you fill all your scripts with the same pharmacist- and run any over-the-counter drugs or supplements by him too.

Use a Safety Net

Add extra insurance against an interaction with a free account at epocrates.com. This database acts as a virtual pharmacist, cross-referencing your meds to see if any don’t play well together. Used by more than 500,000 health-care professionals, Epocrates alos provides a layman’s summary of the indecipherable drug-info pamphlet.

Watch Yourself

Before you start a new medication, take stock of how you feel. While upset stomach, headache and drowsiness are all relatively common reactions, they should pass as your body adjusts to the drug, says Freeman. If they persist for longer than 3 days or you feel any muscle or abdominal pain, see your doctor.(4)

While it may be clear there is a problem with the system, even the strongest critics agree that it is necessary to ensure the safety of drugs brought to market. However, until new safeguards are implemented to prevent people like Brandon from taking advantage of the flaws, there is always a chance there will be skewed results dictating the fate of that new drug. That is a shame, because though I know I am conservative about taking medications, I do believe many drugs provide a benefit that cannot be measured by those people who depend on them. In a scientifically tainted clinical trial, they are the ones who stand to lose the most.

(1) See “Drug-Test Dummies,” Melba Newsome, Men’s Health, April 2008, p128.

(2) See “Drug-Test Dummies,” Melba Newsome, Men’s Health, April 2008, p128, sidebar: the high cost of clinical trials.

(3) See “Drug-Test Dummies,” Melba Newsome, Men’s Health, April 2008, p128.

(4) See “Drug-Test Dummies,” Melba Newsome, Men’s Health, April 2008, p130, sidebar: Prescription Protection by Jenna Stumpf.

By no means will I cover the entire list here — I am but a humble blogger, and there are far too many for me to review for the purposes of my audience. But I have covered several clinical areas in 2007 on this blog, and will try to use that as a framework for what I’ll discuss below. To get a full list and analysis on all the drugs in the pipeline for 2008 and beyond, read “The Pharm Exec Pipeline Report 2007” online at the Pharmaceutical Executive.

Alzheimer’s Disease: Prevention and Management

You may recall, back in July, I wrote a post describing my experience with Alzheimer’s disease in my own family, and about a drug called Affitope AD01 being developed by Austrian pharmaceutical company Affiris. Its purpose is to prevent the deterioration of the mind associated with Alzheimer’s disease. While it didn’t make the list of “drugs in the pipeline,” likely because it was just entering clinical trials at the time, it is a fair representation of the purpose of drugs that are in the pipeline: prevention and management.

All of the upcoming drugs in this category strive to slow the course of the disease by intervening in the ß-amyloyd pathway. This pathway releases a toxic substance that later congeals into amyloyd plaque, itself benign but indicative of the damage done. The drugs, Flurizan, Bapineuzumab, PBT2, Alzhemed and Dimebon, each approach the problem differently and are showing different levels of effectiveness in their clinical trials. Dimebon appears to be the most compelling at this time, its Phase II clinical trials exceeding hopes in Russia. The measurable difference between the effect of the drug vs. the placebo was greater at 12 months than it was at 6, a strong indicator of a disease-modifying compound.

Smoke Down

Again in July, I came across a study that linked smoking with the prevention of Parkinson’s disease. Interestingly, it didn’t have anything to do with any one particular chemical in the cigarettes, but with the act of smoking them (read more here). Well, in spite of that article and the convincing research, I didn’t become an advocate for smoking, even if it raised the question as to whether certain people should start. It didn’t slow down the development of new drugs to help wean people off smoking either, with two new drugs entering the market: TA-NIC and Dianicline.

Pfizer has had some success in this area with its drug Chantix, but as I mentioned in my last blog entry, the drug may have links to suicidal thoughts in patients. Like Pfizer’s drug, Sanofi-Aventis’ Dianicline allows nicotine to enter the brain but binding to the receptors that produce the pleasurable effects associated with it. The similar approach makes me wonder whether patients will suffer the same negative psychological effects as did the patients who took Pfizer’s Chantix during clinical trials. TA-NIC takes a more novel approach, delivered as a vaccine in the bloodstream that produces antibodies that bind to nicotine while still in the bloodstream. This in turn reduces the chemical’s entry into the brain and the positive reinforcement associated with smoking.

Obesity: The Market Gets Bigger

At several points during the year, I wrote about Sanofi-Aventis‘ drug Acomplia, a controversial weight-loss drug that had potential major side-effects, including anxiety, insomnia and depression. The first time I had written about the drug, it was being considered for approval by the FDA in the United States. Since then, an advisory panel rejected its approval here, but Sanofi-Aventis apparently hasn’t given up, according to the report.

In fact, all three compounds in clinical trials right now, Sanofi-Aventis’ Acomplia, Merck’s Taranbant and Pfizer’s CP 945598, are all cannabinoid receptor antagonists, thus they may all be subject to the same side effects that have thus far foiled Acomplia’s introduction to the market. So why continue to pursue these drugs if the precedent demonstrates that they will likely be rejected? Estimates poise the winner to have $3 billion in sales at its peak, giving big Pharmas good reason to pursue the drugs.

RSV: Close to Home

While I didn’t necessarily focus any articles on RSV (Respiratory Syncytial Virus), it is something in which I take a profound interest, because my son suffered not one, but two bouts with the disease in the 5th and 6th months of his life. In both instances, it was suspected he developed viral pneumonia as a result of the infection. I remember the nights at the hospital, and though my wife and I both were aware of how dangerous the pneumonia could be to our infant, I think we were both numbed by the entire experience. I would not wish those kinds of nights on any parents, and I would also hope to limit its effect on its other primary group, the elderly, which is why I was encouraged to see two new treatments on the way down the pipeline for this disease.

AstraZeneca’s Motavizumab, a monoclonal antibody targeted specifically for full-term infants, is quoted as being a breakthrough drug in the article because of its efficacy in clinical trials. It is currently in Phase III clinical trials and is targeted for release in 2008. Alnylam’s ALN RSV01, on the other hand, is a small interfering RNA (siRNA) compound that attacks the RSV infection at the genetic level while in the lungs, rendering it ineffective. There is no current target date for release, though it is currently being tested on adult volunteers and as a nebulized formula appropriate for hospitalized infants.

There are several other drugs in the pipeline, obviously too numerous to mention here, so I encourage you to see the full article in Pharmaceutical Executive magazine. New cholesterol drugs, improved antibiotics, new approaches and solutions for diabetes, even novel cocaine therapy are a hint of what is to come in the future. There is even a whole variety of compounds being developed to ward off and attack cancer.

Encouraging as the news is, it will be hard to get excited about any of these compounds until they are approved. Even then, given the track record of drugs in today’s market, will we need to worry about some unknown complication that was not borne out in the clinical trial data? As we move further into molecular or even genetic manipulation, how will we ascertain whether we are “fixing” ourselves by taking these drugs or just masking the problem with a complex and expensive chemical?

I certainly think there’s a lot of merit in the work that the pharmaceutical are doing to improve our lives. I will be curious to see how and when (or if) these drugs are released, and whether they truly improve the quality of life of the people they are intended to help.

I’d be curious to hear your thoughts. Please add them in the comments field below!

Scientists at Sirtris Pharmaceuticals Inc., however, believe they are ready to unveil a pill that will produce above-average human function now and bring us one step closer to the elusive fountain of youth we strive to reach. In an article posted on Boston.com today, the company claims they have created a drug that mimics the compound in red wine that is linked to longevity, resveratrol, and the cell structures that promote endurance.

Resveratrol is believed to be responsible for some of the benefits of red wine and is found in the skin of red grapes, though in small amounts. The new molecule created by Sirtris is 1,000 times more powerful than the naturally occurring chemical, and according to the authors of the study, could be a catalyst to solutions for the diseases of aging, such as cancer and diabetes. Their research will be published in today’s issue of the journal Nature.

The team indicated that hundreds of thousands of compounds were tested for the best able to activate the immune-system booster enzyme SIRT1, associated with an effect of increased lifespans of 30 to 70 percent in a variety of plants, insects and smaller organisms such as mice. The article indicated that the most promising of the compounds will be evaluated in human trials starting next year.

Experiments on mice showed an increased insulin sensitivity, lower blood-sugar levels and more powerful mitochondria, the energy plants of the cell that typically decline with age. If you give resveratrol to a normal mouse, it can run twice its typical distance, said David Sinclair, the author of the study. The results are supported in humans because tests on David Armstrong, seven-time Tour de France winner, show that he has extra mitochondria that increase his endurance. However, Sinclair was careful to point out that the new drug was not intended for abuse:

“The goal is not to make Lance Armstrongs of everyone, but you can imagine that it would boost the energy of someone who is frail and weak,” Sinclair said. (1)

Could it be that we’ve discovered a drug that would combat the effects of aging? Only in the last 6 or 7 years has the issue become one that concerns me. I have a son, my hair is thinning, and exercise and weight maintenance are more difficult than they once were. I admit the thought of a pill that could potentially keep me strong and healthy for many more years is a tempting option.

But what of its implications? While indications are that it would ward off physical ailments associated with aging, what about mental ailments? If I were to develop Alzheimer’s disease 5 years into my added lifespan thanks to this drug, I don’t think I would want to continue with a healthy body while my mind continues to degrade. I’d also be curious to know if this study was carried out with mice starting in their youth, or if the drug was administered to mice as they aged. Would the pill even be effective for people past their prime? It’s not clear in this article, and I would want to know more myself.

There are so many other issues that could come up as a result of is prolific use. The infrastructure of our society may have to change as a result of people living longer, and increased lifespan means increased need for living space. With our demands on natural resources already reaching critical mass, how could society compensate for the changes this kind of drug will bring in 50 years? 100 years?

I look forward to your thoughts.

(1) See “Sirtris drug may fight diseases of age,” Bloomberg News on Boston.com

As one might think, the FDA has a process for approving and rejecting drugs sold in the United States. From what I remember from my days working at one of the large pharmaceuticals as a consultant in their regulatory department, few drugs are actually rejected; companies don’t even want to risk rejection, because costs to correct problems and then re-apply for approval can be high, and there’s probably a certain amount of stigma attached to a drug that had been rejected its first time around. Approved drugs, on the other hand, have reached the holy grail of the process, and can start showing returns for the millions of dollars that have been spent to develop and market them. However, there is a recent trend of “approvable” letters that are being sent out in larger numbers from the FDA in response to new drug applications (NDAs). These letters are like purgatory for NDAs — they’re not quite approved for consumer use, yet they’re not quite rejected.

Proof of the increase in the use of this device was substantiated thanks to the effort of Chris Milne of the Tufts Center for Drug Development. As of October 1st, 2007, 36 approvable letters had been issued by the FDA since January 2006. By comparison, 35 similar letters had been issued between 2001 and 2004.(1) The approvable vortex generally appears to put the drug into a suspended animation of sorts until certain issues can be resolved as outlined by the FDA in their response. While the prospect of being an approvable drug sounds encouraging, the reality is that the average time a drug remains approvable is 20 months, and drug makers must expend additional resources in order to bring the necessary evidence to the FDA for the drug to be approved. In some cases, as highlighted by the article, this will cause the drug company to throw out the NDA altogether, claiming the requested data would be impossible to retrieve in a timely fashion. Some examples cited:

• After the FDA issued an “approvable” letter for its diabetes drug, Pargluva (muraglitazar), Bristol-Myers Squibb ended up withdrawing the drug because it claimed it would take 5 years to gather the data requested in the letter.
• Sanofi-Aventis’ Acomplia, intended to fight obesity, got an approvable letter from the FDA in 2006 but then was given an unfavorable review from an FDA advisory committee in June this year prompting the French firm to withdraw its NDA. For more information on this, you can see the 2 articles I wrote about the drug here, before the FDA released its findings and here, after the FDA released its findings.
• The anticipated diabetes blockbuster for Novartis, Galvus (vildagliptin), received its US approvable letter in February 2007, but the additional clinical trials required by the FDA are anticipated to push its launch to 2009, putting it well behind its competition Merk and their drug, Januvia. The projected cost for the delay is $500 million in unmet projections.

There is a question as to whether these delays can be attributed to safety concerns, politics, or a little of both. The article indicates that the trend to send an approvable letter indicates that the FDA is raising the standard for drug safety, a sentiment supported by the fact that most of its letters ask for additional data regarding a specific “safety signal” or more general information around heart and liver toxicity. We can surmise this more conservative approach is probably due to pressure it’s receiving from congress to ensure another Vioxx scandal doesn’t ensue, yet they proclaim a desire to recapture their image of being a guardian of public health, unshackled by the burden of politics.

If I had to choose between one or the other, I would prefer an FDA that didn’t answer to lobbyists or politicians, and wasn’t under the pressure to approve blockbuster drugs without the benefit of time to truly study their effect on human subjects. I think most of the confusion stems from the fact that the FDA had no consistent leadership from about 2001 until last spring, when Andrew von Eschenbach was appointed to head up the organization. With his appointment and an in-depth examination of how the organization is run, I’m confident they can regain some of their luster as the custodian of the food and drug market in the US.

In examining the available data, the organization might not be as bad off as it may initially seem. As Tufts’ Chris Milne states in the article, “Withdrawals of Drugs happen in a cluster — every three to five years. But the actual rate of withdrawals is consistent over time at three percent.” Hence, the FDA doesn’t seem to be approving riskier drugs as a result of changes in the length of its approval process. What does need to be better communicated to the public, perhaps, is that there is a safety-to-benefit ratio that is considered for approval of a drug, and for each patient a drug’s advantages need to be weighed against its risks. Chances are that a change to a length in the approval process in order to appease political forces won’t change this safety-to-benefit ratio, and won’t prevent something like Vioxx from happening again.

I find all these demands for a change to the FDA approval process a little overzealous, and while I think a strong, lean organization is necessary to ensure drug safety for all, even the most efficient of organizations will make mistakes. We have a tendency to point fingers at a government agency to protect us in extreme scenarios, and when something unusual occurs we feel the need to “fix” the problem. We must make changes with the anticipation that we’ll never have a perfect organization because the needs of the public will demand change within even the most established organizations.

We saw an increase in the amount of time it takes for people to get through the airport after 9/11/2001 in the name of safety. We needed someone to make us feel like there was a watchdog, a guardian protecting our interest in the skies. Yet, news agencies continually report how mistakes are made at airports and publicized as a horrific collapse of the organization that is meant to protect us. Which do we want, better safety or a more convenient, quicker airport experience? Is the FDA destined for the same fate? Do we anticipate long, drawn-out approval processes for benign drugs while the occasional toxic drug will slip through the cracks? Must we reexamine the organization every time it will make a mistake in the future and have our politicians demand change and reorganization and simplification?

I don’t know what the answer to any of these questions is, but I do know that things seemed a lot simpler when I was younger and regulations didn’t seem to burden the every move of government agencies that were meant to protect us. We almost seem to want to create a scandal where none exists.

It seems to me that the FDA does need to invite change into its charter, but it needs to become a more lean organization. Its established process for drug approvals seems to be thorough enough, and you can see a basic flowchart of a standard approval process here. Perhaps what needs to be better established is what the FDA can do after a drug gets into a market, and establishing rules for Pharmaceutical companies to better communicate the risk-to-benefit ratio of their drugs to the doctors that prescribe them.

What are your thoughts? How well do you think the FDA works? Do you think it actually needs a change? Do you feel the FDA is largely responsible for the Vioxx issue, or is it more in the hands of its owner, Merk? Can you compare the agency to its counterparts in other countries? Do you feel we could learn a lesson from them?

I’d love to hear what you have to say! And please, I encourage you to check out the full article that I analyzed for this blog in this month’s issue of the Pharmaceutical Executive! You can get the full text of the article online here.

(1) See “FDA’s Approval Problem,” Walter Armstrong, Senior Editor, Pharmaceutical Executive, November 2007, pp 56-64, 118.

I was therefore encouraged this week to read about 3 new approaches being taken by scientists in an attempt to attack this disease at its foundation and provide better survival rates to those who are afflicted with it. Each approach is slightly different from the other, and some of the more complex chemistry behind it is lost on me, but their novel approach and heartening results demonstrate the effort that is taking place in order to quell cancer’s devastating effect.

The first two of these therapies I found today on the American Association for Cancer Research page. They both are currently involved in Phase I/Phase II human trials, and were presented on October 24th at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapies.

GlaxoSmithKline funded the study of the new experimental drug, GSK923295A, considered first in its class because of its approach to cancer cells. The drug targets and inhibits a single protein, CENP-E, that functions only during cell division, or mitosis. Without signals from this protein, the mitosis cannot be completed, and the cell dies as a result. This particular protein is a prevalent catalyst in most cancerous cells, and research has demonstrated thus far that damage to healthy cells is limited. This is contrary to most current chemotherapy, which broadly effects all cells in order to destroy the cancer cells.

It has a mesurable effect across a broad range of cancer types, and animal studies have shown complete tumor regression in some cancer types. David Sutton, B.Sc., associate director of biology within the Oncology division of GlaxoSmithKline had the following results to report thus far:

In preclinical tests conducted in 214 solid and 85 hematological tumor cell lines, sensitivity to GSK923295A was seen in 16 out of 17 breast tumor cell lines, 20 out of 25 colon cancer lines, 24 out of 26 lung cancer lines, 11 out of 11 ovarian cancer lines, and six out of six prostate cancer lines, he says. Additionally, laboratory analysis suggests that anti-tumor activity might be achieved with minimal suppression of the bone marrow, which could reduce the typical myelosuppression (reduction in production of blood cells) seen with chemotherapy treatment… (1)

The second anti-cancer drug, being developed by Thallion Pharmaceuticals in association with the Segal Cancer Centre of McGill University, takes a different approach to the disease. ECO-4601 primarily inhibits one of the cell’s communication pathways that is typically mutated by several cancer types (the the RAS/MAPK intracellular pathway, if you must know). This is not an uncommon approach and is in fact the target of several other anti-cancer drugs such as Erbitux, Avastin, Tarceva, Nexavar and Sutent. ECO-4601 distinguishes itself from the others by working at a unique point within the pathway, specifically at the level of the RAS protein itself.

This special protein target is important because RAS acts more as a communications hub rather than a simple line, and blocking its ability to relay messages is more likely to have an effect over a broader ranger of cancers. Other aforementioned drugs that act as inhibitors often face the issue of redundancy in the cell regions on which they work that can keep the communication pathway open, even if it is compromised.

ECO-4601 binds to the peripheral benzodiazepine receptor (PBR), an over-expressed receptor in cancerous cells, leaving less possibility that healthy cells will be attacked. It has also proven to be relatively safe and well tolerated in its initial clinical trial of 26 patients. It is quickly flushed from the body, leaving less possibility of any toxic effects or drug accumulation with each cycle of treatment.

For more information on either of these two drugs, you can get the full article from the American Association of Cancer Research here.

The final, and what I believe is a truly novel approach to cancer treatment is the development of a virus that infects and kills cancer cells while leaving normal cells unharmed. According to an abstract published at EurekAlert!, David Kirn and colleagues at Jennerex Biotherapeutics in San Francisco have managed to genetically engineer a new virus that has shown an antitumor effect in studies done on mice and rabbits. Additional testing has been done on human tissue, and the group believes that the concept could be ready for clinical trials in humans. This process of creating viruses as potential cures for disease is called virotherapeutics. For a much more detailed description, and link to the article that was published by this group, click here. I, unfortunately, am not scientifically minded enough in order to read and regurgitate the findings in this article, but maybe you are!

Certainly, these three instances alone give me hope that scientists are thinking “outside the box” and finding new ways to treat this disease. Cancer is scariest to me because it cannot be identified as something that you “catch.” It’s something that’s written into your DNA on the day you’re born, and may or may not be activated at some point in your lifetime. Certainly, we can avoid things like cigarette smoking as an attempt to prevent the occurrence of certain cancers linked with environment, but as Dana Reeve showed us, even preventative measures is not a guarantee that cancer won’t strike.

Do you think there will be a cure for cancer in our lifetime? Will we ever really call it a “cure?” By using that word, do we associate an assumption that the cancer will never return? Is treatment more appropriate? If we do manage to stamp out cancer, do you think there is another disease that might be worse on the horizon? How will it effect life expectancy?

Let me know your thoughts!

(1) See “Experimental Cancer Pharmaceuticals under Trial,” edited by Greg Lester, American Association for Cancer Research.