MDD Market Snapshot: Depressing Future For Antidepressants
By Lisa LaMotta

Although a significant portion of the U.S. population, approximately 6.5% or 15 million adults annually suffers from depression, the antidepressant drug market is on the decline and sales are expected to decrease further over the next two years as two of the largest products on the market, Forest Laboratories' Lexapro (escitalopram) and Eli Lilly & Co.'s Cymbalta (duloxetine), face patent expirations.

According to IMS Health, antidepressants had sales of $20.2 billion globally in 2010 and the class is expected to decline by another 5%-8% to $13 to $16 billion by 2015. Sales in the U.S. are already on the decline, dropping to $11.6 billion in 2010 from $13.3 billion in 2006. Yet, the depression market is one that most pharmaceutical companies, doctors, and even patients, see as an area of high unmet medical need due to the lack of really effective drugs that work for the majority of patients. While the low-hanging fruit of the depression market has long ago been picked, several companies still have depression drugs in development.

Depression Is Not Easy… To Treat

Major Depressive Disorder, or MDD, is characterized by depressed mood and diminished interest or capacity for pleasure. It is both an inherited condition and can also be caused by events such as losing one's job or experiencing relationship problems. Drug abuse or side effects from certain medications can also give rise to MDD. About 48 million globally are afflicted with the condition.

Like the causes of the disease, the symptoms of MDD are many and varied, including lack of sleep, hopelessness, lack of energy and loss of interest. This variability of presentation makes it extremely hard to find a one-size-fits-all treatment. Doctors and psychiatrists have a difficult time finding drugs that will actually help patients; consequently patients often cycle through several treatments, even trying multiple drugs at a time.

The market is dominated by a slew of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) that are available to patients as low-cost generics, there are 28 to be exact, including Effexor (venlafaxine), Paxil (paroxetine) and Zoloft (sertraline). The widespread availability of generics means that most patients try them first before moving on to newer, branded drugs.

Most doctors and patients agree that the biggest problems with the current antidepressants are that they aren't very effective in most cases and that they tend to have a laundry list of side effects including weight gain, sexual dysfunction, and excessive sweating (all issues that might make a patient more depressed). According to a National Institute of Mental Health study conducted in 2006 to assess the effectiveness of MDD treatments called Star*D, after failure with an SSRI, 58% of patients preferred adjunctive treatment.

Unmet Need Doesn't Equal Blockbuster Anymore

The interest in the antidepressant market has cooled off considerably over the last few years, despite the high unmet need for an effective, tolerable treatment. While virtually all the Big Pharma companies have developed and marketed a blockbuster antidepressant over the last 20 years, most of those companies are no longer interested in the depression  space because of the high barriers to entry, the potentially poor return on investment, the regulatory hurdles associated with proving effectiveness in the space, and the significant amount of marketing needed to differentiate a product.

The problem is that most of those blockbusters that dominated the 1990s and early 2000s are now generic and the few that aren't are set to lose patent protection within the next two years. With a wide variety of generics to choose from, doctors can prescribe a plethora of different medicines, or create a cocktail of therapies, without ever prescribing a branded drug, making it nearly impossible for a new treatment to make any headway.

There is one notable exception: Forest launched Lexapro in 2002 and the drug now has sales of about $2 billion annually, at least until it goes off patent in January when sales are expected to decline significantly. Its success is in part attributable to its single isomer formulation which was thought to confer greater efficacy compared with its predecessor, Celexa . Analysts credit the company's formidable ability to promote that message for the drug's blockbuster status.

To make an impact in this highly genericized and oversaturated market, companies need to significantly differentiate their product, said Leerink Swann analyst Joshua Schimmer. Yet, there have been few new products to enter the therapeutic class recently and only a handful of compounds for the treatment of MDD are in the late-stage pipeline. Schimmer said most of the pipeline is comprised of "iterations" of what is already out there.

"There is nothing in the pipeline that is going to be revolutionary like Prozac was," said Decision Resources analyst Natalie Taylor, Ph.D.

Changing The Depression Landscape

Newton, Mass.-based biotech Clinical Data got approval for its new antidepressant, Viibryd (vilazodone) in January ("Clinical Data Obtains Viibryd Approval In U.S." "The Pink Sheet" DAILY, Jan. 24, 2011). Shortly after gaining approval, the company was acquired by Forest, which had been searching for ways to make up for the revenue it expects to lose when Lexapro goes off patent.

Viibryd is an SSRI that also engages the 5HT1a receptor. Forest claims it has no sexual side effects like other SSRIs, but is still conducting trials to show this. The company is expected to capitalize on the drug's clean tolerability profile and physicians' trust in the drug class to differentiate Viibryd in a crowded marketplace, but analysts are skeptical about  whether Forest can use its formidable marketing machine to bring blockbuster success to Viibryd. Schimmer said that Viibryd's tolerability profile is only a "slight" advantage that could allow the drug to reach peak sales of $500 million. Forest refused to comment for this article.

Following closely behind Viibryd are several Phase III compounds that could enter the market in the next two years, including another SNRI being developed by Forest. Levomilnacipran, an enantiomer of the firm's antidepressant Savella (milnacipran), is expected to be filed with FDA in 2012 despite the drug failing to meet primary endpoints in a Phase III study that was reported out in January. Additional data is expected on the drug later this year, as well as the first quarter of 2012.

The drug that is most likely to hit the market next is H. Lundbeck A/S 's LuAA21004, a multi-modal compound that is thought to antagonize the 5HT3 and 5HT7 receptors, among others.

The company, along with its partner Takeda Pharmaceuticals , plans to file for approval in the U.S. and EU in 2012, and plans to report out further Phase III data during the course of the year. Lundbeck hit a setback when a late-stage trial in the U.S. was unsuccessful. Company representatives said they are now trying new, higher dosing regimens in ongoing Phase III studies to find a dosing range that will be more robust than the lower doses tried previously.

Lundbeck expects the drug will be "quite tolerable" at higher doses and have a good sleep profile as well as no sexual  side effects, said Marianne Dragheim, clinical lead for '21004. Lundbeck is building out its sales force in preparation for the drug entering the market.
Lundbeck VP of Global Product Strategy and Portfolio Development Andreas Eggert, who helped launch Pristiq while at Pfizer Inc. , said 21004 "is very different than what is currently out there."

A drug that could be a potential game-changer is Targacept's TC-5214, a neuronal nicotinic receptor (NNR) antagonist that is currently in five ongoing Phase III trials and has the market all abuzz with its potential.

"The announcement of the Phase IIb data really catapulted the company to another level once people saw the results," said Targacept CEO Donald deBethizy. While some analysts are skeptical about whether or not the company can replicate the positive results from the Phase II trials, the market will be watching as those trials start to report out in the fourth quarter of this year and the first half of 2012.

Targacept and its partner, AstraZeneca , are expected to file with FDA in the second half of 2012. AstraZeneca paid $200 million upfront in 2009 for global development and commercialization rights to the drug. The British pharma has agreed to pay 80% of development expenses, as well as potentially $1 billion in milestone payments and double-digit royalties ("AstraZeneca Pays $200M Upfront For Global Rights To Targacept's MDD Candidate," "The Pink Sheet" DAILY, Dec. 3, 2009).

There is currently only one NNR antagonist on the market, Pfizer's problem-plagued smoking cessation drug Chantix (varenicline), which partially antagonizes the receptor ("Chantix Banned For Pilots; Watchdog Report Cites More Risk," "The Pink Sheet" DAILY, May 21, 2008).

Chantix sales have been dampened by continuing reports of suicidal ideation, causing many people to wonder whether TC-5214 will have the same problems. So far, '5214 has shown a clean safety profile.

There are other concerns about the class, as well. Targacept, which only develops drugs with this mechanism of action, has had several Phase III failures in other therapeutic areas.

deBethizy doesn't think any of these problems will crop up. "'5214 offers a better tolerability profile than previous drugs and even some recently approved drugs to enter the market," he said.

Targacept is hoping that a roundabout approach to entering the crowded marketplace will help the drug make an impact; the company is studying '5214 as an adjunct therapy first. "We believe that once physicians get comfortable with the new mechanism of action and the tolerability profile, we could see sales as good or better than anything on the market," said deBethizy.

He added that becoming a first-line standard-of-care in this market is "a pretty high hurdle". Yet, the drug is also being studied as a monotherapy. Those trials are currently in Phase II. Pfizer is also studying the class for the treatment of MDD; the big pharma currently has an NNR partial agonist in Phase II.

One other class of new antidepressants is catching people's attention; melatonin agonists. While melatonin is usually associated with sleep, a few companies are looking into it for the treatment of depression. Novartis is working with Servier on a melatonin agonist and 5HT2C antagonist that is expected to report out Phase III in the second half of the year. The drug, agomelatine, already is available for the treatment of depression in the EU under the name Valdoxan .

The drug has been shown to be effective in treating depression and has a largely clean tolerability profile. It did show elevated liver function that analysts have called "problematic." Novartis is exploring a new formulation and lower doses as a means of improving the drug's safety profile.

Currently in Phase II is Vanda Pharmaceuticals' tasimelteon, another melatonin agonist. Analysts believe it might have a better safety profile than Novartis' drug.

The next few years will bring a plethora of data that could shape the way depression is treated,  giving options to patients who feel underserved by current drug offerings.

"[Pharmaceutical companies] would not accept that 50% of patients don't respond to current therapies in any other category," said Lundbeck's Eggert. "Depression is not a satisfied or mature market."
 

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