GLG News by Louis Sanfilippo, MD

Implications: “Personalized medical diagnositics” looks to be evolving as a high impact area in neuropsychiatric drug development.  Such ‘genetic biomarker’ platforms, based on either pharmacogenetic profiles coming from DNA blueprints or gene products from a simple blood draw, aim to identify patients who are more likely to respond to a specific drug or less likely to have side effects.  The idea: select out a narrower patient population with a simple screening blood test but treat them with greater efficacy and fewer problems.   

Analysis: From a scientific standpoint, the genetic biomarker platform should ultimately have traction because it makes sense, can be easily demonstrated in research trials, and potentially provides very useful clinical information.  The science, however, is still in its infancy.  Currently there are no specific genetic biomarker tests that clinicians use for psychiatric disorders.  Vanda Pharmaceuticals and Clinical Data Inc hope to have their two CNS drugs, Iloperidone (an antipsychotic) and Vilazodone (an antidepressant) respectively, enter the market with pharmacogenetic platforms if the drugs are approved by the FDA.  So far, these markers don’t look to be the ultra-high efficacy predictive tests one would hope for but will represent important steps scientifically and through the regulatory pathway.  We will have to wait and see how clinicians may use these and whether managed care will be a friend or foe to the pharmacogenetics platform; I suspect the latter until the technology provides greater precision.  

Theragenetics, a small privately held UK company, is looking to crack into the antidepressant and antipsychotic drug space, as far as I can tell.  Their IP acquisition from Canada’s Centre for Addiction and Mental Health looks to be along the lines of identifying individuals at risk for SSRI side effects and they also carry IP positions for genetic markers predicting response to antipsychotic medication.   Exactly what Theragenetics has in hand is not that clear but one kind of pharmacogenetic test that could have profound clinical value would be one that identifies patients at risk of becoming manic on an antidepressant, an area that poses great clinical and research challenges.  Theragenetics is looking at all the right areas: schizophrenia, Alzheimer's dementia, depression, bipolar disorder, anxiety disorders and ADHD.  But they will have to compete against big pharma that is already establishing their own genetic biomarker platforms for their own family of drugs, not to mention a number of other like-minded companies and collaborative networks pursuing the same goals.        

Implications: ‘One drug, many uses’ can make lots of sense clinically and commercially.   Seeking additional FDA indications for a specific drug has obvious business benefits:  greater revenue stream, improved branding, potentially longer market exclusivity, greater franchising potential of the drug into ‘improved’ formulations/uses (ie, Astra Zeneca’s Seroquel and then Seroquel XR; or GSK’s Wellbutrin family -regular, SR, XL), and less financial/regulatory risk.   The costs of developing new drugs are massive and a looming unproven safety record well into development can be extraordinarily costly and even lethal to smaller companies.  Take for instance Pfizer’s torcetrapib which was pulled from Phase III development after safety concerns and $800M spent.  Most importantly, though,‘one drug, many uses’ can provide valuable treatment options to patients when handled properly by pharmaceutical companies and clinicians.  

Analysis: The article highlights Cymbalta – which will no doubt reward Ei Lilly heavily for its broad spectrum of uses (diabetic nerve pain, major depression, generalized anxiety) and now its newest indication, fibromyalgia, a disorder I suspect will increasingly be a target for drug development in the coming years.   There is a biological basis for ‘one drug, many uses’:  at least for central nervous system disorders, a single drug can dynamically affect a complex web of receptor targets, biologic systems, and intracellular events and produce multiple kinds of therapeutic actions.   Affecting a single serotonin-specific receptor (ie, 5-HT2a) can potentially affect mood, anxiety, sleep, appetite, and cognition, and also exert effects on other brain/neurotransmitter systems like dopamine, GABA, norepinephrine, etc…Research seems increasingly to show CNS disorders as mediated by ever more complex and dynamic processes.  One drug, then, may have wide biological potential.  

Clinically, ‘one drug, many uses’ has brought improved, better studied treatments for bipolar disorder by way of several anticonvulsants (ie, valproic acid, lamotrigine, and carbamazapine) and with others coming down the pike.   The class of ‘atypical neuroleptics,’ initially carrying FDA indications for schizophrenia, have reshaped the treatment of bipolar disorder over the past decade.  Bristol Myers Squibb made an important contribution to depression treatment by executing well-designed clinical trials for its blockbuster Abilify as an ‘adjunctive treatment’ for depression, the first such drug approval.  While a boon for BMS, the scientific and financial contributions leading to this added indication are important clinically.   AstraZeneca is seeking anxiety and depression indications for Seroquel XR, building on Seroquel’s success which itself made a mark with data (and an FDA indication) supporting its role in bipolar depression.     

There is risk, though.  Worrisome drug effects may be overlooked when the newer uses steer far from the drug’s underlying central actions or the clinician’s experience.  For instance, if Cymbalta were approved for chronic knee and back pain, it would be important for pain specialists, orthopedists, or whichever kind of clinician is prescribing to consider certain clinical and monitoring issues. Antidepressants like Cymbalta can pose serious risk to certain kinds of patients and potentially make their illness worse, such as those with bipolar disorder or who are prone to the activating effects of such drugs.   

I would take issue with the claim that one drug, many uses comes at the expense of innovation.  While seeking new uses for a particular drug will never carry the scientific cache or glamour of discovering and bringing to market a new chemical entity, considering and then executing a plan to develop other uses can be quite innovative and challenging.  Take for instance Jazz Pharmaceuticals, whose niche narcolepsy drug Xyrem is in the midst of Phase III fibromyalgia trials – a very innovative approach to this disorder.   And if one drug/many uses makes companies a bit leaner and more successful by tapping out the potential of what they already have in hand, well then there might be more in the coffers for the really innovative stuff.

Implications: Lundbeck has now disclosed the mechanism of action of its “mixed serotonin modulator and stimulator,” albeit buried in a first quarter report.   Data on LuAA21004, Lundbeck’s lead antidepressant jointly in development with Takeda, was released at the Scandinavian College of Neuro-Psychopharmacology this past April.  So far, the drug has been shrouded in some mystery with only speculation as to its novelty, especially when viewed against the large pool of generic SSRIs/SNRIs either in the market or soon entering it.  Lundbeck and Takeda hope to advance LuAA21004 through an ambitious Phase III program with an anticipated launch by 2011 just before generic Lexapro arrives.

Analysis: Lundbeck has disclosed LuAA21004 as a mixed serotonin 5-HT3 receptor antagonist and 5-HT1 partial agonist.   In prior GLG News, I have suspected serotonin 5-HT1a partial agonism for this investigational drug, which, when weighed against the latest evidence, is no longer the compelling receptor target for depression or anxiety that was once hypothesized.   Drugs primarily aimed at 5-HT1a have had a couple recent development failures on the depression/anxiety front.  5-HT3 antagonists have been used primarily as anti-emetics, especially for chemotherapy induced nausea/vomiting, with a couple targeting irritable bowel syndrome.  I have not seen much data on 5-HT3 receptor for depression.  Lundbeck and partner Takeda appear to be advancing this compound rapidly into Phase III following positive Phase II proof-of-concept data last fall.  Hopefully the Phase III data will be a bit more compelling than the receptor profile quietly announced over the last few months.

Implications: It’s not clear just how BrainCells’ BCI-540 works but the company claims the drug acts by way of promoting neurogenesis without an effect on serotonin neurotransmission.   While SSRI’s also promote neurogenesis, a downstream effect believed to favorably impact mood and anxiety, they obviously work by targeting serotonin.   At this stage, it’s hard to say what this really means for BrainCells’ potentially novel drug or its proprietary platform – which aims at developing drug candidates that ‘modulate neurogenesis,’ presumably in brain areas like the hippocampus that may experience injury under stress or depression.  But the idea of developing drugs that target downstream neurocellular events such as the production of various neurotrophic factors (i.e, BDNF) or neurogenesis itself without having all the ‘upstream, start-up’ actions associated with serotonin or norephineprhine reuptake inhibition is very attractive, at least in theory.   

Analysis: The key question is what does BrainCells really have here, either in its drug or in its entire CNS drug development platform.  Lots of drugs have potential to impact neurogenesis while helping depression/anxiety and doing so without serotonin effects.  I suspect a number of them are already in the commercial market.   However, if BCI-540 is doing something further ‘downstream,’ it may potentially carry fewer side effects or work more quickly than the standard 4-6 week trial.   This could amount to something clinically very significant.  Even a novel mechanism of action that can target neurogenesis, and possibly depression, in ways outside the monoamine system (i.e, serotonin, norepinephrine, or dopamine) could be compelling.    

BrainCells’ publicly available intellectual property platform seems largely based on ‘modulating neurogenesis’ with some interesting, quite novel CNS targets.  Their scientific team looks good too, including the Nobel Prize winner Erik Kandel.   For sure, BrainCells is certainly on the right track with early stage marketing and financing their company.   I eagerly await data from this Phase II proof-of-concept study which will help determine efficacy and safety.   I also eagerly await further disclosures from the company about just how BCI-540 works to see if this is really something quite new or something old with new packaging.           

Implications: Abbott’s Neuronal Nicotinic Receptor (NNR) partial agonist platform is an innovative target for ADHD and potentially other CNS disorders.  The Phase II data on ABT-089 suggests efficacy for adult ADHD with good safety/tolerability.  NNRs will not have the kind of effect size seen with stimulants but there is certainly a clinical need for drugs that work differently than current treatments including Eli Lilly’s Strattera, a norepinephrine reuptake inhibitor.  I attended the APA annual meeting in Washington DC and was impressed by Abbott’s neuroscience pipeline aiming at novel treatments for Alzheimer’s Disease, ADHD, and schizophrenia - beyond just the NNRs.

Analysis: Adult ADHD represents a potentially large treatment population, with an estimated prevalence of 4-5% of adults and numbers in the range of 5-10+ million individuals depending on the age range one looks at.  Recent studies suggest only 1 in 5 adults that meet criteria for ADHD actually receive medication treatment for it.  Stimulants are highly effective for adult ADHD but may carry certain medical risks in a subset of patients on account of the cardiovascular effects, in addition to ‘perception’ issues for patients and clinicians alike.   Atomoxetine (Strattera; Eli Lilly) is the only non-scheduled FDA-approved treatment for adult ADHD and other off-label choices (Provigil, tricyclic antidepressants, alpha-2 agonists) carry only modest benefit, if much at all in adults.   The ADHD market will likely see one or two alpha-agonists for child/adolescent ADHD in the next year or two, though hypotension and efficacy may be limitations in adults.  The profile of NNRs, especially with its seeming lack of cardiovascular side effects and potential value on executive function/inattention, is attractive for adult ADHD and possibly other disorders (ie, cognitive impairment in schizophrenia, depression). We will need to await larger trials that will bear out efficacy in clearer terms but this is a positive development.

Implications: The USPTO’s proposed rule changes, struck down in this important Glaxo federal court decision, would have added significant burdens to pharmaceutical companies in developing their IP portfolios and ultimately their drug treatments.   The proposed changes were seemingly motivated to make the patent application process run better by creating leaner applications and limiting continuations. However, the downstream result would have seriously hurt the development of new drug treatments, adversely impacting smaller biotech, academic settings, and big pharma.   The federal decision, while clearly favorable to the pharmaceutical business as a whole, will also be beneficial for making better medical treatments available.

Analysis: Intellectual property forms the basis of drug development for medical illnesses.  While it is possible to bring a prescription drug to market without patent protection – there is a period of ‘marketing exclusivity’ for FDA approved drugs – many drugs recoup their development costs (as well as costs associated with the failures a company may suffer too) while patent protected but out of the FDA’s marketing exclusivity.   Incentive to create new and better medical treatments has a strong basis in whether that is financially viable which, obviously, is enhanced with patent protections or a better opportunity to get there.   

Narrowing claims, as was proposed by USPTO, would have limited just how much could be included in the patent but restricting continuations/requests for continued examination would have badly damaged the ability for innovators to protect their inventions.   Such continuations are a way to defend the patent through its examination.  It is not hard to see the repercussions if the USPTO changes were left to stand.   Early stage biotech companies, now a vital springboard to innovative treatments, would have become less attractive to potential investors; larger pharmaceutical companies might have abandoned important clinical platforms not having another chance to file for continued applications.  The federal court’s decision helps dampen some of the risk to drug development, itself highly risky, and ultimately helps advance medicine.  

Implications: Corcept Therapeutics is at it again with yet another clinical trial for its lead candidate mifeprisotone (Corlux), a GR-II (glucocorticoid) receptor antagonist, hoping to show efficacy on the psychotic features of psychotic major depression (PMD).   Corlux clearly offers a potentially novel paradigm unlike anything presently on the market for treating psychiatric disorders – it targets the hypothalamic-pituitary-adrenal (HPA) axis.   The key question to date, however, has been whether Corlux even works at all.  There are no FDA-approved treatments for psychotic depression though combination antidepressant/antipsychotic treatment or ECT is often the standard, with antipsychotic agents specifically used to treat the psychotic features.  

Analysis: Corcept’s latest round of financing and its partnership with MedAvante to handle clinical ratings is another breath of life for a drug that has looked on the brink of death a few times in its life.  In 2006, a published clinical trial for Corlux in psychotic depression received hard criticism on multiple fronts, from study design to flawed statistical analysis, and finally the drug’s efficacy itself on both psychotic and depressive symptoms.   The Corcept team has mustered whatever it could from prior data and is pulling all stops to show some efficacy – higher dosing, centralized video assessments, and a sizable study group.  This 4th clinical trial is designed with Corlux vs placebo for the first week, followed by antidepressant treatment.       

One problem is that prior data suggests Corlux carries only modest utility against either psychotic or depressive symptoms, a rather large obstacle for an illness this challenging to treat and appearing neurobiologically closer to schizophrenia than depression.  The lack of a second active comparator arm in this study will raise questions just how Corlux measures up against the kind of drugs so commonly used to treat the psychotic features of PMD nowadays – the atypical antipsychotics – which have versatility across both positive (ie, hallucinations) and negative (ie, flat affect, disorganization) symptoms of psychosis, and may help associated cognitive problems like verbal working memory. The other problem is that Corcept will require two positive studies for FDA approval. The first three trials don’t look all that helpful and another large trial for a drug with a history of recruitment issues will pose time and financial burdens for Corcept especially if they plan to still learn through this trial.  

Even if Corlux ultimately hits the market, there is the question of how it will fit into a clinical landscape where growing data suggests some atypical antipsychotics confer both antidepressant and antipsychotic effects, potentially with added value in combination with antidepressants.   Seroquel (Astra Zeneca) and Abilify (Bristol Myers Squib) have shown antidepressant and antipsychotic properties, along with FDA-indications spanning mood and psychosis, and Seroquel XR will be aiming broadly to target psychotic, mood, and anxiety disorders.   Unfortunately there is a surprising lack of data in treating psychotic major depression and Corcept has been its own guide at substantial cost.  It will be hard to have another chance.  Hopefully this drug will bring attention to a seriously unmet clinical need in psychiatry and even offer something clinically valuable though it may have better odds for treating weight gain associated with antipsychotic agents (like Zyprexa) and Cushing’s Syndrome, other viable indications.

Implications: The development of a new generation of serortinin 5HT1a agonists for major depression and anxiety disorders has met yet another failure, now from EPIX Pharmaceuticals’  PRX-00023.  Gepirone ER (GlaxoSmithKline), another 5HT1a partial agonist, suffered the same fate last November when the FDA rejected it as a treatment for depression.  The article cites poor efficacy in depression as the reason for dropping development of PRX-00023 though lack of efficacy for generalized anxiety disorder has been reported in the past with published results this month failing to show benefit over placebo on primary endpoints.  Does this failure offer any insights for what’s in the antidepressant pipeline or for other, similarly acting drugs?    

Analysis: Drugs acting primarily by way of this mechanism of action historically have a rather poor track record.  Buspirone, available for treatment of generalized anxiety disorder, is sparsely used nowadays despite some new data shedding light on its potential value to augment antidepressants.  Pindolol, an antihypertensive with 5-HT1a properties, has had mixed results in mood and anxiety studies.  As far as I can  tell,  PRX-00023 may have been the last 5HT1a partial agonist in development for depression or anxiety and perhaps deservedly so, though a number of companies (ie, Lundbeck, Fabre-Kramer, Clinical Data, among them) are betting that this receptor profile in combination with other serotonin receptor actions will add efficacy, improve side effect profile, or speed up response over the commonly prescribed class of SSRI’s.  GlaxoSmithKline has an early stage 5HT1a antagonist for mood and anxiety disorders; Vilazodone, in Phase III trials, could be the first-in-class mixed SRI/5HT1a  partial agonist and carries some favorable data.   While a bad blow for EPIX – having lost 50% of its valuation since the bad news a few weeks ago – one of their novel early stage CNS products, a 5HT6 antagonist, looks quite interesting for memory and weight problems.

Implications: The FDA’s approval of Abilify for treatment of acute manic and mixed episodes of pediatric Bipolar Disorder is a very important milestone.   Treatment with Abilify already has had growing off-label use in the pediatric population, in both acute and chronic settings, because of its favorable profile on weight. Now data is here to support that.      

Analysis: This is very good news clinically and also good news commercially for Bristol-Myers Squibb and Otsuka, coming off the Abilify adult depression augmentation approval last November.   Pediatric bipolar disorder presents challenges beyond managing bipolar symptoms; children and adolescents are moving through a complex developmental period and the medical/psychological sequelae of weight gain (sometimes profound) - common to the class of atypical neuroleptics and other bipolar medications such as Depakote - cannot be overstated.   While this FDA indication is for acute mood episodes, maintenance treatment with Abilify is often utilized longer term in this population because of its better side effect/metabolic profile than drugs such as Zyprexa, Risperdal and DKA, among others.   I anticipate Abilify will obtain a maintenance pediatric bipolar indication though the data is not yet available, which should further support its important place in the treatment of bipolar disorder.     

Implications: Triple-reuptake inhibitors (TRIs) represent an emerging class of antidepressant drugs in development with potential application for other disorders including ADHD and obesity.   By potentiating all three of the main monoamine neurotransmitters implicated in depression  - serotonin, norepinephrine, and dopamine – they potentially offer a degree of efficacy that will separate them from existing antidepressant treatments and may carry an improved side effect profile (ie, less weight gain, enhanced profile on energy/motivation in the short and long term).   It’s too early to say much about DOV Pharmaceutical’s DOV 21,947, which hopes to have this Phase II depression data within a year, but TRI’s should have a significant place in the depression market in a few years. 

Analysis: Looking at Triple Reuptake Inhibitors in general, we don’t see anything profoundly groundbreaking or novel – we’re still in the monoamine system, perhaps providing neurotransmitter effects not unlike that of the rarely used class of Monoamine Oxidase Inhbitors (MAOIs) but with a potentially better side effect and food-drug interaction profile.   But longer term use of SSRIs may lead to downregulation of the dopamine system, contributing to fatigue, apathy and weight gain in some patients.   TRIs may provide a built in counterbalance with their dopamine properties and, at least in theory, may be especially helpful for what is called ‘atypical depression,’ characterized by increased sleep, appetite, and fatigue.   Also, emerging new drugs for depression treatment seem to have a litmus test of whether they cause sexual side effects or weight gain and it would appear TRIs may look good here and there is data showing weight loss with DOV 21,947.
 
There is no hard data to show that there is enhanced efficacy but the mechanism of action suggests the possibility; major depression still carries a full remission rate of less than 50% in most antidepressant studies, with partial responders and non-responders unfortunately all too common.  How these drugs will work on anxiety symptoms, often comorbid with major depression, is not clear either and may have signficant clinical impacts - we know that SSRIs are generally favorable in this regard.    A number of TRIs are in development by other companies, including a GlaxoSmithKline’s 272, 475, in-licensed from Neurosearch, and Sepracor’s SEP-225289, both in Phase II trials for depression.   

Implications: Fluvoxamine, the least known of the selective serotonin reuptake inhibitors in the US, will now have an FDA approved controlled release version - Luvox CR - for the treatment of OCD and Social Anxiety Disorder.   The collaboration between Jazz Pharmaceuticals and Solvay will have only an uphill battle ahead to improve perception of the fluvoxamine/Luvox line.  The Luvox brand once had a stronger connection to OCD treatment but that has slipped considerably over the years to all the other SSRIs, as well as to the serotonin-norepinephrine reuptake inhibitor (SNRI) Effexor XR (Wyeth) which is commonly used to treat OCD and social anxiety, as well as depression.  

Analysis: While Luvox CR may offer something of a small jump start to this nearly forgotten drug line, which I see only infrequently prescribed these days for OCD, much less for social anxiety, I think the kick will be pretty small.  Fluvoxamine failed to gain much traction early in its life, perhaps a consequence that it was the one SSRI that failed to obtain a major depression indication.  That, along with its less than favorable drug-drug interaction profile and recommended twice daily dosing, set it well behind all the others.  I doubt that will change much in the months and years ahead with Luvox CR.  

What may be positive, though, is that this new CR form potentially represents an improvement on fluvoxamine, its tolerability (ie, less peak effect) and even efficacy for patients (ie, if patients are getting the proper dose rather than missing doses which often happens with twice daily dosing).   Also, if this brings some added attention to the treatment of OCD or social anxiety, overshadowed by major depression and generalized anxiety disorder, there may be something else positive here.  

Implications: Deep brain stimulation (DBS), an FDA approved device treatment for Parkinson’s Disease and essential tremor, has demonstrated quite remarkable findings in several very small pilot studies for treatment resistant depression.   There is great hope among the device makers – namely Medtronics and St. Jude Medical– that this innovative approach may be but a couple years away from their own FDA approvals for refractory depression.   With the FDA’s Investigational Device Exemption (IDE) and clearance to begin enrollment for a DBS/refractory depression trial, St. Jude Medical takes a big step forward.  

Analysis: Though DBS data so far is very limited – but a handful of cases – what's there is among the most compelling interventions in severe psychiatric illness I’ve come across.   In some instances, patients refractory to multiple medication trials and even ECT have shown improvement of symptoms shortly after the device was turned on; even more striking is how symptoms recur when the device is switched off.    

There are many unanswered questions regarding DBS and depression.  Which parts of the brain are best targeted is still being worked out and whether side effects, often neuropsychiatric in nature, will present especially problematic risks for patients with severe psychiatric disorders such as refractory depression.   The pioneering work of Mayberg and Lozano, which forms the neurological and patent basis for the St. Jude trial, targets Brodmann Area 25.   Another area of major interest for resistant depression, also the basis of some case reports, is the nucleus accumbens (considered a key part of the brain’s reward system).     

Vagus nerve stimulation (Cyberonics, Inc.) has been a device disappointment for depression treatment.  But the case material on DBS-treated refractory depression patients is enough to suggest something very different and promising.   If indeed DBS works as well as some case reports show and makes it to market, how it will be accepted among psychiatrists and the public is the next major question.     

Implications: The announcement of this small biomarker study for MEM 3454, an alpha-7 neuronal nicotinic receptor (NNR) partial agonist in joint development by Memory Pharmaceuticals and Roche for the treatment of cognitive impairment associated with schizophrenia (CIAS), seems like a step in the right direction in helping clarify treatment issues in this formidable clinical problem.   However, despite the growing attention to find pharmacologic interventions for CIAS, the road ahead will likely carry a number of obstacles. 

Analysis:
Developing effective treatments for CIAS will be challenging, in part because such cognitive deficits may be wide ranging (ie, attention, sensory filtering, linguistic function and priming, verbal working memory, etc..), may vary greatly between patients and be inextricably linked to underlying symptoms of the disorder.   But that hasn’t stopped interest in designing better studies or looking for experimental treatments.   

The NIMH’s MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia) has been an important step to help bridge the gap between the FDA’s regulatory demands and agreed upon outcome measures for evaluating cognitive function in schizophrenia.  However, the jury is out (and hasn’t received much evidence, either) as to whether biomarker studies carried out in clinical drug trials, in their infancy here, will provide additional guidance for assessing treatment interventions or helping the FDA make decisions.  It may, however, help optimize study design and pooling of the data, so that when its time for a New Drug Application (NDA), the best picture can be set forth.  

Nicotinic receptor partial agonists represent an innovative drug development platform.  While varenicline (Chantix; Pfizer), an alpha4/beta2 NNR partial agonist used for smoking cessation, is the best known, there are a number of pharmaceutical companies that have nicotinic partial agonists in development for a range of cognitive disorders, among them CIAS, Alzheimer’s Disease, and ADHD.  Preliminary data from genetic, clinical and post-mortem studies suggest the alpha-7 receptor may play a role in some of the cognitive and attentional deficits in schizophrenia but this too warrants perspective, as such cognitive issues may have a myriad of underlying causes, much less outward presentations.   Measuring P50 evoked responses has been one model of assessing such deficits.   

At least on paper, MEM 3454 is intriguing.  Advancing MEM 3454 to its Phase 2a trial two months ago was the key milestone for Memory and Roche, and the overall data there will be the most telling part of the equation.  The 12 person biomarker pilot study can’t hurt but may not shed much light on this broad problem either. 

Implications: Lundbeck’s pipeline has been gathering some real momentum in recent months, having advanced a number of investigational CNS drugs.  The initiation of this 600 person Phase II study of Lu AA34893 in bipolar depression, yet another Lundbeck drug candidate shrouded in some mystery (ie, we know that it’s likely ‘serotonergic’ or broader yet, ‘monoaminergic’), is another important milestone for Lundbeck.  But what else is known about this drug or the trial?  

Analysis: Lundbeck is working hard to solidify itself in a post-Lexapro/Forest era, though when that new chapter will start seems unclear on account of various generic/patent issues currently under litigation.  For instance, Lu AA21004 entered Phase III for depression this past December; Lu AA24530 entered Phase II for depression in October; Lu AA 47070 and Lu AA37096 both entered Phase I since November.   And now Lu AA 34893 enters Phase II for bipolar depression.  

Overall, the Lu AA34893 trial looks to have a good design – randomized, double-blinded, with depressive symptoms as its primary outcome measure in patients with Bipolar I or II Disorder – and a large patient pool.  In the study, different dose ranges of Lu AA 34893 will be measured against quetiapine (Seroquel; AstraZeneca) and placebo, and the drug will be studied as a monotherapy.    

It’s hard to say anything more substantive about Lu AA34893 at this point.  How this drug actually works is not that clear and just how “new” and “novel” it is also is unclear, because Lundbeck doesn’t identify specific receptor targets.  Much of Lundbeck’s pipeline for mood and anxiety disorders would seem to work by some combination of serotonin reuptake, partial agonist, or antagonist properties.  Even if Lu AA34893 has something of this profile, it’s far too speculative to say what this could mean for bipolar depression.  Also, length of treatment is another potential confounding issue, as patients with Bipolar Disorder may have added risks, over time, of mania (or mixed manic/depressive states) when treated pharmacologically for depression.  

What is significant clinically is that the treatment of bipolar depression is fraught with clinical challenges and there is a great need for effective, safe treatments. Seroquel now carries an FDA indication treatment, as does Eli Lilly’s Symbyax (though I haven’t really seen Symbyax used).  Lamictal, FDA-approved for use as a maintenance treatment of adults with Bipolar Disorder to delay the time to occurrence of mood episodes, is often used to treat bipolar depression but can be slow-going due to dose-titration/side effect issues.  The use (and/or augmentation) with antidepressants, Lithium and atypical neuroleptics, is common practice but with mixed data and clinical perspectives.   

Needless to say I am excited to see what kind of data this trial will bear.  This is a very important clinical area, with major unmet needs pharmacologically, but which unfortunately has taken a back seat to pharma’s development of antidepressants.

Implications: New clinical indications add to a drug’s period of FDA market exclusivity (different than patent exclusivity) and is a common strategy used by pharmaceutical companies to generate additional revenue from a drug, in pharmaspeak referred to as creating a “successful lifecycle management” strategy.      

Analysis: Bringing innovative drugs that are new-compositions-of-matter all the way through development and into the marketplace is extraordinarily costly, time-consuming, and risky.   To balance this, an FDA approval for a New Drug Application is allowed 5 years of market exclusivity regardless of whether or not the new drug is patent protected.   New FDA-approved indications or an approval for pediatric use can extend such exclusivity and can make sense both clinically as well as commercially.  But whether or not expanding clinical indications makes sense for any given drug involves lots of issues.   

Beyond the obvious, that adding new FDA indications extends a branded drug’s presence in the market, delays time against generic competitors, and thereby generates additional revenue, such “lifecycle management” strategies can reach broader.   Added indications may create the perception that such drugs have broader clinical use, leading to ‘off-label’ prescribing of the drug for other conditions.   Such strategies may also be utilized to maximize the development and commercialization of a drug well before the end of its FDA market exclusivity period, with the idea of boosting the “early” part of the lifecycle rather than “late” part which is most typically about preventing generic incursion.   Take for instance AstraZeneca’s Seroquel XR, FDA indicated for acute and maintenance treatment of schizophrenia.  AstraZeneca is looking to expand Seroquel XR to both bipolar mania and depression indications, as well as generalized anxiety disorder.   If successful, this could add significantly to AstraZeneca on multiple fronts.  When ‘patent protection’ exclusivity issues are at hand (ie, the composition-of-matter patent may expire before the period of FDA market exclusivity ends), added indications to lengthen FDA market exclusivity or method-of-use patents (on the patent protection side) can provide added value as well, another rationale for ‘lifecycle management.’      

There is no bottom-line conclusion here other than managing the lifecycle of a drug can have appeal both clinically and commercially.   But many factors need consideration for any prospective drug candidate.

Implications: The NDA submission of Somaxon’s Silenor, a reformulation of the tricyclic antidepressant doxepin at very low doses, for the treatment of insomnia is not particularly compelling news clinically.  Low doses of doxepin provide an anti-histamine effect with less norepinephrine or serotonin reuptake properties, the basis of its antidepressant effect.   At first glance, this would not be a drug to have wide clinical or commercial value – perhaps an expensive version of diphenhydramine (Benardryl) or hyroxyzine (Vistaril).  But that doesn’t necessarily mean bad news for Somaxon….

Analysis: An FDA indication for insomnia with good marketing would still not likely make this drug anything of a winner in the insomnia market, much less a blockbuster.  Its clinical value and comparative side effect profile would need to be seen but even if favorable, market perception of the drug seems to be starting at a distinct negative.  And there are many good FDA-indicated treatments for insomnia, including generic zolpidem (Ambien), as well as frequent off-label uses of drugs with better market perception and clinican comfort than doxepin.    

However, I doubt Somaxon’s goal is to introduce a big winner here.  Even a small sliver of the insomnia population could grant them a relative victory.  By filing the NDA via a 505(b)(2) route, they are able to demonstrate safety based on prior data for doxepin and have their Phase III trials and results without the associated development costs and burdens.  Safety is an increasingly bigger issue for investigational new drugs and the risk is obviously hedged here with a drug used clinically.  An FDA indication with formulary coverage for the branded drug could create a financial base for Somaxon’s pipeline, which appears more attractive than Silenor itself.  Market exclusivity would protect the product for 5 years, patent and related regulatory protections would add some additional time, though I suspect prescribing of the generic 10 mg form of doxepin would occur if, by some measure, Silenor actually picked up steam.  All said, I think Somaxon’s strategy here may be better off than Silenor’s prospects.   

Implications: Agomelatine (Valdoxan; Servier with rights in Europe and Novartis in the US) is a mixed melatonin (MT1 and MT2) agonist and serotonin 5-HT2c antagonist in development as a treatment for major depression and generalized anxiety disorder.  Its melatonergic properties make it unique among antidepressant and anxiolytic drugs in development, with a putative mechanism of action in that it helps resets desynchronized circadian rhythms. Agomelatine carries a potentially favorable profile on sleep, weight and sexual function as compared to marketed selective serotonin reuptake inhibitors (SSRIs). However, will its efficacy be significant enough to bring it to market in Europe and the US?

Analysis: In 2006, agomelatine was refused marketing authorization in Europe by the Committee for Medical Products for Human Use (CHMP) of the European Medicines Agency (EMEA) due to lack of demonstrated efficacy. However, other data including a randomized, placebo-controlled trial published last year demonstrated statistically significant results in acute depression. The data presented at the European College of Neuropsychopharmacology demonstrating a reduction for relapse in depression and significant improvement in Genaralized Anxiety Disorder (GAD) is encouraging for this drug. Preliminary research has shown agomelatine may have clinical benefit in bipolar depression as well.

In October, Novartis announced initiating two Phase III trials of agomelatine (AGO178) in the US and would plan to file its New Drug Application (NDA) for depression treatment sometime in 2008. I suspect that while the efficacy of agomelatine may not be superior to existing treatments of depression and generalized anxiety, if its side effect profile is accurately portrayed (ie, no sexual side effects, limited weight gain, favorable sleep profile), this could advantageous clinically, separate it from SSRIs, and certainly strengthen its position from a marketing point of view. The profile of this drug reminds me a bit of Serzone (nefazadone), which was pulled from the US market due to liver toxicity. Curiously, nefazodone never quite did as well as one would think from its overall profile – whether on account of (lack of ) marketing or the name-branding power of SSRI’s at the time. We will have to see what the final data actually shows and how agomelatine performs in treating acute depression in these US Phase III trials, which will be the basis for Novartis’ NDA for depression.

Implications: GlaxoSmithKline’s Gepirone ER, a serotonin 5-HT1a partial agonist licensed from Fabre-Kramer Pharmaceuticals, was issued a non-approvable letter following an amended NDA submission to the FDA this past spring. This isn’t all that surprising given gepirone’s history, including a similar non-approvable letter in 2004. However, Glaxo must have been attracted to the idea of an antidepressant drug with fewer sexual side effects than SSRIs and a first-in-class serotonin 5HT1a partial agonist for depression. It’s hard to imagine any life left for gepirone, at least for depression (perhaps for anxiety or as augmentation treatment?), but what will this mean for other investigational drugs targeting 5-HT1a receptors?

Analysis:  Drugs acting exclusively as serotonin 5-HT1a partial agonists have been around but never quite shown robust antidepressant activity alone – buspirone and pindolol are among them. However, when added to SSRI’s, there is some data to suggest a potentially quicker response, enhanced antidepressant activity and amelioration of sexual side effects (the latter two shown with buspirone). Gepirone may actually confer greater benefit as an augmentation strategy than a stand-alone treatment for depression.

There are other experimental drugs targeting 5-HT1a receptors but most of them affect more than one receptor system. Clinical Data’s Vilazodone, a mixed SSRI and 5-HT1a partial agonist, leads the pack of investigational antidepressants that have an effect on 5-HT1a. Prospects appear bright for Vilazadone, with results of its recent Phase III trials looking solidly significant on primary endpoints. I suspect there is at least one such kind of drug in Lundbeck’s pipeline of mystery antidepressants, so named because the company offers little description of how they work. Fabre-Kramer - despite this recent setback - has a couple of serotonergic drugs in Phase II trials that appear to have multiple mechanisms of action and that are under development for depression and anxiety. Also in the fray is Epix Pharmaceuticals, which is developing a mixed 5HT1a partial agonist/opioid antagonist for depression. All said, there are prospects for better drugs in the pipeline with Vilazodone now closest to claiming rights to a first-in-class antidepressant.

Implications: Investigational drug candidates that target metabotropic glutamate receptors (mGluR) show promise as novel treatments for a range of CNS disorders which include schizophrenia, anxiety, chronic pain, Huntington’s Disease, epilepsy and Parkinson’s Disease. If Pfizer consummates this deal with Taisho, it will put them on the mGluR map though behind Eli Lilly and AstraZeneca which have mGluR drugs in clinical development.

Analysis: Eli Lilly’s recent announcement of significant positive Phase II results for its LY2140023 mGlu2/3 receptor agonist for schizophrenia has attracted lots of attention in the field, heralding this as one of the most important advancements in schizophrenia treatment since the advent of atypical antipsychotics . Efficacy in that trial was comparable to olanzapine (Zyprexa) but with evidence of a far better metabolic profile and no extrapyramidal or prolactin effects. It is unclear just how Taisho’s drug is proposed to work on mGluR (there are a number of different groups and subtypes) but my best guess would be as an mGluR2 agonist.

Pharmacologic treatments of psychotic disorders have been focused on the dopamine system, with the more widely used second-generation antipsychotics also affecting serotonin 5-HT receptors. Treatment of schizophrenia with a drug that carries a completely new mechanism of action, that may act to augment response to current drugs, and potentially have less medical morbidity (e.g. weight gain, high triglycerides, glucose abnormalities) is quite attractive though it is still too early to draw firm conclusions.  Last month, AstraZeneca acquired the full rights to NPS Pharmaceuticals’ mGluR intellectual property following a previous collaboration and have an mGluR drug candidate in Phase I clinical trials. Pfizer would seem wise to join in even if ultimately things don’t work out or they are second or third to market – because the potential here looks very significant and assuming such drugs end up working, individual profiles may differ.

Implications: Obesity is a major health issue with significant associated morbidity and with rates only rising, especially among the young. OREXIGEN Therapeutics’ Contrave is moving along as a potential treatment of obesity, having initiated its third Phase III trial. Contrave is a novel combination-drug concept using bupropion SR (of the Wellbutrin brand) and naltrexone SR (of the ReVia brand), drugs commonly used to treat mood disorders and alcohol dependence, respectively. But what can we expect to see with this medication approach to obesity?

Analysis: Recent clinical data suggests that low-dose naltrexone, an opioid receptor antagonist, may reduce weight gain associated with smoking cessation. Bupropion SR (a norepinephrine-dopamine reuptake inhibitor) is generally appreciated as a weight-neutral antidepressant, though sometimes will cause mild weight loss. Each drug standing alone – nothing looks groundbreaking in obesity treatment. So what does CEO Gary Tollefson, MD, PhD, know about brain circuitry to support the combination? And just how would treatment look clinically?

The dual action would appear to modulate activity in the brain’s opioid-dopamine-reward system and theoretically, I suspect, dampen eating behavior that may be associated with the release of endorphins and other pleasure-type molecules. The result: a kind of stabilization of appetite and over-eating. If this concept is accurate, it has an intuitively appealing quality in that it may mitigate ‘yo-yo’ dieting, more rapid weight loss, and other faddish approaches that have been shown never to work in the long run. However, my gut impression (pardon the pun here) here is that efficacy may be somewhat limited, effects may take time to establish and may not be in the kind of range to attract many long-term users. The large patient numbers in each trial and the substantial trial length may reflect more modest kinds of weight loss over time. Then again, it is precisely this kind of treatment – more measured and steady that is most likely to have long term success.