GLG News by Lawrence Ginsberg, MD

Implications: 1. Iloperidone has demonstrated efficacy in treating positive and negative symptoms of schizophrenia and also has a favorable safety profile. 2. Vanda has utilized pharmacogenetic studies to identify a group of schizophrenic patients that will benefit from this agent that binds to a number of serotonin and dopamine receptors. 3. Two out of three previous Novartis Iloperidone trials were failed trials but they utilized low to medium doses of Iloperidone.

Analysis: There are a couple of questions that must be answered before jumping on or avoiding the Iloperidone bandwagon. The first is how practical will it be to do pharmacogenetic testing before prescibing an antipsychotic? This will partially be determined by the cost and accessability of such a test. Will third party payers stonewall such a test if they view it as being too pricey? The second question is whether this drug will show postmarking efficacy. Vanda has demonstrated efficacy at higher doses but Novartis did not obtain the same results using lower to middle range doses. Physicians tend to utilize lower doses of a new agent when it is first introduced; the lack of early clinical success using lower than desired doses could potentially deflate early sales of this agent. It took several years for Pfizer to straighten out the dosing issues regarding Geodon. Vanda does not have the same resources as Pfizer and might not be able to fight this impending tough battle.

Implications: 1. DOV 21,947 in a phase Ib study produced a statistically significant reduction in plasma triglyceride levels, body weight, and Body Mass Index (BMI). 2. This compound is believed to not only manage depression but also impact weight gain. 3. A phase II study of DOV 21,947 is being delayed until the first quarter of 2008 to allow for sufficient capital to conduct the study and to further evaluate the protocol design. 4. Phase I studies of DOV 21,947 have shown that the compound was safe and well tolerated with a low incidence of adverse events.

Analysis: Not only is this drug impressive because of being an efficacious triple reuptake inhibitor but also because of a favorable metabolic profile. Most antidepressant agents have the potential to cause weight gain, the most dreaded and feared side effect in America (according to my patients.) Only a couple of antidepressants are weight neutral in the average patient, but they too can add pounds in a minority of patients. In addition to treating depression especially in those with comorbid obesity, this could become the primary choice for patients who are also on antipsychotics (that usually cause weight gain.) Please note the study referenced above was in patients with depression. Before touting DOV 21, 947 as a weight loss agent there most be studies in subjects who are obese but not depressed. The bottom line is that we will have to wait until the end of 2008 in order evaluate the results of the phase II study.

Implications: 1. Shire has withdrawn patches that had defective patch liners. 2. This defect is not related to safety or efficacy issues. 3. The cost to Shire is less than $10 million.

Analysis: More recently my patients have reported a lower incidence of skin problems with the Daytrana patch. If clinicians hear less complaints from their patients they will be more likely to prescribe this agent. This agent has relatively fewer systemic side effects than other stimulants (bypassing first-pass liver metabolism) that are administered orally with the exception of skin irritation at the patch site. This is the only stimulant that the patient has the choice of determining the duration of action by removing it 3 hours before the desired end time. The action of recalling defective patches will increase confidence in Daytrana and help bolster prescribing of this agent.
Daytrana, however, is currently being overshadowed by the newly released Vyvanse, a novel long acting prodrug for the treatment of ADHD. Because of the tremendous effort behind the promotion of Vyvanse I doubt there will be a significant impact on the Daytrana market.
Another benefit that Shire will reap from correcting any defects in patch technology is that there will be more confidence in this technology in a few years when an amphetamine salt patch borrowing this technology could potentially be promoted by Shire.

Implications: 1. Lu AA21004 and Lu AA24530 are two compounds with a great deal of potential and will be co-marketed jointly by Takeda and Lundbeck. 2. Lu AA21004 is the more advanced of the compounds and is currently in phase II development for the treatment of major depression. 3. The compounds potentially address some unmet needs as they have fast onset of effect and increased efficacy.

Analysis: The alliance between Takeda and Lundbeck will benefit both companies. Currently prescribed antidepressants lack expedient onset of action and are lacking in efficacy. A drug meeting such unmet needs and marketed by an aggressive partnership should capture a healthy share of antidepressant market revenue. All of these projections are very early as the most advanced of the two compounds is only in phase II clinical trials. This does come at a good time for these companies as the number of branded antidepressants has narrowed.

Implications: 1. LY2140023 is an antipsychotic agent that is a metabotropic glutamate 2/3 receptor agonist. This agent has a new mechanism of action that is efficacious in treating schizophrenia and potentially other neuropsychiatric conditions. 2. LY2140023 in addition to separating from placebo in a statistically significant manner demonstrated a safety and tolerability profile that lacked many of the problems of atypical antipsychotic agents. 3. This has great significance for Eli Lilly who manufactures Zyprexa. This compound despite having a great deal of efficacy in treating schizophrenia and bipolar disorders has been associated with metabolic side effects including hyperglycemia. (Lilly has recently settled Zyprexa class action suits.)

Analysis: A novel antipsychotic with a new mechanism of action that is effective and is also with a favorable safety and tolerability profile is much desired. Additional clinical trials are needed on LY2140023 to further demonstrate these desired clinical properties. This would certainly put Lilly in a favorable market position as the antipsychotic market could potentially reap billions of dollars per year for a worthy compound. Lilly already has the CNS salesforce in place to capitalize on such a future product launch.

Implications: 1. The Actelion agent (ACT-078573) is not a sedative-hypnotic but is an orexin receptor antagonist. 2. This agent may have a safety and tolerability profile that is better than the sedative-hypnotics. 3. The above implications would make Actelion a prime acquisition for a big-pharma company with a less than desired CNS pipeline.

Analysis: ACT-078573 is an orexin receptor antagonist. Orexins are brian neuropeptides that are produced by a small number of hypothalamic neurons and play an important role in maintaining wakefulness.
Non-benzodiazepine sedative medications such as Ambien CR and Lunesta are useful compounds that are typically effective.  However, there is a significant unmet need for agents that are not sedative-hypnotics for patients that are in need of avoiding relatively rare side effects such as sleep-walking or next-day grogginess. Other indications for the orexin receptor antagonist could be adjunctive treatment for patients that do not experience complete efficacy with sedative-hypnotics, treatment of insomnia in patients with a history of chemical dependency, and perhaps in adolescents.
In animal models, ACT-078573 resulted in an increase in REM sleep. This is in contrast to GABA-A receptor modulators such as Ambien which were associated with a decrease in REM sleep. (REM sleep plays a key role in the consolidation of different types of memory functions.)
Actelion becomes a prime takeover candidate as it has a promising compound in the huge insomnia market.

Implications: 1. A recent psychiatric journal reported a higher incidence of bipolar disorders in the pediatric population and a subsequent increase in antipsychotic medication use in children. 2. Assessment tools (bipolar disorder questionnaires) have significantly increased awareness of bipolar disorder symptomatology and have increased diagnostic accuracy. 3. Other studies in the past have demonstrated the lack of correct bipolar disorder diagnoses. 4. There is a great deal of comorbidity in child psychiatry-having one diagnosis does not necessarily eliminate the possibility of a second diagnosis. (Almost 40% comorbidity between ADHD and Bipolar Disorders in children.)

Analysis: I believe the increase in diagnosis of pediatric bipolar disorders is not real but a departure from a long history of missed or inaccurate diagnosis. Finally clinicians are starting to get it right. It is more difficult to diagnose a child than an adult. One large study performed a few years ago revealed that only 20% of adult patients meeting criteria for bipolar disorders were correctly diagnosed. Another study on adolescents showed that over 50% of adolescents diagnosed with major depression were subsequently diagnosed with a bipolar disorder.
Even the FDA recognizes the importance of studying the efficacy and safety of agents in adolescents that have already been approved for the treatment of adult bipolar disorders. Some of these studies were mandated by the FDA.
The implication for the atypical antipsychotic market is increased use in the under age 18 population. There will not be an exponential increase as these agents are already being used off-label in the pediatric population.

Implications: I am a psychiatrist in private practice in a major metropolitan area that has a diverse population. I offer the following observations based on my clinical post-marketing experience. I have already prescribed Vyvanse to a few hundred patients. My observations: 1. Duration of action: This is a huge issue. Clinical studies have shown significant efficacy of Vyvanse even at the 12-hour mark; this is the only stimulant medication on the market that is able to consistently demonstrate such efficacy. 2. Predictability: Compared with other agents there is a very narrow window of time to maximum concentration  (Tmax) -less than 2 hours from the mean, and duration of action. This is in contrast to Adderall XR, which had been the gold standard but has a great amount of interpatient variability (7 hours) . Vyvanse should not wear off prematurely. 3. Abuse Potential: Patients who "like" stimulants usually subjectively prefer shorter acting agents & Adderall XR.

Analysis: Vyvanse certainly stacks up regarding efficacy and safety, predictability, and abuse potential. Shire has also made an application for adult use of this product. In my clinical experience this drug has been effective for the majority of my adult patients. Shire has marketed this agent as a replacement for Adderall XR however patients on other agents (Concerta, Focalin XR, Daytrana) are being switched to Vyvanse as it has a longer duration of action. There is little pragmatic potential for abuse as this drug is not as subjectively likable as most other stimulants.
All of the above should result in a significant market share for Vyvanse. This agent should supplant Adderall XR as having top market share within 18 months. Managed care companies cannot legitimately force physicians to use a generic substitution for this drug as no such agent exits. This is in contrast to Adderall XR which will go off patent in over a year.

Implications: 1. This agent despite a favorable side effect profile lacks efficacy as compared to other antipsychotic agents already approved by the FDA. 2. This is a temporary setback for Wyeth. 3. This in the long run is to Wyeth's advantage as such an agent would have done poorly in a competitive atypical antipsychotic market. 4. Putting this product on the market would have tarnished Wyeth's reputation/credibility and would have indirectly hurt the promotion of the hopefully soon to be approved desvenlafaxine.

Analysis: It was poor a strategy to try to get approval for an antipsychotic with minimal efficacy. The current agents on the market are barely adequate for schizophrenia. Most patients switch from one agent to another as was demonstrated by the CATIE study. Obviously a new antipsychotic with better efficacy and less side effects is what is needed.
Wyeth pragmatically can work on another antipsychotic compound or buy a compound from another company that has at been successful in phase I and/or phase II trials. Yes this will come at a steep price but it also makes sense.
Wyeth can now hold its head up high when it markets its new antidepressant desvenlafaxine.
This also effects other new antipsychotic drugs that belong to other pharmaceutical companies that will be submitted for FDA approval.

Implications: 1. Most currently marketed oral antidepressants replenish only norepinephrine or serotonin and result in remission in less than 45% of patients over 8 weeks. A triple reuptake inhibitor such as DOV 21,947 has the potential to effect a remission in a higher percentage of patients. 2. Most of the antidepressants currently being used have at least a moderate amount of side effects. It is refreshing that this drug has a favorable metabolic profile. 3. It is not reasonable to predict that this agent will be an effective agent to treat ADHD or to facilitate weight loss unless future studies that specifically examine these issues demonstrate efficacy.

Analysis: Even if this agent is only effective as an antidepressant (and studies continue to show good safety and tolerability) this could be a block buster drug. There is already a drug on the market that enhances serotonin, norepinephrine, and dopamine: Emsam. However, this agent uses patch technology which is a barrier to its use. It is an MOA inhibitor which means that there will be restrictions on concomitant medications as well as diet.
Many large pharmaceutical companies are searching for an antidepressant for their pipeline. Presently there are only 4 branded antidepressants for which a generic is not available (Lexapro, Effexor XR, Cymbalta, and Emsam.) The second in the group is slated to go generic soon which means there will only be two first line choices left(Lexapro and Cymbalta.) 

Implications: 1. An antipsychotic with a novel mechanism of action is highly desirable as currently available atypical antipsychotic agents lack efficacy or cause undesirable side effects (metabolic, extrapyramidal, increased prolactin.) 2. If this agent demonstrated significant efficacy and safety it could be a big factor in the multi-billion dollar antipsychotic market (for schizophrenia, schizoaffective disorders, mood disorders, autism, and even anxiety.) 3. The trial design was open label and a sequential cohort. Open label studies are not as helpful as placebo-controlled trials. With sequential cohorts there could be a positive bias; if a subject was already exposed to a given dose of medication for more than a few days there could be some physiologic adjustments which could minimize perceived side effects. A placebo-controlled fixed-dose multiple dose armed trial with some sites in the U.S. (vs. Eastern Europe) would be an important future step.

Analysis: A novel antipsychotic (with a new mechanism of action) that is effective (on positive symptoms, negative symptoms, affective symptoms, and cognition) and has a good safety and tolerability profile is what everyone is waiting for. Such an agents would have utility in multiple-psychiatric disease (see examples above) markets as a monotherapy and as an adjunct to existing agents. This compound could dominate the market. BioLineRx could reap several billion dollars from such a product. Several large pharmaceutical companies with less than desired CNS pipelines would be potential buyers of the drug (GSK, Pfizer, Wyeth, Forest, Sanofi-Aventis, Novartis.)

Implications: Review of INTUNIV Extended Release for treatment of ADHD: This is still another ADHD Shire drug that is efficacious and has an excellent tolerability profile. I have utilized this agent (as a principal investigator) in several clinical trials and can't wait until I am able to prescribe this agent in my clinic (non-research) patients either as a monotherapeutic or as an adjunctive agent. I have been very successful with immediate release guanfacine in my pediatric ADHD patients. Some patients also report an alleviation of anxiety not seen with stimulants. I can foresee many patients being switched from the immediate release to the extended release version as well as many new prescription starts. Submitted by Lawrence D. Ginsberg, M.D. C.E.O. Red Oak Psychiatry Assoc., Houston, TX

Analysis: This will bolster Shire market share of the ADHD market. It will probably compete most with Strattera. This product is capable of at least 10% market share.

Submitted by Lawrence D. Ginsberg, M.D.
C.E.O. Red Oak Psychiatry Assoc., Houston, TX