Class action settlement in drug for schizophrenia

An article published in the June 30th edition of The Toronto Star:

Some users of antipsychotic drug say they were not warned of risk of diabetes

By Theresa Boyle, Health Reporter

Canadian courts have approved a $17.6 million settlement in a class-action lawsuit launched by individuals who became diabetic after taking an antipsychotic drug.

The settlement with Eli Lilly, manufacturer of Zyprexa, was announced Wednesday. It stems from allegations that the drug giant failed to warn about risks of severe weight gain, diabetes, hyperglycemia and pancreatitis.

Zyprexa is used for treatment of schizophrenia and bipolar disorder.

Eli Lilly denies any wrongdoing and the allegations have not been proved in court.

“While we believe the allegations are without merit, Lilly is taking this difficult step because we believe it is in the best interest of the company as well as the Canadian health care professionals who depend on this important medication,” John Rudolph, legal counsel for Eli Lilly, said in a written statement.

The drug continues to be used, but changes have since been made to its label to include warnings of diabetes.

The class action was filed on behalf of 11 people from Ontario, British Columbia and Quebec and approved by the superior courts of those provinces.

“We acknowledge that Eli Lilly has done the right thing,” said Harvin Pitch, counsel for Stevensons LLP, which represented some of the plaintiffs. “We encourage all users of Zyprexa who qualify to apply for their benefits.”

To receive a settlement payment, an individual must have started taking the drug prior to June 6, 2007 and then been diagnosed with diabetes, hyperglycemia, ketoacidosis or pancreatitis. The size of each payment will depend upon severity of illness and the total number of approved claims.

The settlement was based on an estimate that there would be 1,450 claims, though it is possible that the actual number may be higher, Pitch said.

The total number of prescriptions filled in 2009 in Canadian retail pharmacies for Zyprexa and its generic equivalents was 2,493,081. It is the third most prescribed antipsychotic on the Canadian market.

Further information is available at classaction.ca, from lawyer Daniel McConville at Stevensons LLP: (866) 940-8329, or from lawyer Matthew Baer at Siskinds LLP: (800) 461-6166 x 7782.

Note:

The claims deadline is October 28th, 2010.

Also see:

Notice of Settlement Approval (long version) [PDF Document]

Claim form [PDF Document]

Press Release – June 30, 2010 [PDF Document]

A national settlement has been proposed in the Zyprexa class action

Please click on the images to magnify them.

To view a high resolution version of the second document, please click here.


Also see:

ZYPREXA (OLANZAPINE) CLASS ACTION: NOTICE OF SETTLEMENT APPROVAL HEARING


From Poyner Baxter LLP:

Zyprexa

May 21, 2010

A national settlement has been proposed in the Zyprexa class action. This settlement cannot proceed until it has received court approval. The dates scheduled for the court settlement approval hearings are June 8, 2010 in Ontario, June 14, 2010 in Quebec and June 15, 2010 in British Columbia.

IF YOU OR SOMEONE CLOSE TO YOU TOOK ZYPREXA (OLANZAPINE) PRIOR TO JUNE 6, 2007, PLEASE CLICK HERE TO READ THIS NOTICE CAREFULLY AS IT MAY AFFECT YOUR LEGAL RIGHTS AND YOU MAY BE ELIGIBLE FOR COMPENSATION.

To view the full legal notice, click here.

To view the proposed settlement agreement, click here.

A further notice will be published once the settlement has been approved by the courts which will explain how individuals can make a claim.

For further information email classaction@poynerbaxter.com or phone 604 988-6321.

This Web site is offered for information only and is not legal advice. Use of the site and sending or receiving information through it does not establish an attorney-client relationship. No one should act, or refrain from acting, based solely upon this information without seeking appropriate legal or other professional advice. In particular, you should obtain advice about limitation periods as it may affect your right to bring a legal action on your own behalf. Links to and from from this Web site do not state or imply a relationship between Poyner Baxter LLP and the linked entity.

From Siskinds LLP:

UPDATE (May 21, 2010): We are pleased to announce that a settlement has been reached in this action:

• Settlement Agreement - May 5, 2010 [PDF Document]

The next step is to have the settlement approved by the courts. Settlement approval hearings have been scheduled for Ontario on June 8 , 2010, Quebec on June 14, 2010, and British Columbia on June 15, 2010.

• Notice of Settlement Approval Hearings [PDF Document]

Once the settlement has been approved by each of the courts, a further notice will be published which will explain the steps for making a claim.

Zyprexa (Olanzapine) Class Action - Notice of Class Certification

The Schizophrenia Society of Nova Scotia suggests to its members that they should seek legal advice immediately so that they may be properly apprised of their rights, particularly because of the limited time within which a potential claimant may "opt out".



To view a high resolution PDF of the above document, please click here.

From the above document:

...

This notice does not constitute medical advice. Patients who have been prescribed Zyprexa should consult with their physicians if they have any questions with respect to their medical condition and should not stop taking Zyprexa without consulting with their health care professional.

...

IF YOU WISH TO EXCLUDE YOURSELF FROM THE CLASS PROCEEDING (“opt out”) you must deliver a written notice to one of the solicitors for the parties ... specifying your desire to opt out of the class proceedings. Notice of your decision to opt out must be received by either one of the solicitors by October 16, 2009.

ANY JUDGMENT OBTAINED ON THE COMMON ISSUES IN THE ACTION, WHETHER FAVOURABLE OR NOT, WILL BIND ALL CLASS MEMBERS WHO DO NOT OPT OUT OF THIS ACTION.

...

For further information, please click here.

Schizophrenia therapy: beyond atypical antipsychotics

From Nature Reviews Drug Discovery 7, 471-472 (June 2008) | doi:10.1038/nrd2571:

By Eric M. Snyder & Melanie R. Murphy

Antipsychotics remain the current standard of care for mental disorders including schizophrenia (1% prevalence) and bipolar mania (3% prevalence), and generate over US$16 billion worldwide in annual sales (Fig. 1; Table 1). However, a large trial known as CATIE, sponsored by the US National Institutes of Health, found that 74% of patients discontinue use within 18 months of therapy due to either poor tolerability or incomplete efficacy (1), indicating a need for novel therapies.


Figure 1. The schizophrenia drug market has grown from less than $1 billion annually in 1993 to more than $10 billion. This rapid growth has followed the introduction of Risperdal in 1993, followed by Zyprexa, Seroquel, Geodon [Zeldox in Canada] (ziprasidone; Pfizer) and Abilify (aripiprazole; Bristol–Myers Squibb). Annual prescriptions have increased from approximately 20 million to more than 40 million in this time. Source: IMS. (Click on the figure to magnify it.)


Table 1. Currently marketed antipsychotics. (Click on the table to magnify it.)


The first generation of antipsychotics — termed conventional or 'typical' antipsychotics — such as haloperidol, inhibit dopamine D2 receptors and are moderately effective in treating positive symptoms of schizophrenia (for example, hallucinations), but may cause extrapyramidal movement disorders. Second-generation 'atypical' antipsychotics — such as Lilly's Zyprexa (olanzapine), Johnson & Johnson's Risperdal (risperidone) and AstraZeneca's Seroquel (quetiapine) — inhibit D2 receptors in conjunction with other receptors (notably 5-hydroxytryptamine 2A (5-HT2A) receptors) (Table 1). Atypical antipsychotics have proved less likely to cause movement disorders, but are associated with weight gain, prolactin and glucose elevation, and sedation.

Zyprexa is widely regarded as being the most effective atypical antipsychotic on the market, but in the past 3 years, issues related to side effects have led to the drug losing nearly half its market share, as well as over 28,000 lawsuits, again indicating the need for drugs with better side-effect profiles. Furthermore, with all of the currently marketed atypicals facing generic competition within 5 years, there is a considerable market opportunity for new branded antipsychotics.

A new approach: mGluRs

In September 2007, Eli Lilly announced results of a 4-week Phase II trial of their metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY2140023 for schizophrenia. Although LY2140023 exhibited slightly less efficacy than Zyprexa in reducing positive symptoms, it nonetheless delivered significant improvement (2). Importantly, while treatment with Zyprexa was associated with weight gain, patients who received LY2140023 actually lost an average of 0.5 kg. These data indicate that mGluR agonists could represent a breakthrough in the search for a better-tolerated antipsychotic.

Indeed, this mechanism appears so promising that Eli Lilly, Merck, Johnson & Johnson and Pfizer (as well as partners Addex and Taisho) are all racing to develop mGluR-targeted drugs for schizophrenia. For example, early this year, Merck expanded their commitment to develop a new antipsychotic by entering into an exclusive worldwide license agreement with Addex for their preclinical, positive allosteric mGluR5 modulator ADX63365. This is Merck's second deal for an mGluR modulator for schizophrenia, having previously partnered with Taisho for another preclinical compound.

Eli Lilly clearly holds the lead in the mGluR race, with proof-of-concept data in hand and Phase III trials anticipated to begin later this year, whereas other competitors are not yet in the clinic. However, it remains to be seen whether Eli Lilly's LY2140023 will prove superior in the long run. This compound is a traditional, orthosteric agonist that provides continual activity as long as it is bound to the receptor. Conversely, allosteric modulators such as those being developed by Addex provide activity only when the endogenous agonist is present. This might provide a more normal pattern of signalling and be more attractive for long-term use.

The precise mechanism by which LY2140023 and other mGluR-targeted agents have efficacy in schizophrenia is not understood, although there may be some overlap with previously established mechanisms. Glutamate and dopamine axons converge on the medium spiny neurons of the striatum (3), 4 (Fig. 2). In addition, mGluR2/3 agonists have been shown to inhibit dopamine release, demonstrating functional interconnectivity of these two neurotransmitter pathways. It remains possible that mGluR2/3 agonists may in fact target the conventional pathway of dopamine D2 antagonism. Alternatively, mGluR2/3 may form a complex with 5-HT2A receptors, suggesting that mGluR activation can regulate 5-HT signalling5.


Figure 2. Metabotropic glutamate receptors (mGluRs) in the synapse. (Click on the figure to magnify it.)


Addex and Merck's ADX63365 targets mGluR5, which has no known effect on dopamine signalling, but which can modulate the signalling of the ionotropic NMDA (N-methyl-D-aspartate) glutamate receptor, another receptor that has long been thought to be associated with schizophrenia. This pathway may have additional benefits: while Merck and Addex still await human clinical data for ADX63365, animal studies suggest that this compound can improve cognition as well as positive symptoms. Thus, in addition to being safer than atypicals, mGluR agonists might offer improved efficacy in the cognitive domains of schizophrenia.

Outstanding issues

Long-term studies of mGluR-targeted agents have yet to be conducted and it remains to be seen whether the efficacy seen in Eli Lilly's 4-week study can be maintained. Further-more, although mGluRs appear to offer good tolerability, longer-term trials are needed to gauge safety. If mGluR-targeted drugs can mimic the profile seen so far with Eli Lilly's LY2140023, it will be interesting to see how physicians would use mGluR agonists. Would they be prescribed independently, even though they may not have the efficacy of their atypical predecessors? Would they be used as adjunctive therapies, in combination with lower doses of atypicals? This cocktail therapy model is being pursued by Acadia with their 5-HT2 inverse agonist primavanserin, which improves the efficacy of low doses of risperidone without causing weight gain. A third possibility is that mGluR-targeted agents could be used in conjunction with primavanserin, creating a selective, targeted therapy with few side effects.

Overall, the development of mGluR-targeted drugs for schizophrenia represents an opportunity for a new class of drugs that might represent a superior treatment option to that of currently available antipsychotics, as well as an advance in the understanding of the molecular basis for therapies for psychiatric disorders.

Beyond atypicals

The market for drugs for schizophrenia has grown tenfold in the past decade (Fig. 1, Table 1). In 2007, Risperdal and Zyprexa led the worldwide market with $4.7 billion in sales each. Zyprexa sales have grown, despite continuing concerns with side effects. In addition to the need for novel antipsychotics with improved safety and efficacy profiles, the approaching patent expirations of leading products is creating a challenge for the pharmaceutical industry. Recent data indicate that agents that target mGluRs could represent a promising new class of antipsychotics, and such agents are now being developed by several companies (Table 2).

Table 2. Next-generation antipsychotics. (Click on the table to magnify it.)


References

1. Lieberman, J. A. et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353, 1209–1223 (2005).

2. Patil, S. et al. Activation of mGluR2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Med. 13, 1102–1107 (2007).

3. Sesasck, S. et al. Anatomical substrates for glutamate–dopamine interactions: evidence for specificity of connections and extrasynaptic actions. Ann. NY Acad. Sci. 1003, 36–52 (2003).

4. Moghaddam, B. Bringing order to the glutamate chaos in schizophrenia. Neuron 40, 881–884 (2003).

5. Gonzalez-Maeso, J. et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 452, 93–97 (2008).

Author affiliations

Eric M. Snyder and Melanie R. Murphy are at Mehta Partners Global BioPharmaceutical Investments, 276 Fifth Avenue Suite 1100, New York 10001, USA. Email: snyder@mpglobal.com

Competing interests statement

The authors declare competing financial interests.

To download a PDF of this article, click here.

Schizophrenia Sufferers Flock to Cheap Generic Zyprexa From Canada

To read a November 13th press release from GenericZyprexa.com, click here.

Image of NOVO-OLANZAPINE courtesy of Novopharm.