Lilly’s Intended Successor To Zyprexa Faces Uncertain Future After Phase III Failure
This article was originally published in The Pink Sheet Daily
Executive Summary
Failure to perform better than placebo in the first of two pivotal Phase III trials diminishes chances of success for pomaglumetad methionil, a metabotropic glutamate 2/3 receptor agonist that Lilly hoped to position as a successor to its patent-expired schizophrenia therapy Zyprexa.
Eli Lilly & Co., which long has stated its intention to weather a steep patent cliff through internal R&D rather than merger-and-acquisition activity, suffered a potentially devastating setback July 11 as it reported the failure of the first of two pivotal Phase III trials for pomaglumetad methionil in schizophrenia.
The compound, a first-in-class metabotropic glutamate 2/3 receptor agonist, was being developed as a possible successor to the firm’s atypical antipsychotic Zyprexa (olanzapine), a multi-blockbuster that lost patent protection in 2011.
A prodrug also known as mGlu2/3 and LY2140023, pomaglumetad was the first compound in its class to demonstrate antipsychotic properties in human studies. Lilly’s hope was that it could provide a new therapy for schizophrenia that would avoid the side effects commonly seen with Zyprexa and other schizophrenia drugs, such as motor dysfunction, reproductive hormone irregularity, weight gain and lipid elevation.
In 2009, pomaglumetad failed to show benefit compared to placebo in a Phase II trial, but at that time Lilly pointed to success in a prior Phase II study and also cited an unusually high placebo response in the second, unsuccessful study (Also see "Lilly’s mGlu2/3 Agonist Fails In Phase II For Schizophrenia – But So Does Zyprexa" - Pink Sheet, 30 Mar, 2009.). Despite the latest setback, Lilly said it will await interim data later this year from the other Phase III trial testing the molecule as monotherapy in schizophrenia, as well as from a recently completed Phase II study investigating pomaglumetad as an adjunctive treatment with atypical antipsychotics.
In the H8Y-MC-HBBM trial, pomaglumetad tested at twice-daily doses of 40 mg and 80 mg did not separate from placebo in the primary efficacy endpoint in the overall population or a predefined genetic subpopulation. The drug was tested in patients suffering an acute exacerbation of schizophrenia and measured benefit based on the Positive and Negative Syndrome Scale (PANSS), Lilly said. Pomaglumetad was well tolerated in the study with no new safety findings, the company added, and final data will be presented later at a scientific conference.
Possibly exacerbating the findings was the fact that risperidone (Johnson & Johnson’s Risperdal) was used as a comparator in the trial and did outperform placebo.
“Unfortunately, negative studies are common in the field of psychiatry and a reality of biopharmaceutical innovation,” Jan Lundberg, Lilly’s executive VP for science and technology and president of Lilly Research Laboratories, said in a statement. While other big pharma companies such as GlaxoSmithKline Inc. have exited neuroscience R&D due to a high attrition rate, Lundberg said Lilly remains committed to the field, with more than a half-dozen compounds in development for neuroscience-related diseases and disorders.
In addition to pomaglumetad, Lilly also is investigating solanezumab in Phase III in Alzheimer’s disease and edivoxetine in Phase III for depression. The pharma also has an mGlu 2 receptor agonist in Phase II in migraine prevention.
In addition to Zyprexa, which began facing generic competition last November, Lilly also faces significant upcoming patent expiries in Cymbalta (duloxetine) in 2013 and Evista (raloxifene) in 2014. Combined with Zyprexa and the cancer drug Gemzar (gemcitabine), which went off-patent in 2010, those four products yielded more than 40% of Lilly’s top-line revenue in 2010 (Also see "No Big Surprises From Lilly: Management Sticks To Its Guns On Strategy" - Pink Sheet, 30 Jun, 2011.).
In a July 11 note on Lilly’s announcement, UBS Investment Bank analyst Marc Goodman reiterated a “neutral” rating for the company’s stock. Due to the Phase III setback, he removed $625 million in projected 2020 sales of pomaglumetad from his modeling on Lilly.
“Given that risperidone worked in this study, this is negative news for the molecule,” Goodman wrote. “This is key data for the first of three late-stage CNS assets. … Importantly, one of them needs to work to justify keeping the large CNS infrastructure that has supported Zyprexa/Cymbalta.”