After Lilly shrugs off schizophrenia failure pipeline must deliver

While the failure of Lilly’s pomaglumetad in itself is not a huge disappointment, and expectations for the schizophrenia project had been low, it draws attention yet again to how reliant the company is on near-term R&D success to replace sales lost to patent expiries.

Pomaglumetad was the first of Lilly’s three late-stage neuroscience projects on which study data are expected in the coming months, and analysts believe one of these must work to justify the large CNS infrastructure that had supported Zyprexa and Cymbalta. As such there is a desperate need for the pipeline to deliver in this therapy area and beyond. An analysis of EvaluatePharma data reveals a host of events with projects whose risk-adjusted NPV adds up to $5.7bn that could make or break the company in the second half (see table).

Pomaglumetad failed to show superiority to placebo based on a well known schizophrenia scale in an 880-patient registration study that was technically designated a phase II. The fact that the molecule showed no effect versus placebo, while patients given risperidone as a comparator did report an effect, makes things look pretty terminal.

However, Lilly is ploughing on. A phase III registration study in 1,100 patients is continuing, and Lilly said it would not make a final decision on pomaglumetad’s future until data from this and a phase II trial as an adjunct to atypical antipsychotics read out later this year. Consensus forecasts were for the drug to generate sales of $377m by 2018, and it had an NPV to Lilly of $885m, according to EvaluatePharma.

CNS and beyond

With pomaglumetad out of the picture, or at best delayed significantly, next up for the key CNS assets are norepinephrine reuptake inhibitor edivoxetine and the amyloid-targeting monoclonal antibody solanezumab – which have NPVs of $818m and $675m respectively (see table).

Few analysts expect solanezumab to yield clearly positive results when the first of two pivotal studies in Alzheimer’s disease reads out around August, although with the risk of failure largely priced in a success could have a disproportionately positive effect on Lilly’s share price. Solanezumab is the most advanced R&D hope for a company with one of the toughest patent expiry cliffs in the industry (Event – Amyloid-targeting Alzheimer’s therapies seek crumbs of comfort, June 26, 2012).

A phase III study of edivoxetine, a potential blockbuster in major depressive disorder, could also read out by the end of the year or in early 2013. The drug is being developed as an adjunct in partial responders to SSRIs, and is also in several other phase III studies. As well as efficacy, its safety profile will be closely watched given the increases in pulse rate and blood pressure seen in phase II.

Upcoming phase III results
Product Generic name Pharmacological class Indication Event date 2018 ww sales ($m) Product NPV ($m) NPV as % of market cap Trial ID
LY2963016 recombinant insulin glargine Insulin Diabetes Q4 374 1,854 4% NCT01421147
NCT01421459
Dulaglutide dulaglutide GLP-1 agonist Diabetes H2 566 1,080 2% NCT01064687
Pomaglumetad methionil pomaglumetad methionil mGluR2/3 agonist Schizophrenia H2 377 885 2% NCT01307800
LY2216684 edivoxetine Norepinephrine reuptake inhibitor Major depressive disorder Q4 409 818 2% NCT01185340
Solanezumab solanezumab Anti-beta amyloid MAb Alzheimer's disease Q3 290 675 1% NCT00905372
NCT00904683
BI10773 empagliflozin SGLT2 inhibitor Diabetes Q4 359 396 1% NCT01210001
NCT01177813
NCT01159600
NCT01370005
NCT01164501

Beyond the CNS Lilly is awaiting phase III data in type 2 diabetes from two projects whose NPVs are higher than either of its two remaining late-stage neuroscience assets. Dulaglutide is one of several GLP-1 inhibitors set to challenge the dominance of Novo Nordisk’s Victoza, and boasts an Fc fusion approach that gives it a longer half-life; some analysts think phase III readout could slip into next year.

And LY2963016, a new insulin glargine partnered with Boehringer Ingelheim, could see the first of two phase III trials generate results by the end of the year; these have to be strong if it is to compete with Sanofi’s Lantus and biosimilars.

The phase III programme with a third diabetes agent, empagliflozin, should be completed over the next six months or so. The SGLT-2 inhibitor, subject of a profit share with Boehringer Ingelheim, will be trying to capitalise on last year’s US rejection of AstraZeneca/BMS’s dapagliflozin, and as such safety will again be closely watched.

Disappointments "common"

Meanwhile, the pomaglumetad disappointment leaves the sparse industry pipeline of mGluR2/3 inhibitors even thinner. Addex/Johnson & Johnson’s JNJ-40411813 could yield phase II results in schizophrenia shortly, and its developers will be hoping that selectivity for the mGluR2 subtype could confer an advantage.

While Lilly’s science chief, Jan Lundberg, has referred to the unfortunately common occurrence of negative study results in the field of psychiatry, the failure of pomaglumetad leaves Lilly’s near-stage CNS pipeline with one strike against it. With solanezumab data likely to ring up the second, the heat is on.

Given Lilly’s history the company should know more than most about neuroscience drug development, and the next six months will be pivotal both for it and its embattled CEO, John Lechleiter.

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