Eisai, Purdue reveal eye-opening data for sleep drug lemborexant

Eisai and Purdue Pharma have presented new clinical trial results of their dual orexin receptor antagonist lemborexant, which they think could become a new force in the sleep disorder market.

The SUNRISE 1 trial—which reported top-line data in March—plus two new phase 1 studies were presented at the SLEEP 2018 conference in Baltimore yesterday and, say the partners, reinforce their view that lemborexant can help improve sleep with no hangover effect on waking and no grogginess if patients have to get up in the night.

The phase 3 trial included a head-to-head assessment of lemborexant and an extended-release form of widely used sleep drug zolpidem, which is available generically, and found that Eisai and Purdue’s drug was more effective at keeping patients over the age of 55 asleep throughout the night, avoiding early awakening. The two new phase 1 trials looked at other variables that are important to getting a good night’s sleep.

Study 108 compared the effects of lemborexant, zolpidem and placebo given at bedtime on postural instability after patients were awoken in the night by exposure to noise. The main measure was body sway, and while lemborexant-treated patients overall weren’t as steady on their feet as those on placebo, they did significantly better than those on zolpidem.

With the widely used insomnia drug, body sway occurred at almost three times the level that would be seen if the subject had drunk enough alcohol to put them close to the legal driving limit. A lower dose of lemborexant (5 mg) caused no clinically meaningful increase in body sway, while a higher (10 mg) dose increased it “to just above the clinically meaningful threshold.”

The study also checked on the effects of the drugs the following morning and found no difference between Eisai and Purdue’s drug and placebo on postural instability, which Eisai Chief Medical Officer Lynn Kramer, M.D., notes is “the single best predictor of falls” in older people.

There was no significant difference between placebo and both study drugs in the noise threshold needed to wake subjects up, but those on lemborexant found it easier to fall asleep again thereafter.

The second trial, Study 106, investigated the tendency of lemborexant and another widely used generic sleep drug called zopiclone to impair driving ability in the morning after a bedtime dose. It tested the amount of weaving—or standard deviation of lateral position in scientific parlance—and found that lemborexant had no significant effect on performance, while zopiclone significantly increased SDLP compared to placebo.

No test drives were stopped on safety grounds before completion in the lemborexant group, while three in the zopiclone group were halted, although overall that accounted for less than 1% of all drives tested.

Eisai said earlier this year it intends to file for approval of lemborexant for insomnia later this year once the results of a second, confirmatory phase 3 trial come in.

It’s also got a phase 2 in play for lemborexant in patients with irregular sleep-wake rhythm disorder, and in mild to moderate Alzheimer’s dementia, which is already underway.

https://bit.ly/2M3t8nr

Psychosis Tends to Follow Cannabis Use, Not Vice Versa

Cannabis use preceded onset of psychosis symptoms in teens more often than the reverse, according to researchers analyzing data from a longitudinal study conducted in Quebec.

A total of 3,966 adolescents volunteered to participate annually in an online survey in which they reported their cannabis use in the past year (on a 6-point scale ranging from “never” to “every day”) and any psychosis symptoms they experienced as per the Adolescent Psychotic-Like Symptoms Screener.

With the survey data, a statistical model was created showing the relationship between marijuana use and psychosis symptoms over ages 13-16 (χ²=48.22). Once the model incorporated time-lagged associations between earlier cannabis use and psychosis symptom onset 12 months later, the model acquired a better fit (χ²=26.07, P=0.001), according to Patricia Conrod, PhD, of the University of Montreal, CHU Sainte-Justine Research Center, and colleagues, reporting online in a research letter in JAMA Psychiatry.

“This analysis demonstrates a predominant association at the individual level of cannabis use frequency with increased psychosis symptoms, and not the opposite, in the general population at a developmental stage when both phenomena have their onset.

“[T]hese results emphasize the need for targeted cannabis use prevention as jurisdictions revise their cannabis regulatory policies,” the researchers suggested. Canada is on the verge of legalizing marijuana nationwide, possibly as soon as this week.

“Promoting evidence-based interventions and policies that reduce access to and demand for cannabis among youth could lead to population-based reductions in risk for major psychiatric conditions,” Conrod and colleagues wrote.

The investigators used data from teenagers in the Co-Venture cohort, representing 76% of all grade 7 students at 31 secondary schools in the Montreal area. Data from 3,720 were included in the analysis. The researchers acknowledged that the study’s reliance on unverified, self-reported cannabis use and psychosis symptoms were an important limitation.

Conrod and co-authors reported having no conflicts of interest.

• Primary Source

  JAMA Psychiatry

  Source Reference: Bourque J, et al “Association of cannabis use with adolescent psychotic symptoms” JAMA Psychiatry 2018; DOI: 10.1001/jamapsychiatry.2018.1330.

https://bit.ly/2Jwp2pn

Medicare’s Future: Bad but Not Totally Bleak

Economists agreed that the latest report on the Medicare trust fund — predicting that the hospital insurance trust fund will be depleted by 2026 — was largely without surprises.

“The message … has always been the same, which is, at some point, the program is going to face huge financial challenges unless policy makers take action, and unless the health sector finds ways to deliver appropriate care more efficiently to patients,” said Joseph Antos, PhD, a resident scholar in healthcare and retirement policy at the American Enterprise Institute (AEI).

At an AEI briefing Wednesday, Antos, along with Robert Moffit, PhD, a senior fellow at the Heritage Foundation, did highlight several shortcomings of the 2018 Medicare Trustees report such as the lack of independent expert involvement.

This year’s report was signed only by Trump administration officials, noted Moffit. Such reports should be reviewed by independent experts to “instill confidence” in findings, he pointed out.

“The current situation is simply not good public policy,” Moffit stated.

The report, released Tuesday, forecasts for both the Hospital Insurance and Supplementary Medical Insurance trust funds. The 2026 depletion forecast is 3 years earlier than trustees reported in a 2017 analysis.

Paul Spitalnic, chief actuary for the Centers for Medicare and Medicaid Services, said what’s behind the trustees report is “predominately a revenue story.”

Because payroll taxes were significantly lower than anticipated in the 2017 report, there’s been less income feeding into the hospital insurance trust fund, which is one reason the depletion date of the fund has been bumped up. In addition, since certain taxes on Social Security benefits also funnel into the trust fund, and the 2017 tax billlowered individual tax rates, which had the effect of narrowing the revenue stream, Spitalnic said.

While projections have not “materially changed” over the last 5 years — a 2013 Trustees Report also suggested a 2026 depletion — Spitalnic noted differences between the total projected expenditures for Medicare Part D between 2013 and 2018, which he attributed to a slowdown in hepatitis C virus treatment expenses, and greater reliance on generic drugs.

Antos said the trustees’ supplementary “illustrative” analysis was “somewhat more realistic” than the main findings.

The illustrative example shows that long range costs in the program may be higher if certain cost reduction measures under current law don’t work as intended, Spitalnic explained.

Under the report’s main analysis, Medicare’s current share of gross domestic product (GDP) is expected to grow from 3.7% in 2017, to 6.2% under current law in 2090, and even higher to 8.9% in 2090, under the “illustrative” scenario.

While the main analysis assumes no changes in current law, the illustrative analysis zeroes in on two current policies that could “problematic,” Antos explained, and one of these is the Medicare Access and CHIP Reauthorization Act (MACRA).

MACRA repealed sustainable growth rate formula (SGR), but MACRA itself isn’t a “bed of financial roses” for physicians either, he said.

Under MACRA, payment updates are typically less than 1% a year, whether physicians are in Alternative Payment Models, or the default Merit-based Incentive Payment System.

“It’s unreasonable to think that general inflation will be as low as 1% a year in the future,” he said, adding that it’s accepted that healthcare inflation is expected to rise faster than general inflation.

In other words, basing any forecast on those updates remaining unchanged seems unwise, he stressed. And it’s unlikely that Congress will maintain the current system of updates, he noted.

“They’ll change it…. They’ll buckle under the obvious and probably reasonable pressure coming from the physician community [who will argue] that they really can’t live with such modest increases given their likely cost of operation rising much more quickly,” Antos stated.

Another problem area is the productivity adjustments established under the Affordable Care Act (ACA).

While finding ways for the healthcare sector to become more productive sounds good in theory, using a formula that links payment to productivity improvements in the general economy is flawed, Antos said.

“Economy-wide productivity generally has been measured to grow… much faster than health … sector productivity,” he stated. “Yet payments are going to be reduced because of that factor.”

In 2018, economy-wide productivity is estimated to increase around 1.1% per year over the long-term, while hospital productivity has increased by about 0.4 % a year in recent years, and is expected to have “essentially zero” growth over the long term, he explained.

The core issue is one of feasibility, Antos said. Can the health sector find ways to meet the required productivity adjustments? And if it does “will we be able to detect it?,” he stated, expressing skepticism on both fronts.

Moffit cautioned against taking the report out of its proper context. The media and politicians are likely to claim “Medicare trust fund is going bankrupt,” he said. “The [hospital insurance] trust fund hasn’t gone bankrupt in the last half-century, and I can’t imagine that it will go bankrupt in the next half-century.”

“Medicare has serious financial challenges,” Moffit acknowledged. “It’s better to address them sooner, rather than later, and Congress is going to have to come to grips with this.”

Historically, the two main ways of addressing these issues has been to raise payroll taxes or to reduce hospital payments, he noted, but payment reductions are already scheduled under the ACA, so any more cuts seem unlikely.

Moffit said he wants to see Medicare Parts A and B combined, a catastrophic benefit added, the age of eligibility raised, and a requirement that wealthier enrollees pay more for their benefits.

He said he also supports taking the defined contribution approach of Medicare Advantage and expanding it to the entire program.

“The Medicare trustees have done their job,” he stressed. “It’s time for Congress and the White House to do their job.”

But, he added, “I’ll make an iron-clad prediction that, in 2018, nothing will happen.”

https://bit.ly/2JnBHaM

Pfizer Cuts Neuroscience Development, Then Adds $150M to Neuroscience JVs

In late January, Pfizer Inc. abandoned its research and development of new neuroscience programs. Along with the news came 300 job cuts. It was terminating eight different projects. Two were in Phase II while six others were in Phase I. The two Phase II projects were PF-06372865 for epilepsy and PF-06649751 for Parkinson’s disease. Four of the Phase I projected targeted Alzheimer’s disease. The other two Phase I candidates were for a cognitive disorder and schizophrenia.

Now Pfizer is throwing an additional $600 million into its venture capital fund, with a quarter of it earmarked for neuroscience research investments. It will bring Pfizer Ventures’ total funding to over $1 billion. Business Insider notes, “Several drugmakers, including Pfizer, have cut back on neuroscience research after a string of costly trials yielded disappointing results, with some of them betting on startups that are focusing on such areas. Pfizer has already invested in six neuroscience companies and, alongside drugmakers such as GlaxoSmithKline and Eli Lilly, is part of the Dementia Discovery Fund, which has raised more than $190 million since its 2015 launch.”

Those six companies include Aquinnah, Autifony, Cortexyme, MindImmune, MISSION, and Neuronetics.

Glenn Larsen, co-founder, president and chief executive officer of Aquinnah, said in a statement, “Pfizer’s investment in Aquinnah is helping advance two exciting Stress Granule neurodegenerative programs in Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease. By being located in LabCentral within the Pfizer building in Kendall Square and through our joint efforts, Aquinnah has access to a leading group of scientific advisors, as well as state of the art technology facilities.”

About $150 million will be invested in early-stage neuroscience companies, with a particular focus on neurodegeneration, neuroinflammation and neuro-metabolic disorders.

Pfizer’s vice president, Worldwide Business Development and senior managing partner of Pfizer Ventures, Barbara Dalton, said in a statement, “By expanding Pfizer’s venture capital efforts under Pfizer Ventures, we hope to extend both the breadth and depth of Pfizer’s support for the development of cutting-edge science from concept to products. Building on our existing investments and proven track-record, we will look to identify and invest in emerging companies that are advancing compounds and technologies with the hope of delivering life-changing therapies to patients in need.”

In addition to the additional funding, Pfizer is expanding the Pfizer Ventures team. It will be still led by Dalton with Elaine Jones and Bill Burkoth. But Denis Patrick, vice president, Pfizer Worldwide Research and Development and managing partner of Pfizer Ventures, Laszlo Kiss, Margin McLoughlin, Chris O’Donnell and Nikola Trbovic will also be joining the group. It consolidates R&D Innovate, Pfizer’s R&D equity investment vehicle with Pfizer Venture Investments.

“By changing the way we invest in neuroscience, we hope to support an energized community of biotech entrepreneurs who are progressing the understanding of the molecular mechanisms of neurologic diseases and help advance potential treatments for people with neurological conditions,” Denis Patrick said in a statement.

About 80 percent of Pfizer Ventures investments will be made in the U.S. It will also commit up to $10 million when it first invests.

https://bit.ly/2sMZiKO

Genentech and Microbiotica Ink Multi-Year Collaboration Deal

Genentech, a Roche company, and Microbiotica, in Cambridge, England, signed a multi-year strategic collaboration to discover, develop and commercialize biomarkers, targets and drugs for inflammatory bowel disease (IBD).

Microbiotica was spun out of the Wellcome Sanger Institute 18 months ago, and focuses on microbiome-based therapeutics. Under the deal, Microbiotica will use its precision metagenomics microbiome platform to analyze samples from clinical trials of Genentech’s IBD drugs. The goal is to identify microbiome biomarker signatures of drug response, with hopes of finding novel IBD drug targets and potentially develop live bacterial therapeutic products.

This is a relatively new area of drug development and health, the study of how different bacterial strains of bacteria living in the human body effect various disease states.

Genentech is paying Microbiotica an undisclosed upfront payment. It will be eligible for various milestone payments up to $534 million. Also, Microbiotica will be eligible to receive royalties on sales of specific products that might come out of the collaboration. Genentech also has the option to license assets the company might develop out of the collaboration.

“This brings together a world-class pipeline of investigational IBD medicines from Genentech with the world-class microbiome capability of Microbiotica,” said Mike Romanos, chief executive officer of Microbiotica, in a statement. “We are excited by the opportunity to work with Genentech scientists in order to bring precision metagenomics into the clinical arena for the first time, enabling us to develop biomarkers and medicines for the benefit of patients.”

In early May, Genentech signed a strategic drug discovery collaboration with Lodo Therapeutics, a New York City-based company. That deal could potentially be worth more than $1 billion. Under the terms of that deal, Genentech will use Lodo’s proprietary genome mining and biosynthetic cluster assembly platform to identify potential therapeutics against multiple disease targets. Again, there was an undisclosed upfront payment, but Lodo is eligible for various milestone payments that could hit $969 million. Lodo will also be eligible for tiered royalties.

Lodo’s platform identifies and produces bioactive natural products directly from the microbial DNA sequence information contained in dirt. The information in the organisms’ genomes drive the company’s discovery programs. It was founded on the scientific work of Sean Brady, head of The Rockefeller University’s Laboratory of Genetically Encoded Small Molecules.

These two deals indicate a strong interest on the part of Genentech in developing new drugs based on microbiomes. James Sabry, senior vice president and global head of Genentech Partnering said in a statement, “We believe the microbiome represents a new paradigm in biomedicine, both for understanding drug response and as a novel therapeutic modality. We have chosen to collaborate with Microbiotica because of its high-quality science and look forward to working together to potentially bring new medicines to people suffering from IBD.”

Overall, there’s quite a bit of movement—no pun intended—in this area of research. In April 2018, Ferring Pharmaceuticals, headquartered in Saint-Prex, Switzerland, acquired Roseville, Minnesota’s Rebiotix. Ferring focuses on reproductive medicine and women’s health, with specialty areas within gastroenterology and urology. Rebotix is a late-stage clinical microbiome company.

In April 2017, Takeda Pharmaceutical Company signed a global collaboration deal with Somerville, Massachusetts-based Finch Therapeutics. They will jointly develop FIN-524, a live biotherapeutic product made up of cultured bacterial strains that have been associated with favorable clinical outcomes in research of microbiota transplantations in IBD.

And in April 2018, Synlogic, based in Cambridge, Massachusetts, dosed its first patient in its Phase Ib/IIa clinical trial of SYNB1020 for hyperammonemia, a metabolic disorder characterized by excess ammonia in the blood. SYNB1020 is a Synthetic Biotic, taken orally. It can act in the gut to compensate for the dysfunctional metabolic pathway. The company’s approach is to program naturally-occurring microbes using synthetic biology tools. The engineered microbiome then effects the body’s metabolic dysregulation.
Although these examples all focus on bowel diseases, there is quite a bit of work looking at how the microbiota affect every organ system and disease state.

https://bit.ly/2sBMlUW

What’s with Longevity Firm Unity Biotechnology and its $700M Valuation?

Early biotech company valuations are a type of voodoo made up of interesting ideas, talented management, investor enthusiasm and wishful thinking. How to explain UNITY Biotechnology,which wants to help you stay young until you die? The company has raised $222 million in venture capital, raised $85 million in an initial public offering (IPO) in May, and has a value of $700 million. All without having a product to sell.

Unity Biotechnology’s focus is on killing senescent cells. These cells are essentially aging cells that aren’t quite dead, but aren’t actually doing anything anymore, and they build up in the body and are part of what makes people feel old—related to achy joints, diminished eyesight and some diseases of aging, potentially Alzheimer’s. The company believes that if you can kill those senescent cells, you can eliminate many of the symptoms of aging.

“Like, how awesome would it be?” said Nathaniel “Ned” David, the co-founder and president of the company, to Forbes. “The problem is you have to take the first baby step to demonstrate it’s possible. That’s what chapter one is: demonstrate in a human being that the elimination of senescent cells takes a heretofore inescapable aspect of aging and can either halt it or reverse it.”

“Just that,” responds the company’s chief executive officer and chairman, Keith Leonard. “It’s easier to talk to the Food & Drug Administration about treatment of a disease once it’s diagnosed than it is to work really early and prevent disease. But [prevention] is what we’d love to get to.”

At the moment, the company’s pipeline is all early stage. UBX0101 is close to Phase I for osteoarthritis. Its UBX1967 is in lead optimization for diabetic retinopathy and diabetic macular edema, glaucoma, and age-related macular degeneration. It also has other programs in pulmonary diseases, cognition, and kidney disease, all in the preclinical stages. UBX0101 is currently recruiting patients for a Phase I trial.

UBX0101 is described as “a potent senolytic small molecule inhibitor of the MDM2/p53 protein interaction. Disruption of this protein interaction can trigger the elimination of senescent cells.”

UBX1967 is for diseases of the eye and is a senolytic small molecule inhibitor of specific members of the Bcl-2 family of apoptosis regulatory proteins. The company notes, “Senescent cells utilize pro-survival mechanisms to remain viable and rely on specific Bcl-2 protein family members to persist and accumulate in tissues.” The company plans to submit its IND application and begin a Phase I trial in the second half of 2019.

Ned David co-founded Unity in 2011 because, he said, it was “simply the coolest biology he had ever seen.” Prior to co-founding the company, he co-founded four other biotech companies that in total have raised over $1.5 billion in financing. These include Syrrx, which was acquired by Takeda, Achaogen (AKAO), Kythera Biopharmaceuticals, later acquired by Allergan, and Sapphire Energy.

Kristina Burow, managing director at Arch Venture Partners, who has invested in four of David’s companies, told Forbes, “He’s probably the best person in the world at finding great academic science and shaping it into a fundable story and a sellable business plan.”

There may be two other factors involved as well. First, the timing just may be right for research into longevity—science has a much deeper understanding of aging based on things like senescent cells and telomere shortening—a function of cell division that places a limit on the number of times a cell can divide. And secondly, a lot of investors, especially of the billionaire-variety, are aging.

It was recently noted that a number of billionaires who are fifty years or older in age, have been investing in health care and longevity-related startups companies. That includes Bill Gates, 62, Michael Bloomberg, 76, Richard Branson, 67, Tim Disney, 57, Andrew Russel, 56, Jeff Bezos,65, Peter Thiel, 50.

Another factor, not really related to age, is that there are a number of people who have created enormous amounts of wealth, often via tech companies, and longevity research just seems like a good idea whose time has come. Which may be why Mark Zuckerberg, Facebook founder and his wife, physician Priscilla Chan, have invested $3 billion toward basic research over the next 10 years. Both of them are 33 years old. And Bill Marris, who is 42, the founder and former chief executive officer of GV (Google Ventures), invested and founded Calico, a Google/Alphabet company, whose focus is aging and related diseases.

It’s possible that betting on a potential fountain of youth is just a good investment.

https://bit.ly/2Jm3ZlQ

Biogen Pays Alkermes $50 Million Milestone for MS Drug

Alkermes, headquartered in Dublin, Ireland, received a $50 million milestone payment from Cambridge, Massachusetts-based Biogen. The payment occurred after Biogen reviewed preliminary gastrointestinal tolerability data from an ongoing Phase III clinical trial of BIIB098 (diroximel fumarate) for relapsing forms of multiple sclerosis (MS).

Under the terms of their agreement, Biogen has exclusive commercialization rights to the drug. Alkermes is eligible for a royalty in the mid-teens on worldwide net sales, should the drug be approved. Alkermes is also eligible for a $150 million milestone payment if the U.S. Food and Drug Administration (FDA) approves the drug, on or before December 31, 2021.

Alkermes is expected to submit a New Drug Application (NDA) for the drug to the FDA in the last quarter of this year.

The original deal was signed in November 2017, when the drug was dubbed ALKS 8700. It is a novel, oral, monomethyl fumarate (MMF) small drug molecule. Biogen reimbursed Alkermes for half of the 2017 development costs and paid Alkermes an upfront payment of $28 million, which represented Biogen’s share of development expenses already incurred that year.

Starting at the beginning of 2018, Biogen handled all development expenses related to the drug. Alkermes is eligible for milestone payments up to $200 million—which is already received $50 million. Alkermes will handle regulatory applications with the FDA, and Biogen will handle commercial activities for the drug, if approved.

The primary components of the EVOLVE-MS (Endeavoring to Advance Treatment for Patients Living with Multiple Sclerosis) clinical program of ALKS 8700/BIIB098 include a two-year safety trial and pharmacokinetic bridging studies comparing the drug and Tecfidera. The program also includes an elective head-to-head study comparing the GI tolerability of the drug and Tecfidera.

“The clinical data generated from this program underscore the potential value of BIIB098 for patients with multiple sclerosis,” said Richard Pops, Alkermes’ chief executive officer, in a statement. “Our focus remains on completing the registration requirements and preparing the BIIB098 NDA for submission in the fourth quarter of 2018, as we advance this important potential new therapeutic option for patients with MS.”

Alkermes is a busy company, with a market cap of $7.19 billion. It markets Aristada for schizophrenia, Vivitrol for alcohol and opioid dependence, Risperdal Consta for schizophrenia and bipolar I disorder, Invega Sustenna for schizophrenia and schizoaffective disorder, Xeplion, Invega Trinza, and Trevicta for schizophrenia, Ampyria/Fampyra to enhance walking in MS patients, and Bydureon for type 2 diabetes. It currently has ALKS 5461 in Phase III trials for depressive disorder, ALKS 3831 in Phase III for schizophrenia, ALKS 8700 for MS, and ALKS 6428 in Phase III to assist physicians transition patients from physical dependent on opioids. Its Aripiprazole lauroxil recently finished a Phase I trial for schizophrenia, and ALKS 4230 is in Phase I clinical trials for cancer immunotherapy.

Biogen, a leader in MS treatments, announced yesterday that it had expanded its strategic collaboration with Ionis Pharmaceuticals to discover and develop novel antisense drugs for neurological diseases. Biogen paid Ionis $1 billion in cash, including $625 million for 11,501,153 shares of Ionis common stock at a price of $54.34 per share and a $375 million upfront payment. The expansion was originally announced on April 20, 2018. The companies expect to advance programs for diseases including dementia, neuromuscular diseases, movement disorders, ophthalmology, diseases of the inner ear, and neuropsychiatry.

https://bit.ly/2xPHtAx