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Friday, December 6, 2019

Step aside, biomarkers: Look to the bank account for early signs of dementia

One crucial missing piece to the devastating puzzle of Alzheimer’s disease and other types of dementia is how to detect them early. Many researchers are hard at work evaluating biomarkers like levels of proteins known as beta-amyloid and tau in cerebrospinal fluid or imaging-detected changes in the brain.
There might be another, easier-to-detect signal. The first clinical markers of cognitive decline are found not in the brain but in the bank account. Impaired financial decision-making can appear decades before the emergence of other traditional signs or symptoms, like memory loss.
Whether they know it or not, financial industry professionals identify early warning signs of cognitive impairment and dementia in their clients long before medical clinicians or even the individuals themselves become aware.
Early signs of dementia can manifest themselves financially in ways big and small. While individuals with dementia are particularly vulnerable to financial exploitation and scams, those with unrecognized cognitive impairment likely make up a larger percentage of victims of fraud and exploitation, which cost older adults billions of dollars a year. But impaired financial decision-making goes beyond vulnerability to financial exploitation and poor decisions about savings or investment, and can be seen in everyday financial decisions like managing credit cards, calculating tips, and unnecessary spending. Unfortunately, we are not properly identifying those who are vulnerable, both financially and cognitively.
In discussions I have had with financial planners and members of the community, I have seen examples of impulsive and irrational investment and spending decisions that signaled a change from prior financial values. I’ve heard from concerned family members who notice subtle changes in financial decision-making in their loved ones, sometimes with major repercussions like spending down retirement assets too quickly or donating beyond appropriate means.
Why might financial decisions offer insight into subtle brain changes? Because even a relatively common financial decision is a complicated cognitive task. It involves risk assessment, timing, future planning, judgement, relationships, emotions, and more. Everyday financial decisions activate multiple areas of the brain simultaneously, making subtle changes more apparent at very early stages of impairment.
That’s why my colleagues and I have established a broad, cross-disciplinary research team to study the relationship between money management and diseases like Alzheimer’s and other forms of dementia. In collaboration with numerous academic departments at the University of Denver, along with partners in the financial industry, government, and the community at large, the Financial Security and Cognitive Health Initiative is developing a screening test to detect mental impairment early, increase awareness of it, and enhance both cognitive and financial health.
Nearly 6 million Americans are living with Alzheimer’s. It affects more than 16 million unpaid caregivers in the United States alone and costs hundreds of billions of dollars each year. Early identification of cognitive impairment and dementia needs more attention because we have made enormous strides in enhancing cognitive health. Promising research suggests that we can delay the onset and decrease the severity of symptoms.
Researchers and clinicians have made incredible strides in identifying and treating other major health issues early, including heart disease, diabetes, and several types of cancer. We check blood pressure, cholesterol, and blood sugar in children and adults. We perform mammograms and colonoscopies in adults.
But there’s not much we are doing to identify early signs of dementia. We have no standard screening for a set of diseases that is arguably the most significant health challenge in the U.S. and around the world. And we have limited and uninformed approaches with respect to effective next steps after early detection through impaired financial decision-making or other subtle signs of cognitive impairment.
While the financial industry has a strong incentive to prevent fraud and exploitation, it has no interest in playing doctor. Without business-smart solutions or industry-wide guidelines, the financial industry would rather look the other way than tell you that you might be experiencing cognitive decline. On the other hand, you’d likely not appreciate getting medical advice from your financial planner, credit card company, or investment firm.
Testing that is easy and accessible — like an app on your phone or a quick test from a financial planner or health care practitioner — could be used in ways that encourage protection and prevention through team-oriented approaches, social connection, and interdisciplinary solutions. I foresee a future where individuals can be screened for early signs of impairment at a point in their lives well before any noticeable symptoms are apparent; a future when we abundant options to prevent cognitive impairment and protect against poor decisions, financial and otherwise, that are accessible to all.
Eric Chess, M.D., is director of the Financial Security and Cognitive Health Initiative at the University of Denver’s Knoebel Institute for Healthy Aging.

Upcoming events – Gilead’s Nash refocus and an early chance for Ionis and Roche

Data from Gilead’s Atlas combination trial in Nash could point to a way forward, while Roche and Ionis are hoping to confirm earlier signals seen with a Huntington’s disease project.
Welcome to your weekly roundup of approaching clinical readouts. Gilead’s focus on Nash turned to a combination approach after its ASK1 inhibitor selonsertib flunked two phase III trials when used as monotherapy. Data from the phase II Atlas trial, which tests seven different combinations of selonsertib with two other Gilead agents – the ACC inhibitor firsocostat and cilofexor, an FXR agonist – are due before year-end.
The company noted at its third quarter results that Atlas will “allow us to think about how we pivot our Nash strategy moving forward”. Given that selonsertib is essentially a failed asset, little will be expected from the arms that contain this project.
Atlas recruited advanced patients, many with compensated cirrhosis and stage 3-4 fibrosis. Alongside safety the trial is evaluating the proportion of patients achieving at least a one-point improvement in fibrosis score, without worsening of Nash, at 48 weeks. This is the endpoint selonsertib missed as a monotherapy.
Data from a proof-of-concept trial have hinted at the efficacy of the combos. The first batch was released at EASL in 2018 and the second came earlier this year; the trial showed that a combination of firsocostat plus cilofexor produced the largest median decline in liver fat fraction. Patients had stage 2-3 fibrosis and were treated for 12 weeks.
COMBINATION DATA FROM PROOF-OF-CONCEPT STUDY
EASL 2018 dataEASL 2019 data
Selonsertib 18mgFirsocostat 20mgCilofexor 30mgSelonsertib+ FirsocostatSelonsertib+ CilofexorFirsocostat+ Cilofexor
Number of patients101010202020
MRI-PDFF reduction at 12 wks7.1%-42.7%*-15.6%*-32.0%*-9.4%-45.3%
No of pats w ≥30% reduction in MRI-PDFF10%70%0%50%15%74%
ALT reduction at 12 wks-1.2%-33.5%29.7%-27.2%*-3.0%-37.0%*
*p<0.05 vs. baseline. MRI-PDFF=magnetic resonance imaging-proton density fat fraction; ALT=alanine aminotransferase, a marker of liver inflammation and damage. Source: EASL 2018EASL 2019.
The issue with ACC inhibitors such as firsocostat is that they are known to increase triglycerides. Notably, early this month Gilead added another arm to this proof of concept study, adding Vascepa to firsocostat plus cilofexor. Another new cohort includes fenofibrate, a generic lipid-lowering drug, with the same combination. The study has a primary completion date of May next year.
This seems to hint at the way Gilead is moving forward here. The Atlas does not have patients taking anti-hyperlipidaemics, so will clarify firsocostat’s lipid impact, but the expanded proof-of-concept trial is also one to watch now.
Gilead had been the front-runner in Nash until its failure with selonsertib. Intercept’s FXR agonist Ocaliva now leads the space with a PDUFA in March next year despite having shown modest effects on fibrosis. Readouts are also due from Genfit’s phase III Resolve-It trial of elafibranor.
BIGGEST SELLING NASH PRODUCTS BY 2024
ProductCompanyAnnual Nash sales, 2024e ($m)Phase
OcalivaIntercept Pharmaceuticals923Marketed
MGL-3196Madrigal Pharmaceuticals811Phase III
ElafibranorGenfit508Phase III
Source: EvaluatePharma.
Going hunting
The Huntington’s disease project being developed by Roche and Ionis Pharmaceuticals is in a pivotal phase III trial, due to report fully in 2022. But it is possible that the groups could obtain accelerated FDA approval of RG6042 next year, based on a combination of several trials. One key readout contributing to this is the data from a small extension study, due in the next few months.
The 46 patients enrolled in Roche and Ionis’s placebo-controlled phase I/II trial are being followed for another 14 months on an open-label basis. Data from both these studies are expected to be used in an FDA submission, along with interim biomarker data from the pivotal trial, Generation-HD1 (Readouts approach for biggest Huntington’s hopes, March 26, 2019).
RG6042, which is also known as Ionis-HTTrx, is an antisense agent which blocks production of the mutant protein that causes Huntington’s. Achieving accelerated approval for the asset will be crucial for Roche and Ionis if they are to get the drop on rivals Wave Life Sciences and Takeda. These partners are collaborating on two antisense projects, one of which, WVE-120101, is forecast to launch in 2022.
TRIALS OF RG6042/IONIS-HTT-RX
Trial details NData
Placebo-controlled phase I/II trial46Post-hoc analysis reported April 2018
Open-label extension trial46Expected by end Q1 2020
Pivotal, placebo-controlled phase III trial (Generation-HD1)909Expected 2H 2022
Source: EvaluatePharma.
Half the patients in the extension trial will receive RG6042 intrathecally once a month, with the other subjects being treated every two months. The study is focused on the agent’s safety, with the primary endpoint being incidence of treatment-emergent adverse events. Secondaries include the concentration of Huntingtin protein in the cerebrospinal fluid and assessments of patients’ cognition.
The earlier trial showed significant, dose-dependent reductions in mutant huntingtin protein of up to 60%, and mean reductions of around 40% at the two highest doses, 90mg and 120mg. But a definitive link between reduction in mutant huntingtin and improvement in symptoms has yet to be proven. The closest Ionis has come is an exploratory post-hoc analysis of the phase I/II trial that suggested a correlation.
The extension will have to confirm RG6042’s safety – the earlier study threw up no serious adverse events with the drug and no discontinuations – over a longer period. Any signs of improving patient symptoms would be a major bonus, but this kind of proof is not expected until the full pivotal readout two years hence, if indeed it comes at all.
FORECAST WW SALES OF RG6042/IONIS-HTTRX ($M)
Company2021e2022e2023e2024e
Roche (in-licensed)2570219398
Ionis Pharmaceuticals (originator)15-19% royalties on WW sales
Source: EvaluatePharma.

FDA greenlights generics of Novartis’ $3B MS star Gilenya amid legal fight

In June, a U.S. district court judge temporarily shielded Novartis’ $3 billion-a-year multiple sclerosis (MS) drug Gilenya from generic competition—but that’s not preventing generics makers from lining up at the starting gate.
Thursday, the FDA approved the first three generic versions of Gilenya, which will be made by HEC Pharm, Biocon and Sun Pharmaceutical. They won’t hit the market anytime soon due to the aforementioned ruling, but the approval starts the clock on a patent expiration Novartis investors have long been dreading.
Novartis turned to the U.S. courts to help it fight off generic competition to Gilenya in the summer of 2018, when the U.S. Patent Office issued a ruling that protected the branded version of the drug until 2027. The company filed four lawsuits in federal court to hold off generic launches.
U.S. District Judge Leonard P. Stark ruled in favor of Novartis in one of those cases, broadly stating that allowing generic launches would threaten the company’s ongoing patent cases in federal court. The timing of that litigation is uncertain—some analysts expect it won’t be resolved until the first half of next year at the earliest—so Stark ruled that Novartis should maintain its market exclusivity.
“After what might be as long as a year of generic competition by the time we get to trial and I get a post-trial opinion done,” Stark wrote (PDF), “Novartis will not be able to raise the price back to where it is now, or to where it would have been at that post-trial date in the absence of defendants’ at-risk infringement.”
Novartis declined to comment in response to a query from FiercePharma.

The approval of Gilenya generics comes at a pivotal time in the MS market. Several new drugs to treat the neurological condition have premiered this year, including Merck’s Mavenclad, Biogen’s Vumerity and Novartis’ own Mayzent. Some analysts estimate that Mayzent could eventually hit blockbuster territory.
Novartis has certainly done its part to try to make Mayzent as popular among physicians as Gilenya has been. In May, the company rolled out data from a phase 3 study showing that Mayzent produces significant benefits in cognitive processing speed—the ability of patients to understand and respond to information. More recently, Novartis showed the new drug delays wheelchair use by four years when compared to placebo.

Still, the entry of Gilenya generics could be a threat to Mayzent and all of the other new MS products. In November, analysts at SVB Leerink polled five doctors who treat MS, and they all predicted future generics of “category pioneers” like Gilenya will be more popular in the market than newer entries.
The physicians SVB Leerink polled felt Mayzent was only slightly better than Gilenya based on the newer drug’s improved toxicity profile, but that might not be enough to justify premium pricing, the analysts concluded.
During Novartis’ third-quarter report, the company said Gilenya sales fell 3% in the first nine months of the year to $2.4 billion. The company still upped its expectations for the full year, forecasting that net sales in its innovative medicines unit would grow by the high single digits. But that’s assuming no Gilenya generics enter the market in 2019, the company said.

3M exploring $1 billion sale of drug delivery systems unit

Industrial conglomerate 3M Co is exploring a sale of its drug delivery systems unit, which could fetch around $1 billion, Bloomberg reported on Friday, citing people with knowledge of the matter.

The company is currently working with an adviser to run an auction process for the business, Bloomberg reported, adding that the business is likely to draw interest from private equity firms.
A 3M spokeswoman said the company does not comment on rumors and speculations.
Shares of the company rose about 4% to $171.01 in morning trading.
3M’s drug delivery business, which manufacturers inhalers and skin patches, accounted for about 1.4% of the company’s 2018 revenue of $32.77 billion. Sales from the business were flat on an organic local currency basis in the recently reported third quarter.
The company, known for its Scotch tapes and Post-it notes, reported third-quarter revenue well below analysts’ estimates and cut its full-year profit forecast in October, signaling that American corporations are suffering from the protracted trade war with China.

Cassava up on encouraging data on PTI-125 in Alzheimer’s

Thinly traded nano cap Cassava Sciences (NASDAQ:SAVA) is up 41% premarket on increased volume in reaction to new data from a Phase 2a clinical trial evaluating lead drug PTI-125 in patients with mild-to-moderate Alzheimer’s disease (AD). The results were presented at the Clinical Trials on Alzheimer’s Disease Conference in San Diego.
Consistent improvements in AD biomarkers in plasma and lymphocytes were noted including evidence that each patient showed biomarker responses to PTI-125.
Significant reductions in both nitrated and phosphorylated forms of tau protein were observed.
Early clinical validation of the drug target, altered filamin A, as a facilitator protein between amyloid beta and both neuroinflammation and tau pathology.
Topline data are expected in 2020.
Small molecule PTI-125 targets an altered form of filamin A, a scaffolding protein found throughout the body. A highly toxic form of the protein is present in the brains of AD sufferers which disrupts the normal function of neurons, leading to neurodegeneration and brain inflammation. PTI-125 is designed to restore the normal shape of filamin A in the brain, improving the function of multiple brain receptors and dampening neuroinflammation.

Rocket Pharmaceuticals (RCKT) PT Raised to $41 at Baird, Added to Fresh Pick List

Baird analyst Madhu Kumar raised the price target on Rocket Pharmaceuticals (NASDAQ: RCKT) to $41.00 (from $30.00).

UCB’s bimekizumab tops Humira in late-stage psoriasis study

UCB SA (OTCPK:UCBJFannounces positive results from a Phase 3 clinical trial, BE SURE, comparing bimekizumab, an IL-17A and IL-17F inhibitor, to AbbVie’s (ABBV +0.5%) TNF inhibitor Humira (adalimumab) in adults with moderate-to-severe plaque psoriasis.
The study met the co-primary endpoints at week 16, demonstrating bimekizumab’s superiority as measured by the proportion of patients achieving PASI 90 (90% improvement in psoriasis index score) and IGA 0/1 (clear or almost clear skin).
All key secondary endpoints were also met.
Detailed data will be submitted for presentation at a medical conference in 2020.
The results were consistent with two other late-stage studies, BE VIVID and BE READY.
Topline results from studies in psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis should be available by late 2021.