Rapamycin May Prevent Age-Related Brain Vascular Deterioration

Could an immunosuppressant boost cognition in senior citizens? A recent animal study from the University of Texas Health Science Center at San Antonio suggests the possibility. The study shows age-related decreases in blood flow to the brain and memory loss can be modified with the drug rapamycin.

Recent research in the Framingham Heart Study led by Sudha Seshadri of the Glenn Biggs Institute has shown that among the risk factors for Alzheimer’s disease is a reduction of blood flow to the brain. Neurons require glucose and oxygen to function and blood vessels supply those necessary components. When the blood flow is reduced, so too are the requirements the brain needs.

The University of Texas study, which was published this week in the journal Aging Cell, found that rats who were dosed with rapamycin maintained solid blood flows in their brains through the end of life. The lab animals were fed food laced with the medication beginning at the age of 19 months, which is about middle age for rats, and the dosing continued until they were 34 months old, which is considered an advanced age for rats. Senior study author Veronica Galvan said 34 months, this is about as old as rats will get and brain scans showed that even at an advanced age, the blood flow in the brains of the animals was “exactly the same as when they started treatment.” Galvan is a researcher with the university’s Sam and Ann Barshop Institute for Longevity and Aging Studies and Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases.

If the findings hold throughout continued studies, research first author Candice Van Skike suggested that treatment with rapamycin could hold implications in preventing Alzheimer’s disease or other forms of dementia in some people. The study followed the natural aging patterns of the animals. Van Skike said the researchers did not engineer disease states or the like in the animals.

Van Skike said that untreated aged rats that took part in the study mirrored the loss of blood flow to the brain and the loss of memory that is observed in adult humans who are of advanced years.

“We were looking at just regular aging. These rats had natural cognitive decline that was not provoked by a forced disease process,” Van Skike said in a statement provided by the university. “In contrast, the old rats treated with rapamycin looked like middle-aged rats in our study.”

Rapamycin inhibits the activation of both T cells and B cells by reducing sensitivity to interleukin-2 through the inhibition of mTOR, a “master controller” of cell growth and aging. Galvan said the results of the rat study provide “very good evidence” that “TOR drives the loss of synapses and cerebral blood flow during aging.”

Seshadri, who led the Framingham Heart study, said researchers are already studying the safety of rapamycin in people with mild cognitive impairment, a precursor to dementia. She said it is exciting that rapamycin may “help preserve the integrity of brain circulation and memory performance in older adults.”

https://www.biospace.com/article/animal-study-shows-rapamycin-may-prevent-age-related-brain-vascular-deterioration/

Daiichi Sankyo’s Hypertension Drug Hits Mark in Diabetic Nephropathy Trial

Tokyo-based Daiichi Sankyo Company announced that its ESAX-DN Phase III trial of esaxerenone met the primary endpoint in diabetic nephropathy. The company presented the results in a late-breaking presentation at the annual meeting of the American Society of Nephrology held in Washington, DC. Daiichi Sankyo partnered with Alameda, California-based Exelixis on the drug.

Esaxerenone is a novel mineralocorticoid receptor (MR) blocker. It is approved for hypertension in Japan and marketed as Minnebro. Daiichi Sankyo is solely responsible for its development and commercialization, although Exelixis is eligible for commercial milestones and low double-digit sales royalties.

Diabetic nephropathy is also called diabetic kidney disease. Patients with diabetes are at high risk of chronic loss of kidney function. Approximately 50% of all type 2 diabetics will develop evidence of diabetic nephropathy. In Japan, it is the leading cause of dialysis.

ESAX-DN is a randomized, double-blind, two-arm, parallel group comparison study in incipient diabetic nephropathy patients taking an angiotensin II receptor blocker (ARB) or an angiotensin converting enzyme (ACE) inhibitor. The study was conducted in Japan. The primary endpoint was rate of remission of microalbuminuria after 52 weeks.

The trial demonstrated that patients receiving esaxerenone has a significantly higher Urine Albumin-to-Creatinine Ratio (UACR) of 22.1% compared to 4.0% on placebo. It also significantly decreased UACR -58.3% to 8.3% for placebo. A secondary endpoint was significant reduction of progression from incipient to overt diabetic nephropathy. No new safety signals were observed.

“The ESAX-DN study is the second successful Phase III pivotal trial our collaborators at Daiichi Sankyo have undertaken since assuming responsibility for esaxerenone’s development and commercialization,” said Michael M. Morrissey, president and chief executive officer of Exelixis. “We congratulate our colleagues on a well-run trial in diabetic nephropathy, one of the most significant complications for patients with diabetes, which is itself a major health issue in Japan. We look forward to Daiichi Sankyo’s continued progress with esaxerenone.”

Minnebro launched in Japan  for advanced hypertension in May 2019, which triggered a $20 million milestone payment to Exelixis. The two companies entered into a research collaboration in March 2006. When Minnebro’s application was accepted in Japan in 2018, that also triggered a $20 million milestone payment.

Yesterday, it was reported that Daiichi Sankyo was suing Seattle Genetics over technology the two companies utilized to develop antibody-drug conjugates during a seven-year partnership. In March, Daiichi Sankyo and AstraZeneca inked a development and commercialization agreement for an ADC called trastuzumab deruxtecan (DS-8201) that came out of the partnership. DS-8201 is the lead compound in the ADC franchise of the Daiichi Sankyo Cancer Enterprise and targets HER2-expressing cancers. The compound is also being paired with drug from Bristol-Myers Squibb and Merck.

In March, AstraZeneca paid Daiichi Sankyo $1.35 billion up front in relationship to the ADC. Daiichi Sankyo is eligible for up to $6.9 billion in development and regulatory milestones on the deal. Seattle Genetics argues that it is entitled to some of that money, because DS-8201 originated in the company’s cytotoxin and linker technology developed in their two companies’ collaboration. Seattle Genetics claims that when Daiichi Sankyo and AstraZeneca entered into their deal, Seattle Genetics’ intellectual property was used to develop DS-8201, making them the rightful owner of the drug. Daiichi Sankyo disagrees, which is the basis of the lawsuit.

https://www.biospace.com/article/daiichi-sankyo-s-esaxerenone-hits-primary-endpoint-in-diabetic-nephropathy/

FDA panel for Lilly and BI’s Jardiance for Type 1 Diabetes

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee will meet on Wednesday, November 13, to review and discuss the marketing application from Boehringer Ingelheim seeking approval to use Jardiance (empagliflozin) to treat adults with type 1 diabetes.

Jardiance is currently approved in the U.S. for type 2 diabetes.

Meeting materials

Related ticker: Eli Lilly (LLY +0.6%)

https://seekingalpha.com/news/3517323-ad-com-lilly-bis-jardiance-t1d

Ocular Therapeutix launches cost-cutting initiative; shares up 3% after hours

Aimed at sharpening its focus on Dextenza (dexamethasone ophthalmic insert) 0.4 mg, Ocular Therapeutics (NASDAQ:OCUL) initiates a restructuring initiative that, it says, will save ~$11M in annual operating costs. It has not as yet specified the exact number of job cuts, but it will record a $0.7M charge this quarter for related expenses.

Shares up 3% after hours.

https://seekingalpha.com/news/3517332-ocular-therapeutix-launches-cost-cutting-initiative-shares-3-percent-hours

Magellan nabs Medicaid administration contract in California

California’s Department of Health Services has awarded a five-year contract to a subsidiary of Magellan Health (NASDAQ:MGLN) to manage its pharmacy benefit services statewide.

The company expects the agreement, effective January 1, 2021, to generate $70M – 80M in annual revenue.

https://seekingalpha.com/news/3517347-magellan-nabs-medicaid-administration-contract-california

Cardinal Health Inc wins $2.25 billion U.S. defense contract: Pentagon

Cardinal Health 200 LLC, a unit of Cardinal Health Inc (CAH.N), has been awarded a maximum $2.25 billion modification for a contract with the Defense Logistics Agency for ordering and distribution of medical surgical supplies, the Pentagon said on Thursday.

https://www.reuters.com/article/us-cardinal-health-pentagon/cardinal-health-inc-wins-2-25-billion-u-s-defense-contract-pentagon-idUSKBN1XH2WZ

Economist who backed Warren health plan has doubts on her wealth tax

Mark Zandi, chief economist at Moody’s Analytics, also voiced skepticism that the wealth tax provision in Warren’s plan – a key funding mechanism – will produce predicted levels of revenue because those targeted by the tax will seek to dodge it.

“It’s not hard to believe billionaires are going to use every resource to avoid paying the tax,” Zandi said.

Taken in isolation, Zandi said, Warren would be able to find the revenue necessary to cover the massive cost of reform. “I stand by the funding estimates, as a standalone plan,” Zandi said.

Even if the wealth tax projections fall short, Zandi believes Warren may still be able to make up the difference through other taxes in her plan, including those on corporations and employers.

Yet Zandi warned the wealth tax revenue predictions may not hold up if she also simultaneously tries to fund her proposed expansion of government programs, including free child-care and student debt forgiveness.

“I’m skeptical the wealth tax will generate the same amount of revenue after considering all her plans together,” he said.

Warren, a U.S. senator from Massachusetts, estimates her healthcare overhaul will cost an additional $20.5 trillion in federal spending over 10 years without the need to raise middle-class taxes, a claim questioned by some of her rivals in the 2020 White House race.

Zandi said despite signing a highly touted letter last week backing the calculations for Warren’s Medicare for All plan, he does not support shifting Americans off the private health insurance they have in favor of a single-payer, government-run regime.

“I am not a fan of Medicare for All,” said Zandi, who is not affiliated with any Democratic presidential campaign and does not speak for the Warren campaign. “We have 160 million people who have private insurance and are pretty happy with what they have. Why change that?”

A Warren campaign official, speaking on the condition of anonymity, said other leading economists who did not sign last week’s letter have defended the wealth tax’s revenue estimates and its enforcement mechanisms.

The official said the wealth tax will be straightforward to administer because it applies to only 75,000 ultra-wealthy families who typically already keep careful track of their wealth.

The wealth tax revenue estimates factored in significant discounts for evasion, and the plan includes measures to sharply strengthen IRS enforcement, the official said.

At a campaign stop in North Carolina on Thursday, Warren was asked to respond to criticism that her Medicare for All plan is a “pipe dream” and “fairy dust.”

Warren replied: “You don’t get what you don’t fight for.”

Zandi said he prefers the less far-reaching healthcare plan being pushed by Pete Buttigieg, the mayor of South Bend, Indiana, and one of Warren’s chief competitors for the Democratic presidential nomination.

Buttigieg’s plan is similar to other moderate Democrats’ healthcare proposals, because it does not eliminate private insurance. Instead, it seeks to set up competition between a public, government-run option and private plans to lower costs and potentially move Americans onto a Medicare for All system over time.

WEALTH TAX

A key part of Warren’s revenue calculations to pay for her healthcare overhaul comes from a new tax on the wealthiest 1% of U.S. individuals, or a “wealth tax”.

Warren initially proposed a tax that would impose a 2% federal tax on every dollar of a person’s net worth over $50 million and an additional 1% tax on every dollar in net worth over $1 billion. She upped the “billionaire’ s surcharge” to a total of 6% when she released her plan to pay for Medicare for All.

Zandi, and the other economists who signed the letter, estimated the tax would generate an extra $3 trillion in revenue between 2020 and 2029, part of $20.5 trillion they say can be generated overall through additional taxes, but without raising middle-class taxes.

Zandi said a wealth tax would be hard for the government to enforce. “There will be more avoidance and IRS enforcement may not be up to the task,” he said.

Wealth taxes have been tried in many European countries, with limited success. Many affluent people moved assets abroad and the tax resulted in far less revenues than predicted.

Betsey Stevenson, an economics professor at the University of Michigan and another of the signatories on the Warren funding letter, said Warren’s plan shows it is possible to pay for Medicare for All without raising middle class taxes.

“The point of the letter was to show whether it is possible, rather than if it is desirable,” Stevenson said.

https://www.reuters.com/article/us-election-warren-healthcare-exclusive/exclusive-economist-who-backed-warren-healthcare-plan-has-doubts-about-her-wealth-tax-idUSKBN1XI01T