Medical Innovation Exchange


Super-fit mice reveal anti-inflammatory protein that could boost search for Alzheimer's drugs

What happens when a three-month-old mouse racks up more than four miles a day exercising on his running wheel? His body produces a protein that tamps down inflammation in the brain. That discovery, from Stanford University’s School of Medicine, could inspire new treatments for Alzheimer’s and other neurodegenerative diseases, the researchers suggested.The Stanford team found that when they took blood from the young “marathoner” mice and injected it into sedentary mice, the latter group showed improvements in brain health. They went on to discover that a protein called clusterin was more prevalent in the exercising mice and was largely responsible for the anti-inflammatory brain-boosting effects of the blood injections, they reported in Nature.
The researchers started their experiment by comparing young mice that had unlimited access to a running wheel to those that didn’t. They then gave some of the sedentary mice blood from the marathoner mice and put all the non-running mice through two memory tests.

The treated mice outperformed the controls on those tests. “The runners’ blood was clearly doing something to the brain, even though it had been delivered outside the brain,” said Tony Wyss-Coray, Ph.D., professor of neurology and neurological sciences at Stanford, in an article posted by the university.
The Stanford team went on to study more than 200 proteins in the blood of the super-fit mice. They found 26 that were more prevalent in the exercising mice. Several of those proteins were associated with the “complement cascade,” a set of proteins that prompts the immune response to foreign invaders.
That was a key discovery, because when the complement system doesn’t work properly, chronic inflammation can occur, speeding up the advance of several brain disorders, Wyss-Coray said. They zeroed in on clusterin because they found that when they removed it from the blood of the fit mice, injecting the blood into sedentary animals did not produce anti-inflammatory effects.
RELATED: How exploiting a protective gene mutation might shield the brain from Alzheimer’s disease
Much of the Alzheimer’s research over the past several years has focused not on beneficial proteins, but rather on amyloid beta and tau, two proteins that form the toxic brain plaques and tangles seen in the disease. That continues to be the focus of several research groups, including one at the University of Houston, which recently published a study suggesting a new strategy for preventing amyloid beta peptides from forming plaques.
Wyss-Coray and his colleagues at Stanford are focused on clusterin and its effect on the complement cascade. As part of their study, they conducted experiments that showed clusterin attaches to endothelial cells that line the brain’s blood vessels. These cells are often inflamed in Alzheimer’s.
In a separate experiment, the Stanford team recruited 20 veterans with signs of cognitive impairment for a six-month exercise program. When they collected their blood after the program ended, they found elevated levels of clusterin.
Wyss-Coray concluded that a drug that reduces inflammation in the brain by mimicking the binding of clusterin to endothelial cells could prove effective in slowing Alzheimer’s and other neurodegenerative diseases.

Moderna, hoping to prove it's no one-trick COVID pony, posts early peek at mRNA flu shot hopeful

Moderna is set to make tens of billions of dollars this year and next from its mRNA COVID vaccine and booster, but the market won’t let the Big Biotech rest on its laurels and wants broader applicability from its programs. The jury is out as to whether Moderna has delivered some of the potential of that today with some early phase 1 data from its influenza shot trial for mRNA-1010, which only entered the clinic in the July, not showing a clear picture whether it can better newer shots already on the market.
Data from the phase 1 trial, posted in a release Friday morning, showed it “successfully boosted” hemagglutination inhibition assay geometric mean titers (GMTs) against all tested flu strains 29 days after vaccination, at all doses, tested in both younger and older adults.

It has also finished off enrollment in its phase 2 and is prepping for a phase 3 as it adds two new flu candidates, mRNA-1011 and mRNA-1012, to the rota, and will come with additional hemagglutinin (HA) antigens. This may suggest it wants to focus more on a next-gen approach if this one doesn’t pan out so well.
RELATED: Sanofi, Translate Bio start seasonal mRNA flu vaccine trial, gaining early lead over Moderna and Pfizer
The Cambridge, Massachusetts-based company, made famous by the success of its COVID-19 vaccine, is developing mRNA-1010 to protect against common flu strains as recommended by the World Health Organization.
The company is hoping to improve on traditional flu shots, which are typically about 40% to 60% effective. Most of these shots are developed using eggs, which Moderna said can cause unintended changes to the vaccine virus. The strains to be used in the vaccines are also decided six to nine months ahead of time, meaning a lot of guesswork as to which strain might be dominant during flu season.
The technology works by teaching a patient’s cells to make a protein that can trigger an immune response in the body and spur the creation of antibodies and therefore protection against a virus. While the authorization of the COVID-19 vaccines marked the first time mRNA had been cleared by regulators, the technology has been studied for decades.
Moderna has used mRNA vaccines in trials before, though, aimed at specific flu strains: Back in 2019, it dropped early data from several phase 1 tests showing its mRNA vaccines against H10N8 and H7N9 influenza viruses “were well-tolerated and elicited robust immune responses.”
This latest attempt is aiming wider using a seasonal approach that targets multiple strains, including influenza A H1N1, H3N2 and influenza B Yamagata and Victoria. It’s competing with the likes of Pfizer, its mRNA COVID rival, and GlaxoSmithKline to make mRNA work in flu.
In the phase 1 data, mRNA-1010 was assessed at three doses—50 µg, 100 µg and 200 µg—in younger adult (age 18-49) and older adult (age 50-plus) cohorts.
At the lowest dose level (50 µg) in younger adults, Day 29 GMTs against influenza A strains were 538 (H1N1) and 530 (H3N2); GMT against influenza B strains were 467 (B/Yamagata) and 261 (B/Victoria).
Boosts on baseline for influenza A strains were approximately tenfold (H1N1) and eightfold (H3N2), and approximately threefold for B/Yamagata and twofold for B/Victoria. Minimal dose response was observed between the 50-µg, 100-µg and 200-µg dose levels, “suggesting the potential to explore even lower doses.”
At the lowest dose level (50 µg) in older adults, Day 29 GMT against influenza A strains were 310 (H1N1) and 263 (H3N2); GMT against influenza B strains were 305 (B/Yamagata) and 215 (B/Victoria). GMFR for influenza A strains were around sixfold (H1N1) and sixfold (H3N2), and then threefold for B/Yamagata and twofold for B/Victoria. Safety data were generally clean.
The phase 2, made up of 500 patients, and the upcoming phase 3 will be more important in telling us just how efficacious this shot can be, with these early data telling us that the shot is producing some protection.
Shares in the company were off 12% on the data drop in premarket trading Friday morning after a bearish response to the data, which were not as strong as investors had hoped.
Analysts at Jefferies set out the debate. “On one hand, the antibodies increased to good levels, but on the other hand, the levels aren’t necessarily seen as high or necessarily better than some high-efficacy vaccines such as Flublok or Fluzone HD,” the analysts said in a note to clients.
“Compared to current flu vaccines, we see this is an improvement vs. some flu vaccines. Current flu vaccines GMT range from low 100’s (SNY – Fluzone) to as high as ~400-700. MRNA-1010 was, at minimum, on par with some flu vaccines and better than some (Fluzone – SNY) at the lowest doses (50 µg).”

Eli Lilly pens $1.5B biobucks pact with China's Regor for metabolic disease work

Eli Lilly is making a $1.5 billion biobucks bet on Chinese biotech Regor Therapeutics to seek out, develop and hopefully sell new therapies for metabolic disorders.

The biobucks pact is heavily backloaded, with just $50 million coming upfront, as Lilly gains access to the biotech’s so-called CARD (Computer Accelerated Rational Discovery) platform. 
Regor taps CARD with structural biology, computational chemistry, therapeutic biology, medicinal chemistry and clinical development to find what it believes are the best- and first-in-class molecules.

Under the deal, Lilly nabs a license to select Regor IP with an option to extend the license. Lilly will be responsible for clinical development, manufacturing and commercialization worldwide except for the People’s Republic of China, Macau, Hong Kong and Taiwan, where Regor will maintain these rights and responsibilities.
Neither company has specifics on disease targets, though Lilly has a major metabolic focus with its line of diabetes products and research.
“Through this collaboration, we will have the opportunity to expand treatment options available to patients suffering from metabolic disorders,” said Ruth Gimeno, Ph.D., vice president, diabetes research and clinical investigation at Lilly. “Regor’s technology will also allow Lilly to further accelerate innovation and deliver breakthrough therapies in obesity and diabetes.”


Roche posts 'impressive' TIGIT combo lung cancer data, but trial deaths weigh down shares

New follow-up data for Roche’s Tecentriq-tiragolumab combination therapy in certain lung cancer patients have analysts sighing in relief that the anti-TIGIT element appears to be pulling its weight, but two deaths in the combination arm hit the company’s shares Friday morning.TIGIT, or T-cell immunoreceptor with immunoglobulin and ITIM domain, is a promising new target for cancer immunotherapy and is upregulated by immune cells including activated T cells, natural killer cells and regulatory T cells.
Roche has already posted some early data from a phase 2 trial, known as CITYSCAPE, at the American Society of Clinical Oncology (ASCO) cancer conference last year. Here, it showed its approved PD-L1 blocker, Tecentriq, combined with its experimental anti-TIGIT antibody tiragolumab shrank tumors in 31% of patients with metastatic lung cancer—twice as many patients as Tecentriq alone.

Now, we have much longer follow-up data from CITYSCAPE, which followed patients for a median of 2.5 years and “continued to show an improvement” in the intention-to-treat (ITT) population of 67 patients, driven by the PD-L1-high population.
In that ITT population, the combo therapy reduced the risk of disease worsening or death (i.e., progression-free survival) by 38% and improved overall response rates (ORR) at 38.8% compared with 20.6% for Tecentriq alone.
A predefined exploratory analysis in the PD-L1-high population showed a 71% reduction in the risk of disease worsening or death (median PFS was 16.6 vs. 4.1 months) and a clinically meaningful improvement in ORR (69% vs. 24.1%) with the combo compared with Tecentriq alone.
Roche also saw improved overall survival (OS), a secondary endpoint of the study but a golden data point in all cancer tests, seeing this in the ITT population, which was driven by the PD-L1-high population.
RELATED: ASCO: Roche’s closely watched TIGIT combo shows 2 checkpoint inhibitors could be better than one
After 2.5 years, median OS was 23.2 vs. 14.5 months in the ITT population. The exploratory data in the PD-L1-high population showed a “clinically meaningful” OS improvement. The median was not reached for the tiragolumab regimen but “is projected to be greater than 30.3 months based on the lower confidence interval.”
Safety data weren’t clean, however, as there were two grade 5 events—which in trial speak means deaths—specifically both from the combo arm of the trial. The two treatment-related deaths were the results of pyrexia—or fever—and infection, according to detailed data presented at the European Society for Medical Oncology Immuno-Oncology virtual congress. Shares were off nearly 1% in early premarket trading on this update, taking the shine off the data.
There have also been some concerns after ASCO 2020 that perhaps it was more that Tecentriq underperformed, rather than tiragolumab adding something special. But analysts at Jefferies said the updated follow-up data “should allay concerns the benefit initially reported was driven by underperformance of Tecentriq.”
A phase 3 trial program is already underway, with data set to start coming in from next year. The phase 2 follow-up data “should build confidence in ongoing tiragolumab phase 3 trials,” Jefferies added, highlighting the SKYSCRAPER-01 trial in PD-L1-high non-small cell lung cancer, with data expected later in 2022, “as a blockbuster opportunity.”
“These encouraging results suggest that combining anti-TIGIT and anti-PD-L1 cancer immunotherapies such as tiragolumab and Tecentriq could potentially represent a novel approach to address unmet needs in cancer,” said Levi Garraway, M.D., Ph.D., chief medical officer and head of global product development.
“With tiragolumab, we have the largest and most advanced anti-TIGIT clinical program, and we look forward to the results of our phase 3 trials in lung cancer and other challenging tumor types.”
Roche is fighting with Merck—and, further back, Bristol Myers Squibb—to make TIGIT work big in cancer, with checkpoint inhibitor combos appearing to be the way to go for both pharmas.

Novartis poaches Roche's neuro and rare disease R&D lead, replacing Shanker

Novartis has been busy selling off its stake in Roche but quietly this month also got a little extra from its fellow Swiss native after nabbing Bob Baloh, M.D., Ph.D., to run its growing neuroscience division. Baloh joins the company as Novartis Institutes for BioMedical Research’s (NIBR’s) global head of the neuroscience disease area. He comes from a similar position at Roche, where he served as vice president and global head of research in neuroscience and rare diseases in the Pharmaceutical Research and Early Development division.
He had a relatively short stint at Roche—just a year—but spent nearly a decade before that at the Cedars-Sinai Medical Center in California as a renowned neurodegeneration and peripheral nervous system disease expert as well as a passionate physician-scientist.  

Novartis also tells me he is a talented surfer, and that skill will be needed to ride the choppy waves of neuro that have caused so many to wipe out.
He comes amid a loss of neuro talent from the Big Pharma, and takes over from Gopi Shanker, Ph.D., who had been the NIBR’s head of neuroscience before leaving in May for a transfer-RNA-based gene therapy startup.
RELATED: Novartis loses another NIBR exec as neuro expert Shanker joins a gene therapy biotech
At Novartis, Baloh will help work on a host of diseases and disorders in a field beset with setbacks for the industry but containing some of human biology’s biggest unsolved problems.
Novartis is currently working on new therapies for spinal muscular atrophy, Rett syndrome, autism spectrum disorders, intellectual disabilities and epileptic encephalopathies as well as bipolar disorder, depression, substance use disorders and schizophrenia.
It’s also got its eyes on Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and several rare monogenic diseases along with multiple sclerosis.

Albireo CMO Horn is out the door 5 months after US, EU approvals of rare liver disease drug

Patrick Horn, M.D., Ph.D., is exiting Albireo Pharma just a few months into the marketing of the biopharma’s rare liver disease drug.The FDA and European regulators approved the treatment, sold as Bylvay, within days of each other in July. The oral drug is the first treatment for pruritus in patients with progressive familial intrahepatic cholestasis, and the med was available just a few days of the approval, the company said. 
In his 3.5 years with the company, Horn, who was the chief medical officer, completed the phase 3 study that led to Bylvay’s approval and helped initiate two ongoing pivotal studies in other conditions, Alagille syndrome and biliary atresia. 

If given the green light in those diseases, too, Bylvay could become a blockbuster drug before the world rings in 2030, the company said. The drug has distribution and supply partners in Central and Eastern Europe, Israel, Turkey, Saudi Arabia, Japan and elsewhere.
RELATED: Albireo’s rare liver disease drug Bylvay scores back-to-back approvals in US, Europe
Horn notified the Boston biopharma Dec. 3 that he would leave by the end of the year for a different job. His resignation was “not the result of any disagreement regarding any matter relating to Albireo’s operations, policies or practices,” the company said in a Securities and Exchange Commission filing.
Temporarily taking over R&D operations will be co-founder and Chief Scientific Officer Jan Mattsson, Ph.D.
Prior to Albireo, Horn was a senior vice president at Orphan Technologies for less than a year and before that spent seven years at TetraPhase Pharmaceuticals, where he was chief medical officer.

Nanomedicine shrinks vascular lesions in mice and could pave path to new treatments

Most therapies for vascular diseases aim to treat risk factors like high blood pressure and cholesterol rather than repairing the damaged blood vessels. Now, a team of researchers at the University of Chicago has shown that a targeted nanomedicine may be able to address vascular lesions.The researchers designed a peptide that targets vascular cell adhesion molecule 1, which populates inflamed endothelial cells at high levels, and tested it in mouse models of atherosclerosis, a vascular disease in which the walls of blood vessels form plaques that clog the arteries. The vascular lesions shrank, they reported in the Proceedings of the National Academy of Sciences.
Now, the scientists who led the study planning to form a company to prepare the drug for clinical trials, said Matthew Tirrell, Ph.D., dean of the Pritzker School of Molecular Engineering, in an interview. “We can deliver an inflammation-reducing therapeutic oligonucleotide to sites of inflammation in the vasculature and we showed how this retards the progression of atherosclerotic plaques” in animals, Tirrell said.

Tirrell said the results are what the team anticipated, but they didn’t predict how effective the treatment could be. 
“If you deliver the same oligonucleotide systemically, without packaging it in our nanoparticle, it also retards the development of atherosclerosis, but our way of doing it is … twice as effective. It really showed a clear benefit in delivering the therapeutic right to the site of inflammation in the vascular endothelium,” Tirrell said. 
The researchers will likely test the treatment in other conditions first, because vascular disease can be hard to diagnose. One potential route would be to test the nanoparticles during angioplasty or stent insertions, which cause inflammation and disturbed blood flow. The team’s nanoparticles are able to assuage blood-flow issues in mouse models, Tirrell said.  Another potential use for the drug is in arteriovenous fistulas, or AVFs, which connect arteries to veins and are critical for vascular access in kidney dialysis. 
RELATED: How a discovery in ‘junk’ DNA could protect against heart disease
Other researchers working on new approaches to atherosclerosis include a team at Brigham and Women’s Hospital that found a long, noncoding RNA molecule played a role in the cellular aging of blood vessels. And a team at the University of Oxford discovered Plexin D1, part of a key cell-surface receptor group, that helps promote plaque formation, which leads to atherosclerosis. 
The University of Chicago researchers believe the nanoparticle constitutes a platform technology that could show promise in reducing inflammation in other endothelial tissues. The team also has preliminary data on acute respiratory distress in COVID-19 and other respiratory diseases, Tirrell said. 
The next step for the team is to design large-animal studies to prove out the treatment’s effectiveness in various complications of vascular disorders.

ASH: 2 years in, the survival data on J&J’s rival to Bristol Myers' BCMA cell therapy are still growing

Responses to Johnson & Johnson’s BCMA CAR-T therapy are going on and on and on. After a median follow-up of 22 months, a phase 1b/2 clinical trial of the Legend Biotech-partnered cell therapy is yet to hit the median progression-free or overall survival (PFS/OS), suggesting the drug has an edge over Bristol Myers Squibb’s rival product Abecma.J&J has delivered a series of eye-catching data drops on ciltacabtagene autoleucel (cilta-cel) from its CARTITUDE-1 study, with the 18-month update shared in June linked the CAR-T to an 80% complete response rate. Two-thirds of patients, all of whom had received at least three lines of prior therapy, were alive and progression free as of that cutoff point.
The cilta-cel team used the American Society of Hematology (ASH) 2021 annual meeting to share updated data, extending the follow-up out to a median of 22 months. After another four months of follow-up, J&J and Legend are still yet to hit the median PFS or OS. Legend CEO Ying Huang was quick to compare the data to BMS’ Abecma.

“If you compare this dataset to Abecma, which was approved by FDA to treat a similar patient population with refractory and relapsed myeloma, you’ll see the overall median PFS was 8.8 months in the KarMMa trial. We can safely say that the cilta-cel PFS is going to be longer than 23 months,” Huang said.
RELATED: Legend’s status put on hold as FDA delays Janssen-partnered CAR-T decision
Huang’s prediction that the median PFS will top 23 months is underpinned by the lower bound of the 95% confidence interval of PFS in CARTITUDE-1, which currently stands at 22.8 months. “That’s probably the low end of the estimated PFS,” Huang said. The two-year PFS and OS rate are 61% and 74%, respectively.
The results add to the impression that J&J may be able to overcome the head start it has ceded to BMS. The FDA approved BMS’ Abecma in March. J&J was following close behind, but the FDA delayed its decision on cilta-cel until late February 2022 to give itself more time to review information on an updated analytical method. 
J&J also used ASH to share results from another cilta-cel study, CARTITUDE-2, in patients who had received one to three prior lines of treatment. The update revealed the deepening of responses to cilta-cel, with the complete response rate rising from 75% to 85% between the two latest data drops.

K36 emerges with $30M to bankroll multiple myeloma drug in-licensed from Novartis

K36 Therapeutics has come out of the gates with $30 million in venture funding to back a small-molecule oral treatment from Novartis. The Cambridge, Massachusetts, biotech emerged Thursday to take its sole asset into the clinic next year. The biotech claims it will be the first to test a therapy targeting overexpression of histone methyltransferase (MMSET), which impacts about 20% of people with multiple myeloma. 
In t(4;14) multiple myeloma, MMSET activity is enhanced, which leads DNA to express genes that boost the development of multiple myeloma. K36’s drug, dubbed KTX-1001, aims to inhibit MMSET to in turn shut down chromatin and silence the expression of genes that induce cancerous growth. 

The biotech in-licensed the drug from Novartis. Details of the deal size and timing were kept under wraps. The startup’s president and CEO, Terry Connolly, Ph.D., joined in February. 
RELATED: Vertex joins Skyhawk’s roster of A-list partners, securing options on RNA splicing modulators
Connolly was previously chief operating officer of Skyhawk Therapeutics, a frequent partner of pharmas including Vertex, Merck Roche, Takeda, Bristol Myers Squibb and Biogen. Before Skyhawk, he spent less than a year as chief business officer at Dragonfly Therapeutics. Prior to those two upstarts, he was executive director of business development at Celgene. 
K36 says it will ask regulators to approve its first human study before next summer. Heading up clinical development is Travis Quigley, who was previously Takeda’s global platform leader for CAR-NK.
F-Prime and Atlas Venture co-led the financing and were joined by Eight Roads Ventures.

Totus tots up $40M in series A funding to go after competitive cancer space

Totus Medicines is making a play for the PI3Kα inhibitor market. Exiting stealth with a $40 million series A round, the Massachusetts-based biotech plans to advance a molecule designed to improve on existing PI3Kα inhibitors such as Novartis’ Piqray.PI3K, in both its alpha and delta forms, is a long-standing target of interest to oncology drug developers. With studies implicating overactivity of the kinase in multiple cancer types, researchers have delivered a series of approvals ranging from Gilead Sciences’ Zydelig to TG Therapeutics’ Ukoniq. Many of the drugs hit the delta form of kinase, but Piqray is specific to PI3Kα.
Totus references the competition in the statement to disclose its $40 million series A round, arguing that there is an opportunity for its asset because, after spending “decades and billions of dollars,” the pharma industry has only achieved “moderate success in