Autophagy: Eating up Alzheimer's disease?
The Nobel Prize awarded yesterday to Yoshinori Ohsumi for unraveling the mystery of autophagy — the orderly self-destruction of cells — has sparked interest in how that mechanism could be harnessed for drug development.
At least one drug on the market does just that: Novartis’s Tasigna, or nilotinib, a chemotherapy approved in 2013 that’s used to help prevent the recurrence of tumor cells in leukemia. Dr. Charbel Moussa, a researcher at Georgetown University Medical Center, leads one of two groups planning a phase 2 trial of the drug in patients with Parkinson’s disease.
His goal: To jump-start autophagy in the brain to destroy the buildup of faulty proteins that's been linked to diseases such as Alzheimer’s and Parkinson’s. The trick, of course, is doing that while leaving the brain cells intact. Proof-of-concept trials of nilotinib were published this June in the Journal of Parkinson’s Disease, but it needs considerably more testing.
So what is it that you’re doing with autophagy?
About five years ago, my lab discovered that the garbage disposal machinery in the cells of people with Parkinson’s disease and Alzheimer’s disease is not working. The machinery is defective, because it’s unable to remove the trash — that is, the toxic proteins that cause neurodegenerative disease.
So we looked at this leukemia drug, nilotinib, and found that you can use it to initiate just a little bit of autophagy — and the brain cells will clear the neurotoxic proteins.
But won’t the neurons themselves self-destruct?
If you use 800 milligrams of nilotinib in cancer, autophagy’s induced 24 hours a day. This constantly degrades cell contents: That’s how you kill a tumor.
In neurodegenerative disease, we used 150 milligrams rather than 800. That only activates autophagy for three or four hours — and then it halts once the drug clears. Basically, we turn on the garbage disposal machine for a few hours, it gets rid of the toxic proteins, then shuts off. If the autophagy isn’t on for 24 hours straight, that’s not enough time to kill the cells.
Are there any other drugs that could show similar effects?
We’ll probably start investigating bosutinib, another tyrosine kinase inhibitor. It’s a very similar drug, and also activates autophagy.
At last, the end of ‘luddite biology’
Silicon Valley, in its never-ending quest to fix the world, has turned to biotech in recent years, training its many buzzphrases on the humble world of making drugs. And its latest foray doesn’t disappoint.
Meet Recursion Pharmaceuticals, a “platform 2.0” company using “machine learning” to “fundamentally [alter] how we do science.” With a $13 million investment round, Recursion is ready to “scale its endeavor” and generate “100 new treatments in 10 years.”
Translated from Andreessenese, Recursion is a company that specializes in drug repurposing. It screens existing compounds against disease models and, applying its proprietary technology, determines whether the drugs might treat those diseases. Other people already do this. Recursion might do it better. Who knows. Sanofi’s on board.
What Recursion has perfected is the lexicon of tech hype. In a Medium post announcing his firm’s investment in the company, Lux Capital’s Zavain Dar dismisses traditional drug discovery as “luddite biology” and claims Recursion's approach to machine learning is “in essence disrupting the scientific method.”
So there's that.
A bicoastal rush to research new drugs
It's no surprise that companies in California spend a ton on science R&D. But a new report from the National Science Foundation finds that, at least as of 2013, Massachusetts companies were spending even more on research into pharmaceuticals and medicines. The tally: $14 billion for the Bay State compared to just over $11 billion for the Golden State.
Other states that focus heavily on biopharma are Illinois, New Jersey and Pennsylvania. All told, US companies spent nearly $46 billion on R&D in the sector in 2013.
Turning CAR-T cells into 'micro-pharmacies'
As Kite Pharma pushes for regulatory approval for its first CAR-T immunotherapy, others are racing to build a better mousetrap. Or rather, engineer a more effective killer T-cell.
Dr. Hans-Guido Wendel, a researcher with Memorial Sloan Kettering, is engineering the T cells to manufacture biologic drugs. Think of it as hyper-local drug delivery: CAR-T cells are already trained to find and kill cancer, so why not also have them produce anti-cancer drugs and bring them straight to the target?
“We figured out that the best way to deliver a protein that we know cures lymphoma cells is to make CAR-T cells that can make the protein for us,” Wendel told STAT. “They function like a pharmacy.”
He plans to insert a suicide gene into the CAR-T cells, so they self-destruct when there’s no more need for them.
This concept could be particularly useful for B cell lymphomas, Wendel said, which have been trickier to treat with cell therapies than the leukemias. His team has already identified a gene mutation that appears to drive many B cell lymphomas. And they've been able to make a CAR-T cell that can produce and secrete a molecule that binds to a key receptor and suppresses tumor growth.
Wendel does not have any deals with biotech or pharma companies. His lab's research was recently published in Cell.
Risk-averse drug companies buy into the biotech mystique
For years, Allergan CEO Brent Saunders downplayed the importance of spending big money on research, arguing that it’s not the best use of funds for big-time drug companies. And Danish giant Novo Nordisk didn't try to keep pace with rivals' R&D budgets, preferring to focus on incremental advances in a handful of areas.
But each is now widening its aperture. Allergan has signed away billions of dollars over the past month in an effort to expand its pipeline, and Novo is taking on riskier ideas in hopes of boosting revenue.
Both companies are responding to changing winds in their industry. As Saunders noted last month, drug companies are going to have a harder and harder time demanding premium prices for treatments that only marginally improve on what’s out there. For Novo, which competes in the crowded field of diabetes, this is especially true.
And so they’re pushing for first-in-class, difference-making therapies that go down untrodden paths. Risk-averse no more?
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- Ra Pharmaceuticals is planning to raise $86.3 million in an IPO, hoping to compete with Alexion Pharmaceuticals in rare diseases. (Filing)
- Dr. Allen Roses, a pioneer in Alzheimer's disease research, died at the age of 74. (Obituary)
- Benchling, billed as a Google Docs for life sciences companies, raised $7 million from Andreessen Horowitz and others. (TechCrunch)