Reports Q4 grant revenue $1.69M, consensus $760,000.
Thursday, March 14, 2019
Repurposing Novartis cancer drug Tasigna in Parkinson’s disease
A research team at Georgetown University Medical Center previously repurposed Novartis’ blood cancer drug Tasigna for Parkinson’s disease, and turned up promising results in a preclinical mouse study and in a small group of patients. Now, they have returned with further insight into how the drug works in people with Parkinson’s.
A pharmacology analysis of 75 Parkinson’s patients who are currently participating in a phase 2 study showed that Tasigna can reduce levels of toxic alpha-synuclein protein clumps that are the hallmark of the disease. That increases the levels of dopamine in the patients’ brains. The Georgetown team reported their findings in the journal Pharmacology Research & Perspectives.
Tasigna (nilotinib) is approved by the FDA as a treatment for chronic myeloid leukemia. It is meant to be given twice daily at a recommended dose of as much as 400 mg for adults. In the Parkinson’s study, the Georgetown researchers found that the drug could improve Parkinson’s biomarkers at a lower dose.
The team, led by Charbel Moussa, first demonstrated Tasigna’s anti-neurodegeneration potential in 2013, testing the drug in mice that over-express alpha-synuclein. When the protein folds in the wrong way, it can block the brain from releasing neurotransmitters such as dopamine from small storage vesicles. That loss of dopamine can lead to motor symptoms like the impaired coordination that’s commonly seen in Parkinson’s.
After the mouse trial showed that Tasigna could help clear the harmful accumulation of alpha-synuclein and improve movement, Moussa and colleagues moved to a small trial of 12 people with either advanced Parkinson’s or dementia with Lewy bodies. The observed improvements in motor functioning and cognitive outcomes, according to a 2016 report in the Journal of Parkinson’s Disease. But in an editorial that ran alongside it, critics cautioned that the small sample size and lack of a control group made it impossible to rule out a placebo effect.
In collaboration with the Michael J. Fox Foundation and others, the Georgetown researchers started the larger phase 2 trial. While the primary goal was to determine the safety of Tasigna, the researchers also searched patients’ cerebral spinal fluid (CSF) for traces of Parkinson’s biomarkers. They measured levels of 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the CSF. Because these molecules are produced when dopamine is metabolized, they could indicate how much dopamine was being used in the brain.
The patients were divided into five groups that received Tasigna at 150 mg, 200 mg, 300 mg or 400 mg or a placebo. After a single dose of Tasigna, the researchers found higher levels of DOPAC and HVA than were seen in the control group.
“When the drug is used, levels of these breakdown molecules quickly rise,” Moussa said in a statement. “This is exciting because this kind of potential treatment for Parkinson’s could increase use of a patient’s own dopamine instead of using or periodically increasing drugs that mimic dopamine.”
Furthermore, Tasigna at 200 mg—which the team found to be the optimal dose for elevating DOPAC and HVA—also significantly increased the level of TREM-2 in the central nervous system. Because of TREM2’s anti-inflammatory role in the brain, some have suggested it could target misfolded alpha-synuclein and other harmful plaques in neurodegenerative disorders.
Other scientists are also investigating potential new uses of approved drugs in neurodegeneration. A team at University College London, for example, previously showed that GLP-1 receptor agonist exenatide, which is the active ingredient in AstraZeneca’s Byetta and Bydureon for Type 2 diabetes, also improved motor functions in some Parkinson’s patients.
Fernando Pagan, principal investigator of the Tasigna phase 2 trial and first author of the paper said the findings suggest the Novartis drug can reduce protect dopamine-secreting neurons. But how that can be translated into clinical outcomes remains to be seen. The trial is expected to be completed in mid-2020, according to a listing on ClinicalTrials.gov.
Using Pfizer smoking-cessation Chantix to control neurons for drug research
Scientists have been using noninvasive methods to selectively control cellular activity in medical research. Now a team led by scientists at the Howard Hughes Medical Institute has identified Pfizer’s nicotine-addiction drug Chantix as a chemical switch that can help control neurons, a system they believe could enable precision treatments for neurological disorders.
After searching through several FDA-approved drugs, the Howard Hughes-led team found that Chantix (varenicline) can bind to proteins expressed in certain groups of neurons. With that knowledge, the scientists successfully manipulated targeted neurons in live mice and monkeys and changed the animals’ behaviors, according to a study published in the journal Science.
The approach is based on a technique known as chemogenetics. It works by engineering macromolecules that can interact with particular foreign small molecules to affect the activity of cells. Usually, in neuroscience, viral vectors encoding those proteins are delivered into specific brain regions. Once expressed, they can be exclusively activated by small molecules and activate or inhibit neuronal activities.
Chemogenetic tools have gained popularity in medical research, as they can help scientists non-invasively control and study cell signaling in live animals. Columbia University spinout Kallyope, which collected $66 million in series B last February, is using chemogenetics to help map out gut-brain interactions for clues of therapeutic targets in different diseases, including Parkinson’s. Recently launched Coda Biotherapeutics is using the technology in a more direct therapeutic way—to develop gene therapies that can be switched on and off.
One popular method involves G protein-couple receptors (GPCRs), which are cell-surface receptors that are responsible for signal transmission. But so far the small-molecule drugs that have been used to latch onto them have shown side effects that make them inappropriate for human use, according to the authors of the new Science paper.
Scott Sternson and colleagues at Howard Hughes designed a system based on ion channels, which are proteins that control electrical signals by gating the flow of ions across cell membranes. To find the best small-molecule partner that is both potent and safe, the team screened 44 clinically used drugs, and Chantix emerged as the best candidate.
Then, the researchers improved the structure of two ion channel proteins to make them more sensitive to Chantix. They also designed Chantix analogs that are potent and that have improved selectivity.
In mice, the researchers used the platform to act on GABAergic neurons, which produce the neurotransmitter GABA and are often targeted by scientists to fight CNS disorders. The chemogenetic pair successfully induced behavioral changes in the animals, the team reported. And a similar effect was observed in rhesus monkeys.
“These are the most potent chemogenetic receptors described so far,” Sternson said in a statement.” Even low doses of varenicline—well below the level used for smoking cessation—can have a big effect on neural activity.”
Howard Hughes has licensed Sternson’s platform to a startup called Redpin Therapeutics, which is running preclinical studies. In the future, the researchers hope the technology’ ability to selectively turn cells on or off could lead to more targeted treatments. For example, in severe epilepsy patients, drugs that target problematic neurons could serve as a less invasive alternative to surgery. For pain management, drugs can be sent to an injured area rather than to the entire body, potentially reducing addiction to painkillers, Sternson said.
JPMorgan Seen Managing SmileDirectClub IPO
SmileDirectClub will file for an IPO this summer, according to a report that said JPMorgan will manage the public offering.
The company, which provides “invisible aligner” products for teeth straightening, has raised nearly $400 million in capital, Axios reported Thursday.
SDC announced in October that it had completed its first institutional private placement of equity capital for a total of $380 million.
The products, which SDC calls “at-home, doctor-directed aligner therapy,” allow customers to use clear aligners to straighten their teeth without getting braces. Part of SmileDirectClub’s pitch to customers is that they can get treatments at home without having to visit a dentist or orthodontist. The company sends materials to customers through the mail and can evaluate progress by photos.
The Nashville-based company started four years ago and expects $1 billion in 2019 revenue.
Earlier this month, an arbitrator ruled in favor of SDC in a lawsuit against its biggest competitor, Align Technology Inc. ALGN 2.62%, which was an investor in SmileDirectClub.
The suit alleged Align’s Invisalign stores violated a non-compete agreement with SDC and misused confidential SDC information. Align was ordered by the arbitrator to close its 12 Invisalign stores.
SmileDirectClub said in a press release earlier this month that it is valued at $3.2 billion and employs more than 4,300 people.
Abbott Gets FDA Approval for Expanded Indication for MitraClip™ Device
Abbott (NYSE: ABT) today announced it received approval from the U.S. Food and Drug Administration (FDA) for a new, expanded indication to its leading MitraClip™ device used to repair a leaky mitral valve without open-heart surgery. Supported by the results of the landmark COAPT™ Trial, MitraClip is the first transcatheter mitral valve intervention therapy approved to treat select heart failure patients with clinically significant secondary, or functional, mitral regurgitation (MR).
The MitraClip transcatheter clip-based therapy, available in the U.S. since 2013 and now on a third generation of product innovations, has been used to treat more than 80,000 patients worldwide over the last 10 years. The new, expanded indication addresses the secondary form of MR and significantly increases the amount of people with MR able to be treated with MitraClip. Based on this approval, Abbott will begin discussions with the Center for Medicare and Medicaid Services (CMS) and physician specialty societies to request a revision to the national coverage determination (NCD) that would expand Medicare coverage to include secondary MR patients.
“Since severe secondary MR is extremely difficult to manage and associated with a poor prognosis, people have historically had few options,” said Neil Moat, M.D., chief medical officer of Abbott’s structural heart business. “The expanded indication of MitraClip opens new doors for these ailing patients and can improve their quality of life and chance of survival despite their complex condition.”
Approximately four million Americans suffer from MR, specifically one in 10 adults age 75 and older.i,ii,iii,iv It’s estimated two to three times as many patients may benefit from MitraClip treatment for secondary MR as a result of underlying heart failure than those treated for the primary (or degenerative) form of the disease associated with the structure of the valve.v People with heart failure may develop secondary MR when the left chamber of the heart becomes enlarged, preventing the mitral leaflets from closing normally and allowing blood to flow backwards through the heart.vi
Significant secondary MR can lead to reduced quality of life, recurrent hospitalizations and decreased survival.vii,viii Medication alone is the current standard of care for most heart failure patients with secondary MR, but this approach only helps manage the symptoms and does not address the underlying cause. MitraClip is now an effective treatment option for these ailing patients.
The MitraClip device repairs MR without open-heart surgery and is delivered to the heart through a small incision in the leg. The device clips portions of the leaflets, or flaps, of the mitral valve together to reduce the backflow of blood, restoring the heart’s ability to pump oxygenated blood more efficiently. MitraClip provides almost immediate symptom relief and patients are released from the hospital on average after two days.
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