Friday, December 14, 2018
Sage Therapeutics initiated at Wolfe Research
Sage Therapeutics initiated with an Outperform at Wolfe Research
https://thefly.com/landingPageNews.php?id=2837389
Alkermes initiated at Wolfe Research
Alkermes initiated with an Underperform at Wolfe Research
https://thefly.com/landingPageNews.php?id=2837391
Thursday, December 13, 2018
How Big Pharma Decides to End R&D Programs
Although every year, big biopharma companies give up on some programs, 2018 seems like it has been marked by unusually extensive program abandonment.
AstraZeneca sold off numerous drugs in November. Mark Fallon, AstraZeneca’s executive vice president, Global Product and Portfolio Strategy, stated at the time, “One of our strategic objectives is to divest parts of our portfolio, allowing us to allocate resources to develop innovative new medicines to address unmet patient needs.”
In mid-2017, GlaxoSmithKline shook things up, killing more than 30 preclinical and clinical programs and allocating 80 percent of its R&D budget to respiratory and HIV/infectious diseases.
And Novartis has been making extensive changes in the last 18 months or so. In October 2018, however, it indicated it was abandoning about 20 percent of its research projects after a strategic review.
And although those three are most notable, they’re not the only ones. For example, in early January, Pfizer indicated it was abandoning R&D into new neuroscience development, including Alzheimer’s and Parkinson’s disease.
Bloomberg recently took a closer look at the decision-making paradigms that often go into these “kills.”
Mene Pangalos, head of AstraZeneca’s research programs, told Bloomberg, “The way you get good kills is ‘I’ve tested the hypothesis and it does or doesn’t work.’ Fundamentally, it’s about being ruthless with your decision-making.”
This ruthlessness, Bloomberg reports, appears to be a shift in the industry. In previous years, the size of the pipeline meant greater chances of more drugs making it to market. That could be called the more-shots-on-goal strategy. And it certainly seems to work in hockey, soccer and basketball.
But drug development isn’t a sport and increasingly biopharma companies are eyeing the growing costs of R&D while simultaneously taking into consideration the payer market—high drug prices have been a hot-button political topic for several years and governments and payers are increasingly looking for ways to push back on drug pricing. According to Deloitte, bringing a new drug to market costs about $2 billion. That’s a massive amount of overhead to recoup.
Nooman Haque, managing director of life sciences and health care at Silicon Valley Bank’s UK unit told Bloomberg that chasing a drug to a dead end “becomes part of the baggage and the bloat” that makes for strategically sluggish companies. “If I’m an investor I’d like to see more of that offloading.”
Some biopharma companies are attempting to change their research cultures. AstraZeneca and GSK, for example, are tweaking their incentives. GSK’s R&D head Hal Barron spoke at a London conference in November, saying, “If you reward progression, you will get progression.” As a result, he wants researchers to “thoughtfully evaluate the data and kill molecules that aren’t going to work.”
Of course, scientists may be reluctant to kill their pet projects, either for fear of being thrown out along with the project, or because they legitimately believe there’s hope for them.
One of the key problems in killing programs is that they are the lifeblood of biopharma companies. Without new products stimulating sales, profits stagnate. Bloomberg reports, “Astra has released treatments for cancer and heart disease in recent years that helped lift its market value above that of Glaxo for the first time. Meanwhile, Glaxo fell the most in a decade on Dec. 3 after announcing a $5.1 billion acquisition, raising concern that it was overpaying to bolster its pipeline.”
And if drug development is an obstacle course, there are barriers and missteps that can occur anywhere from preclinical development to post-marketing, if safety issues develop. Companies would undoubtedly rather abandon a drug earlier in the process, rather than after it’s spent millions and possibly billions of dollars on large clinical trials, regulatory submissions and marketing campaigns.
At the moment, at least, big pharma companies appear to be working in a much more targeted fashion, picking and choosing their most promising programs carefully. This also means they may be paying closer attention to the competition, abandoning projects that are “me-too” drugs trying to improve on well-established brands with marginal advantages. They’re also utilizing artificial intelligence, machine learning, big data and robotics to create any edge they can in improving the odds of a new and innovative drug.
Interesting, Pangalos indicates his goal is to emulate Genentech, which has a very high success rate. “That’s kind of an aspiration of where we’d like to be,” he told Bloomberg. “We’ve done it for a period. Right now it’s a blip; if we do it for another five or ten years, I’d say we’re doing okay.”
Depression: Ketamine prevents loss of pleasure in primates
New research, which features in the journal Neuron, shows that primates lose excitement in anticipation of a reward when a specific area of their brain becomes overactive. The study also shows that ketamine affects this brain region and prevents the loss of pleasure.
Depression is “the leading cause of disability worldwide” and one of the most common mental health problems in the United States.
The symptoms of major depression include depressed mood and loss of interest or pleasure in daily activities. Some people may also experience difficulty sleeping, eating, and focusing or have intrusive thoughts of death or taking their own life.
The loss of interest, pleasure, or excitement in anticipation of activities that the individual once perceived as enjoyable is called anhedonia.
The brain mechanisms that underpin anhedonia in depression have remained unclear until now, and this lack of knowledge has hindered the success of many antidepressant treatments.
Now, a new study casts much-needed light on this symptom. Leading a team of researchers, professor Angela Roberts from the Department of Physiology, Development, and Neuroscience at the University of Cambridge, United Kingdom, and doctoral researcher and medical student Laith Alexander set out to study this phenomenon in marmosets.
Marmosets are a type of nonhuman primate with frontal lobes that are very similar to those of humans. This physical similarity means that the findings are more easily translatable to humans than they would be if the study involved rodents instead.
Prof. Roberts and colleagues tested the effects of ketamine, a hallucinogenic drug that has recently garnered interest as a potential treatment for depression, and found that it had a positive effect on the primates.
Studying anhedonia in primates
Prof. Roberts explains the motivation behind the study, saying, “Imaging studies of [people with depression] have given us a clue about some of the brain regions that may be involved in anhedonia, but we still don’t know which of these regions is causally responsible.”
“A second important issue,” she adds, “is that anhedonia is multi-faceted — it goes beyond a loss of pleasure and can involve a lack of anticipation and motivation, and it’s possible that these different aspects may have distinct underlying causes.”
To find out more about the brain mechanisms behind anhedonia, Prof. Roberts and her team devised an experiment in which they trained primates to react to two sounds. Sound A indicated that the marmosets would receive marshmallows as a treat while no treat followed sound B.
After the training, blood pressure measurements and head movements showed that the marmosets would get excited on hearing sound A but would not respond in this way to sound B.
Next, the scientists surgically implanted very thin metal tubes into the marmosets’ heads, through which they injected either a drug or a placebo into the brains of the primates.
The researchers targeted a specific brain region called “area 25,” which the drug made temporarily hyperactive. They used PET scans to study the primates’ brain activity.
Brain’s area 25 is key in anhedonia
The primates that received the drug showed increased activity in area 25 in the brain and also displayed significantly lower excitement in anticipation of the marshmallows.
In contrast, there was no change in either the brain activity or behavior of the primates that received the placebo.
In a second experiment, the primates had to work for their rewards. At first, they received a treat after touching a colored shape on a screen just once.
However, over the course of the experiment, the primates had to press the shape an increasing number of times before they received the marshmallow. Eventually, the animals would give up because the treat was no longer worth the effort.
The researchers found that the marmosets with a hyperactive area 25 gave up much more quickly. PET scans also revealed that abnormal activity in this brain area overflowed into other brain areas, which also became overactive when the anticipatory excitement dwindled.
How ketamine prevents the loss of pleasure
Finally, the researchers tested the effect that ketamine had on the primates. They gave the marmosets ketamine 24 hours before repeating the same experiments as before.
This time, ketamine blocked the activity of the drug that overactivated area 25. The brain activity of the primates that received ketamine looked normal in PET scans, and the primates continued to exhibit just as much excitement in anticipation of the marshmallow treats.
“Understanding the brain circuits that underlie specific aspects of anhedonia is of major importance,” says first author Laith Alexander, “not only because anhedonia is a core feature of depression but also because it is one of the most treatment-resistant symptoms.”
Studies show that as many as 30 percent of people living with depression have a form of the condition that does not respond to treatment.
Is it possible to reverse ‘chemo brain?’
Chemotherapy can affect a person’s brain for years after coming to an end. How does it actually change the brain, and is there anything that scientists can do to reverse these effects?
Many people who undergo chemotherapy will notice cognitive impairment and behavioral changes. This might include difficulty with movement.
Some people refer to this effect as “chemo brain.”
It can last for months or years, impacting people’s quality of life following cancer treatment.
Researchers at Stanford University School of Medicine in California recently conducted a study to find out exactly how and why chemotherapy agents affect the brain, and to see whether or not there is any way to block or reverse that effect.
The results — which appear in the journal Cell — appear to indicate that methotrexate, a common chemotherapy drug, affects the normal functioning of three important types of cell present in the brain’s white matter.
Chemo brain’s impact
The scientists also report learning that a drug currently undergoing clinical trials for other uses can address these ill effects in a mouse model.
“It’s wonderful that [people who have undergone chemotherapy are] alive, but their quality of life is really suffering,” claims lead study author Erin Gibson. “If we can do anything to improve that, there is a huge population that could benefit,” she notes.
“Cognitive dysfunction after cancer therapy,” explains senior study author Dr. Michelle Monje, “is a real and recognized syndrome.”
“There [is] real hope that we can intervene, induce regeneration, and prevent damage in the brain,” she adds.
Specifically, chemo brain tends to severely affect children who have undergone cancer treatment. Dr. Monje and team believe that finding a way to address this problem could truly improve these children’s lives.
The chemo drug that disrupts brain cells
In the recent study, the researchers focused on three important types of cell that are present in the brain’s white matter. These are:
- Oligodendrocytes. These generate and protect myelin, which is the substance that insulates axons. Axons are the fibers through which nerve cells communicate with one another.
- Astrocytes. These help keep the neurons well-irrigated, and they maintain a healthy environment for these cells, allowing them to communicate properly.
- Microglia. These are specialized immune cells that normally destroy any foreign agents that may be harmful to the brain.
When the scientists compared frontal lobe brain tissue collected postmortem from children who had received chemotherapy with tissue from children who had not, they saw that the former presented significantly fewer oligodendrocyte lineage cells.
To understand why oligodendrocytes were not doing well in the chemotherapy-exposed brain, the researchers turned to young mouse models that they injected with methotrexate.
They aimed to replicate the dosage and practice performed in human cancer treatment, so they gave the mice three doses of the drug once per week.
After a period of 4 weeks, the mice that received methotrexate had sustained damage to their oligodendrocyte precursor cells, which are the fresh cells that normally develop to replace oligodendrocytes that can no longer function.
Following exposure to methotrexate, more precursor cells began to start the maturation process, but they remained stuck in an undeveloped state, unable to actually reach maturity. This was the case even 6 months after the mice’s treatment with the chemotherapy drug.
This also impacted the thickness of myelin, and the mice even faced the same behavioral problems as people who undergo chemotherapy often do. These include motor impairment, anxiety, and problems with attention and memory.
Some of these effects also persisted for 6 months following treatment with methotrexate.
The importance of ‘intercellular crosstalk’
When they tried injecting oligodendrocyte precursor cells from the brains of healthy mice into those of the experimental mice, the investigators noticed that these cells also started the maturation process at higher rates, but they did not get stuck midway through this process.
This, the team suggests, meant that there were problems in the cells’ environment following treatment, which stopped them from completing their normal process.
The researchers next turned to study the microglia and found that these were abnormally active for at least 6 months following the chemotherapy treatment, thus interfering with the normal functioning of astrocytes and disrupting the healthy nutrition of neurons.
However, when the researchers gave the experimental mice a drug whose effect was to selectively deplete microglia, this allowed the oligodendrocyte precursor cells to resume their normal process of maturation; it stopped astrocyte disruption and renewed normal myelin thickness.
Also, this approach reversed numerous cognitive impairment symptoms in the mice that received the new drug.
“The biology of this disease really underscores how important intercellular crosstalk is,” says Dr. Monje, adding, “Every major neural cell type is affected in this pathophysiology.”
“If we understand the cellular and molecular mechanisms that contribute to cognitive dysfunction after cancer therapy, that will help us develop strategies for effective treatment. It’s an exciting moment,” she concludes.
How your imagination can help you overcome your fears
New research assessing brain scans shows that our imagination can also help us get rid of our anxieties and fears.
Our imagination is an incredibly useful tool. It can soothe us during difficult times and help us solve problems, create new things, and consider possible courses of action.
Some researchers have argued that our imagination, which gives us the ability to consider different scenarios, is at the core of what makes humans different from the rest of the animal kingdom.
Moreover, existing research has suggested that what we imagine can actually affect our minds and bodies in very concrete ways.
For instance, a study that the journal Psychological Science published in 2009 found that when we imagine doing something, our minds and bodies anticipate the imagined action as though it were a real action.
The results of another study, which featured in Current Biology in 2013, suggest that imagining that we hear certain sounds or see particular shapes can change how we perceive the world in real time.
New research by a team from the University of Colorado Boulder and the Icahn School of Medicine at Mount Sinai in New York, NY, now proves that what we imagine can seem just as real to our brains as actual experiences.
As the investigators explain in their study paper, which appears in the journal Neuron, we can harness the “magical powers” of our imagination to help us overcome persistent fears and anxietydisorders.
“This research confirms that imagination is a neurological reality that can impact our brains and bodies in ways that matter for our wellbeing,” says Prof. Tor Wager, co-senior author of the study.
The power of what you imagine
When it comes to helping people address their phobias or anxiety disorders, psychologists may recommend “exposure therapy.” This approach aims to desensitize a person to stimuli that trigger a fear response by repeatedly exposing them to these stimuli in a completely safe environment.
This can help a person disassociate those stimuli from a sense of threat and impending negative consequences.
In the new study, the researchers used functional MRI to scan participants’ brains and assess brain activity both in real and imagined situations involving unpleasant triggers. The aim was to see whether and how imagination may help us discard negative associations.
“These novel findings bridge a long-standing gap between clinical practice and cognitive neuroscience,” notes the study’s lead author Marianne Cumella Reddan, who is a graduate student in the Department of Psychology and Neuroscience at the University of Colorado Boulder.
“This is the first neuroscience study to show that imagining a threat can actually alter the way it is represented in the brain,” she adds.
In the current study, the research team recruited 68 healthy participants, whom they conditioned to associate a particular sound with receiving an electric shock that was uncomfortable but not painful.
They then split the participants into three groups. To those in the first group, the researchers played the sound that the participants now associated with an unpleasant physical experience.
Those in the second group had to imagine hearing that same sound instead, while those in the third group — the controls — had to imagine pleasant sounds, such as the trills of birds and the pitter-patter of rain. None of the participants received any further electric shocks.
Imagining a threat repeatedly can help
While the volunteers were either hearing the triggering sound, imagining it, or imagining a pleasant sound, the researchers assessed their brain activity using functional MRI. The team also measured their physiological responses by placing sensors on their skin.
The investigators found that brain activity was very similar in the participants who actually heard the threatening sound and those who only imagined hearing it.
In all of these volunteers, the auditory cortex (the brain region that processes sound), the nucleus accumbens (associated with learned fear), and the ventromedial prefrontal cortex (which signals exposure to risk) became active.
However, after the participants repeatedly heard or imagined hearing the triggering sound without receiving the expected electric shock, they stopped being afraid. The process had extinguished the association between that sound and an unpleasant experience. This phenomenon is known as “extinction.”
In the control group, in which the participants had imagined pleasant sounds only, other brain regions lit up in the functional MRI scans, and the negative association between the triggering sound and the electric shock never went away.
“Statistically, real and imagined exposure to the threat were not different at the whole brain level, and imagination worked just as well,” explains Reddan.
You can ‘update’ bad memories
The researchers also suggest that, thanks to the power of imagination, we may even be able to “revise” and “update” memories that are unpleasant or unhelpful.
“If you have a memory that is no longer useful for you or is crippling you, you can use imagination to tap into it, change it, and re-consolidate it, updating the way you think about and experience something,” says Reddan.
However, just how vivid each of our imaginations is may affect the outcome of such experiments. Thus, the investigators explain, those with particularly vivid imaginations may benefit the most from “manipulating” unpleasant associations, while those with less active imaginations may not see much of a difference.
There is a real need for more research into the powers of imagination, say the researchers, but the current findings emphasize one thing — namely, that we should not underestimate the effect of what we imagine.
“Manage your imagination and what you permit yourself to imagine,” encourages Prof. Wager. “You can use imagination constructively to shape what your brain learns from experience,” he adds.
What’s Next For For Applied Genetic After 50% Plunge?
Applied Genetic Technologies Corp AGTC 47.14%, a biotech focused on adeno-associated virus-based gene therapies for the treatment of rare diseases, reported disappointing results from an X-linked retinoschisis clinical study.
The company also confirmed Biogen Inc BIIB 0.77% terminated its partnership effective March 8.
The Analysts
H.C. Wainwright & Co’s Joseph Pantginis maintains a Buy rating on Applied Genetic Technologies’ stock with a price target lowered from $8 to $5.75.
Wedbush’s David Nierengarten maintains at Outperform, price target lowered from $12 to $11.
BMO Capital Markets’ Matthew Luchini downgrades from Outperform to Market Perform, price target lowered from $13 to $5.
HC Wainwright: Here’s What Happened
Applied Genetic’s XLRS clinical study consisted of 27 patients. The 13 who received a high dose showed no improvements, with just two patients showing improvements in one of the four endpoints, OCT, Pantginis said in a research report. Zero pediatric patients at the middose showed efficacy at any endpoint, he said.
Given the disappointing announcement, investor confidence has taken a hit and the company is now entering a “show me stage,” the analyst said.
The bullish case for the stock can still be made, as there are some differentiating factors between the reported XLRS programs and XLRP programs, Pantginis said:
- XLRS included intravitreal injections and was dosed into a highly heterogeneous population.
- The XLRP programs are dosed in subretinal fashion.
Wedbush: Silver Lining In Biogen Announcement
Applied Genetic’s Biogen termination announcement has a “silver lining,” as the company now has full rights to the XLRP gene therapy program, which is seen as a primary value driver, Nierengarten said in a research report.
Biogen previously controlled worldwide rights to the XLRS program and Applied Genetics merely received a low-teens royalty payment, the analyst said.
Applied Genetic is now positioned to benefit from more upside in the XLRP program, which boasts multiple advantages over XLRS, Nierengarten said:
- A larger market.
- Better-defined biology through validated higher order animal models.
- Clinical POC established by other sponsors.
- Superior benefits of subretinal delivery.
On the flipside, Applied Genetics will likely need incremental financing to proceed, but there is nevertheless a “positive path forward” with its XLRP opportunity, according to Wedbush.
BMO: Negative Signal From Biogen
Although the return of full rights related to XLRP from Biogen is a positive development for Applied Genetic, the fact that Biogen decided to return rights ahead of proof-of-concept data — which is expected in the third quarter of 2019 — is a “negative signal,” Luchini said in the downgrade note.
This also implies incremental risk to the company’s success in XLRP, for which BMO lowered its probability of success from 15 percent to 10 percent, the analyst said.
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