Merck (MRK) will cut the price of one of its core cancer drugs in half for its China launch following a similar move by competitor Bristol-Myers Squibb (BMY), Caixin Global reports
Wednesday, September 19, 2018
Novartis’ Kymriah for adult lymphoma ‘to expensive to recommend,’ says NICE
https://thefly.com/landingPageNews.php?id=2792362
Piper more worried about AbbVie co-pay accumulator risk than California suit
While shares of AbbVie may move lower today on news of California’s insurance regulator suing the company over promotion of Humira, a more fundamental potential drag on Humira remains the advent of co-pay accumulators, Piper Jaffray analyst Christopher Raymond tells investors in a research note. The analyst sees the California lawsuit as more headline risk than anything but thinks “it may nevertheless serve as a minor overhang on shares.” He points out that new research this week by Drug Channels suggests that more than one-third of commercial lives are enrolled in plans that have implemented copay accumulators for 2018, higher than his prior best estimate of 17%. Raymond keeps a Neutral rating on AbbVie with a $100 price target.
https://thefly.com/landingPageNews.php?id=2792331
Tuesday, September 18, 2018
Drug combo shows promise for treating sleep apnea
During decades of lab experiments and dozens of clinical trials, scientists have searched in vain for drugs to defeat obstructive sleep apnea, the risky and increasingly prevalent condition in which a person’s upper airway repeatedly collapses during sleep, causing them to briefly stop breathing dozens or hundreds of times each night. Now, a new drug combination has reawakened hopes.
A team led by researchers in Boston has identified a pair of medications—approved for other uses and with solid safety records—that appear to work in concert during sleep to activate the muscles that dilate the upper airway. In a study of 20 patients, the scientists found that a combination of atomoxetine and oxybutynin, taken as two pills at bedtime, reduced patients’ frequency of airway obstruction—called the apnea-hypopnea index, or AHI—from a median of 28.5 hourly obstructions on placebo to 7.5 on the pills. In the 15 patients with the highest AHIs, the median reduction was 74%—and every patient experienced at least a 50% reduction, Andrew Wellman and Luigi Taranto-Montemurro at Brigham and Women’s Hospital in Boston reported today at the European Respiratory Society’s International Congress in Paris. Patients’ blood oxygenation also improved strikingly, the group found.
“We’ve never had a drug combination, or any sort of a drug, that consistently improved everybody’s AHI. That’s actually unbelievably exciting,” says Sigrid Veasey of the University of Pennsylvania (UPenn), a physician-researcher who studies sleep. It’s “a great first step,” adds Martina Mason, a sleep physician at the Royal Papworth Hospital in Cambridge, U.K., who co-authored a 2013 review of 30 previous, underwhelming drug trials.
The trial turned up one potentially problematic finding: Although the drug combination reduced patients’ AHIs, their number of subconscious arousals—the subtle awakenings that leave patients exhausted—remained high. But if this combination proves safe and effective in larger trials, it could free many sleep apnea patients from the current gold-standard remedy, the cumbersome “continuous positive airway pressure” (CPAP) machines that blow air into the throat to keep the airway open, but require users to wear a mask and headgear at night.
Mason, Veasey, and other sleep apnea experts caution, however, that the findings are extremely preliminary. They note that the pilot study, although double-blind and randomized, included just a small number of patients who took the drug combination for just 1 night.
The search for sleep apnea treatments has become pressing as its prevalence has grown, as widespread noncompliance with CPAP has been charted and as researchers have documented the disease’s long-term dangers. In addition to enduring daytime sleepiness, sleep apnea sufferers—some 13% of U.S. men and 6% of women aged 30 to 70—are at higher risk for depression, cognitive impairment, high blood pressure, heart attack, stroke, and premature death. The obesity epidemic is thought to be increasing the incidence of sleep apnea, though thin individuals can also be afflicted.
Wellman, a physician who has been studying sleep apnea since 2001, began to test various drugs for the condition in clinical trials more than 10 years ago. “I had given up, really,” he recalls. Then, in 2015, an enthusiastic postdoc, Taranto-Montemurro, arrived in his lab. Wellman reluctantly let him launch a new trial of a drug combination suggested by animal studies from other labs. “I wasn’t really happy about it,” Wellman says, “until all of a sudden the data started coming in.”
Atomoxetine, approved by the U.S. Food and Drug Administration in 2002 to treat attention deficit hyperactivity disorder, increases messaging in the brain by the excitatory neurotransmitter norepinephrine, whose levels normally fall off markedly during sleep. Giving a stimulating drug at bedtime seems counterintuitive. But animal work led by Richard Horner, a sleep physiologist at the University of Toronto in Canada, had shown that injecting rats with a norepinephrine-mimicking drug in an area of the brainstem that controls the hypoglossal nerve, which powers the upper airway muscles, improved activity of the genioglossus, a large tongue muscle that is critical for keeping the throat open. The drug was consistently effective only during nonrapid eye movement sleep, not during rapid eye movement (REM) sleep, when throat muscles are especially prone to relaxation and collapse, making sleep apnea worse.
The other half of the combination, oxybutynin, improves genioglossus responsiveness during REM sleep. Again, work by Horner’s team provided the crucial clue. It found that during REM sleep the neurotransmitter acetylcholine acts on certain receptors on the hypoglossal nerve to powerfully inhibit activation of the genioglossus. Oxybutynin, Wellman and Taranto-Montemurro knew, blocks acetylcholine’s action at the same receptors—and it had a long track record as a marketed drug used for decades to treat overactive bladder.
As the drug pair progresses through clinical trials, sleep apnea specialists will be watching to see whether the drugs actually reduce subconscious arousals and improve sleep quality. “What if you can improve the AHI, the obstructions, but the patients are as sleepy as they were before the treatment?” asks UPenn’s Leszek Kubin, a neurophysiologist who studies the mechanisms of sleep-disordered breathing.
The study researchers propose that the patients’ arousals may have been due to the invasive instrumentation attached to them during the night, and the associated discomfort. And they note that in the 13 patients with the highest AHIs, the number of arousals did decline a statistically significant amount on the pill combination.
Some are already betting that the drug pair, on which a patent for use in sleep apnea is expected to be published next month, will find a large and eager market. Apnimed, Inc., a new Cambridge, Massachusetts, company formed to commercialize the discovery, recently landed $25 million from Morningside Venture Capital in Newton, Massachusetts. It is planning a phase II trial involving more than 100 patients, to study dosing and side effects, says CEO Larry Miller. (Wellman and Taranto-Montemurro have a financial interest in the firm but are not involved with planning or running the trial.)
Sleep physicians note that side effects unrelated to breathing may make the drug combination a nonstarter for some sleep apnea patients. In a population at risk for hypertension and heart attacks, the stimulant effects of atomoxetine will have to be watched. And oxybutynin’s dampening effect on bladder muscle activity may prove problematic for a typical group with sleep apnea: “old men who have trouble urinating in the night,” says J. Steven Poceta, a sleep physician at the Scripps Clinic Torrey Pines in San Diego, California. Still, he says, he’s excited about the drug combination’s promise. “It could be great for a lot of people.”
NIH Using Vaccines from Startup FluGen in New Clinical Trial
Researchers are testing a flu vaccine developed by FluGen, a Madison, WI-based startup, to determine whether it can protect recipients against strains of the virus that vary from the predominant strain flu predicted by health experts each year.
Many people get a flu shot this time of year in hopes that it will help them avoid catching the virus during flu season, which typically begins in October or November. The Centers for Disease Control and Prevention (CDC) recommends that everyone six months of age or older get a seasonal flu vaccine, and the most recent flu season in the U.S. was the worst in nearly a decade.
But even those who get vaccinated sometimes fall ill. Forecasts by the CDC, World Health Organization, and other groups that predict what the predominant flu strain will be in the coming season sometimes miss the mark. Such forecasts influence how vaccine manufacturers formulate the flu shots tens of millions of Americans get each year.
The challenge of predicting which strain of the virus will predominate in a given flu season is one reason investors and research organizations have been funding companies seeking to commercialize a “universal” flu vaccine that could protect people against most strains of the disease.
FluGen has made progress in early-stage trials of its vaccine, which it calls RedeeFlu. Meanwhile, the startup is also providing flu vaccines for a current clinical trial. The National Institute of Allergy and Infectious Diseases, which is one of the National Institutes of Health (NIH), and researchers at Saint Louis University are co-managing the trial. It began in August but was not announced publicly until earlier this week.
The NIH and university researchers are conducting and managing the study, but FluGen is providing the vaccines that some participating patients will receive, says Paul Radspinner, co-founder and CEO of FluGen.
That distinguishes the trial from past and ongoing trials of RedeeFlu, which FluGen has led. Radspinner notes, however, that his startup hasn’t been acting alone. FluGen has had “funding partners” for the trials it has conducted previously, including the U.S. Department of Defense, he says.
The phase 1 trial the NIH is co-managing is aimed at assessing the safety of RedeeFlu, and whether its recipients produce an immune response, according to the agency. Fifty children ages nine to 17 are enrolled, the NIH says.
The design of RedeeFlu is aimed at giving the vaccine the ability to protect against so-called drifted—or mismatched—flu strains. That versatility could allow the vaccine to protect against strains of the virus that vary from the one the CDC and other forecasters predict will predominate in a particular season.
FluGen is not charging the NIH or its collaborators for the RedeeFlu vaccines they’ll give to some subjects, Radspinner says. For FluGen, one likely benefit of providing vaccines used in the trial will be learning how younger patients’ immune systems respond to RedeeFlu. Radspinner says that up to this point, FluGen has only studied the effects of RedeeFlu on adults.
The trial is the first FluGen has done in conjunction with the NIH, Radspinner says.
Half of the subjects in the trial will be dosed with RedeeFlu, a nasal spray manufactured with a strain of flu that was used in vaccines during the 2008 through 2010 flu seasons. The other half will receive a placebo. About three months after subjects are dosed, they will receive this flu season’s recommended vaccine.
Radspinner says the results of the study could reveal what effect, if any, receiving a different flu vaccine three months later has on subjects’ immunology, Radspinner says. That’s something FluGen has not tested previously, he says.
Depending on the results of the NIH- and Saint Louis University-led trial, the two organizations may conduct subsequent studies of flu vaccines in younger patients. The next subjects would be five- to nine-year-olds, Radspinner says.
The live flu virus in RedeeFlu has been altered so it is missing a key protein, M2. Without it, the virus will live in the body long enough to trigger an immune response, but it won’t be strong enough to cause the disease’s severe effects or infect others, FluGen says.
57% Say OK with Genetically Engineering Animals for Organ Transplants
A recent survey by the Pew Research Center found that 57 percent of Americans surveyed thought it was appropriate to use genetically engineered animals to grow organs for human transplants. However, 41 percent said they thought that was going too far. It’s possible, that with modern developments in 3D printing and other technologies, it won’t be necessary.
The Pew Research Center says, “The findings are part of a larger pattern that reveals Americans are more likely to support the bioengineering of animals if it benefits human health.”
Pew points out that in 2017, more organ transplants were performed than ever in the U.S., and organs were recovered from more than 10,000 donors, an increase of more than 25 percent over the past decade. The increase is largely attributed to breakthroughs in medical technology that have made it possible to harvest organs that were previously found to be unsuitable.
Based on individual responses, the objections had to do with the ethics of using animals in a “factory-like” manner, comparing it to how they are treated for food sourcing. One individual stated, “When you mix human and non-human genetics I believe that will cause extreme problems down the road.”
Researchers, however, are working on different approaches. One is 3D bioprinting. Typical 3D printing uses carbon fiber as a source material, but there are examples of 3D printing using biological source materials to create biologically-active or interactive materials.
In June 2018, France-based Poietis, along with another company, Prometheus, a division of Skeletal Tissue Engineering in Leuven, Belgium, signed a two-year Collaborative Research Agreement to develop high-precision 3D Bioprinting of tissue engineered Advanced Therapeutic Medicinal Products (ATMPs) for skeletal regeneration.
Essentially, the companies are working to “print” bone that can be used in transplants or other orthopedic, musculoskeletal or spine-related applications.
A San Diego company, Organovo, is working with researchers at Amgen and Medikine to develop new applications for Organovo’s ExVive Liver and Kidney Tissue. It uses 3D printing to create functional human tissues and hopes to someday be able to print tissues that could be transplanted into the human body.
Also in June of this year, San Francisco-based Prellis Biologics recorded a speed and resolution record for its attempts to print human tissue with viable capillaries. Its holographic 3D printing technology creates complex microvascular scaffolding that allows human tissue to survive.
InvivoSciences, located in Madison, Wisconsin, has developed micro-engineered heart tissues, now called NuHeart. It uses 3D culture technology, not bioprinting, which is similar to growing specific heart tissues out of stem cells. It can reconstitute muscle, such as skeletal, cardiac, or smooth muscles, as well as connective tissue like dermis of the skin in micro-well plates.
And in May, Emulate signed a deal with AstraZeneca’s Innovative Medicines and Early Development (IMED) Biotech Unit to embed its Organs-on-Chips technology within the laboratories of the IMED Drug Safety organization. Initially, the two companies will use Emulate’s Liver-Chip to evaluate drug candidates’ safety. The companies also hope to develop three other Emulate Organ-Chips — the Lung Tumor-Chip, Lung-Chip, and Glomerulus Kidney-Chip.
And in September, researchers at the University of California, San Diego (UCSD) published their work in the journal Stem Cells and Development describing a fast, cost-effective method to grow human cortical organoids in Petri dishes using primary cells. Because of ethical considerations as well as physiological limitations of animal models, work on the brain can be difficult. However, recently there have been in vitro human organoids, which are three-dimensional, miniaturized, simplified version of an organ developed and grown from pre-programmed stem cells.
“And that includes the brain,” said Alysson R. Muotri, professor in the UC San Diego School of Medicine departments of Pediatrics and Cellular and Molecular Medicine, and director of the UC San Diego Stem Cell Program, in a statement. “Cerebral organoids can form a variety of brain regions. They exhibit neurons that are functional and capable of electrical excitation. They resemble human cortical development at the gene expression levels.”
Early progress in the area is typically to use the organs or mini-organs and tissues as models for research and drug development. Perhaps in the future, as the research grows more mature, they will be used for transplants. It’s not inconceivable that artificially-grown brain tissue could be used at some time in the future to treat brain injuries.
Biotech IPOs Are Booming … But For How Long?
According to BioPharmCatalyst, there have been (or soon will be) 58 biopharma initial public offerings (IPOs) in 2018, and there’s still more than three months to go. The first listed on the BioPharmCatalyst database was Menlo Therapeutics on January 25, 2018. The most recent listing was Elanco Animal Health, whose offer date is September 21, 2018.
A recent Bloomberg article described 38 new U.S. stock listings by biotech companies, noting they had raised almost $3.9 billion, the highest marked since 2000. The 2000 boom was related to genetic therapies. In July, Crunchbase noted that in the second quarter of 2018, there were at least 16 U.S. venture-backed biotech and healthcare IPOs, compared to only 11 tech IPOs in the same period this year.
Bloomberg writes, “This time around, amid the recent approvals of the world’s first gene therapy and Alnylam Pharmaceuticals, Inc.’s RNA-interference drug, investor enthusiasm isn’t confined to any one area. Companies that sold stock for the first time in 2018 include Translate Bio Inc.,which is using messenger RNA to develop drugs for rare diseases such as cystic fibrosis, and Neon Therapeutics Inc., which describes itself as a platform for developing cancer immunotherapy treatments.”
The upcoming Elanco Animal Health IPO isn’t typical of biotech public launches. Most tend to be relatively recent biotech startups that have raised venture capital and brought a compound or therapy through proof-of-concept, or sometimes even into Phase I clinical trials. They are looking for more funding to pay for the larger and more expensive Phase II and III clinical trials.
Elanco is part of Eli Lilly, and it expects to raise up to $1.45 billion in its IPO. Elanco has been part of Lilly for 65 years and is being spun off. The Indianapolis Business Journal reported, “But Elanco has been struggling, ringing up losses of more than a half-billion dollars in the past three years, much of it connected to restructuring and other special changes. The new management’s first challenge will be to stabilize the company, launch new products and win back market share it has been losing to competitors.”
Compare that to one of this year’s most successful biotech IPOs, Cambridge, Massachusetts’ Rubius Therapeutics, which raised $240 million in its July IPO. Rubius Therapeutics’ focus is on genetically engineered long-circulating Red-Cell Therapeutics (RCT) products. They are genetically engineered, enucleated red blood cells that have broad therapeutic applications for cancer, enzyme replacement therapy, and autoimmune diseases.
Bloomberg suggests that even though many companies are rushing to the stock market, others are waiting. “One reason is that thanks to low interest rates and a hunt for higher returns by institutional investors, biotech startups have access to more capital than ever. Founders of several startups told Bloomberg News in recent weeks that they are raising more money earlier than expected.”
Which isn’t without its drawbacks. One of the primary business models for biotech startups is getting to Phase I or Phase II and either partnering with a large pharmaceutical company or be acquired by one. But Bloomberg observes that larger drugmakers have been complaining recently about the high valuations some of these biotech companies have.
For investors who pick the right biotech at the right time, it can be a big win. For example, in 2014, Juno Therapeutics raked in $176 million in its first large financing round. A few months later its IPO gave it a valuation of $1.9 billion. And where some biotechs drop quickly, Juno took off, jumping 46 percent on the first day of trading to give the company a valuation of $2.7 billion. Then in January 2018, Celgene acquired the company for $9 billion.
An example from this year would be Tilray, which is something of an outlier. Tilray focuses on medical cannabis research, cultivation, processing and distribution. Shares launched at $17 per share in July 2018, and have since risen over 463 percent, trading on September 12, 2018 for $104.36.
But others may not be so wonderful. Eyenovia, which launched in January 2018 at $10 per share, has dropped more than 51 percent. This Reno, Nevada-based company is focused on changing the delivery of drugs for eye diseases, such as glaucoma, dry eye, allergic eye disease and others, using a piezo-dispersion and microdosing technology. Shares are trading on September 12 for $4.80. On the other hand, at least two analysts cited by Zacks Investment Research give it a “strong buy” rating, suggesting they believe it’s ready to pop.
All this is probably good news for biotech companies, who indicate that the ready supply of investment capital allows them to focus on research. For example, Kaleido Biosciences raised $101 million, which the company’s executive chairman, Michael Bonney, said should carry them through at least 2020. “The general understanding of human biology and what’s driving various diseases is improving, and that creates a broader audience to go to and try to find the funding that we need,” Bonney told Bloomberg.
However, investors should know what they’re getting into when it comes to biotech stocks. Notoriously volatile, investments don’t always pay off with actual commercial products—ever—or for many years. Investing in biotech companies is a gamble on many things, including good science, market needs, competition and government regulation.
And Bloomberg points out that previous booms have corrected quickly, noting drops of more than 10 percent in the Nasdaq Biotechnology Index after run-ups in 2000 and 2014. And some analysts are wondering if this year’s boom is close to an end.
Hartaj Singh, an analyst with Oppenheimer & Co., told Bloomberg, “We’ve already had a really good 12- month period. They don’t tend to be much longer than that.”
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