Phathom Pharmaceuticals readies IPO

Phathom Pharmaceuticals (PHAT) has filed a preliminary prospectus for a 7.9M-share IPO at $18 – 20 per share.

The Buffalo Grove, IL-based biopharmaceutical firm develops treatments for gastrointestinal diseases. Lead candidate is vonoprazan, a potassium-competitive acid blocker (P-CAB), for the potential treatment of gastroesophageal reflux disease (GERD), H. pylori infection (can lead to ulcers in the stomach and upper part of small intestine) and other acid-related disorders. P-CABs work by blocking acid secretion in the stomach. The company says they work better than standard-of-care proton pump inhibitors (PPIs) in acid-related diseases, adding that 15-45% of GERD patients do not achieve adequate symptom relief with PPIs.

It in-licensed the rights to vonoprazan in the U.S., Europe and Canada from Takeda Pharmaceutical Company (NYSE:TAK) in May. Two Phase 3 GERD studies should launch this quarter.

2019 Financials (6 mo.): Operating Expenses: $84.2M (+999%); Net Loss: ($89.0M) (-999%); Cash Burn: ($6.0M) (-999%).

https://seekingalpha.com/news/3507088-phathom-pharmaceuticals-readies-ipo

Opioid settlement talks fail, landmark trial expected Monday

A landmark trial over the U.S. opioid epidemic is on track to begin on Monday after drug companies and local governments failed to agree on a settlement on Friday that had been expected to be valued at around $50 billion.

Top executives of the largest U.S. drug distributors and drugmaker Teva Pharmaceutical Industries Ltd left a Cleveland courthouse on Friday and lawyers for states and thousands of local governments said there was no agreement.
The parties and four state attorneys general had been summoned by U.S. District Judge Dan Polster, who could be seen on Friday shuttling between the groups in separate rooms.
Paul Hanly, a lawyer for local governments that brought the bulk of the thousands of lawsuits stemming from the addiction crisis, said his team “fully expect” a trial to begin Monday.
Talks featured chief executive officers from drug distributors AmerisourceBergen Corp, Cardinal Health Inc and McKesson Corp. Teva, which is based in Israel, also sent a team, as did Walgreen Boots Alliance Inc, a pharmacy chain.
Hanly said local governments which brought the bulk of the 2,600 lawsuits were “not on the same page” as the state attorneys general involved in the talks.

After nearly 11 hours of negotiations, Pennsylvania Attorney General Josh Shapiro told reporters it was “profoundly disappointing” that local governments would not go along with a settlement he valued at $48 billion, including $22 billion in cash and $26 billion in products and services.
The chief executive of small drug distributor Henry Schein Inc also attended talks.
The companies declined to comment or did not respond to requests for comment.
Earlier in the week, the three big distributors and Teva proposed a $50 billion settlement, two sources told Reuters. That proposal also included Johnson & Johnson, although the healthcare conglomerate was not invited to Friday’s talks because it has already settled with the plaintiffs in Monday’s trial.
Shares in the companies rallied through the week with hopes that a settlement was within reach. After Hanly’s comments late on Friday, shares of the companies sank as much as 3% in after-market trading.
Together, the companies will be defending themselves at Monday’s trial over allegations they fueled an opioid addiction crisis that caused roughly 400,000 U.S. deaths from 1999 to 2017, according to government statistics.

The distributors have been accused of failing to flag and halt suspicious orders for opioids, while drugmakers are accused of promoting benefits of the drugs while playing down their risks.
The distributors have insisted that they were shipping FDA approved medicines prescribed by doctors. The drugmakers have also denied any wrongdoing.
Hanly said discussions would continue, although he did not expect face-to-face talks to go through the weekend.
Another attorney for local governments, Paul Farrell, said the attorneys general are attempting to decide among themselves how to allocate the settlement money, without input from the local governments.
While the cases pit governments against large companies that profited from the use of opioids, there is also tension between cities, towns and counties and their state governments over the right to bring the cases and control the settlement proceeds.
Farrell said there was also an effort underway to reach a narrow settlement with just the two Ohio counties of Cuyahoga and Summit that are the plaintiffs in Monday’s trial.
A bellwether trial gives the parties a chance to assess a jury’s reaction to the allegations, which could then shape a settlement of all the litigation.

Other defendants in lawsuits overseen by Polster include Johnson & Johnson, Mallinckrodt Plc, Endo International Plc, Walmart Inc and Allergan Plc, among others.
OxyContin maker Purdue Pharma, viewed as one of the main culprits in fueling the opioid crisis, is also no longer part of the Ohio trial after declaring bankruptcy.
https://www.reuters.com/article/us-usa-opioids-litigation-settlement/opioid-settlement-talks-fail-landmark-trial-expected-monday-idUSKBN1WX22O

Huge opioid settlement hits late snag

The first federal case in the opioid crisis seems headed to trial Monday after an 11th-hour settlement appeared to be breaking down.
A $50B bid from four state AGs and corporate executives to settle hundreds of lawsuits and head off the federal trial faced opposition from local officials.
There’s been no progress in getting three distributors — McKesson (NYSE:MCK), Cardinal Health (NYSE:CAH) and AmerisourceBergen (NYSE:ABC) — to boost a settlement offer from $18B over 18 years, according to the lead attorney for 2,400 cities and counties.
And Teva (NYSE:TEVA) isn’t budging from its offer of a few hundred million dollars plus anti-addiction drugs, and there’s been little negotiation with Walgreens (NASDAQ:WBA), he says.
Johnson & Johnson (NYSE:JNJ) has agreed to contribute $4B over a shorter time frame.
After hours: MCK -3.1%; CAH -3%; ABC -1.8%; WBA -0.4%; JNJ +0.1%; ENDP -2.4%; TEVA -1.6%.
https://seekingalpha.com/news/3507076-huge-opioid-settlement-hits-late-snag

FDA approves Alexion Pharma’s Ultomiris for second rare blood disease

Alexion Pharmaceuticals (NASDAQ:ALXN) says the U.S. Food and Drug Administration approved its Ultomiris treatment for a second rare blood disorder.

The newest approval allows its use in treating atypical hemolytic uremic syndrome, an ultra-rare disease that can cause progressive injury to vital organs, primarily the kidneys, through damage to the walls of blood vessels and blood clots.

Ultomiris already has been approved in the U.S., Japan and the European Union to treat adults with a blood disorder called paroxysmal nocturnal hemoglobinuria.

The FDA approval is a boost for ALXN, which has been pushing to expand the Ultomiris label as U.S. market exclusivity for its best-selling drug, Soliris, is being threatened.

https://seekingalpha.com/news/3507082-fda-approves-alexion-pharmas-ultomiris-second-rare-blood-disease

Medicare-For-All Is A Plot To Pillage You

Medicare-For-All (M4A) is gaining some steam. Two prominent Democratic candidates for the presidency, Senators Elizabeth Warren and Bernie Sanders, support it, and several polls show that the idea is supported also by a majority of Americans.
In recent days, two academics from U.C.-Berkeley have even argued that a transition to M4A from the current system would dramatically cut taxes for the majority of workers by replacing all insurance premiums with taxes based on ability to pay.
That outcome sounds great until you ask how we will pay for it. According to a new study by the Urban Institute, M4A will cost $32 trillion over ten years. This estimate is in line with that of my colleague Charles Blahous. That’s more than the federal government will be projected to pay over the coming decade for Social Security, Medicare, and Medicaid combined, according to the most recent Congressional Budget Office projections. According to Urban, you could reduce the damage down to $16 trillion with some cost sharing and some limits on benefits. Either way, that’s a lot of money.
As Brian Riedl notes recently, one of the ideas floating around is that we simply need to come up with a $35 trillion tax to pay for it all (I am not kidding). He writes, “Proponents [of M4A] assert that the $35 trillion that families and businesses are currently projected to pay over the next decade in health premiums, out-of-pocket expenses, and state taxes to fund Medicaid would all be replaced with a $35 trillion federal ‘single-payer tax….”
Yet we have no details of how that would work in practice, and no one who supports M4A so far has offered an actual plan for the elusive $35 trillion replacement tax. Riedl writes, “Congressional Budget Office data show that raising $35 trillion would require a payroll tax increase of 39 percentage points, or a value-added tax of 91 percent – an enormous burden even for families no longer paying premiums.”
The scale of the tax hike it would require probably explains why no one wants to talk about it seriously. During the last Democratic debate, Senator Sanders acknowledged that it would require raising taxes on the middle class. He said, “At the end of the day, the overwhelming majority of people will save money on their health care bills. But I do think it is appropriate to acknowledge that taxes will go up.” But he has failed to give us any details about which taxes will go up and by how much and his campaign has only pointed out some options to pay for part of this extra government spending.
Meanwhile, Elizabeth Warren has vehemently refused to say if the middle class would see its taxes go up to pay for M4A or how she would pay for this. As the Wall Street Journal reported, for instance, during the debate Ms. Warren, the new leader in the polls, was given at least six chances to answer yes or no. She ducked every time. “Will you raise taxes on the middle class to pay for it, yes or no?” asked one of the media questioners.” The Journal continues, Ms. Warren replied:
“So I have made clear what my principles are here, and that is costs will go up for the wealthy and for big corporations, and for hard-working middle-class families, costs will go down.”
Later on she added, “Costs are going to go up for the wealthy,” and “costs will go down for hard-working, middle-class families.”
Got it; costs will go down for some and costs will go up for others. Yet we still have no clue just who will pay for what and how much the bill will be. Even those Berkeley professors won’t tell us how to pay for it. They have mentioned having a plan for some taxes as replacement of the cost of the employer side of insurance premiums. But, if this was even doable, it may raise between $10 trillion to $18 trillion (depending on how you measure it) of the $32 trillion.
While Warren doesn’t want to talk about, we can still do the calculation for her.
For one thing, she has been open about paying for all her new spending ideas with a wealth tax on the rich, a corporate surtax, an increase in the estate tax, and the elimination of President Donald Trump’s tax cuts. Her wealth tax would raise, she claims, $2.75 trillion over ten years. Reversing the tax cuts would raise revenue by another roughly $2 trillion over ten years. You can add to that another $3 trillion that her campaign says she will raise through other taxes on the rich.
However, once you spend $32 trillion on M4A, $1.07 trillion for universal childcare, $610 billion for free college, $640 billion for eliminating student debt, $100 billion to combat the opioid crisis, and some other smaller programs, you are still left with a $30 trillion gap.
That’s 30,000,000,000,000 over ten years. It also ignores the deadweight losses of all this spending and new taxes on top of their inability to truly raise as much revenue as planned.
The bottom line is this: while M4A is getting a lot of favorable attention these days, proponents will continue to tout the benefits of a reform that lowers costs for some, while staying as far as they can from actually proposing a way to pay for it. But as PJ O’ Rourke famously said, “If you think health care is expensive now, wait until you see what it costs when it’s free.”
Veronique de Rugy via The American Institute for Economic Research
https://www.zerohedge.com/political/medicare-all-plot-pillage-you

Knee, Hip Steroid Injections May Speed Joint Damage in Some Patients

Steroid injections are frequently used to relieve pain associated with osteoarthritis of the knee and hip, but new evidence suggests the treatment may do more harm than good for some people. Experts now stress the need for better informed consent about potential risks and benefits of injections.
Data from more than 450 patients who received intra-articular corticosteroid injections for osteoarthritis at Boston University show that the treatment may speed the pace of osteoarthritis and contribute to joint destruction.
The article was published online October 15 in the journal Radiology.
“We are now seeing [that] these injections can be very harmful to the joints, with serious complications such as osteonecrosis, subchondral insufficiency fracture, and rapid progressive osteoarthritis,” senior author Ali Guermazi, MD, PhD, said in a press release. Guermazi is chief of radiology at the Veterans Affairs Boston Healthcare System and professor of radiology at Boston University School of Medicine.
Some patients may be more prone than others to poor outcomes from the treatment, but it’s not yet known how to identify these people. The researchers stress the importance of informed consent, and urge radiologists to take x-rays before administering steroid injections, in order to identify underlying problems that may contribute to adverse events.
“Intra-articular corticosteroid injection should be seriously discussed for pros and cons. Critical considerations about the complications should be part of the patient consent, which is currently not the case right now,” Guermazi added.

Long-term Data Has Been Lacking

The first-line treatment for osteoarthritis, which most commonly affects the hip and knee, is conservative pain control, but many patients eventually need joint replacement. Yet people with osteoarthritis are often older and have multiple medical problems that make them ineligible for surgery or long-term treatment with acetaminophen or nonsteroidal anti-inflammatory (NSAIDs) medication.

Steroid joint injections have been widely used for decades to treat patients like these, and others with inadequate pain control. While short-term complications are rare, most studies on the long-term effects are of low quality. Some evidence from animal and human laboratory studies suggests steroid joint injections may contribute to progression of osteoarthritis. Professional societies differ on whether or not to recommend steroid joint injections for osteoarthritis.
Therefore, Andrew Kompel, MD, also from Boston University School of Medicine, and colleagues reviewed the records of 459 individuals who received at least one corticosteroid injection in the hip or knee joint in 2018 at an inner city hospital in Boston.
Overall, 8% (n = 36) of patients experienced an adverse joint event after receiving a steroid joint injection. These individuals ranged in age from 37 to 79 years (mean age, 57 years) and most (72%) showed moderate osteoarthritis at baseline. They received an average of 1.4 injections and developed joint complications anywhere between 2 to 15 months after injection, with an average of 7 months.
The authors identified four main adverse joint events after steroid joint injections. The most common was accelerated progression of osteoarthritis, found in 6% of individuals (n = 26).
The second most common adverse joint event was subchondral insufficiency fracture, found in 0.9% (n = 4) of individuals. Subchondral insufficiency fracture has traditionally been thought to occur in older individuals with weak bones, but recent evidence suggests it may be more common and affect younger patients.
The condition is potentially underdiagnosed due to lack of awareness. Delayed diagnosis can lead to joint damage and eventual joint replacement.  Diagnosis is important before giving steroid joint injections, which can impair healing in these kinds of fractures, according to the authors.
In addition, osteonecrosis and rapid joint destruction each affected 0.7% (n = 3) of patients, respectively.

Osteonecrosis refers to decreased blood flow to the bone that can cause breakdown of the bone, eventual fracture, and need for joint replacement. Patients with osteonecrosis but without fracture sometimes receive steroid joint injections. The authors emphasize the need to inform such patients that steroid joint injections could potentially worsen their condition.
They also note that rapid joint destruction and accelerated bone loss may occur after the first steroid injection and in patients without evidence of underlying disease on x-ray. In these patients, they suggest closely reviewing the need for injection and repeating x-rays before giving further injections.
The authors conclude: “The radiology community should actively engage in high-quality research to further understand these adverse joint findings and how they possibly relate to [intra-articular corticosteroid] injections to prevent or minimize complications.”

In an accompanying editorial, Richard Kijowski, MD, of the University of Wisconsin School of Medicine and Public Health, notes several limitations of the study, including the small number of patients and lack of standardized methods.
“The report is neither a prospective clinical trial nor a retrospective observational study…The objective is to educate radiologists that the intra-articular corticosteroid injection they routinely perform with little, if any, thought about long-term safety may cause more harm than benefit,” he writes.
He agreed with the authors about the importance of informed consent.
“Patients might be more than willing to take the small risk of an adverse joint event requiring eventual joint replacement for the possibility of at least some degree of pain relief after intra-articular corticosteroid injection,” he concludes. “However, patients have the right to make this decision for themselves, and this requires radiologists to discuss all potential risks and benefits with the patient when obtaining written informed consent.”
The study authors acknowledge that they could not determine whether these adverse joint events were already present when patients had their steroid joint injections, or if the injections caused these problems.
One or more authors owns shares in and/or has been a consultant for one or more of the following: Boston Imaging Core Lab, TissueGene, Merck Serono, Pfizer, AstraZeneca, Galapagos, and/or Roche. Kijowski has disclosed no relevant financial relationships.
Radiology. Published online October 15, 2019. Full text, Editorial
https://www.medscape.com/viewarticle/920029#vp_1

Creatine powers T cells’ fight against cancer

Creatine, the organic acid that is popularly taken as a supplement by athletes and bodybuilders, serves as a molecular battery for immune cells by storing and distributing energy to power their fight against cancer, according to new UCLA research.
The study, conducted in mice and published in the Journal of Experimental Medicine, is the first to show that creatine uptake is critical to the anti-tumor activities of CD8 T cells, also known as killer T cells, the foot soldiers of the immune system. The researchers also found that creatine supplementation can improve the efficacy of existing immunotherapies.
“Because oral creatine supplements have been broadly utilized by bodybuilders and athletes for the past three decades, existing data suggest they are likely safe when taken at appropriate doses,” said Lili Yang, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and the study’s senior author. “This could provide a clear and expedient path forward for the use of creatine supplementation to enhance existing cancer immunotherapies.”
The findings of the paper stem from the Yang lab’s research into the metabolic needs of tumor-infiltrating lymphocytes, immune cells that travel into tumors to fight cancer. Examining these cells, the team observed that killer T cells taken from inside of tumors possessed a large number of creatine transporter molecules, which sit on cells’ surfaces and control creatine uptake into cells.
“As biologists, we are always asking ‘why?'” said Yang, who is also an assistant professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. “We could see that these tumor-battling T cells had increased their capacity to take in creatine, likely for a good reason, so we designed experiments to determine what happens when they can’t get it.”
The lab genetically engineered mouse models so that their killer T cells were deficient in a gene called CrT, or Slc6a8, which is responsible for producing creatine transporter molecules. They found that mice whose killer T cells could not take in creatine were less capable of fighting tumors.
The team then tried validating their hypothesis from the opposite angle, giving non-engineered mice a daily dose of creatine comparable to the safe dose recommended to athletes and bodybuilders. This creatine boost—which was given to some mice via injection and others as an oral supplement—made both groups better equipped to suppress both skin and colon cancer tumor growth.
“Taken together, these findings suggest that killer T cells really need creatine to fight cancer,” Yang said. “Without it, they simply can’t do their jobs effectively.”
Creatine is naturally occurring in humans and other vertebrates; it is primarily produced in the liver and kidneys. Most humans take in additional creatine through their diets, with meat and fish as major sources. In addition to these natural sources, creatine supplements are widely popular among athletes and bodybuilders looking to gain muscle mass and improve performance.
The popularity of creatine supplements stems from the knowledge that cells with high-energy demands, like those found in muscle and brain tissue, use creatine to store excess energy for when they most need it.
These new findings add killer T cells to the list of creatine-dependent cells, all of which utilize two distinct sources of power, much like hybrid cars. The first power source is a metabolic process that is similar to a fuel engine, converting nutrients like glucose, amino acids and lipids into ATP, the energy currency of cells. The secondary power source is creatine, which—like a hybrid car’s battery—absorbs excess energy (in this case, ATP) and stores it to be released when fuel is in short supply to keep the cells working until more fuel can be burned.
“This creatine-powered hybrid engine system enables killer T cells to make the most of their available energy supply in an environment where they have to compete with fast-growing tumor cells for nutrients,” Yang said.
Next, the team tried combining creatine supplementation with PD-1/PD-L1 blockade therapy, a form of cancer immunotherapy that prevents T cell exhaustion and has been approved to treat a broad range of cancers including melanoma, lymphoma, colon, lung, liver, kidney and cervical. They found that creatine supplementation and anti-PD-1 blockade therapy worked synergistically, tipping the metabolic scales in T cells’ favor and enabling them to avoid exhaustion and fight cancer effectively for an extended period.
Four out of five mice that received this combination therapy were found to have completely eradicated their colon cancer tumors and remained tumor-free for over three months. Furthermore, when they were given a second round of tumor cells, all these “cancer survivor” mice were protected from tumor recurrence and remained tumor-free for an additional six months.
As a next step, the team is repeating these experiments using special mouse models that harbor human tumor grafts and human immune cells. If they are able to replicate these effects in human cells, the team will work to determine the proper dose, timing and method to give people creatine supplements to enhance existing immunotherapies. Because the strategy has proven effective in mouse models of both melanoma and colon cancer, the team expects the findings could apply to a range of cancers.
The experimental combination therapy described above was used in preclinical tests only and has not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans. This newly identified therapeutic strategy is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Yang and Stefano Di Biase as co-inventors.
The researchers recommend that people consult a doctor before incorporating a new supplement such as creatine into their routine as supplements can carry risks of drug interactions and other harmful side effects. There is concern that long-term use of creatine at high doses could damage the liver, kidneys or heart.

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Engineered killer T cells could provide long-lasting immunity against cancer

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More information: Journal of Experimental Medicine (2019). DOI: 10.1084/jem.20182044

https://medicalxpress.com/news/2019-10-creatine-powers-cells-cancer.html