U.S. review of CVS deal for Aetna may end soon

The U.S. Justice Department’s antitrust review of CVS Health Corp’s planned purchase of Aetna Inc may conclude soon, a source familiar with the review said on Monday.

That said, arranging divestitures needed to resolve antitrust concerns in the proposed transaction takes time and it is not clear that possible approval will come in September, said the source.

The $69 billion deal was announced in December.

https://www.marketscreener.com/CVS-HEALTH-CORPORATION-12230/news/CVS-Health-U-S-review-of-CVS-deal-for-Aetna-may-end-soon-27273301/

‘No Documented Reason’ for 1 in 3 Outpatient Opioid Prescriptions

The United States is in the grip of an epidemic of opioid painkiller addiction. But now, research shows that in nearly a third of cases there’s no medical reason documented for opioids prescribed in an outpatient setting.

The findings show the need for stricter rules on recording patients’ needs for the highly addictive drugs, the research team said.

When medical records fail to spell out the reason a patient got an opioid painkiller, this “undermines our efforts to understand physician prescribing patterns and curtails our ability to stem overprescribing,” study lead author Dr. Tisamarie Sherry said in a Harvard Medical School news release. She’s an instructor in medicine at Harvard and an associate physician at Brigham and Women’s Hospital in Boston.

One addiction specialist said real solutions to overprescribing are needed.

“Despite numerous policy changes, recent analyses suggest national opioid prescribing rates have not meaningfully decreased,” noted Dr. Harshal Kirane, who directs addiction services at Staten Island University Hospital in New York City.

Kirane described the rate of poorly documented prescribing seen in the study as “alarming,” suggesting that “lax prescribing practices remain widespread.”

There were more than 63,600 drug overdose deaths in the United States in 2016, according to the U.S. Centers for Disease Control and Prevention. About two-thirds involved an opioid. On average, 115 Americans die every day from an opioid overdose.

In the new study, Sherry’s group tracked data on opioid prescriptions given during nearly 809 million doctor’s office visits nationwide between 2006 and 2015.

Of those prescriptions, just over 5 percent were for cancer-related pain and 66.4 percent were for treating non-cancer pain.

For the other 28.5 percent, there was no record of pain or a pain-related condition, the researchers said.

Of the prescriptions for non-cancer pain, the most common conditions included back pain, diabetes and arthritis.

Of the prescriptions with no record of pain, the most common conditions were high blood pressure, high cholesterol and opioid addiction (2.2 percent).

Prescriptions with no record of pain were more common in visits where opioid prescriptions were being renewed (30.5 percent) than in visits that involved new prescriptions (22.7 percent), the study found.

The researchers said there’s been a sharp rise in opioid prescriptions in the past 20 years — an increase that exceeds actual rates of pain in the population. It’s possible that too often, opioids are being prescribed for conditions that don’t warrant treatment with the drugs, Sherry and colleagues said.

Dr. Robert Glatter is an emergency physician at Lenox Hill Hospital in New York City. He’s seen the ravages of opioid addiction firsthand, and believes many cases were avoidable.

When patients come to a doctor seeking pain relief, “we have to ask ourselves why we are prescribing an opioid in the first place?” Glatter said.

“Are there other alternatives that may work, but also help reduce risks for side effects, dependence, abuse or misuse?” he said.

And even if an initial prescription of an opioid was justified, that “does not automatically justify a refill of that medication for future and ongoing care,” Glatter said.

He said even though the paperwork might be time-consuming, it’s important for physicians to record their rationale for giving someone an opioid.

Non-opioid medications and other alternative approaches must be considered, Glatter said. All of this “requires creativity and taking time to ‘think outside the box,’ ” he said. “We owe it to our patients and their families.”

The study was published Sept. 10 in Annals of Internal Medicine.

More information

The U.S. National Institute on Drug Abuse has more about prescription opioids.

SOURCES: Harshal Kirane, M.D., director, addiction services, Staten Island University Hospital, New York City; Robert Glatter, M.D., emergency physician, Lenox Hill Hospital, New York City; Harvard Medical School, news release, Sept. 10, 2018

https://consumer.healthday.com/mental-health-information-25/addiction-news-6/no-documented-reason-for-1-in-3-outpatient-opioid-rxs-study-737534.html

Chronic pain surgery called too risky, costly

With high costs, risks of adverse events, and scant evidence of effectiveness, surgery for chronic pain is a prime example of overutilization of healthcare services.

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KEY TAKEAWAYS

More than 100 million Americans suffer with chronic pain.

Annual costs associated with chronic pain range as high as $635 billion.

Research shows the risk of adverse events is significantly higher for invasive procedures (12%) than sham procedures (4%).

There is inadequate evidence to justify surgical procedures to treat chronic pain, recent research shows.

“Given their high cost and safety concerns, more rigorous studies are required before invasive procedures are routinely used for patients with chronic pain,” researchers reported this month in the journal Pain Medicine.

Chronic pain is a widespread and costly condition in the United States, affecting more than 100 million people and costing as much as $635 billion annually.

The Pain Medicine research features a review of 25 clinical trials involving 2,000 patients with conditions including lower back pain, arthritis, angina, abdominal pain, and endometriosis.

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The researchers compared outcomes for invasive procedures and sham procedures. In a sham procedure, the patient goes through the rituals of a surgical procedure such as preparations and set up, anesthesia if needed, and tissue penetration. However, the tissue is not manipulated in a way that is thought to correct the underlying problem, and the patient is closed up or the instrument withdrawn.

For adverse events, there was a significantly higher risk for invasive procedures (12%) than sham procedures (4%).

The risks associated with surgery for chronic pain are too high and more clinical trials should be conducted, the researchers wrote.

“The risks of surgical and invasive procedures are not minor and appear to be higher with real compared with sham procedures. Risks in both groups include anesthesia, permanent injury to the body, psychologic stress, and time, cost, and productivity losses. Without more rigorous examination, large numbers of patients are exposed to risky and possibly unnecessary procedures.”

The lead author of the research, Wayne Jonas, MD, executive director of Samueli Integrative Health Programs at H&S Ventures in Alexandria, Virginia, says physicians and chronic pain patients should consider surgery carefully.

“Right now, the scientific evidence does not justify doing these procedures for chronic pain. However, patients and circumstances vary, and physicians and patients need to decide individually what’s appropriate for any particular patient. Taking this evidence and discussing it with the patient in shared decision-making is the best approach,” Jonas told HealthLeaders last week.

ALTERNATIVES TO SURGERY

Surgery for chronic pain is a prime example of overutilizationof healthcare services and poor care coordination, Jonas says.

“It takes a multidisciplinary team of healthcare professionals at its center to help manage chronic pain. Yet one of the things the U.S. healthcare system as a whole systematically fails at is fostering coordinated care. Most care is piecemeal with little communication among providers. So, people with chronic pain are left to jump from provider to provider, often undergoing unnecessary, costly, duplicative procedures, and taking ineffective drugs—with ultimately little relief.”

There are several options for treating chronic pain that do not involve invasive procedures or addictive medications such as opioids, he says.

“The American College of Physicians, the Centers for Disease Control and Prevention, the National Institutes of Health, and many other national bodies have recommended nonpharmacological approaches for the treatment of chronic pain. These include acupuncture, yoga, massage, and other such approaches. In addition, behavioral medicine has been demonstrated for many decades to be effective for chronic pain.”

https://www.healthleadersmedia.com/clinical-care/chronic-pain-surgery-called-too-risky-and-too-costly

DOJ clears Cigna deal with Express Scripts

Cigna (CI) announced that the Antitrust Division of the United States Department of Justice has cleared its pending merger with Express Scripts (ESRX). Shares of Aetna (AET), which has agreed to merge with CVS Health (CVS), are up 1% following Cigna’s announcement.
https://thefly.com/landingPageNews.php?id=2791567

JUUL Presents on Cytotoxicity Study at Tobacco Science Research Conference

JUUL Labs, Inc. today announced results from a preliminary study on the cytotoxicity of aerosol generated from JUUL’s Menthol, Mint and Cucumber 5% nicotine-e-liquid filled pods. The findings, “Neutral Red Uptake (NRU) Cytotoxicity Analysis of Aerosol Generated from a Temperature-Regulated Nicotine-Salt Based Ends Product,” were presented at a poster session at the 72^ndTobacco Science Research Conference in Memphis, TN.

In accordance with the Organisation for Economic Co-operation and Development (OECD) guidelines, an independent contract laboratory, Enthalpy Analytical, measured and compared the toxicity to living cells of aerosol generated from JUUL’s Menthol, Mint and Cucumber 5% nicotine-e-liquid filled pods with that of tobacco cigarettes. The study demonstrated no significant aerosol toxicity at any of the observed concentrations for JUUL’s Menthol, Mint and Cucumber pods compared to a cigarette control.

“We are encouraged by the results of this study, in which tested aerosols generated from JUUL were not cytotoxic to living cells,” said Dr. Manoj Misra, study author and head of Toxicology at JUUL Labs. “These findings add to the growing body of evidence regarding use of JUUL as an alternative to combustible cigarettes, and we are committed to future rigorous, independent and peer-reviewed clinical trials and behavioral studies.”

Authors of the study include Dr. Manoj Misra of JUUL Labs and Drs. I. Gene Gillman and Pooja Desai of Enthalpy Analytical.

https://www.biospace.com/article/releases/juul-labs-presents-findings-from-cytotoxicity-study-at-the-tobacco-science-research-conference/

Argenx moves to make the most of its lead

Promising mid-stage data in a third indication for efgartigimod have given the Belgian company another boost.

Argenx’s efgartigimod is one of the leading projects to promise an alternative to decades-old therapies like plasma exchange and intravenous immunoglobulins. And, after announcing success in a mid-stage study in a third indication today, the Belgian company made it clear that it wants to win the race to market.

Having started a phase III trial in in generalised myasthenia gravis this month, Argenx today said it would push into pivotal trials in primary immune thrombocytopenia (ITP) as soon as possible. The mid-stage data in ITP were certainly encouraging, though having been generated in a small patient set the usual warnings apply.

Only topline data were released from the trial, which enrolled 38 patients with primary ITP. Response rates were encouraging, as the table below shows, and seem to compare favourably with one of efgartigimod’s biggest competitors, UCB’s rozanolixizumab.

Both projects work by reducing the levels of IgG circulating in the body, which is the goal of treatments for IgG-mediated autoimmune diseases like ITP. Both bind to FcRn (neonatal Fc receptor), which controls the recycling of IgG, though UCB has taken an antibody approach and Argenx is using an antibody fragment, specifically the Fc-portion of an IgG1 antibody.

Aside from the usual caveats of cross-trial comparison, it should be noted that the UCB study did not have a placebo arm; Argenx said the placebo response in its study was surprisingly high. On a conference call today this was blamed on one individual patient who had a dramatic and seemingly spontaneous rebound in platelet count that is virtually never seen.

RACING TO MARKET? ITP TRIALS FOR FC-TARGETING PROJECTS
	Efgartigimod			Rozanolixizumab (interim results)
	5mg/kg (n=6)	10mg/kg (n=6)	Placebo (n=3)	4 mg/kg (n=15)	7 mg/kg (n=13)
Clinically relevant improvement in platelet counts (≥50×109/l)	46%	46%	25%	53%	31%
Source: Company press releases.

In the coming weeks UCB will unveil the final results from its trial of rozanolixizumab in ITP, which will include additional dosing groups. Both companies are expected to hold presentations at this year’s Ash conference in December, when investors should get a much clearer picture of these projects’ safety and efficacy profiles.

Potentially, however, UCB still holds an important card in this race. Rozanolixizumab is already being tested in a subcutaneous formulation, while efgartigimod will be delivered intravenously across its pivotal programme.

A subcutaneous formulation will enter phase II shortly, Argenx stressed today. But, if efgartigimod fails to demonstrate real safety or efficacy advantages over the UCB project, Argenx could find its pole position quickly eroded by a more convenient contender that is not that far behind.

Weighty expectations

For now, however, the sellside appears convinced that efgartigimod has a rosy future. Exuberant sellside analysts expect it to reach the market in 2020 and generate sales of $1.9bn by 2024, according to consensus data from EvaluatePharma – huge numbers to be attached to a project that has only recently gone into phase III.

Those forecasts equate to an NPV of $6.5bn, making efgartigimod the industry’s most valuable unpartnered asset, a recent Vantage analysis found (Most valuable unpartnered assets reveal a changing of the guard, August 14, 2018).

Investors are taking a slightly more cautious stance, but have still embraced the Argenx story pretty enthusiastically; the company’s market cap currently stands at $3.1bn.

Executives clearly believe that speed is of the essence here. Another contender from Syntimmune is also looking encouraging, so Argenx is right to be looking over its shoulder. But, with such huge expectations already attached to efgartigimod, Argenx cannot trip up in its rush to market.

LEADING ANTI-FCRN ASSETS
Product	Company	Mechanism	Administration
Phase III
Efgartigimod (ARGX-113)	Argenx	Anti-FcRn Mab (fragment)	Weekly IV infusions tested phase III; subcutaneous phase II trials planned.
Phase II
Rozanolixizumab	UCB	Anti-FcRn MAb	Weekly subcutaneous doses tested in phase II.
Synt001	Syntimmune	Anti-FcRn MAb	Weekly IV infusions tested in phase I/IIa.
Source: EvaluatePharma.

http://www.evaluate.com/vantage/articles/news/trial-results/argenx-moves-make-most-its-lead

Allogene spells out its interest in Cellectis

As Allogene moves to follow Autolus onto the public markets, its IPO document could give hope that Cellectis’s allogeneic assets will at long last make meaningful progress through development.

Since two big events a year ago, when Gilead bought Kite Pharma for $11.9bn and Novartis’s Kymriah became the world’s first CAR-T therapy, investors interested in cell therapy have had little to shout about. But now there are signs of a resurgence.

The latest came on Friday, as the team that sold Kite revealed that its new venture, Allogene, would seek a $100m flotation – barely five months after being founded. Allogene is now Cellectis’s key partner, and so investors in the French group should be poring over newly revealed information in the IPO document.

The most interesting details concern the pipeline assets on which Allogene will focus. Most of these date back to Cellectis’s initial alliance with Pfizer, focusing on the discovery of 15 antigens of which only BCMA and EGFRvIII had been disclosed.

Allogene, of course, took over Pfizer’s rights to this deal, as well as rights to Cellectis’s lead, UCART19, which Pfizer had licensed from Cellectis’s partner Servier (Pfizer washes its hands of Cellectis, April 3, 2018). Allogene’s IPO filing also reveals previously secret financial terms of this last tie-up.

ALLOGENE PIPELINE
Antigen target	Asset	Detail
CD19	UCART19	Ongoing phase I trials in paediatric & adult ALL
CD19	ALLO-501	NHL; manufacturing differs from UCART19
BCMA*	ALLO-715	Multiple myeloma IND filing 2019
Flt3*	ALLO-819	AML, same target as Rydapt
CD70*	Unnamed	NHL & renal cell cancer, same target as cusatuzumab
DLL3*	Unnamed	SCLC, same target as Rova-T
CD52	ALLO-647	Lymphodepleting MAb, same target as Campath
Note: *Talen-edited, allogeneic CAR-Ts derived from 15-target alliance between Pfizer and Cellectis. Source: Allogene S-1 filing.

As for targets, Allogene says it will continue to pursue BCMA, fast becoming a crowded space, and newly discloses a focus on Flt3, CD70 and DLL3, which are far less popular with CAR-T players. DLL3 is the target of Abbvie’s ill-fated Rova-T, so Allogene will hope that a CAR-T approach delivers better efficacy than an antibody-drug conjugate.

ALLO-501 is structurally identical to UCART19, but uses a different manufacturing process, while ALLO-647 seems to be an attempt to develop a better lymphodepleting chemo than Campath. It appears that the EGFRvIII asset is not being taken forward.

The IPO proceeds will primarily fund UCART19, an asset that has proceeded at a glacial pace since clinical trials began in 2016. If Pfizer had lost interest in UCART19 then Allogene’s involvement will be viewed positively, and investors will also note the light the IPO document sheds on the details of the 2015 deal under which Pfizer acquired rights to UCART19.

This asset had been optioned to Servier, and Pfizer outmanoeuvred Cellectis by licensing it directly from Servier once that company had exercised its option with Cellectis. Until now all that was known was that the exercise, announced on November 19, 2015, cost Servier $38.2m up front, plus $300m in milestones.

Allogene’s IPO document reveals that Pfizer’s end of the deal cost the US big pharma giant just $29m up front and $381.5m in milestones, making Servier’s acquiescence seem puzzling. Moreover, Allogene states that the Pfizer/Servier deal was done “in October 2015”, meaning that by the time Servier triggered the Cellectis option in November the asset was effectively already Pfizer’s.

Resurgence

Whatever the details, the fact that Allogene is already attempting to float is remarkable. The company was born with a huge, $300m series A financing round in April, and this month added $100m in private cash.

In June the UK CAR-T player Autolus floated in a $150m listing, and the relatively early development stage at which both companies are going public will raise eyebrows. That said, if this is the sign of a resurgence, then neither company should find it difficult to raise more cash on Nasdaq.

Much of the sentiment behind Allogene stems from Arie Belldegrun and David Chang, the management team that sold Kite to Gilead. Both now run Allogene, and have attracted numerous other key ex-Kite employees – though one, Margo Roberts, inventor of an important Kite patent and formerly chief scientific officer, passed up this opportunity and recently emerged as a director of Celyad.

The next move from another private cell therapy group, Tmunity, based on work at University of Pennsylvania and run by Oz Azam, former head of cell therapy at Novartis, is eagerly awaited.

http://www.evaluate.com/vantage/articles/news/deals/allogene-spells-out-its-interest-cellectis