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Friday, February 1, 2019

Protein Degradation: Finally, A Way To Treat ‘Undruggable’ Diseases?

A maddening syndrome has frustrated pharmaceutical companies for decades: the notion that most proteins in the human body are “undruggable.” But companies are challenging that idea now with a process called protein degradation.
Up to now, some diseases related to malfunctioning proteins — Alzheimer’s disease and several types of cancer, to name a few — can’t be treated with most pharmaceutical products.
Drug development in the works at a small biotech stock, plus a few Big Pharma companies such as Pfizer (PFE) and Merck(MRK), aims to change that. With protein degradation, drugs could hijack the body’s natural garbage disposal to rid patients of troublesome proteins.
One analyst calls protein degradation a multibillion-dollar opportunity that could even approach the $1 trillion mark. It could provide hope to countless patients with devastating diseases.
A small biotech company, Arvinas, went public in September on the premise that it could make protein degradation work. And pharmaceutical companies back a number of protein degradation firms, including Arvinas.
Arvinas (ARVN) has deals worth nearly $2 billion with Pfizer, Merck and Roche(RHHBY). Celgene (CELG), Novartis (NVS), GlaxoSmithKline (GSK) and Biogen (BIIB) have partnered with other companies.
The fact that big pharmaceutical companies have flocked to biotechs working in protein degradation says a lot, Aprilakis says.
“It’s incredibly telling for the promise of the technology and for just how exciting it is,” he said.

Pharmaceutical Companies Eye Protein Degradation

For decades, pharmaceutical companies have used drugs to inhibit problematic proteins.
A number of traditional drugs block excessive proteins. Researchers believe the buildup of amyloid or tau proteins could cause Alzheimer’s disease. Another rare disease, amyloidosis, is a result of abnormal protein that builds up in the heart or nerves.
In traditional drug development, pharmaceutical companies and biotech stocks look for proteins that, when mutated or in excess, cause disease. Researchers then create drugs that bind to specific proteins, thus blocking them and preventing further damage. (Looking for growth? Take a look at these top biotech stocks.)
But the method only works when the protein has a “groove” for the drug to grab onto, JMP’s Aprilakis says. And that’s an ongoing frustration in drug development. Estimates vary, but some researchers say only 20%-25% of proteins have the necessary groove to be inhibited.
Enter protein degradation. It’s a natural process in the body. When a protein mutates or nears the end of its life cycle, the cell tags it with another protein called ubiquitin. Ubiquitin signals to the proteasome — the cell’s trash compactor — that the protein is ready for degradation.
The degraded protein is “chewed up” into its amino acid and peptide components, Andrew Benowitz, senior director for Glaxo’s protein degradation unit, told IBD in an interview. The cell can then reuse those components.
Benowitz calls the proteasome “the garbage disposal” of the cell.

Sending Proteins To The Garbage Disposal

In terms of drug development, protein-degrading drugs wouldn’t need to have a secure binding to a protein. These drugs only need to circulate near a bad actor protein. Then, the drug recruits ubiquitin to ensure the problematic protein heads to the cell’s trash compactor.
“This is a very transient interaction,” Arvinas Chief Executive John Houston told IBD. The protein degradation process allows the medicine to do its job multiple times in one dose. Eventually, the drug leaves the body. This is key to staving off permanent side effects, he says.
https://research.investors.com/ibdchartswp.aspx?cht=pvc&type=daily&symbol=ARVN
JMP’s Aprilakis says the technology has the potential to be “totally disruptive.” If viable in human tests, protein degradation could treat any disease caused by a faulty protein, he says. Due to the potential for side effects, he acknowledges researchers will need to be picky when selecting proteins to degrade.
Arvinas is targeting androgen receptors in metastatic castration-resistant prostate cancer and estrogen receptors in metastatic breast cancer. The biotech company plans to begin clinical studies in prostate cancer early this year. Breast cancer tests will follow in mid-2019.
Houston expects Arvinas to have early data from its prostate cancer test in the second half of 2019. That could include PSA levels after treatment with a protein degrader. High levels of PSA, or prostate-specific antigens, are associated with prostate cancer. He expects to have breast-cancer data in mid-2020.
Piper Jaffray analyst Edward Tenthoff applauded Arvinas’ strategy in a recent research note. Scientists understand well the biology of prostate and breast cancers. He expects Arvinas to compare its breast-cancer drug against AstraZeneca‘s (AZN) rival drug Faslodex. (Learn more about biotech companies’ plans to attack cancer and other diseases in 2019.)

Partnerships Abound In Protein Degradation

Arvinas will likely be the first company to test protein degradation in human studies. But others are likely to follow suit. The technology has pharmaceutical companies putting up big investments.
Celgene is partnered with Evotec. Roche and Biogen are partnered with C4 Therapeutics. Glaxo and Kymera Therapeutics have a deal. Amgen‘s (AMGN) and Eli Lilly‘s (LLY) venture capital arms also funded Kymera. Evotec, C4 and Kymera are all private firms.
Others have academic partnerships. Novartis partners with researchers at the University of California, Berkeley, and privately owned Boehringer Ingelheim has a deal with the University of Dundee.
JMP’s Aprilakis notes the moves by large pharmaceutical companies are particularly interesting.
“I’ve noted Amgen, AstraZeneca, Glaxo, Novartis and Roche each have their own internal programs,” he said, “or are collaborating with other companies.”
Most pharmaceutical companies are mum on their specific targets. AstraZeneca is exploring protein degradation in oncology, cardiovascular, renal and metabolic and respiratory disease, a representative told IBD via email. But he wouldn’t say how far along the research is.
Glaxo’s Benowitz says the company doesn’t have a protein degrader in clinical studies yet. He wouldn’t comment on when Glaxo expects to enter clinical testing.

Areas Of Drug Development

Protein degradation is exciting because it’s “therapy-area agnostic,” Glaxo’s Benowitz said. The technology could work across multiple areas of drug development including oncology, cardiovascular, lung diseases, central nervous system disorders and more.
“I think what you would be looking for is diseases where the presence of a protein is what is causing disease,” he said. “You can ameliorate that by getting rid of the protein. In some diseases, you want more of the protein or to modify the function of the protein.”
JMP’s Aprilakis sees hope for protein degradation in oncology. For example, researchers agree a gene sequence known as KRAS provides codes for a protein with ties to pancreatic cancer. But there’s a “graveyard” of failed experiments in drug development trying to inhibit KRAS.
“We can’t drug KRAS,” he said. “But if you can knock out KRAS, you could be looking at your first drug for pancreatic cancer. It’s difficult to drug, but we may crack it with protein degradation.”
If successful, these proteins would no longer be “undruggable.”
“Difficult to drug is a better term,” he said.
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Novartis Under The Microscope With Novel Gene Therapy

The biotech world is feverishly awaiting the Food and Drug Administration’s potential approval of a gene therapy from Novartis (NVS), due in May.
Spark Therapeutics (ONCE) was the first biotech to grab approval in the U.S. for a gene therapy. Its drug, Luxturna, treats a rare blindness-causing disorder. But Novartis’ Zolgensma is targeting a much larger population of patients who suffer from spinal muscular atrophy. And that’s why it’s important.
Brad Loncar, a portfolio manager, calls 2019 a pivotal year for the gene therapy. Novartis has the potential to set an important precedent in gene therapy pricing. Other biotechs are also watching to see how Novartis builds up its manufacturing — a key challenge in the space.
“That’s an amazing therapy for a terrible disease,” Loncar told Investor’s Business Daily. “But, if after that gets approved, they have a hard time getting payers to buy into that and it has a poor launch, that’s going to have a bad effect on the entire gene therapy field.”

Why Gene Therapies Could Be Expensive

Spinal muscular atrophy results in muscle atrophy and weakness. The Spinal Muscular Atrophy Foundation estimates 10,000 to 25,000 children and adults in the U.S. are afflicted with it.
Spark’s Luxturna, on the other hand, targets an inherited retinal disease. An estimated 1,000-2,000 patients in the U.S. have vision loss due to the genetic mutations Luxturna targets, Spark says. Luxturna costs $425,000 per eye.
Novartis maintains its gene therapy would be cost effective at a price tag of $4 million to $5 million.
The reason is gene therapy could be a one-time treatment. So far, the data are promising but short-lived. Biotechs working in the space say the one-time payout could be less expensive than the lifetime cost of living with the disease — including chronic medicines and hospital visits.
Novartis also could take a clue from Biogen (BIIB) which sells Spinraza, the first approved treatment for spinal muscular atrophy. The drug, developed in a partnership with Ionis Pharmaceuticals (IONS), goes for $750,000 in the first year.

Will Insurers Pony Up For Gene Therapy?

But will insurance cover that cost? Audentes Therapeutics (BOLD) Chief Executive Matthew Paulson says biotechs will have to innovate on the commercial side. For Novartis, that could potentially mean value-based pricing where the drug’s price declines if the effect wears off over time.
“We’ve solved the scientific and development challenges,” he said during a recent talk at an industry conference. “But what if patients can’t get access because of challenges in the medical system?”
Bluebird Bio (BLUE) Chief Financial Officer Jeffrey Walsh says pricing, manufacturing and distribution will all get a face-lift as gene therapies become more popular. Bluebird is at a unique junction. The biotech works in gene therapy, gene editing and cell therapy.
“Novel therapies are coming in and they are going to change all of that,” he said during the conference. “I can’t see how the infrastructure looks the same — not just around pricing and distribution, but also how it’s going to get delivered.”

Cell Therapy Challenges Offer Some Clues

Manufacturing remains a key challenge for both cell and gene therapies.
It’s important to remember these are two different modalities. Gene therapy involves the transfer of genetic material — oftentimes within an emptied-out virus — and the uptake of appropriate cells in the body. Cell therapy involves the transfer of cells with key functions into a patient.
In medicine generally, it’s easiest to manufacture in batches. That’s not possible in current cell therapy which is tailored to individual patients.
Some companies, though, are working on the possibility of using donor cells. In this method, known as allogeneic cell therapy, the treatment could become an “off-the-shelf” drug.

Quick Manufacturing Moves

Meanwhile, Novartis’ gene therapy will go after a bigger group of patients than Spark’s Luxturna, so its manufacturing efforts will be of interest to rivals.
Gene therapy ramped up much quicker than most expected, Bluebird’s Walsh said.
“I think as an industry we weren’t quite expecting the number of bold moves we needed to take to implement this unique care paradigm,” he said during the conference. “Now we’re getting out in the open all of the challenges of how to commercialize a therapy like this.”
He added: “We knew we were going to stumble because you’re trying to create something that doesn’t exist.”
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Biotech Investors: Mark Your Calendar For These February FDA Dates

The year got off to a slow start for the pharma sector from the perspective of regulatory decisions, with the partial government shutdown not helping matters.
FDA Commissioner Scott Gottlieb clarified that applications submitted before the shutdown will be reviewed using its limited carryover user fee but it will not accept any new applications until the shutdown ends.
Last week, Bristol-Myers Squibb Co BMY 0.99% decided to withdraw its sBLA for its lung cancer combo drug as certain data required by the FDA is less likely to be available within the review cycle of the current application.
PDUFA dates are deadlines for the FDA to review new drugs. The FDA is normally given 10 months to review new drugs. If a drug is selected for priority review, the FDA is allotted six months to review the drug. These time frames begin on the date that an NDA is accepted by the FDA as complete.
Here’re the key PDUFA dates scheduled for February.

Evolus Looks To Smile With Anti-Frown Drug

  • Company: Evolus Inc EOLS 12.11%
  • Type of Application: BLA
  • Candidate: DWP-450
  • Indication Glabellar lines, also known as frown lines
  • Date: Feb. 2
The original BLA was issued a complete response letter last May, citing issues with chemistry, manufacturing and controls processes. The FDA accepted a resubmission in late August. At that time, the company said it expects the approval to come through and plans a commercial launch in the U.S. in Spring 2019.
DWP-450 is talked up as a potential rival to Allergan plc AGN 0.06%‘s Botox.

Motif’s Antibiotic

  • Company: MOTIF BIO PLC/S ADR MTFB 9.22%
  • Type of Application: NDA
  • Candidate: Iclaprim
  • Indication acute bacterial skin and skin structure infections (ABSSSI)
  • Date: Feb. 13
Motif announced FDA acceptance of the NDA for Iclaprim, a gram-positive investigational antibiotic last August. The application, which has been accorded priority review designation, was filed based on data from two Phase 3 trials, namely REVIVE-1 and REVIVE-2.

Bausch Health Has Twin PDUFA Dates

  • Company: Bausch Health Companies Inc BHC 0.29%
  • Type of Application: NDA (both)
  • Candidate: Duobrii (Plaque psoriasis) as well as Loteprednol gel 0.38 percent
  • Date: Feb. 15/Feb. 25
Duobrii, chemically halobetasol propionate and tazarotene, a corticosteroid and retinoid combination, is being studied for treating plaque psoriasis. The FDA handed down a complete response letter for the lotion in June, with the agency raising questions about pharmacokinetic data. Following a resubmission done in August, the FDA set a new PDUFA date of Feb. 15.
Meanwhile, Bausch’s subsidiary Baush + Lomb had submitted the NDA for its sub-micron loteprednol etabonate ophthalmic gel in July. It’s being studied for the treatment of post-operative inflammation and pain following ocular surgery.

Will Merck’s Wonder Cancer Drug Garner Yet Another Approval?

  • Company: Merck & Co., Inc. MRK 2.58%
  • Type of Application: sBLA
  • Candidate: Keytruda
  • Indication as adjuvant therapy in the treatment of patients with resected, high-risk stage III melanoma
  • Date: Feb. 16
The sBLA, which was accepted by the agency in June, is based on a significant benefit in recurrence-free survival demonstrated in the pivotal Phase 3 EORTC1325/ KEYNOTE-054 trial.

Incyte/Novartis Seek Approval For Jakafi In GVHD

  • Company: Incyte Corporation INCY 2.88%/ Novartis AG NVS 0.16%
  • Type of Application: sNDA
  • Candidate: Ruxolitinib
  • Indication acute graft-versus-host disease, or GVHD, in patients who have had an inadequate response to corticosteroids.
  • Date: Feb. 24
The sNDA was accepted with a priority review designation and was supported by data from the REACH1 study. GVHD is a condition that occur after an allogeneic transplant. In GVHD, the donated bone marrow or peripheral blood stem cells view the recipient’s body as foreign and attack the body.
Ruxolitinib was initially approved for the treatment of people with polycythemia vera and later for intermediate or high-risk myelofibrosis. It’s marketed in the U.S. by Incyte and by Novartis outside of the U.S. under the brand name Jakavi.

Novo Nordisk Awaits FDA Nod For Blood Disorder Drug

  • Company: Novo Nordisk A/S NVO 3.38%
  • Type of Application: BLA
  • Candidate: N8-GP
  • Indication: Hemophilia A
  • Date: Feb. 26 (estimated)
N8-GP is an extended half-life factor VIII for treatment of people with hemophilia A, a blood disorder. Novo Nordisk submitted the BLA last February. Assuming the application was accepted within the customary 60-day period, and providing for 10 months for a standard review, the PDUFA date is expected to fall in February.
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Calories of frequently purchased restaurant meals: multi-country study

BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4864 (Published 12 December 2018)Cite this as: BMJ 2018;363:k4864

Abstract

Objective To measure the energy content of frequently ordered meals from full service and fast food restaurants in five countries and compare values with US data.
Design Cross sectional survey.
Setting 223 meals from 111 randomly selected full service and fast food restaurants serving popular cuisines in Brazil, China, Finland, Ghana, and India were the primary sampling unit; 10 meals from five worksite canteens were also studied in Finland. The observational unit was frequently ordered meals in selected restaurants.
Main outcome measure Meal energy content, measured by bomb calorimetry.
Results Compared with the US, weighted mean energy of restaurant meals was lower only in China (719 (95% confidence interval 646 to 799) kcal versus 1088 (1002 to 1181) kcal; P<0.001). In analysis of variance models, fast food contained 33% less energy than full service meals (P<0.001). In Finland, worksite canteens provided 25% less energy than full service and fast food restaurants (mean 880 (SD 156) versus 1166 (298); P=0.009). Country, restaurant type, number of meal components, and meal weight predicted meal energy in a factorial analysis of variance (R2=0.62, P<0.001). Ninety four per cent of full service meals and 72% of fast food meals contained at least 600 kcal. Modeling indicated that, except in China, consuming current servings of a full service and a fast food meal daily would supply between 70% and 120% of the daily energy requirements for a sedentary woman, without additional meals, drinks, snacks, appetizers, or desserts.
Conclusion Very high dietary energy content of both full service and fast food restaurant meals is a widespread phenomenon that is probably supporting global obesity and provides a valid intervention target.
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Entera Bio: Positive Guidance from FDA on Oral Hormone for Osteoporosis

Entera Bio Ltd. (Nasdaq: ENTX), announced today the positive outcome of a pre-IND meeting held with the US Food and Drug Administration (FDA) to discuss the Company’s development plan for Oral PTH for the treatment of osteoporosis. The feedback and guidance were summarized in the formal meeting minutes that Entera subsequently received from the FDA.  In addition to discussing various aspects of the nonclinical and clinical development plan, the meeting focused on the 505 b(2) regulatory pathway and the use of bone mineral density (BMD) rather than fracture incidence as the primary endpoint to support a New Drug Application (NDA). Based on the FDA’s response, Entera believes that the Phase 3 study may use BMD as the primary efficacy endpoint and that a fracture endpoint study will not be required.
“We were very pleased with the positive pre-IND meeting with the FDA in late 2018 and greatly appreciate the detailed guidance in FDA’s official minutes of the meeting,” stated Dr. Arthur Santora, Chief Medical Officer of Entera Bio. “As we anticipated, the FDA expressed its willingness to accept Entera’s plan to bridge nonclinical and clinical study data for our oral PTH (1-34) to data from prior studies of the commercially available PTH (1-34) injection (Forteo®). The FDA provided us with an overall direction for the nonclinical and clinical and regulatory path forward; successful bridging between the effects of oral PTH and subcutaneous PTH would allow Entera to conduct a Phase 3 study with a bone mineral density efficacy endpoint rather than fracture endpoint study.  While a BMD endpoint study comparing Oral PTH and subcutaneous PTH is still a large study, it would be substantially less costly and several years shorter than a fracture endpoint trial.”
Entera Bio’s Oral PTH (1-34) has been shown to produce a blood level profile similar to Forteo® (teriparatide), which was approved by the FDA in 2002 for the treatment of osteoporosis in men and postmenopausal women who are at high risk for fractures. “Forteo® is currently one of two injectable treatments for osteoporosis which are classified by the FDA as “bone building” (anabolic). The potential osteoporosis drug market is estimated at almost $20 billion worldwide. If a “blockbuster” drug with comparable efficacy to injectable Forteo® were available as a once-daily pill, we believe that it would potentially win market share and significantly expand the market for anabolic agents to osteoporotic patients at high risk of fracture who are reluctant to use an injectable medication,” stated Dr. Phillip Schwartz, CEO of Entera Bio.
Post FDA feedback, the Company is proceeding with the development of EB-613 for osteoporosis. The next step in this clinical development program will be to conduct a dose-ranging study in approximately 140 osteoporosis patients, in order to study both safety and the optimal dose to advance into a Phase 3 pivotal study. This dose-ranging study will commence in the first half of this year and will include bone marker, bone mineral density and safety endpoints.  The Company will be conducting several nonclinical safety assessment studies in parallel.  Assuming a favorable outcome of these studies, the Company is planning a single Phase 3, multicenter study comparing Oral PTH with Forteo® over a 12-month treatment period, to begin in 2020. Although still at the early stages of planning, such a study would likely be conducted in the U.S. and Europe, and potentially enroll between 600 and 800 patients in total, depending on statistical powering assumptions.
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Endovascular Therapy: Glue Works When Coils Fail

In situations where coils or other methods didn’t complete the embolization job, doctors reached into their bag of off-label tricks and found cyanoacrylate glue — approved for use in cerebral aneurysms — which appeared to be successful in closing difficult endoleaks and hemorrhages elsewhere in the body, researchers reported here.
In a retrospective look at the off-label use of cyanoacrylate glue (n-butyl-2-cyanoacrylate, Trufill), Amit Ramjit, MD, a resident in diagnostic radiology at Staten Island (New York) University Hospital, Northwell Health, identified 14 cases in which the substance was used by the hospital’s five interventional radiologists from 2016 to 2018.
“Cyanoacrylate glue is used relatively frequently for non-cerebral measures, as reported in the medical literature,” Ramjit told MedPage Today at his poster presentation at the 2019 International Symposium on Endovascular Therapy. “But because these uses are off-label, it had not been extensively studied. Cyanoacrylate glue can be used to embolize visceral aneurysms, gastrointestinal hemorrhage, or reduce flow in arteriovenous fistulas.”
He suggested that “liquid embolic agents can offer the interventional radiologist another tool to treat these various conditions when traditional means fail.”
“Due to the rapid polymerization of cyanoacrylate when in contact with blood, glue is considered to require more technical expertise relative to re-deployable endovascular coils,” Ramjit continued. “The most commonly cited risk of liquid embolic agents is non-target embolization or bowel ischemia.”
Ramjit explained that in reviewing his hospitals records, he found that the glue was most commonly used in endoleaks, such as those occurring after placement of abdominal aortic aneurysm (AAA) graft stents. Six of the 14 cases described were aimed at fixing this problem, especially when coils or other embolization procedures failed or were not practical.
“The AAAs are probably the most common endoleak situation we have,” he said. The interventional radiologist would seek help in stopping an endoleak after the device has been positioned. “The first choice is to use coils but then, for whatever reason, there is still evidence of bleeding, so we use the glue,” Ramjit said. “The glue can flow into smaller places, which gives it a unique role in some of these cases.”
He said that the off-label use of the glue is most often employed as a second-line treatment to correct ongoing bleeding, but there are also cases in which because of the size or location of the bleed, the glue would be applied as a first-line treatment. “Our institution routinely uses cyanoacrylate glue as an option in certain situations, primarily where superselective cannulation cannot technically be achieved,” he said.
“In all these cases, we just had to employ the glue one time,” Ramjit said, adding that technical success was achieved in all cases. He described one case in which the glue was deployed after several attempts to correct colonic bleeding. The patient eventually required surgery and colostomy, but Ramjit said he did not consider that the glue caused this complication.
He said that in five cases the glue was used in emergent gastrointestinal or postoperative hemorrhage. The glue was also used in cases of arteriovenous fistula or arteriovenous malformation.
Francisco Contreras, MD, an interventional radiologist at Florida State University, University of Central Florida, and Florida Hospital in Orlando, who was not involved with the study, told MedPage Today that using glue in situations such as endoleaks is a reasonable approach: “Even though cyanoacrylate glue is approved for use in the brain, we often will adopt technology that is aimed at one part of the body and use it in other areas where things are similar in terms of physiology.”
Ramjit and Contreras disclosed no relevant relationships with industry.
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Early Norepinephrine Stabilizes Septic Shock Patients Faster

The early use of norepinephrine in patients with septic shock was associated with increased shock control within 6 hours of diagnosis in a randomized, placebo-controlled trial conducted in Thailand.
Patients treated with early norepinephrine in the single-center, 310-patient study also showed about half the rate of cardiogenic pulmonary edema. But a trend toward improved 28-day survival did not achieve statistical significance.
The phase II randomized trial is the among the first to assess the benefits of early norepinephrine administration during sepsis-related hypotension resuscitation on surrogate shock control endpoints.
Writing in the American Journal of Respiratory and Critical Care Medicine, Chairat Permpikul, MD, of Mahidol University, Bangkok, Thailand, and colleagues, noted that additional studies will be needed to confirm the findings before early norepinephrine is introduced into clinical resuscitation practice.
“Future studies should investigate the effect of early norepinephrine on organ dysfunction and mortality,” they wrote.
In a press release, Permpikul explained that the early use of norepinephrine at the beginning of resuscitation has been widely advocated, including in the “Surviving Sepsis Campaign Bundle.”
“However, firm supporting evidence is lacking: therefore, we conducted a randomized control study to examine the precise benefits of administering norepinephrine at the beginning of sepsis/septic shock resuscitation.”
The study was conducted at a single hospital in Bangkok, Thailand, from October 2013 to March 2017. During this period, adult patients who presented to the emergency department with arterial blood pressure lower than 65 mm Hg and infection as the suspected cause were eligible for enrollment if they met the diagnostic criteria for sepsis according to the Surviving Sepsis Campaign’s 2012 guidelines and met other study entry requirements.
After enrollment, 310 patients were randomized 1:1 to receive either early norepinephrine or placebo along with fluid resuscitation at the initiation of hypotension resuscitation. The primary outcome was shock control rate, defined as achievement of mean arterial blood pressure ≥65 mm Hg, with urine flow ≥0.5 mL/kg/h for 2 consecutive hours, or decreased serum lactate ≥10% from baseline by 6 hours after diagnosis.
Patients in both groups were well matched in background characteristics and disease severity, but median time from emergency room arrival to norepinephrine administration was significantly shorter in the early norepinephrine group (93 vs 192 minutes; P<0.001).
Among the main findings:
  • Shock control rate by 6 hours was significantly higher in early norepinephrine group (76.1% vs 48.4%; P<0.001).
  • Twenty-eight day mortality was not different between groups: 15.5% in the early norepinephrine group versus 21.9% in the standard treatment group (P=0.15).
  • The early norepinephrine group was associated with lower incidences of cardiogenic pulmonary edema (14.4% vs 27.7%; P=0.004) and new-onset arrhythmia (11% vs 20%; P=0.03).
“The results of our study, which is the first randomized controlled trial to investigate the effect of early norepinephrine, revealed a shorter shock interval in the early norepinephrine group than in the standard treatment group,” the researchers wrote.
They addressed the concern that early norepinephrine use could lead to vasoconstriction of abdominal organs leading to splanchnic hypoperfusion.
“Splanchnic hypoperfusion is an important concern when norepinephrine is given early,” they wrote. “Vasoconstriction induced by norepinephrine may aggravate internal organ ischemia and lead to patient deterioration. Recent studies examined this concern and revealed that norepinephrine did not alter perfusion to the gut and kidney. Although no objective measures were made in the present study, there was no difference in prevalence of organ failure between groups.”
Study limitations cited by the researchers include the fact it was conducted at a single hospital, not all patients were treated in the hospital’s ICU, and resuscitation fluid rates were not standardized, resulting in variations that may have biased results.
“Physicians who decide to apply the results of this study to their routine clinical practice should carefully evaluate the context of this study and compare it with their own situation and setting,” they concluded.
“A multicenter trial with a larger population size, control of the rate of fluid resuscitation, and the timing of norepinephrine initiation is certainly required to assess the survival benefit of early norepinephrine as an intervention.”
This study was funded by Siriraj Critical Care Research Fund.
The researchers reported no relevant relationships with industry related to this study.
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