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.

https://www.benzinga.com/general/biotech/19/02/13041771/attention-biotech-investors-mark-your-calendar-for-these-february-pdu

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

https://sandpit.bmj.com/graphics/2018/meals/index.html

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.

https://www.bmj.com/content/363/bmj.k4864

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.

https://globenewswire.com/news-release/2019/01/31/1708294/0/en/Entera-Bio-Announces-Positive-Feedback-and-Guidance-from-the-US-FDA-Regarding-its-Development-Plans-for-Oral-PTH-in-Osteoporosis.html

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.

• Primary Source

  International Symposium on Endovascular Therapy

  Source Reference: Ramjit A, et al “Off-Label Use of Cyanoacrylate Glue in Interventional Radiology: Single-Institution Retrospective Review” ISET 2019, Abstract 52.

https://www.medpagetoday.com/meetingcoverage/additionalmeetings/77794

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.

• Primary Source

  American Journal of Respiratory and Critical Care Medicine

  Source Reference: Permpikul C, et al “Early use of norepinephrine in septic shock resuscitation (CENSER): a randomized trial” AJRCCM 2019; DOI: 10.1164/rccm.201806-1034OC.

https://www.medpagetoday.com/criticalcare/sepsis/77787

Typhus Epidemic Worsens in LA

A veteran Los Angeles City Hall official is one of the latest victims of an epidemic of the infectious disease typhus that continues to worsen across LA County.

For months, LA County public health officials have said typhus is mainly hitting the homeless population.

But Deputy City Attorney Liz Greenwood, a veteran prosecutor, tells NBC4 she was diagnosed with typhus in November, after experiencing high fevers and excruciating headaches.

“It felt like somebody was driving railroad stakes through my eyes and out the back of my neck,” Greenwood told the I-Team. “Who gets typhus? It’s a medieval disease that’s caused by trash.”

Rats Could Be Causing Typhus Outbreak in Los Angeles

Armies of rats running through the streets of downtown Los Angeles are the suspected cause of a Typhus outbreak hitting the city. NBC4 I-Team’s Joel Grover reports for NBC4 News at 11 p.m. on Oct. 9, 2018.

(Published Wednesday, Oct. 10, 2018)

The Symptoms of Typhus

Greenwood believes she contracted typhus from fleas in her office at City Hall East. Fleas often live on rats, which congregate in the many heaps of trash that are visible across the city of LA, and are a breeding ground for typhus.

“There are rats in City Hall and City Hall East,” Greenwood added. “There are enormous rats and their tails are as long as their bodies.”

Last year set a new record for the number of typhus cases — 124 in LA County for the year, according to the California Department of Public Health.

Last October, Mayor Garcetti vowed to clean up piles of garbage throughout the city to combat the typhus epidemic.

The Mayor allocated millions of dollars to increase clean-ups of streets in the Skid Row area, known lately as “the typhus zone.”

Typhus Outbreak in L.A.: 5 Things to Know

There is an outbreak of typhus near downtown L.A. Here are five things to know about the disease.

(Published Wednesday, Oct. 10, 2018)

But four months later, the I-Team documented huge piles of garbage just outside the “typhus zone.”

“You can’t solve it (the typhus epidemic) until you hit the cause,” says Estela Lopez of the Downtown Industrial Business Improvement District, “and the cause of it is that you still have these mountains of trash.”

Added Greenwood: “This is a terrible illness and I wouldn’t wish this on anybody. But it’s not just homeless folks getting it.”

She believes the city should fumigate City Hall and City Hall East to protect the thousands of workers and visitors who could be at risk from getting typhus.

Responding to complaints from other city workers fearful of getting typhus, LA has already fumigated LAPD’s Central Division office and parts of the LAPD’s main headquarters.

Garcetti’s office did not respond to NBC4’s questions about why the city hasn’t fully fumigated City Hall buildings as well.

Increased Effort to Stop Typhus Outbreak in LA County

A typhus outbreak across LA County is creating a lot of concern. John Cádiz Klemack reports for NBC4 News at 6 p.m. on Oct. 9, 2018.

(Published Tuesday, Oct. 9, 2018)

Greenwood says she doesn’t want to return to work at City Hall East until the entire building is fumigated for typhus-carrying fleas.

“I am concerned about going back to work and getting this again, because I thought I was going to die,” Greenwood said.

Statement from Mayor Garcetti’s Office:

“Last fall we directed multiple City departments to begin a coordinated and comprehensive effort to improve cleanliness and protect public health in the Civic Center, including City Hall and City Hall East. In addition to increased trash collection and cleanings, aggressive action has been taken to address pests both in the buildings and in the surrounding outside areas — including abatement treatments and the filling of 60 rodent burrows and 114 tree wells. This work in busy and highly populated public buildings is executed carefully to protect workers and visitors, and the scheduling of extermination activities takes these factors into consideration.” — Vicki Curry, spokeswoman, city of Los Angeles

https://www.nbclosangeles.com/investigations/Typhus-Epidemic-Worsens-in-Los-Angeles-505166301.html

Cigna reports strong Q4, shrugs off potential impact of drug rebate plan

Insurance giant Cigna posted strong year-end results following its merger with Express Scripts.

Cigna pulled in $49 billion in revenue for the year, a 15% increase over 2017. Its income from operations was $3.6 billion or $14.22 a share, up more than 30% over $2.7 billion, or $8.77 a share, in 2017.

While the year-end results did not meet analysts expectations, Cigna reported a strong fourth quarter with $14.3 billion in revenue for the quarter ending Dec. 31, up more than 35% compared to revenue of $10.6 billion in the same quarter of 2017.

The insurer reported earnings of $647 million, or $2.46 a share in the fourth quarter, up 33% from $483 million, or $1.83 a share in the fourth quarter of 2017. Revenue, customer, and earnings growth were driven by continued innovation across the business, said David Cordani, president and chief executive officer, in a statement: “We enter 2019 further strengthened by our combination with Express Scripts and positioned to deliver outstanding growth fueled by accelerated innovation that will improve whole person health and affordability for customers and clients.”

 

In December, Cigna officially absorbed one of the largest pharmacy benefit managers in the country with its $67 billion purchase of Express Scripts. However, these fourth-quarter earnings come just a day after HHS announced a plan to eliminate drug rebates to pharmacy benefit managers to instead require them to be passed on to consumers, in what’s expected to be a hit to the industry.

The Trump administration said it plans to eliminate safe harbor protections for drug rebates negotiated by pharmacy benefit managers. Department of Health and Human Services Secretary Alex Azar said in a statement that eliminating the safe harbors would increase transparency in the black box of the pharmacy supply chain.

When asked about the proposed rebate rule, Cordani shrugged it off, saying it would “not have a meaningful impact on our growth or earnings trajectory” and said they are not considering it a “headwind” in 2019.

“The proposed rule, as it will be evaluated over the next 60 days, applies to Medicare Advantage and PDP. The mechanisms that exist in terms of the way rates are built up for Medicare Advantage, PDP, largely by design, flow and respect the rebates and pass-through the way the rates are built so we don’t see a major implication to that business portfolio,” Cordani said.

It does not apply to the commercial marketplace, Cordani said in regards to a question about whether the rule was expected to have a broader impact or potentially create a two-tiered system.

He did say Cigna sees some opportunities in the proposed rule.

“For example, it provides a mechanism to even further accelerate value-based care programs with the pharmaceutical manufacturers,” Cordani said. “You recall from the day we announced our proposed combination on March 8, we talked about how that is an important initiative that we passionately believe in. This will provide some accelerant to that. … But big picture, we do not see it having a material effect on the business portfolios as configured and are on track to deliver the 17% to 20% EPS growth in 2019.”

However, being the first insurer-PBM to hold an earnings call since HHS announced the proposed rule, Cigna faced several additional questions about its potential impact.

About 95% of all discounts and rebates within Express Scripts portfolio pass through and are shared and about half of all clients opt for full pass-through rebate relationships, Cordani said. That equates to about two-thirds the volumes and Express Scripts retains about $400 million before taxes.

“Those tools and levers continue to evolve, and you’ll see us continue to move away from trying to maximize a single lever as opposed to maximizing the overall value which is total cost and total quality as we go forward,” Cordani said.

https://www.fiercehealthcare.com/payer/cigna-reports-fourth-quarter-results-following-express-scripts-merger