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Tuesday, July 6, 2021

IVERIC Bio Gets FDA Agreement for Phase 3 Clinical Trial

 IVERIC bio Inc. said Tuesday the U.S. Food and Drug Administration has agreed to the overall design of its clinical trial for its treatment of geographic atrophy secondary to age-related macular degeneration, sparking a premarket rally in its shares.

The investigational drug company said it received written agreement from the FDA under a special protocol assessment, a procedure that provides a clinical trial sponsor with an official evaluation and written guidance on the design of a proposed protocol intended to form the basis for a new drug application. It doesn't ensure the receipt of marketing approval or that the approval process will be faster than conventional regulatory procedures.

In premarket trading, IVERIC's shares were 32% higher after ending Friday at $7.94, up 15% so far in 2021

The company said it expects to complete enrollment in its GATHER2 study in late July, and topline data to be available in the second half of 2022, about one year after the enrollment of the last patient plus the time needed for database lock and analysis.

GATHER2 is designed to be well-controlled clinical trial that, if positive, would support a new drug application for Zimura in the treatment of geographic atrophy secondary to age-related macular degeneration. The special protocol assessment agreement firms the company's plans to file an application with the FDA if the ongoing GATHER2 clinical trial meets its primary efficacy endpoint at 12 months, it said.

https://www.marketscreener.com/quote/stock/IVERIC-BIO-INC-57355605/news/IVERIC-Bio-Gets-FDA-Agreement-for-Phase-3-Clinical-Trial-of-Zimura-35797037/

CytoSorbents Gets FDA Approval To Conduct Trial

 CytoSorbents Corp. said it received Food and Drug Administration approval of its investigational device exemption to conduct the Safe and Timely Antithrombotic Removal -- Ticagrelor trial in the U.S., sending shares higher in premarket trade.

The company said it is performing this under the FDA breakthrough designation granted for the removal of ticagrelor in a cardiopulmonary bypass circuit during urgent and emergent cardiothoracic surgery with CytoSorbents' proprietary polymer adsorption technology.

The primary objective of the study will evaluate if the use of DrugSorb-ATR with standard of care in patients on ticagrelor undergoing cardiothoracic surgery reduces the risk of peri-operative bleeding complications compared to standard of care alone.

CytoSorbents said it believes the study can be completed in 2022 "based on the high level of excitement and engagement we are seeing from participating sites."

https://www.marketscreener.com/quote/stock/CYTOSORBENTS-CORPORATION-19475884/news/CytoSorbents-Gets-FDA-Approval-To-Conduct-Trial-Shares-Up-35798776/

EU orders nearly 40 million additional J&J COVID vaccines

 European Union countries have ordered nearly 40 million additional doses of the COVID-19 vaccine produced by Johnson & Johnson, a spokesman for the EU Commission said, despite the company's supply shortfalls in the first half of the year.

The move is a sign of confidence in the single-dose vaccine but it also shows a cautious approach as the order placed is far below what was possible under the contract.

EU nations initially ordered 200 million doses of the J&J vaccine and under the contract could buy up to another 200 million optional shots.

Some EU nations have decided to take on a first option and have ordered 36.7 million additional doses, a spokesman for the EU Commission, which coordinates the purchases, told Reuters.

He declined to say which nations activated the option and when the doses would be delivered.

Under the contract this option had to be exercised by March, but the EU negotiated an extension. Only one-third of the 100 million doses that could have been ordered under the first additional tranche have been bought.

The EU spokesman said the EU was negotiating the extension of the terms for a second option for extra doses. That option expired at the end of June.

Jonhson & Johnson confirmed the extra order for nearly 40 million doses and said talks were under way about the possible supply of further vaccines. It declined to comment on the timing of the deliveries.

The EU spokesman declined to say whether the additional doses were to be used in the countries that bought them or would be donated to poorer nations outside the EU. EU officials had told Reuters that J&J additional doses would be most likely channelled abroad.

The EU is largely relying on the jab developed by BioNTech and Pfizer to vaccinate its own population. It also wants to donate at least 100 million doses to poorer nations by the end of the year.

Johnson & Johnson was expected to deliver 55 million doses to the EU in the second quarter of this year, but fell far short of that target. EU data show that by the end of June only about 15 million vaccines were shipped to the EU, as the company faced production problems. 

https://www.marketscreener.com/news/latest/EU-orders-nearly-40-million-additional-J-J-COVID-vaccines--35800442/

Cytisine Hits Snag as Smoking Cessation Aid

 A generic drug widely used in Eastern European and Asian countries for smoking cessation took on the West's leading non-nicotine agent in a randomized trial, coming out on the short end, researchers said.

Cytisine for 25 days failed to meet criteria for noninferiority in comparison with varenicline (Chantix) given for 84 days in an open-label trial involving 1,452 smokers hoping to quit the habit, reported Ryan J. Courtney, PhD, of the University of New South Wales in Randwick, Australia, and colleagues in JAMA.

The finding was a major disappointment in that cytisine -- a plant alkaloid that, like varenicline, stimulates nicotinic acetylcholine receptors -- had previously been shown to be superior to placebo and to standard nicotine replacement therapy (NRT) in separate trials. Moreover, a trial involving some of the same researchers and reported earlier this year, conducted among native Maori and family members in New Zealand, found that cytisine was more effective than varenicline.

But Courtney's group was clear that the new trial doesn't spell doom for cytisine. Extended dosing would be worth testing in a future study, they indicated. And the contrary results in the Maori trial might suggest that populations more accepting of "natural" products would respond better to cytisine than to varenicline.

Some of these questions could be answered in an ongoing, placebo-controlled, phase III trial with a proprietary cytisine formulation called cytisinicline, in which the agent is given for up to 12 weeks.

In its native form, cytisine has been in common use outside the West for some 50 years. As a partial agonist for nicotinic acetylcholine receptors, it reportedly suppresses nicotine cravings and withdrawal symptoms when people stop smoking cigarettes. The standard treatment interval has been 25 to 30 days, although Courtney and colleagues noted that this isn't necessarily optimal -- as a cheap plant derivative, it hasn't had the financial backing to test multiple dosing regimens as Big Pharma would do for a product that needs FDA approval. (Cytisine appears not to be carried by U.S.-based herbal supplement vendors, but it can be ordered online from overseas.)

For its part, varenicline first won FDA approval in 2006, with recommended dosing set at 12 weeks. It's not without controversy, of course -- early reports of psychiatric disturbances including suicidality led to label warnings, although the FDA still considers it a safe and effective drug. Then just last week, drugmaker Pfizer recalled nine lots of varenicline (which hadn't yet been shipped to pharmacies) because of possible nitrosamine contamination. The FDA said it asked Pfizer to extend the recall "to the consumer level" because pills already sold could potentially have the same contamination, but the company didn't yet do so.

Nevertheless, varenicline has been the leading non-NRT drug for smoking cessation in the the Western world. For cytisine to stake a claim as an effective agent -- particularly in countries other than the U.S. that would want evidence of at least noninferiority for it to be included in national formularies -- a head-to-head trial in a Western-type population could help its case.

Hence, the Australian government sponsored the new trial, dubbed CESSATE, which had no involvement from Pfizer or cytisine suppliers. Participants were daily smokers, recruited from ads in print, radio, and online media, as well as from a telephone quit line, who said they wanted to quit and weren't currently using other smoking-cessation pharmacotherapies. Some 5% were Aboriginal or Torres Strait Islanders. Half were men, and mean participant age was 43. Mean smoking intensity was 18 cigarettes per day; total smoking history in pack-years wasn't reported, but the mean starting age for smoking was 16. They were randomized 1:1 to the two study agents, unblinded for pragmatic reasons.

The trial's primary endpoint was smoking abstinence -- i.e., not having smoked more than five cigarettes in the past 6 months when evaluated at study month 7 -- as reported by participants and checked with a carbon monoxide (CO) breath test. Those lost to follow-up or who missed or failed the CO test were considered to be still smoking.

Not surprisingly, given that most cessation attempts fail, the primary endpoint was met by 11.7% of the cytisine group and 13.3% of the varenicline group. To be considered noninferior, the lower bound of the risk difference's one-sided 97.5% confidence interval had to be no more than -5%. In the end, the risk difference was -1.62% with a confidence interval of -5.02% to infinity. A secondary Bayesian analysis found only a 15% probability of noninferiority, with other statistical tests also pointing toward lower efficacy with cytisine.

Two findings did fall in cytisine's favor. First, when participants were contacted by phone at the end of 1 month -- at which point those in the cytisine group had finished dosing -- self-reported abstinence in the previous week stood at 42.5% with cytisine versus 32.3% for varenicline. That was one reason why Courtney and colleagues suggested a longer cytisine dosing period could be beneficial.

Also, adverse events were less common with cytisine. Across all events, those that were clearly more common with varenicline were abnormal dreams and nausea.

Serious events, almost all requiring hospitalization, also appeared more common with varenicline (32 people vs 17 with cytisine), but the difference was not statistically significant. These events made somewhat of a puzzle, showing no clear pattern. Twelve were orthopedic, whereas only five could be considered neuropsychiatric. However, one of the latter was a suicide attempt by a varenicline recipient with a mental illness history. (On the other hand, the previous trial comparing cytisine to standard NRT found more adverse events with the former.)

Courtney and colleagues acknowledged a number of limitations and cautions. Past research has shown that behavioral support in addition to pharmacotherapy boosts quit rates, but participants in the trial got almost nothing other than referral to a telephone quit line. Also, the CO breath test only identifies smoking within the past 24 hours, so its reliability for assessing long-term abstinence is questionable. And the open-label design could have led to biases in adherence and self-reported outcomes.


Disclosures

The study was funded by the Australian government.

Study authors reported relationships with Pfizer (varenicline's manufacturer), various manufacturers of cytisine, Juul Labs, and other commercial entities.

Jardiance prevails where Entresto could not

 Right now the only drug approved for heart failure with preserved ejection fraction is Novartis’s Entresto – and only in some patients. This could be about to change, with Lilly and Boehringer Ingelheim reporting a topline win in HFpEF today with their SGLT2 inhibitor Jardiance. The companies are saving details of the Emperor-Preserved trial for the European Society of Cardiology meeting in August, and the magnitude of benefit will be closely watched. By way of comparison, Entresto showed a 13% reduction in the risk of cardiovascular death and heart failure hospitalisations; this narrowly missed statistical significance but was enough for the FDA to broaden that drug’s label. Hopes will now be building for a class effect with the SGLT2s in HFpEF; a benefit had already been suggested with Lexicon’s SGLT1/2 inhibitor sotagliflozin, while the Deliver trial of Astrazeneca’s Farxiga is set to complete early next year. Jardiance, currently marketed for type 2 diabetes, is forecast to sell over $5bn by 2026, according to Evaluate Pharma sellside consensus, but this might soon get a bump. Lilly and Boehringer do not have too long to benefit from any heart failure approvals, though, with the drug set to come off patent in 2028.  

Selected studies in HFpEF 
ProductCompany/iesHFpEF trialDataNote
EntrestoNovartisParagon13% risk reduction in CV death & HHF, p=0.059Approved for HF pts with LVEF "below normal"
Sotagliflozin LexiconSoloist & ScoredPooled analysis: 37% risk reduction in CV death, HHF & urgent HF visit, p=0.0092021 filing planned in HF with T2D
JardianceLilly/BoehringerEmperor-PreservedMet primary endpoint of time to CV death or HHF; full data at ESC 20212021 filing planned in HFpEF; filed in HFrEF with decision due 2021
FarxigaAstrazenecaDeliverCompletes Jan 2022 (prev Nov 2021)Approved in HFrEF in May 2020
Injectable sema 2.4mgNovo NordiskStep-HFpEF in HFpEF & obesity*Completes Mar 2023 
TirzepatideLillySummit in HFpEF & obesityCompletes Nov 2023 
Finerenone BayerFinearts-HF in pts with EF ≥40%Completes Mar 2024 
*Second ph3 study planned in pts with obesity-related HFpEF & T2DM. HHF=hospitalisation for heart failure; LVEF=left ventricular ejection fraction; T2D=type 2 diabetes. Source: company releases & clinicaltrials.gov.

https://www.evaluate.com/vantage/articles/news/snippets/jardiance-prevails-where-entresto-could-not

Supermarkets are stockpiling inventory as food costs ris

 Supermarkets are stocking up on everything from sugar to frozen meat before they get more pricey, girding for what some executives anticipate will be some of the highest price increases in recent memory.

Some supermarkets said they are buying and storing supplies to keep their shelves full amid stronger demand. Grocery sales in the U.S. for the week ended June 19 rose about 15% from two years earlier and increased 0.5% from a year earlier, according to Jefferies and NielsenIQ data.

Stockpiling by food retailers is driving shortages of some staples, grocery industry executives said, and is challenging a U.S. food supply chain already squeezed by transportation costs, labor pressure and ingredient constraints.

The move is a reversal from last year when consumers hoarded groceries because of concerns about food availability, disrupting the food industry. Now, retailers themselves are stockpiling to keep costs down and protect margins.

"We’re buying a lot of everything. Our inventories are up significantly over the same period last year," said David Smith, chief executive officer of Associated Wholesale Grocers Inc. The nation’s largest wholesaler for more than 3,000 grocery stores recently purchased 15% to 20% more inventory, mainly of packaged foods with longer shelf life, he said.


Keeping bigger supplies also helps Associated offer higher in-stock levels, as the food industry fights shortages of items like beverages and frozen food.

When prices start rising, food sellers often purchase more inventory than they need to protect their profit. Price changes have been minor in recent years, executives said, generally involving a pool of specific products. The current price increases are bigger and are playing out more broadly across supermarket aisles, executives said.

General Mills Inc., Campbell Soup Co. , and J.M. Smucker Co. are among food makers raising prices to compensate for higher costs. Meat and produce prices have been climbing, too, with retailers anticipating more increases through the rest of the year.

Supermarkets say they are passing along some of those increases to shoppers, who continue to buy more groceries than they did before the pandemic, as prices also climb for used cars, airline tickets and other products. So far consumers have yet to see the same price increases confronting supermarket operators, as grocers said they hold down some prices to better compete against discount or low-price chains.


Few retailers expect pricing pressure to ease soon. Worker shortages are keeping labor and transportation expensive, industry executives said, as companies boost wages and offer bonuses to recruit and keep employees.

"When you have a uniquely inflationary period like now, it’s a feeding frenzy," said Tony Sarsam, chief executive officer of SpartanNash Co. The Grand Rapids, Mich.-based retailer and distributor is stockpiling about 20% to 25% more groceries such as frozen meat and boxed foods after more than 100 suppliers notified SpartanNash that they would raise prices, he said.

Other supermarkets are rethinking how they store inventory as consumer spending remains strong and pushes up sales.

Ahold Delhaize USA is holding more safety stock, said Chris Lewis, president of Ahold’s supply-chain company. He said total inventory is higher than it was two years ago, including 20% more supply of paper and cleaning products. Ahold Delhaize USA, which owns the Food Lion and Stop & Shop chains, is also expanding capacity in its warehouses.

For food sellers, stockpiling can require complicated math to determine what to purchase, when and how much. For instance, perishable foods can’t be stored for a long time, while bulky products take up more space. Grocers face the possibility of losing money if prices drop after they purchase inventory, though that isn’t expected to happen this year, executives say.


Stockpiling can also worsen shortages as food makers and sellers look toward recovery. The supermarket industry has bounced back from last year’s widespread shortages driven by consumers’ panic buying early in the pandemic. But retailers said they are now running low on some items, with many receiving about 80% of their orders from suppliers, compared with more than 90% before the pandemic.

"It runs the risk of making a bad situation worse," said Mark Griffin, president of B&R Stores Inc., which is storing 10% more groceries including sugar, flour and cereal. B&R tries to negotiate lower prices if manufacturers push back on the volume the chain wants to secure, he said, while monitoring competitors.

"If Walmart raises prices, so will we," Mr. Griffin said.

https://www.foxbusiness.com/economy/supermarkets-stockpiling-inventory-food-costs-rise

Arrowhead: Positive Interim Results from Phase 1b Study of ARO-HIF2 for Kidney Cancer

 Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today announced positive interim results from the first two cohorts of AROHIF21001, a Phase 1b dose-finding clinical study of ARO-HIF2, the company’s investigational RNA interference (RNAi) therapeutic being developed as a treatment for patients with clear cell renal cell carcinoma (ccRCC). ARO-HIF2 is the first tumor-targeted investigational medicine to utilize Arrowhead’s proprietary Targeted RNAi Molecule (TRiM™) platform in a clinical trial. Arrowhead is currently enrolling the third planned patient cohort of AROHIF21001 and the company intends to present additional data at an appropriate medical congress.

James Hamilton, M.D., MBA, senior vice president of discovery and translational medicine at Arrowhead, said: "The AROHIF21001 Phase 1b study is designed to evaluate safety as well as preliminary pharmacodynamics and efficacy in an advanced ccRCC patient population. We believe that in the first two dose cohorts investigational ARO-HIF2 is showing clear signs of meaningful target engagement and some potentially early signs of efficacy in at least one patient. This is an encouraging start for the study. Specifically, in seventeen patients treated with investigational ARO-HIF2, nine had tumor biopsy material that could be evaluated. Seven of these nine tumor samples demonstrated reductions in HIF2α protein, as measured by immunohistochemistry H-score. The mean of these reductions was -48% with a range from -9% to -82%. In addition, one patient achieved a partial response with tumor shrinkage of approximately 65% and four additional patients in cohort 2 remain on study drug with stable disease. Tumors typically have a high level of heterogeneity and the patients in AROHIF21001 have advanced ccRCC and have failed multiple lines of treatment including checkpoint inhibitors and anti-VEGF regimens, so these early results in a heavily pre-treated population are encouraging for investigational ARO-HIF2 and our tumor-targeted platform broadly. ARO-HIF2 has been generally well-tolerated and we look forward to continued dose escalation."