Epizyme files U.S. application for tazemetostat for follicular lymphoma

Fresh off today’s positive advisory committee vote backing tazemetostat for epithelioid sarcoma, Epizyme (NASDAQ:EPZM) files another marketing application with the FDA for the EZH2 inhibitor.

The new indication is relapsed/refractory follicular lymphoma, with or without EZH2 mutations, in patients who have received at least two prior lines of therapy.

The company is seeking accelerated approval of the filing.

Shares up 2% after hours.

https://seekingalpha.com/news/3527295-epizyme-files-u-s-application-for-tazemetostat-for-follicular-lymphoma

Monopar Therapeutics prices IPO at $8, low end of range

Monopar Therapeutics (NASDAQ:MNPR) prices its IPO of 1,111,112 common shares at $8/share.

Underwriters have an option to purchase up to an additional 166,666 shares.

Trading commences today.

Closing date is December 23, 2019.

Source: Press Release

https://seekingalpha.com/news/3527308-monopar-therapeutics-prices-ipo-8-low-end-of-range

Appeals Court Upholds Invalidating of Obamacare Individual Mandate

Sends case back to district court to decide if the rest of the ACA still stands

A federal appeals court on Wednesday upheld a lower-court ruling that the Affordable Care Act’s (ACA) individual mandate is unconstitutional, but told the district judge in the case to look again at whether other parts of the law can still stand.

“The individual mandate is unconstitutional because it can no longer be read as a tax, and there is no other constitutional provision that justifies this exercise of congressional power,” wrote Judge Jennifer Walker Elrod for the three-judge panel of the U.S. Court of Appeals for the Fifth Circuit. “On the severability question, we remand to the district court to provide additional analysis of the provisions of the ACA as they currently exist.”

The individual mandate was the ACA provision requiring people to buy health insurance or pay a financial penalty. Because Congress eliminated that penalty in 2017, rendering the “mandate” toothless, no immediate practical impact will ensue from Wednesday’s ruling. Its chief significance is that it keeps alive the possibility that the entire ACA will eventually be struck down.

Texas v. United States of America — also called Texas v. Azar, as Health and Human Services (HHS) Secretary Alex Azar is charged with implementing the law — was filed in early 2018 by Texas and 19 other Republican-controlled states.

In December 2018, lower-court Judge Reed O’Connor of the U.S. District Court for the Northern District of Texas sided with the plaintiffs that the ACA was unconstitutional after Congress scrapped the individual mandate penalty as part of the Tax Cuts and Jobs Act (TCJA) of 2017. Congress had unequivocally stated time and again that the mandate was “essential” and “inseverable” from the rest of the ACA’s provisions, O’Connor explained, but that rewriting the law without its “essential” feature was beyond the power of his court.

In her 60-page decision, Elrod noted that regarding the court’s reasons for remanding the rest of the case back to the district court, “it may still be that none of the ACA is severable from the individual mandate, even after this inquiry is concluded. It may be that all of the ACA is severable from the individual mandate. It may also be that some of the ACA is severable from the individual mandate, and some is not.”

“But it is no small thing for unelected, life-tenured judges to declare duly enacted legislation passed by the elected representatives of the American people unconstitutional,” she wrote. “The rule of law demands a careful, precise explanation of whether the provisions of the ACA are affected by the unconstitutionality of the individual mandate as it exists today.”

In addition, the district court can carefully consider what remedy should be given to the plaintiffs, considering that the defendants requested in their appeal that the remedy only apply to the states involved in the lawsuit and only to those ACA provisions that injure the plaintiffs, she added. “We place no thumb on the scale as to the ultimate outcome; the district court is free to weigh the federal defendants’ changed arguments as it sees fit.”

Judge Carolyn Dineen King dissented from the decision, arguing that on the question of whether the rest of the ACA is enforceable if the individual mandate is invalidated, “answering that question should be easy, since Congress removed the coverage requirement’s only enforcement mechanism but left the rest of the Affordable Care Act in place. It is difficult to imagine a plainer indication that Congress considered the coverage requirement entirely dispensable and, hence, severable.”

“And yet, the majority is unwilling to resolve the severability issue,” she continued. “Instead, it merely identifies serious flaws in the district court’s analysis and remands for a do-over, which will unnecessarily prolong this litigation and the concomitant uncertainty over the future of the healthcare sector.”

As to whether the rest of the ACA is still valid, “contrary to the suggestion of the majority … Congress did not alter the coverage requirement’s operation when it amended the ACA in 2017” under the Tax Cuts and Jobs Act (TCJA), King said. “All the TCJA did, with respect to healthcare, was change the amount of the shared-responsibility payment to zero dollars. Thus, despite textual appearances, the post-TCJA coverage requirement does nothing more than require individuals to pay zero dollars to the IRS if they do not purchase health insurance, which is to say it does nothing at all … Nobody has standing to challenge a law that does nothing.”

“When Congress does nothing, no matter the form that nothing takes, it does not exceed its enumerated powers. And since courts do not change anything when they invalidate a law that does nothing, every other law retains, or at least should retain, its full force and effect.”

“The district court’s opinion is textbook judicial overreach,” King concluded. “The majority perpetuates that overreach and, in remanding, ensures that no end for this litigation is in sight.”

What might happen next? “It’s complicated, but it seems pretty likely that the blue states who have intervened will ask the Supreme Court to hear the case,” Nicholas Bagley, JD, a law professor at the University of Michigan in Ann Arbor, wrote on Twitter. “If the Supreme Court doesn’t hear the case, we’re back into a waiting game. Judge O’Connor will ask for briefing, argument, and then he’ll have the unenviable job of writing a long opinion undertaking the more “granular” severability analysis that the Fifth Circuit demanded … After that, it’s back up to the Fifth Circuit, and from there to the Supreme Court. But that could take years, all the while with this (stupid) cloud … hanging over the ACA.”

https://www.medpagetoday.com/publichealthpolicy/repeal-and-replace/83995

Half of U.S. Adults Obese by 2030?

Ten years from now, nearly half of U.S. adults will be obese if current trends continue, researchers predict, noting that almost one-quarter will be severely obese, and the epidemic will hit some states even harder.

By 2030, 48.9% of adults nationwide will be obese, defined as having a body mass index (BMI) of 30 to 35 (95% CI 47.7%-50.1%). The prevalence of obesity will be more than 50% in 29 states, and it will not be less than 35% in any state, noted Zachary Ward, MPH, of the Harvard T.H. Chan School of Public Health in Boston, and colleagues.

Also by 2030, 24.2% of adults will be severely obese, with a BMI of 35 or greater (95% CI 22.9%-25.5%). The prevalence of severe obesity will be higher than 25% in 25 states, Ward’s group said in their study online in the New England Journal of Medicine.

The estimates, based on national survey data, corrected for self-reporting bias also indicated that severe obesity is likely to become the most common BMI category among women (27.6%), non-Hispanic blacks (31.7%), and low-income adults (31.7%) by 2030.

“The high projected prevalence of severe obesity among low-income adults and the high medical costs of severe obesity have substantial implications for future health care costs, especially as states expand access to obesity-related services for adult Medicaid beneficiaries,” Ward and co-authors wrote.

“Although severe obesity was once a rare condition, our findings suggest that it will soon be the most common BMI category in the patient populations of many health care providers. Given that health professionals are often poorly prepared to treat obesity, this impending burden of severe obesity and associated medical complications has implications for medical practice and education,” the researchers stated.

A state-by-state analysis found that obesity prevalence will reach 58% in Alabama, Arkansas, Mississippi, and Oklahoma. States projected to have the lowest prevalence of obesity by 2030 include California (41%), Colorado (38%), and Hawaii (41%). The District of Columbia was projected to have the lowest prevalence of all, at 35%.

The predictions are likely to be accurate because they are based on data from more than six million adults who participated in the Behavioral Risk Factor Surveillance System Survey in 1993-1994 and 1999-2016, the researchers said. Although survey participants self-reported their height and weight, the team corrected for potential self-reporting bias using data from more than 57,000 adults whose height and weight were actually measured in the National Health and Nutrition Examination Survey (NHANES).

“By adjusting the entire distribution of reported BMI to be consistent with measured BMI in NHANES, we adjusted for self-reporting bias while preserving the relative position of each person’s BMI,” the researchers explained. “Specifically, we estimated the difference between participant-reported BMI and measured BMI according to quantile and then fit cubic splines to smoothly estimate self-reporting bias across the entire BMI distribution. Each person’s BMI was then adjusted for this bias given his or her BMI quantile.”

June Stevens, PhD, of the University of North Carolina at Chapel Hill and a spokesperson for The Obesity Society, said the potential public health implications of the study “are, in a word, devastating. The projection that nearly one in four adults will have severe obesity in 2030 is particularly distressing,” she wrote in an email to MedPage Today. “Severe obesity is associated with much more disability, disease, and death than moderate obesity. The high rates of severe obesity will impact our country’s medical costs and productivity, and potentially our national defense.”

Stevens, who was not involved in the study, said that while the projections are glum, they are based on the assumption that increases in obesity prevalence will continue at the same rates as they have in past years. That assumption need not hold, however, she said. With work, the trend can be changed.

“Obesity is a difficult disease to prevent and treat, and there is no magic bullet,” she said. “It is understandable that some members of the public are frustrated with the current therapies, but they indeed do work if implemented. There is a lot we as a nation could do to better apply current approaches, and to discover new approaches. We need to do both. Prevention and treatment of obesity should be a national and personal priority.”

Ward’s group acknowledged that the assumption that current trends will continue is a chief limitation of the work. “Although our predictive validity checks from 2010 through 2016 help build confidence in our approach, projections through 2030 involve a much longer period, so the uncertainty around our projections may be larger than estimated,” they said.

Last Updated December 18, 2019

Disclaimer

The study was funded by the JPB Foundation.

Stevens is co-investigator on a research project funded by WW (formerly Weight Watchers) International.

Primary Source

The New England Journal of Medicine

Source Reference: Ward ZJ, et al “Projected U.S. state-level prevalence of adult obesity and severe obesity” N Engl J Med 2019; 381: 2440-2450.

https://www.medpagetoday.com/endocrinology/obesity/83987

Boehringer’s $250M NASH drug hits the skids as development path gets rockier

We may be nearing the first-ever approval for a nonalcoholic steatohepatitis (NASH) drug next year, but the road to approval is not getting easier.

Just ask German pharma Boehringer Ingelheim and partner Pharmaxis, which today have dumped their effort to treat fatty liver disease when the midstage drug, an SSAO/VAP-1 inhibitor known as BI 1467335, didn’t so much fail directly but was canned due to interactions with other meds.

Boehringer spent $250 million on Sydney-based Pharmaxis’ NASH drug back in 2015, when it was in phase 1, on the hopes that it could get in on a market potentially worth billions of dollars a year.

Intercept and Genfit are currently the front-runners, vying for a first approval that could come next year, but both those companies and a host of others, including the likes of Gilead Sciences, have been beset by setbacks and failures in this area, with questions over marketability and diagnosis also still to be decided.

BI and Pharmaxis’ drug is designed to work by blocking leukocyte adhesion and tissue infiltration during inflammatory processes, an approach that differs from those taken by Intercept and Genfit.

But in this instance, while the drug met its “pre-specified targets for inhibition of plasma amine oxidase copper-containing 3 (AOC3) activity compared to placebo as well as clinically relevant changes in NASH biomarkers,” it will now be discontinued after a phase 1 test found it increased “the risk of drug interactions of the compound in NASH patients” the company couldn’t resolve.

The investigators did not specify which drug interactions, but many NASH patients would likely also be on a series of other meds for conditions such as diabetes and cardiovascular disease.

But while dead in the water for NASH, other tests are ongoing for BI 1467335, including a phase 2a study in diabetic retinopathy that has completed recruitment and is due to report in the second half of next year.

Pharmaxis’ shares were nearly halved on the news.

https://www.fiercebiotech.com/biotech/boehringer-s-250m-nash-drug-hits-skids-as-development-path-gets-rockier

Senators blast Lilly’s generic insulin, but CEO Ricks strikes back

Insulin producers have faced years of negative headlines as prices and rebates rose in lockstep. So Eli Lilly tried to thwart the rebate effect with a half-priced version of its top insulin Humalog—and it attracted some positive coverage in the process.

But did Lilly’s move really amount to a positive for patients? Not so much, according to a report (PDF) from senators Elizabeth Warren and Richard Blumenthal. A national survey of pharmacies found the authorized generic isn’t widely available.

Lilly “failed to take consequential steps—such as simply lowering the list price of Humalog—to provide lower-cost access to this important diabetes drug,” the report noted, echoing what critics have been saying of the plan all along.

Not surprisingly, Lilly CEO David Ricks disagrees. In an interview with CNBC’s Jim Cramer, Ricks said the conclusions drawn in the senators’ report are “nonsense.” What’s limiting uptake for the cheaper option is that pharma middlemen prefer higher list prices and higher rebates, he said. One national wholesaler opted not to pick up the discounted option at all, he added.

“This doesn’t show that we didn’t try,” he said during the interview. “We did try. … This shows what’s broken in the rest of the pharmaceutical system.”

In their survey, the senators found that the authorized copycat wasn’t available at 83% of pharmacies surveyed. When the cheaper option was in stock, half of the pharmacies didn’t offer it as the first option for patients.

The senators’ report concluded that “despite Eli Lilly’s public promise about the availability of a less expensive, authorized generic version of its brand-name insulin drug, the vast majority of pharmacies do not offer access to this drug.”

Lilly and its peers Sanofi and Novo Nordisk produce 80% of the world’s insulin, the senators note, and have gradually raised prices over the years. Now, many patients ration insulin and have trouble affording the key drugs.

For their part, the drugmakers have argued they’ve had to offer increasingly bigger rebates to pharmacy benefit managers to secure formulary positioning.

The drugmakers haven’t denied the affordability problems. Even as Lilly has rolled out its authorized generic, Sanofi went another route and has kicked off a $99-per-month subscription for its insulins.

Novo Nordisk is pursuing both options with programs starting in January. It’s rolling out authorized generics to its insulins at half price, as well as a flat-rate cash offer that would cover most insulin users for $99 per month.

https://www.fiercepharma.com/pharma/senators-say-lilly-s-discounted-insulin-program-has-failed-patients-but-ceo-ricks-calls

Seattle Genetics, Astellas get quick FDA nod for bladder cancer-fighter Padcev

Historically, metastatic bladder cancer has been “a very bad prognosis,” in the words of Seattle Genetics CEO Clay Siegall. But his company and partner Astellas now have a shot at trying to change that.

Wednesday, the FDA handed the duo an early approval for Padcev, a first-of-its kind antibody drug conjugate. The product targets Nectin-4, a protein on the surface of cells that’s highly expressed in bladder cancer, and it’s now cleared for patients who have already received chemo and a checkpoint inhibitor from the PD-1/PD-L1 class.

Regulators based their decision on data from a phase 2, single-arm study known as EV-201. That trial showed that Padcev could shrink tumors in 44% of patients and eliminate them in 12%.

A full course of Padcev cost between $110,000 to $120,000, Seattle Genetics estimates, with the final tally varying based on a patient’s weight and how long he or she stays on treatment. The net price, though, will be closer to $90,000 because of government discounts for older patients, Siegall said.

While “we understand it’s expensive, it’s a reasonable price when you look at the world of cancer therapies that have come out” recently, with some of them ranging up to $200,000, he said. The company tried to “do what we thought was a fair job at assessing this in a way that payers would see the value and the cost and think it was appropriately priced,” he added.

Meanwhile, the drug should be available to patients within two days of launch, Siegall said, noting that the company’s goal was to be “launch-ready in November.” The partners will field just over 100 sales reps, with a “full complement of activity for commercial to complement and support with marketing and reimbursement and medical affairs.”

“We will be out in full force from approval,” Siegall said, adding that “we think there will be good uptake of this drug.”

https://www.fiercepharma.com/pharma/seattle-genetics-astellas-snag-quick-fda-approval-for-bladder-cancer-fighter-padcev