AbbVie unit Forest faces more antitrust litigation on Alzheimer's drug as judge rejects bid to toss case

 AbbVie subsidiary Forest Laboratories has been battling in the courts for seven years over its efforts to extend patents for its Alzheimer's drug Namenda. But with a new ruling, the fight is set to drag on longer as the sides prepare for a jury trial next year.

In a suit brought by pension fund the Sergeants Benevolent Association (SBA) Health & Welfare Fund, AbbVie's Forest Labs faces claims that it made unlawful pay-for-delay deals to keep generic versions of its Alzheimer’s disease drug Namenda off the market.

The fund had sought summary judgement against Forest for its “unlawful maintenance of monopoly power," court filings show. On Friday, U.S. District Judge Colleen McMahon rejected the motion as well as a bid by Forest and fellow defendant Merz Pharmaceuticals to throw the suit out.

There are “myriad factual disputes” which make a quick resolution impossible, Judge McMahon wrote in her order. Those disputes surround a settlement Forest made with generic drugmaker Mylan to manufacture a generic version of its antidepressant Lexapro.

“Fundamentally, the parties dispute whether the reverse-payment settlements were anticompetitive and—if they were anticompetitive—whether they caused a delay in generic competition,” McMahon wrote. “But since they are disputes of fact including, but not necessarily limited to, the issues of the ‘fair value’ of the Lexapro Amendment and causation, these cross-motions for summary judgement are denied—just as they were in the direct-purchaser case.”      

The court will apply for a trial date in the first quarter of 2022, McMahon said.

In a small win for Forest, one aspect of the suit that will not go forward is SBA’s claim that the company illegally executed a “hard switch,” moving patients from Namenda to a timed-release version of the drug, Namenda XR, to retain monopoly power.

Forest first came under fire for its management of Namenda in 2014 when it was accused of the “hard switch,” also known as “product hopping,” when it pulled the drug off shelves before its patent expired, compelling users to shift to the more expensive and patent-protected version, Namenda XR. 

When purchasers sued Forest, saying the scheme was illegal under antitrust law, the company threatened to take the case all the way to the Supreme Court. 

In 2015, Forest agreed to stop the switch and pay litigation fees in exchange for dropping its legal defense. 

By then, generic drugmakers Dr. Reddy’s and Mylan had brought their cheaper versions of Namenda to the market. But purchasers came at Forest again, claiming they had paid too much for the drug because of the company’s actions to delay the generic rollout. 

In October of 2019, Forest avoided an oncoming trial with a $750 million settlement. 

Namenda’s sales plummeted during the litigation, dropping from $899 million in 2014 to $71 million in 2018. Sales of its follow-on, Namzaric, have been weak, declining each year from $116 million in 2018.

AbbVie acquired Forest through its massive purchase of Allergan. 

https://www.fiercepharma.com/pharma/abbvie-subsidiary-forest-faces-more-litigation-over-alzheimer-s-drug-as-judge-rejects

Legal Stakes of a Lab Leak

 In 2012, researchers at the Rotterdam laboratory of virologist Ron Fouchier, PhD, noticed that an artificially created variant of the H5N1 avian flu virus began to spread among ferrets. H5N1 is a highly pathogenic virus that targets poultry but only rarely sickens people. Spread among ferrets was highly problematic because ferrets are a model for human-to-human flu transmission. Virologist Yoshihiro Kawaoka, PhD, of the University of Wisconsin-Madison and the University of Tokyo observed a parallel occurrence. These findings ignited a worldwide debate about whether research that causes viruses to become more dangerous, known as gain-of-function research, should be openly published in scientific journals.

Some argue that gain-of-function research is crucial for those who seek to perfect surveillance methods for pandemic outbreaks and to develop defense strategies like novel vaccines. Others argue that this kind of research only increases the chance for deadly virus outbreaks by intentional bioterrorism or through unintended lab leaks. In both cases, the consequence would be the potential devastation of the human population.

The implication of this dual-use research -- research that can both benefit and harm the public -- is not a new idea. Archimedes used his knowledge of mathematics to design defensive machines to protect his city from invasion. Regarded as the father of the atomic bomb, J. Robert Oppenheimer came to regret his recommendation to build an atomic bomb, voicing his objection through a quote from the Bhagavad Gita: "Now I am become death, the destroyer of worlds." In 1963, author Kurt Vonnegut speculated the end of the world as a result of science gone wrong through the creation of ice-nine in Cat's Cradle.

Gain-of-function is an example of dual-use research. It was the kind of research carried out on H5N1, leading the NIH to put in place a moratorium on funding such research in 2014. The fear was that gain-of-function research was just too risky. Yet that moratorium was short-lived. Based on a report by the National Science Advisory Board for Biosecurity that government-funded gain-of-function research was seldom a risk to public safety, the ban was repealed in 2017. The NIH once again funded this research but promised to exercise more scrutiny.

In late 2019, the first cases of SARS-CoV-2 emerged in Wuhan, China. In this same time period in Wuhan, at least two separate labs were studying coronavirus that originated in bats: the Wuhan Institute of Virology, which reports to the Chinese Academy of Sciences, and the Wuhan Center for Disease Control and Prevention, which reports to the Chinese Center for Disease Control and Prevention. Both of these labs are close to the wet markets that were deemed to be the original source of the outbreak. Recently, the narrative has shifted away from the theory that SARS-CoV-2 occurred naturally in those Wuhan wet markets to the idea that it leaked from a Wuhan lab and possibly man-made.

Coronaviruses were first described in 1965 and have previously been the cause of two serious diseases: SARS in 2003 and MERS in 2012. Research on gene sequencing, spike proteins, receptor binding domains, and the creation of hybrid viruses for the purpose of better understanding infectivity was actively underway before and after these outbreaks. When the U.S. government suspended the funding of gain-of-function research, China did not.

What would be the aftermath in a world where Chinese research actions were shown to be the source of the mistaken release of SARS-CoV-2? Negligence is defined as an action that departs from the standard practice and harm is the result. It seems likely that if SARS-CoV-2 was man-made, releasing it to the world was not part of the plan. Many in Wuhan and in China suffered and died. If the creation of SARS-CoV-2 was a conspiracy, the benefits of such a plan cannot be understood. Most likely, SARS-CoV-2 escaped through a mistake or a breach. These actions are negligent.

Consider as a round number that 1 million Americans have died from COVID-19. If SARS-CoV-2 was released through negligence, the families of these 1 million Americans could bring a class-action wrongful death claim against the laboratories in Wuhan and the Chinese government. As a round number, a wrongful death claim might pay $1 million per person. The total settlement value would therefore be $1 trillion dollars -- the entire amount of U.S. debt owed to China.

If a judgment were issued against China, the obvious problem would be how to collect the money. There is no international court of civil wrongs and China might simply object based on a lack of jurisdiction on the part of the court. On the other hand, the U.S. could decide that the most straightforward way to collect the debt from China would be to begin to seize Chinese assets. If a ship from China docked at a U.S. port, the court could send the bailiff to seize the ship. Chinese funds in U.S. banks could be frozen. The U.S. could request neighboring countries to seize Chinese assets on the basis of pre-existing collaboration agreements.

What would likely be China's reply, particularly given that it continues to claim that SARS-CoV-2 occurred naturally and not because of a lab leak?

In another recent dispute, China demonstrated its willingness to escalate tensions when it feels its interests are at stake. In 2018, Canada detained Huawei executive Meng Wanzhou, the daughter of the founder of the Chinese telecommunications giant. The detention was enacted at the request of the U.S. government through an existing Canada-U.S. agreement that regulates such things. The U.S. is seeking the extradition of Wanzhou over alleged violations of U.S. sanctions on Iran. Just days later, China arrested former Canadian diplomat Michael Kovrig and businessman Michael Spavor in what is widely regarded as an act of retaliation. Both men currently remain held in China. Canada has little leverage in this dispute and China is willing to burn through any good will on the part of Chinese-Canadian relations.

This recent example underlines how a U.S. negligence claim against China would be likely to result in counteractions and escalations with worldwide implications. In the worst-case scenario, it could be a casus belli, and start a war. The U.S. would not be the only country with a potentially valid dispute against China. Other countries might follow the U.S. example and bring similar actions against the Chinese government for reparation payments after COVID-19. The total dollar amount of such a claim would be enormous, suggesting that China's defensive measures might be aggressive.

As the origin story of SARS-CoV-2 continues to unfold, based on the evidence, the likelihood of an accidental and negligent lab leak is increasingly taking hold. What is at stake in the search for causes of the COVID-19 outbreak? What do we hope to gain or what might we lose in the process? The extent of the damage done to humanity by this virus staggers the mind. These next weeks and months will be critical in determining the truth about the origin of COVID-19, and how the world responds to this information will very likely be nation changing.

The U.S. is not completely blameless, however. Our concern over the funding of gain-of-function research was brief. America did fund and collaborate on what was inarguably gain-of-function research on coronavirus. American scientists worked with Chinese counterparts and many such collaborations are easily accessible in the medical literature. The highly ironically named "Operation Warp Speed" told a false story that speedy vaccine development occurred because of super-human insight based on de novo hard work. Many scientists already knew this virus very well. Coronavirus gain-of-function research is another example of the insufferable hubris that infects morally careless scientists, and we are all the losers as a consequence.

Dr. Joel B. Zivot is a member of the faculty of Emory University School of Medicine an adjunct professor at Emory University School of Law. During the fall semester 2016, Dr. Zivot co-taught—with Michael Perry, Robert W. Woodruff Professor of Law—a seminar on “Law, Medicine, and Human Rights”.  Dr Zivot’s clinical expertise and research are broad and include care of critically ill patients in the OR and ICU, education and scholarly work in bioethics, the anthropology of conflict resolution, pharmaco-economics, and a variety of topics related to anesthesiology/critical care monitoring and practice. Dr. Zivot has written and spoken extensively on the subject of physicians and lethal injection. In that capacity, Dr. Zivot has examined inmates on death row and considers the dilemma of health care delivery for inmates facing execution.

https://www.medpagetoday.com/opinion/second-opinions/93065

Lymphoblastic Leukemia in Children With Obesity

 For almost 40 years, the incidence of pediatric B-cell acute lymphoblastic leukemia (B-ALL), the most common malignancy seen in children and adolescents and young adults (AYAs), has risen steadily, accompanied by explosive growth in the prevalence of childhood obesity.

Although obesity has been strongly linked to 13 cancers in adults, and is suspected as a risk factor in many hematologic malignancies, the relationship between obesity and childhood cancer is less clear. Experts agree that managing outcomes in young patients with leukemia who are overweight or obese remains a significant clinical challenge.

"Obesity is a real problem when it comes to childhood and adolescent B-ALL outcomes," Lucie M. Turcotte, MD, of the University of Minnesota School of Medicine in Minneapolis, told MedPage Today. "Multiple studies have shown that obesity is associated with inferior post-induction MRD [minimal residual disease] outcomes, along with worse event-free survival. Additionally, obesity is associated with increased rates of morbidity, which can make these children challenging to treat."

"Malnutrition, including both overweight and underweight, is an independent modifiable prognostic factor in children with leukemia," Paul C. Rogers, MD, of the University of British Columbia and BC Children's Hospital in Vancouver, Canada, told MedPage Today.

"Despite growing evidence, nutrition supportive care during therapy is not a priority for clinicians," emphasized Rogers, who is former chairman of the nutritional committee of the Children's Oncology Group (COG). "Nutritional assessment should be undertaken from time of diagnosis and continue through therapy."

Two recent studies provide novel evidence of the association between obesity and increased risk of high-risk B-ALL and the effectiveness of a non-pharmacologic intervention for reducing MRD risk.

In the first, the authors of a COG study point to an analysis of data from 4,726 children and AYAs with high-risk B-ALL who participated in five COG frontline treatment studies. Associations between prognostic B-ALL characteristics and body mass index (BMI) categories were compared with data from the National Health and Nutrition Examination Survey.

The results, reported by Turcotte and colleagues in 2020 in Cancer Medicine, showed that obesity was associated with B-ALL among boys (OR 1.57, 95% CI 1.30-1.91) and children of Hispanic descent, particularly during adolescence (OR 1.78, 95% CI 1.39-2.29).

There was also an association between obesity and risk for ALL central nervous system (CNS) involvement. Obesity was associated with higher rates of CNS 1-2 status in boys but not in girls, and in participants who were Hispanic. In addition, the findings confirmed an association between underweight status and ALL.

These findings have important implications for the prevention and treatment of obesity in children and adolescents to reduce cancer risk, and point to the need for more research to determine the relationship between obesity and other pediatric malignancies, the investigators said.

"ALL is a rare outcome and our data require further validation, but I think [high-risk B-ALL risk] can be added to the long list of reasons obesity can be detrimental to children's health," Turcotte noted. "It really is a public health and public policy issue."

"We should continue to advocate for public health initiatives that bridge the gap between dietary guidelines and affordability, availability, and accessibility of healthy foods to children in all environments," agreed Neha Manjari Akella, PhD, a postdoctoral fellow at University of British Columbia.

Meanwhile, the prospective, randomized Improving Diet and Exercise in ALL (IDEAL) trial shows that nutrition and exercise interventions can work. In 40 overweight/obese pediatric patients between the ages of 2 and 30 with newly diagnosed B-ALL, the IDEAL plan reduced calories by 20% or more prior to day 4 of induction.

When compared with 80 historical controls treated with the same COG-style induction regimen but not the IDEAL intervention, the strategy significantly reduced MRD risk in all patients, regardless of initial BMI (OR 0.30, 95% CI 0.09-0.92, P=0.02). The IDEAL plan also increased circulating adiponectin and reduced insulin resistance, identifying both as potential biomarkers of B-ALL chemosensitivity, the researchers reported.

"This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response," wrote Etan Orgel, MD, director of the Medical Supportive Care Service at the Cancer and Blood Disease Institute of Children's Hospital Los Angeles, and colleagues in Blood Advances.

An NCI-funded consortium trial will validate the findings, beginning this summer, Orgel told MedPage Today. "We are excited by the success of the intervention."

Patients and their families "enthusiastically embraced" the intervention early in therapy, Orgel added. "We found that our patients were happy to be actively involved in their leukemia therapy, beyond simply taking the pills and medicines prescribed. The high levels of adherence in the trial open a new door for timing of these types of interventions with the possibility of making positive changes from day 1 of therapy."

The strategy, which includes an at-home exercise program, can be implemented wherever patients are being treated: in hospital or at home, and in larger centers or smaller clinics, Orgel pointed out. "If the IDEAL intervention is successful in this broader setting, it could easily be incorporated into routine practice for all patients with B-ALL."

The next study will explore whether adiponectin acts directly on ALL cells or is an indirect marker of something else, co-author Steven Mittelman, MD, PhD, chief of pediatric endocrinology at UCLA Mattel Children's Hospital, told MedPage Today. "Understanding the multiple different ways that obesity, diet, and exercise interact to affect leukemia cell chemoresistance will hopefully allow us to better hone our interventions to make them even more effective."

Although more than 75% of patients stuck to the IDEAL diet, most did not adhere to the strategy's home-based exercise regimen, Orgel noted. In the successor trial, weekly visits with a physiotherapist have been added to encourage patients, with step goals and movement reminders aimed at increasing general activity each day.

"Together, we believe these will help improve the intervention response, and particularly, help reduce the loss of muscle in the first month of therapy," he said.

"I am hopeful that non-pharmacologic strategies like this could improve outcomes in B-ALL," Turcotte said of the IDEAL intervention. "As a pediatric oncologist, I can envision the challenges of carrying out an intervention like this during induction, but if we have data to support its efficacy, we may have greater success at getting patient and family buy-in. We are often asked by families if there are things they could or should be doing to optimize treatment and this seems promising."

Disclosures

The pediatric B-ALL risk study was funded by the University of Minnesota and the National Cancer Institute.

The IDEAL trial was funded by Gabrielle's Angel Foundation for Cancer Research, the National Cancer Institute, and the National Center for Advancing Translational Sciences.

Turcotte and colleagues reported having no potential conflicts of interest.

Rogers reported having no conflicts of interest.

Akella reported having no conflicts of interest.

Orgel reported a relationship with Servier Pharmaceuticals.

Primary Source

Blood Advances

Source Reference: Orgel E, et al "Caloric and nutrient restriction to augment chemotherapy efficacy for acute lymphoblastic leukemia: the IDEAL trial" Blood Adv 2021; DOI 10.1182/bloodadvances.2020004018.

Secondary Source

Cancer Medicine

Source Reference: Turcotte LM, et al "Body mass index associated with childhood and adolescent high-risk B-cell acute lymphoblastic leukemia risk: A Children's Oncology Group report" Cancer Med 2020; DOI: 10.1002/cam4.3334.

https://www.medpagetoday.com/clinical-challenges/asco-leukemia/93086

National Task Force for Obesity? AMA Delegates Debate the Idea

 Could a national task force addressing America's growing epidemic of obesity help turn the tide on maternal mortality and other adverse health outcomes?

Members of the American Medical Association (AMA) debated the benefits and potential harms of establishing such a task force during a virtual discussion at the Special Meeting of the AMA House of Delegates.

Leadership is about "doing the right thing, despite how difficult it might be," said Myriam Mondestin-Sorrentino, MD, author of the proposed policy and an alternate delegate from New Jersey, paraphrasing AMA President Susan Bailey, MD.

Minority women are the demographic most affected by obesity, she noted. Given that fact, "how do we effectively talk about equity without confronting obesity?" she asked.

Michael Knight, MD, an obesity medicine physician and the National Medical Association representative of the AMA's Minority Affairs Section Governing Council, noted that African-American women in particular have the highest rates of obesity in the country.

"We cannot effectively address disparities in health, including maternal mortality, COVID-19 morbidity and mortality, [and] cardiometabolic disease, without confronting obesity as a key contributor that requires comprehensive and effective care," he said.

The AMA has a policy related to reducing obesity, Knight noted, but he argued that a policy resolution specific to the impact of obesity on minoritized communities was needed.

Carrie DeLone, MD, an alternate delegate from Pennsylvania, supported the resolution. She said it worries her that obesity has been normalized in the U.S., simply because of its "excessive prevalence."

According to the CDC, prior to the COVID-19 pandemic, approximately 74% of U.S. citizens over age 20 were overweight and 40% were obese.

The AMA must lead on this problem by raising the public's awareness that being overweight increases the risks of multiple disease states, including cancer and coronary artery disease, DeLone said.

However, not everyone embraced the new policy resolution by Mondestin-Sorrentino.

Cee Ann Davis, MD, an alternate delegate from Virginia speaking on behalf of the American College of Obstetricians and Gynecologists, said that while ACOG appreciates its intent, the proposed policy seems to over-simplify a complex issue. She recommended the resolution be referred back to the AMA's Board of Trustees for further study.

"The drivers of maternal mortality are multifaceted," she added, calling attention to a 2019 CDC report published in the Morbidity and Mortality Weekly Report.

Joanna Bisgrove, MD, a delegate from Oregon speaking on behalf of the American Academy of Family Physicians, agreed with Davis, noting that addressing obesity without also tackling institutional racism and other social determinants of health would not reduce inequities in health outcomes.

Nicole Plenty, MD, an alternate delegate from Texas for the AMA's Women Physicians Section, said she agreed with "the sentiment" of the resolution and the fact that obesity has greatly contributed to maternal mortality, especially among minority women.

But any task force that's established must also examine the root causes of obesity and seek to address them, she added. "Otherwise, it looks like the resolution is blaming minority women for being obese." While that wasn't the author's intent, it could still be misinterpreted, she noted.

If it isn't possible to "get the language right," Plenty said she would also recommend that the policy be referred.

Despite some estimates that the resolution would cost the AMA close to $600,000, Mondestin-Sorrentino said she is not asking the association to build and implement the task force itself, but rather to use its influence to urge the federal government to create one. In that case, the costs to the AMA "should be negligible," she noted.

The committee on public health will offer its own recommendation in a forthcoming report, and delegates will have the opportunity to discuss the policy resolution further on the virtual "floor" during the House of Delegates meeting.

https://www.medpagetoday.com/meetingcoverage/ama/93090

Landos Biopharma: FDA Meeting Clears Path for Omilancor Phase 3 Program

 Landos Biopharma Inc. said it had a successful outcome of an end-of-Phase 2 meeting with the U.S. Food and Drug Administration for omilancor, its lead candidate for mild-to-moderate active ulcerative colitis.

Landos said it and the FDA agreed on key elements necessary for regulatory approval, clearing a path for a Phase 3 program with omilancor.

The program will include two Phase 3 clinical trials and evaluate a single dose of omilancor, with primary objectives of clinical remission at weeks 12 and 52, the company said.

Landos said it is working to finalize the details of the Phase 3 protocols based on feedback and guidance from the FDA.

Ulcerative colitis is a chronic, autoimmune, inflammatory bowel disease that is estimated to affect more than 900,000 patients in the U.S. and over 1 million patients throughout the rest of the world, Landos said.

https://www.marketscreener.com/quote/stock/LANDOS-BIOPHARMA-INC-118621689/news/Landos-Biopharma-nbsp-FDA-Meeting-Clears-Path-for-Omilancor-Phase-3-Program-35598363/

Exelixis in Clinical Trial Collaboration with Bristol Myers

 Exelixis Inc. said it is in a clinical trial collaboration and supply agreement with Bristol Myers Squibb Co. for a Phase 1b trial evaluating XL092 in combination with immuno-oncology therapies in advanced solid tumors.

The objective of the study is to evaluate the safety, tolerability and efficacy of Exelixis' XL092, in combination with: nivolumab, or Opdivo; nivolumab and ipilimumab, or Yervoy; and nivolumab and bempegaldesleukin.

Exelixis said it is sponsoring the trial and Bristol Myers Squibb will provide nivolumab, ipilimumab and bempegaldesleukin for use in the trial.

Nektar Therapeutics will supply bempegaldesleukin to Bristol Myers Squibb through their existing global development and commercialization collaboration.

The STELLAR-002 study will begin with a dose-escalation phase to determine the recommend dose for each of the combination therapies.

Expansion cohorts to include patients with advanced kidney, prostate and bladder cancers, Exelixis said.

https://www.marketscreener.com/quote/stock/BRISTOL-MYERS-SQUIBB-COMP-11877/news/Exelixis-in-Clinical-Trial-Collaboration-with-Bristol-Myers-35599871/

G7 split on reallocating $100 bln IMF funds to COVID-hit nations

 Group of Seven leaders were trying to resolve differences over a proposal to reallocate $100 billion from the International Monetary Fund's warchest to help countries struggling to cope with the COVID-19 crisis.

An almost final version of the G7 communique seen by Reuters showed Germany and Italy had yet to back the inclusion of the $100 billion figure in the final statement by leaders.

The IMF's members agreed in April to a $650 billion increase in IMF's Special Drawing Rights and the G7 countries are considering whether to reallocate $100 billion of their rights to help poor countries fight the COVID pandemic.

SDRs are the IMF's reserve asset, and are exchangeable for dollars, euros, sterling, yen and Chinese yuan or renminbi. Member states can loan or donate their SDR reserves to other countries for their use.

The head of the IMF, Kristalina Georgieva, told reporters on the sidelines of the summit that she had been heartened by the G7's support for the plan and that she expected a clear indication later on how best to proceed, adding that the $100 billion target had been in discussion.

https://finance.yahoo.com/news/1-g7-split-reallocating-100-100306496.html