FDA: Don’t rush a move to change the Covid-19 vaccine composition

 On Tuesday, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted 19-2 to approve the use later this year of Covid-19 vaccines based on an Omicron variant sequence. One of us (P.A.O.) was among those voting “no.” It is possible these vaccines will be two-component designs that also include the current version. Will Americans soon be better protected against Covid-19?

The Covid-19 vaccines currently authorized for use in the U.S. are all based on the sequence of the original SARS-CoV-2 virus, which was obtained early in 2020. The virus has evolved over the past 30 months, creating variants that are either more infectious, or harder to counter by vaccination, or both. In late December 2021, the Omicron variant (BA.1) emerged, becoming the most dominant strain in the U.S. BA.1 has now been almost completely replaced by other Omicron-based variants. The BA.4 and BA.5 viruses currently account for 50% of all circulating strains. Earlier variants, like Alpha and Delta, have essentially vanished.

While vaccines made from the original SARS-CoV-2 strain provided strong protection against SARS-CoV-2 circulating in 2020 and 2021, the Omicron variants have been more problematic. They are highly resistant to neutralizing antibodies, which the human immune system uses to prevent infection. As a result, the Omicron viruses find it easier to break through this protective barrier, causing what are mostly mild infections. That’s true whether the neutralizing antibodies were elicited by vaccination or by earlier infection with Alpha or Delta variants. Fortunately, most people have enough neutralizing antibodies to strongly protect them against severe disease and death — that key task requires immune memory cells and lower neutralizing antibody levels than are needed to completely fend off the virus.

Once it became clear that the Omicron variants resisted neutralizing antibodies, thereby increasing the frequencies of mostly mild infections, vaccine companies began rapidly redesigning their Covid-19 vaccines. The revised vaccines were all based on the initial Omicron BA.1 sequence, which was an appropriate step to take. By now, most Americans already have antibodies against SARS-CoV-2’s spike protein because they were vaccinated or infected or both. As a result, the most frequent use of an Omicron-containing vaccine will be as a booster dose for certain high-risk groups.

What is known about Omicron-based vaccines? BA.1 versions have been tested as boosters in experimental animals and also in small-scale human trials. The goals of the studies were to measure the levels of neutralizing antibodies produced, compared to using the original vaccine as a booster under similar conditions.

The animal data have been around for several months. They are quite similar to what’s recently emerged from various human trials. Two to four weeks after the booster shots, neutralizing antibody levels against Omicron BA.1 were about twofold higher with the Omicron-based vaccine than with the original vaccine. Moderna recently released some information on a two-component Omicron plus original booster vaccine. The Omicron (BA.1) neutralizing antibody levels induced were higher than when the original vaccine was used by itself but, again, by less than two-fold. In contrast, Pfizer showed data at the VRBPAC meeting indicating that its two-component vaccine actually performed less well than an Omicron-only booster. Even allowing for the nature of very early data, the story on two-component vaccines is far from clear.

What do an approximately twofold higher level of neutralizing antibodies mean in practice? Is an Omicron-based booster sufficiently superior to the standard one to justify a switch?

That kind of twofold difference is, for example, similar to the modestly greater peak in neutralizing antibodies triggered by the first two doses of the Moderna vaccine compared with the Pfizer vaccine. Those two vaccines provided almost identical protection against mild and severe Covid-19, although the benefits of the Pfizer vaccine waned a bit quicker over time.

We would all gain from having more insights into the performance of the Omicron-based Covid-19 vaccines. The full datasets from all the variant booster trials should now be analyzed using the best available models to provide an informed judgement about whether — and to what extent — the slightly superior neutralizing antibody response to Omicron-based boosters translates into significantly greater protection against BA.4/BA.5-mediated infections and severe or fatal disease.

Moderna and Pfizer executives have claimed that the Omicron vaccines will be protective for longer. That may be true, but how long is longer? A few weeks? A month or two? Again, detailed modeling of the data might provide important information. It’s important to be sure that changing the booster vaccine to include the Omicron sequence offers enough of an advantage to justify the cost and complexity associated with making the switch.

The reason why the Omicron and earlier variant boosters are little or no better than a standard booster is rooted in immunology. The immune system responds to the first sight of the viral spike protein by making neutralizing antibodies and by starting to lay down memory cells that are an archive of what it is seeing. Those memory cells improve over a multi-month period and are then triggered into action when the immune system reencounters the spike protein, either as an infection or in a booster vaccination. The resulting neutralizing antibody response doesn’t appear to depend very much on whether the boost was with the original sequence, the Beta sequence, the Delta sequence, or the Omicron sequence — all are about equally as good at reawakening immune memory cells. The Omicron vaccines also seem to elicit some neutralizing antibodies that are unique to that variant and that make a minor contribution to the overall response. It’s possible that component could improve over time or after additional boosts, but we have no data to evaluate.

Because no one can predict how SARS-CoV-2 will further evolve, there’s no way to tell whether one or more Omicron-based boosts over the next year would be beneficial against what may emerge. What is known is that the increasingly prevalent BA.4 and BA.5 variants are even more resistant to neutralizing antibodies, typically by three- or four-fold, than the now-vanished BA.1 variant on which the Omicron vaccines are based. The trend toward greater resistance of neutralizing antibodies may well worsen.

Some experts have suggested that a booster should be based not on the BA.1 sequence but on BA.4/BA.5 sequences. To do that in a relevant time frame would mean foregoing clinical trials to obtain immunogenicity data. A reasonable assumption is that a booster based on BA.4/BA.5 would be better tailored to those now dominant strains. Nonetheless, the increase in neutralizing antibodies over the standard vaccine boost may still be only modest — probably on par with what’s being seen with the BA.1 boosters.

If an Omicron-based booster provides little advantage over the vaccine stocks that already exist, is it worth the switch? Making and rolling out an entirely new supply of Covid-19 vaccines on a nationwide basis is no trivial matter, particularly when Congress seems reluctant to provide the funds. Would the country be better off using the available resources to accelerate the creation of next-generation vaccines that can produce neutralizing antibodies in amounts high enough to deal with most variants? Or vaccines that can be delivered into the nose, a route that may provide stronger protection against infection? Strategic decisions of this nature require a deep dive into the immunology of how vaccines work; and the use of sophisticated models on neutralizing antibody actions.

Vaccines remain of critical importance at this stage of the pandemic. We strongly urge that everyone who needs a vaccine dose gets one, particularly never-vaccinated people who have been fooled by distortions about vaccine safety. But it’s important to understand what vaccines can and cannot now do, and what any composition switch really means for protection against Covid-19.

Perhaps researchers will learn that particularly vulnerable people, like those who are older or sicker, might benefit sufficiently to justify the use of an Omicron-based booster, but the wider population would not. Decisions could be tailored to specific sub-populations.

Whatever the decision, Americans will need to receive accurate information about how the new boosters perform against mild infections and virus transmission. It isn’t likely that an Omicron-based booster will be a magic bullet, although it might be perceived that way. It is essential to avoid offering people a false sense of security. Those who recently received an Omicron booster should not think they are now bulletproof against SARS-CoV-2 and increase their infection risk by altering their behavior. There are signs that behavioral changes may already be visible in infection statistics from the Centers for Disease Control and Prevention.

A multibillion-dollar decision to launch a vaccine based wholly or in part on the BA.1, BA.4, or BA.5 sequence that would affect more than 100 million people need not be unduly rushed. A decision of this magnitude should be based on as much expertise and analysis as is reasonably practical. Our joint concern is that this may not be what happens in the coming days, when the FDA will likely accept the majority advice given by its advisory committee without fully weighing what the exact composition of the new vaccine should be, and assessing whether it confers significant advantages over the current vaccine. Using an additional week or two to obtain more input seems a prudent step to take.

John P. Moore is a professor of microbiology and immunology at Weill Cornell Medicine in New York City. Paul A. Offit is a pediatrician, professor of pediatrics, and director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, and a member of the FDA’s Vaccines and Related Biological Products Advisory Committee.

https://www.statnews.com/2022/06/29/fda-dont-rush-to-change-covid-19-vaccine-composition/

Open the books on NIH royalty payments

 Recently, Sen. Rand Paul (R-KY) pressed Dr. Anthony Fauci for details of hidden royalty payments made to the National Institutes of Health, its leadership, and scientists. Once again, Fauci was evasive and misleading in a congressional hearing. If his agency has nothing to hide, he should open the books and share all the information with the public.

For years, the NIH has worked to keep hidden a stream of third-party royalties paid to its scientists by for-profit companies. These payments flow when a medical innovation made as part of NIH research is used by the private sector and government employees are considered “co-inventors” on the patent. There were approximately 55,000 of those payments during the past decade. Each royalty could be a conflict of interest that requires transparency to investigate.

After the agency ignored Freedom of Information Act requests from OpenTheBooks's data capture team, we sued the agency, represented by the group Judicial Watch. Only recently and under court order has the NIH begun disclosing the amount of money changing hands with the private sector for these innovations. As officials slow-walk the royalty data release, we can say that the NIH and its scientists received an estimated $400 million in third-party paid royalties between March 2010 and today and that they dole out around $32 billion a year in research grants across the medical community. Concurrently, decisions inside the NIH, the Food and Drug Administration, and the wider Department of Health and Human Services were made regarding product approvals, public health guidance, and continuing research priorities.

These huge financial stakes make it critical for patients and the public to have full transparency from the NIH. People, the press, pundits, and watchdogs must be able to follow the money.

However, in the production of this information, the NIH is redacting every individual payment amount, the identity of the payer, and the patent license numbers. So we know hundreds of millions of dollars enrich the NIH and its scientists, but the NIH refuses to tell who is paying, at what amounts, and for which innovations. It renders these document dumps effectively useless.

Our OpenTheBooks investigation has thankfully sparked interest and action from Congress, which began last month in a budget hearing in which acting NIH Director Lawrence Tabak answered questions about 2023 funding levels. Rep. John Moolenaar (R-MI) got Tabak to concede that this whole arrangement appeared to be a conflict of interest. But Tabak contended that there are “firewalls” in place to ensure decision-makers were not receiving payments for innovations their subagencies were researching or overseeing. We are meant simply to take their word for it, it seems.

Based on Fauci’s testimony this week, that approach won’t suffice.

When Paul asked whether Fauci ever received royalty payments from entities he later regulated or made funding decisions for, Fauci demurred, saying he didn’t know, “but I doubt it.” In 2005, though, he was sure. Back then, Fauci confirmed that the payments were a conflict of interest because the National Institute of Allergy and Infectious Diseases, the institute where Fauci is the director, was spending $36 million to test his invention on patients — the interleukin-2 experimental AIDS drug.

However, the concern here is much broader than the behavior of the NIH’s most famous scientist.

Take another example, Dr. Doug Lowy, the acting director of the National Cancer Institute, another NIH institute. He is tied for 19th of 1,805 scientists receiving the most royalty payments between 2010 and 2016. Lowy studied papillomaviruses for decades, from how they reproduce to how they encode cancerous cells in the human body. He wrote hundreds of papers on these viruses, and then his laboratory developed and tested the ingredients now used in three HPV vaccines approved for use by the FDA: Gardasil, Gardasil 9, and Cervarix. From his new perch as acting director, Lowy makes all manner of decisions about grant-making priorities and cancer research using tax dollars.

Presciently, in the hearing, Paul asked Fauci a vaccine-related question as well: Has anyone on the vaccine approval committees ever received money from vaccine manufacturers? Fauci’s answer mirrored Tabak’s: Existing statutes and regulations don’t require these disclosures.

Paul is right to be asking for transparency here. He was joined by Sens. Tim Scott (R-FL), Ron Johnson (R-WI), Josh Hawley (R-MO), and Jim Lankford (R-OK) in sending Tabak a letter demanding the answers the NIH had refused to give to OpenTheBooks. They set a deadline of June 17, which has come and gone.

The public deserves the unredacted information because it’s the public's tax dollars being used to fund this revolving door of grants and royalties. If the NIH can hide behind the law, Congress should press forward with its oversight authorities by holding more hearings — and also update relevant statutes to ensure it serves the public’s present-day interests.

Let’s vaccinate our government bureaucracies, leadership, and scientists against these myriad conflicts of interest. Transparency is needed to build back trust.

Adam Andrzejewski is the CEO and founder of OpenTheBooks, the largest private database of public-sector expenditures.

https://www.washingtonexaminer.com/opinion/op-eds/open-the-books-on-nih-royalty-payments

Mo. Health System Briefly Halts 'Plan B' Amid Abortion Ban Confusion

 A Missouri-based health system will once again provide emergency contraception after briefly stopping days earlier, in another example of the legal confusion affecting healthcare systems in the aftermath of the Supreme Court overturning Roe v. Wade last week.

Early this week, Saint Luke's Health System, a network of 16 hospitals and campuses in the Kansas City area, announced it would stop providing emergency contraception -- including Plan B -- to patients in their Missouri-based locations. The decision was made in an effort to avoid legal ramifications for their physicians based on the state's abortion ban that went into effect on June 24.

On Wednesday, Saint Luke's reversed its decision.

According to a statement provided to MedPage Today, the reversal was made after additional "internal review." The health system will resume offering emergency contraception "under new protocols," while they monitor the evolving legal status of contraceptives.

"The ambiguity of the law, and the uncertainty even among state officials about what this law prohibits, continues to cause grave concern and will require careful monitoring," the statement said. "This is especially true because the penalty for violation of the statute includes the criminal prosecution of healthcare providers whose sole focus is to provide medically necessary care for their patients."

The health system's announcements highlight the legal uncertainty of providing reproductive healthcare in the aftermath of the Supreme Court's decision, as well as new potential legal jeopardy for physicians practicing in states with newly enacted abortion bans.

Part of that uncertainty was fueled by statements made by Missouri Governor Mike Parson and Missouri Attorney General Eric Schmitt over the past week.

Last Friday, Gov. Parson's office announced that the state law banning abortion -- which he signed in 2019 -- would formally take effect immediately. Attorney General Schmitt's office also released an official opinion confirming that the new law would go into effect immediately.

The law, known as the "Right to Life of the Unborn Child Act," contained several provisions outlawing abortion services in the state. At least two of those provisions target actions taken by physicians directly, according to a press release from the governor's office.

One provision prohibits performing abortions unless for medical emergencies, and the other establishes criminal liability for anyone who "knowingly performs or induces" an abortion that is not required by a medical emergency. The law also states that physicians could have their professional licenses suspended for performing an abortion, the press release noted.

Missouri is one of more than a dozen states with similar "trigger laws" that were set to go into effect after Roe was overturned.

The announcement prompted Saint Luke's initial decision to stop providing emergency contraception to avoid any potential legal liability for the health system's physicians. Then, state officials provided more detail about the legal use of emergency contraceptives, prompting the change to resume the practice, Saint Luke's said.

On Wednesday, Gov. Parson sent a tweet to clarify the legal status of contraceptives under the new law. "To address any misinformation: Missouri law has not changed the legality of contraceptives. Contraceptives are not abortions and are not affected by the Right to Life of the Unborn Child Act," the tweet read.

Saint Luke's stated that it will continue to "closely monitor legal developments regarding Missouri's abortion trigger law," as it resumes providing emergency contraception.

https://www.medpagetoday.com/special-reports/features/99526

InflaRx Update For Vilobelimab In Skin Disorder, COVID-19

 

• InflaRx N.V. 
  IFRX+2.84%+ Free Alerts
   provided a development update for its monoclonal anti-C5a antibody, vilobelimab, in pyoderma gangrenosum (PG) and severe COVID-19.
• The FDA and the European Medicines Agency (EMA) have granted orphan drug designation to vilobelimab for PG.
• PG is a rare condition that causes large, painful sores (ulcers) to develop on the skin.
•  In addition, the company had a productive FDA end-of-phase II meeting to its plans for a Phase 3 development program in PG. 
• The FDA indicated its support for a randomized, controlled Phase 3 study and offered to review the study protocol. 
• Based on the agency's feedback and recommendations, InflaRx is now finalizing the design for a Phase 3 trial.
• InflaRx requested a meeting with the FDA to obtain guidance for a potential emergency use authorization submission of vilobelimab in COVID-19 patients.
• This has been scheduled as a Type B meeting for early Q3. In addition, the company is in ongoing dialogue with the EMA about the next steps in developing vilobelimab in mechanically ventilated severe COVID-19 patients.

https://www.benzinga.com/general/biotech/22/06/27900753/inflarx-provides-development-update-for-vilobelimab-in-skin-disorder-covid-19

Genmab Applies to FDA on Large B-Cell Lymphoma Trials

 Genmab A/S (Nasdaq: GMAB) today announced its intent to submit a biologics license application (BLA) to the U.S. Food and Drug Administration (FDA) for subcutaneous epcoritamab (DuoBody®-CD3xCD20), an investigational bispecific antibody, for the treatment of patients with relapsed/refractory large B-cell lymphoma (LBCL), in the second half of 2022.

The BLA submission is supported by results from the large b-cell lymphoma (LBCL) cohort of the pivotal EPCORE™ NHL-1 open-label, multi-center trial evaluating the safety and preliminary efficacy of epcoritamab in patients with relapsed, progressive or refractory CD20+ mature B-cell non-Hodgkin lymphoma (B-NHL). In April 2022, Genmab and AbbVie announced the topline results from EPCORE™ NHL-1 trial. In June 2022, primary results were presented in a late-breaking oral presentation as part of the Presidential Symposium at the 27th Annual Meeting of the European Hematology Association (EHA2022) in Vienna, Austria.

https://finance.yahoo.com/news/genmab-submit-biologics-license-application-182400689.html

Blueprint Draws Combined $1.25B Investment in Tough Market

 Blueprint Medicines announced strategic financing collaborations with Sixth Street and Royalty Pharma totaling up to $1.25 billion. The deals with the life science-focused investors provide capital to expand Blueprint’s pipeline toward commercialization and will enable the company to continue pursuing business development opportunities.

The collaboration with Sixth Street has three main components. First, Sixth Street will pay Blueprint a $250 million upfront cash payment in exchange for 9.75% royalties on the latter's products AYVAKIT and BLU-263, both potential treatments for systemic mastocytosis (SM). There is an annual cap of $900 million in net sales and a cumulative cap of 1.45 times the invested capital.

Second, Sixth Street offered up to $400 million in a senior secured credit facility from which Blueprint can draw in delayed tranches. And third, Blueprint gets $260 million in a potential credit facility to support business development opportunities.

"Blueprint Medicines is an impressive and differentiated biopharmaceutical company, with a proven track record of success in developing and commercializing precision therapies. We are particularly excited about the opportunity for AYVAKIT to meet the substantial need in patients with non-advanced systemic mastocytosis," Vijay Mohan and Jeff Pootoolal, partners at Sixth Street, said in a statement. 

Blueprint's NSCLC/Thyroid Cancer Drug Attracts Royalty Pharma

In the second collaboration, Royalty Pharma plans to monetize royalties receivable from Blueprint’s drug Gavreto, a treatment Blueprint developed with Roche for certain types of non-small cell lung cancer and thyroid cancer. Royalty Pharma will receive royalties from net sales outside of the U.S., not including Greater China, with $175 million cash paid to Blueprint upfront and up to $165 million in potential milestone payments based on future sales.

"Gavreto is an important precision therapy that has been incredibly meaningful for patients with metastatic, RET fusion-positive non-small cell lung cancer who may have otherwise had limited options," Pablo Legorreta, Royalty Pharma's founder and CEO, said in a statement. "We are pleased to establish a partnership with the experienced team at Blueprint Medicines to help fuel their execution on the significant commercial and development opportunities they have ahead."

Blueprint CEO Kate Haviland added, "This attractive deal puts Blueprint Medicines in a very strong financial position to drive rapid growth while maintaining our path to profitability in the coming years."

Blueprint Drawing Investment in Tough Market 

These collaborations are the latest in a series of successes for Blueprint. At the European Hematology Association (EHA) 2022 Congress in early June, the company announced positive data for AYVAKIT, showing that the drug significantly improved overall survival in advanced SM.

In February, Blueprint forged another collaboration, this time with Proteovant Therapeutics to advance novel targeted protein degrader therapies. In March, AYVAKIT (branded AYVAKYT) received approval from the European Commission to treat adults with SM. Ayvakyt was the first approved therapy in the European Union designed to selectively target the KIT D816V mutation.

Now with the two latest collaborations, Blueprint is confident in its successful future. 

"Executing this deal with such favorable terms in the current market environment speaks to the quality of the assets, the aligned confidence in the commercial opportunities, and the investment opportunity that Blueprint Medicines represents overall for firms like Sixth Street and Royalty Pharma, with whom we are building long-term strategic relationships," Haviland said.

https://www.biospace.com/article/blueprint-medicines-forges-two-collaborations-totaling-1-25b/

Aura Biosciences Gets Fast Track Designation for AU-011 Bladder Cancer Treatment

 Aura Biosciences Inc. said the U.S. Food and Drug Administration has granted Fast Track designation for belzupacap sarotalocan AU-011 for the treatment of non-muscle invasive bladder cancer.

The company said its planned Phase 1 clinical trial with belzupacap sarotalocan, a virus-like drug conjugate product candidate, would evaluate the safety and early proof of mechanism, assess distribution, local necrosis and evidence of immune activation.

Aura expects to initiate the trial in the second half of 2022, with initial Phase 1 data expected in 2023.

Fast Track designation is an FDA process designed to facilitate the development of products that address high unmet medical needs and may expedite the review of drugs intended to treat serious or life-threatening diseases.

Belzupacap sarotalocan has also been previously granted Fast Track and Orphan Drug designations by the FDA for the treatment of choroidal melanoma and is currently in Phase 2 clinical development in this indication.

https://www.marketscreener.com/quote/stock/AURA-BIOSCIENCES-INC-128747413/news/Aura-Biosciences-Gets-Fast-Track-Designation-for-AU-011-Bladder-Cancer-Treatment-40865868/