Healthineers collaboration aims to link antibodies to immunity

The effort has implications for international travel and allocating vaccines – but the precise quantitative tests necessary for this do not, as yet, exist.

As Covid-19 antibody tests proliferate, one central question has yet to be answered: does an antibody response actually confer immunity to reinfection? Siemens Healthineers, which is quietly making a name for itself as a company to watch in Covid-19 antibody testing, is collaborating with health protection agencies on both sides of the Atlantic in order to find out. 

The German group is to work with the Centers for Disease Control and the Joint Research Centre of the European Commission on a project to identify the minimum antibody titre necessary for a person to be considered immune, and thereby standardise antibody tests for the coronavirus. 

While a basic comparison of some antibody tests can be made using figures for sensitivity and specificity, this does not take account of which kind of antibodies they detect. Post-infection, a patient can generate antibodies to various parts of the coronavirus: the spike protein; its separate binding sites, S1 and S2; the receptor-binding domain of the S1 site; or the nucleocapsid protein, for example. 

And the various antibody tests available – more than 40 are currently authorised by the US FDA – detect different antibodies. But do all these antibodies protect against reinfection? Do any of them? If some of them do, how high do levels of each have to be? It is these questions that Healthineers, the CDC and the JRC aim to answer.

Titre ye not

The partners intend to develop a reference standard for Sars-CoV-2 assays by determining the neutralisation antibody titre – how much of each antibody confers viral neutralisation – for different manufacturers’ viral antigen targets. All antibody test manufacturers would be expected to adopt the resulting framework in the future, Healthineers said. 

Individuals with levels of an antibody meeting one of these thresholds could, theoretically, be considered immune. And if these standards are recognised internationally, as the presence of US and EU authorities suggests they might be, it could be possible to confer a sort of immunity passport on certain people, allowing them more freedom to travel than those without. 

And people need not come by these antibodies via infection. The availability of a Covid-19 vaccine, should this come to pass, will change the game again.  

Most of the major vaccine candidates that have reached mid- or late-stage development contain – or in the case of the mRNA vaccines, encode – parts or all of the spike protein. This is because antibodies against these antigens are believed to have the best chance of neutralising the virus (Healthineers’ Covid-19 antibody test spikes an interest in vaccines, June 2, 2020).

Those antibody tests that detect the viral proteins used in any successful vaccine will become crucial to establishing immunocompetence in vaccinated people, and determining who might need a booster shot. All of Healthineers’ Covid-19 antibody tests detect antibodies to the S1 receptor-binding domain.

More precision 

A test that can identify immunocompetent individuals or track vaccination status would be incredibly useful. But no such assay yet exists.

Most of the antibody tests currently available can indicate whether a person has had the virus or not, but no more than that. A few go further: the FDA has authorised two “semi-quantitative” tests, both developed by Healthineers, that can estimate the levels of coronavirus antibodies in a person’s blood. More of these kinds of tests are known to be in development, including one by Roche, but truly quantitative tests, that give a definitive reading of antibody titres, are as yet unavailable. 

Healthineers is thought to be the commercial partner for this initiative because of its leading position in semi-qualitative tests. It is unclear how happy other diagnostics groups will be with any standards that might emerge; still, if the political will to put these standards in place is sufficiently strong, they may have no choice. 

https://www.evaluate.com/vantage/articles/news/corporate-strategy/healthineers-collaboration-aims-link-antibodies-immunity

Arrowhead gets a $1.4bn boost from flattering data

Arrowhead previously played down hopes for its rare liver disease candidate ARO-AAT, so investors were pleasantly surprised by the limited data released yesterday. But it is hard to see why the group added $1.4bn in market cap on results that theoretically might have come from one patient. Arrowhead claimed to be reporting interim six-month liver biopsy data from four subjects in a phase II open-label study of ARO-AAT. The project is being developed for alpha-1 antitrypsin deficiency (AATD), a genetic disorder characterised by the build-up of mutant AAT protein (Z-AAT) in the liver. However, rather than reporting average values, Arrowhead only gave the best reported patient outcome for most endpoints – so, for example, serum and total intra-hepatic Z-AAT decreased by a maximum of 93% and 95% respectively. The group also reported a maximum 97% reduction in Z-AAT polymer – this was considered encouraging, since investors had previously been told that it might be too early to see a benefit here. This is no doubt what caused the excitement yesterday, but much more complete data are needed to draw reliable conclusions. Arrowhead hopes to present results from all four patients at the AASLD meeting in November; the pivotal Sequoia trial is ongoing.

Selected AATD projects in development
Project	Company	Description	Status	Note
ARO-AAT	Arrowhead Pharmaceuticals	RNAi therapeutic	Phase II/III, NCT03946449 & NCT03945292	Interim data reported
VX-814	Vertex Pharmaceuticals	Alpha-1 proteinase inhibitor	Phase II, NCT04167345	Data due YE 2020/Q1 2021
VX-864	Vertex Pharmaceuticals	Alpha-1 proteinase inhibitor	Phase II, NCT04474197	Trial began Jul 2020
DCR-A1AT	Dicerna Pharmaceuticals	RNAi therapeutic	Phase I/II, NCT04174118	Dicerna & Alnylam co-developing
ALN-AAT02	Alnylam Pharmaceuticals	RNAi therapeutic	Phase I/II, NCT03767829	Dicerna & Alnylam co-developing
Source: EvaluatePharma, clinicaltrials.gov.

https://www.evaluate.com/vantage/articles/news/snippets/arrowhead-gets-14bn-boost-flattering-data

Encouraging lupus data lifts Kezar Life Sciences

Kezar Life Sciences (NASDAQ:KZR) is up 9% after hours in reaction to data from the Phase 1b portion of the Phase 1/2 MISSION study evaluating lead candidate KZR-616 in patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN). The results were presented virtually at the Pan-American Congress on Rheumatology.

As of May 4 data cutoff, 39 participants were enrolled across five dose cohorts evaluating 45 mg and step-up dosing to 60 mg for 13 weeks. Patients were followed to week 25 and kept on stable background treatment. At this time point, 22 patients completed 13 weeks of treatment.

At week 13, five patients with increased DNA antibodies (biomarkers of SLE disease activity) experienced reductions from -6.3% to -76.7%. At week 25, the reductions ranged from -18.8% to -82.0%.

Two of two patients with active proliferative LN experienced more than 50% decreases from baseline in proteinuria, a biomarker of disease severity.

On the safety front, most treatment-related adverse events were mild or moderate. The most common were transient injection site reactions.

KZR-616 is a immunoproteasome inhibitor that the company says delivers a broad anti-inflammatory response and has shown potential efficacy in reducing the severity of certain autoimmune diseases (e.g., lupus, rheumatoid arthritis, IBD, MS, type 1 diabetes) in animal models.

The study is ongoing. The estimated primary completion date is June 2021.

https://seekingalpha.com/news/3615152-encouraging-lupus-data-lifts-kezar-life-sciences-up-9-after-hours

FDA OKs early-stage study for MorphoSys/I-Mab solid tumor monoclonal antibody

MorphoSys’s (NASDAQ:MOR) and its collaborating partner, I-Mab (NASDAQ:IMAB) announce that the FDA has signed off Phase 1 trial for MOR210/TJ210 for the treatment of relapsed or refractory advanced solid tumors.

MOR210/TJ210 is a monoclonal antibody that is directed against complement factor C5a receptor 1.

The trial is designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of MOR210/TJ210, and is expected to commence subsequently.

MorphoSys and I-Mab announced exclusive licensing agreement to develop and commercialize MOR210/TJ210 in November 2018, and I-Mab received exclusive rights to the compound in Greater China and South Korea, while MorphoSys retains rights in other parts of the world.

Both the companies are also collaborating on MorphoSys’ investigational human CD38 antibody MOR202/TJ202. I-Mab owns the exclusive rights for development and commercialization in mainland China, Taiwan, Hong Kong and Macao and started two registrational trials to evaluate MOR202/TJ202 in patients with relapsed or refractory multiple myeloma in 2019.

https://seekingalpha.com/news/3615130-fda-gives-go-ahead-signal-for-early-stage-study-for-morphosys-i-mab-monoclonal-antibody-in

Pfizer vaccine trial bets on early win against coronavirus – documents

Pfizer Inc is betting that its coronavirus vaccine candidate will show clear evidence of effectiveness early in its clinical trial, according to the company and internal documents reviewed by Reuters that describe how the trial is being run.

In recent weeks, Pfizer has said it should know by the end of October whether the vaccine, developed together with Germany’s BioNTech SE, is safe and effective. If the vaccine is shown to work by then, Pfizer has said it would quickly seek regulatory approval. It has not said what data it would use.

President Donald Trump, who is seeking re-election, has said a vaccine to fight the coronavirus pandemic is possible before the Nov. 3 U.S. vote, raising concerns over political interference. Scientists have questioned whether drugmakers will have enough evidence to achieve success by that time.

Pfizer’s clinical trial protocol outlines for the company, scientists and regulators how the drugmaker could show that its vaccine meets efficacy and safety standards set by the U.S. Food and Drug Administration.

A company’s protocol is submitted to the FDA for review and is overseen by an independent panel of experts known as a Data and Safety Monitoring Board.

The protocol calls for a first assessment of the vaccine’s performance by the monitoring board after 32 participants in the trial become infected with the novel coronavirus. So far, more than 29,000 people have enrolled in the trial that started in July, some receiving the vaccine and the others receiving a placebo.

The FDA has said that a coronavirus vaccine must prove to be at least 50 percent more effective than a placebo in a large-scale trial to be considered for approval. However, a smaller sample of infections in a clinical trial changes the calculation of how that standard is met, according to researchers.

Pfizer’s vaccine would need to be at least 76.9% effective to show it works based on 32 infections, according to its protocol. That would mean that no more than six of those coronavirus cases would have occurred among people who received the vaccine, the documents showed.

If the drugmaker’s vaccine does not meet the 76.9% efficacy target at this first interim analysis, it would face tougher statistical significance thresholds during subsequent interim assessments, biostatisticians who reviewed the protocol said.

Pfizer said its interim analyses were designed to show conclusive evidence “as quickly as possible amid the devastating pandemic if our vaccine meets the stringent standards set by FDA.” Pfizer would not say whether it would use an interim analysis as the basis for seeking approval.

The FDA declined to comment on whether it would consider such data sufficient for approval.

SUFFICIENT EVIDENCE?

Interim analyses typically are used by data and safety monitoring boards to determine whether an experimental drug appears safe and effective enough to continue a trial, or whether it should be stopped if a safety problem arises.

But if a vaccine meets FDA benchmarks at an interim analysis without any serious safety problems, it could make sense to use it as a basis for authorization to help curb a pandemic that has killed about 940,000 people globally, said Thomas Lumley, chair of biostatistics at the University of Auckland in New Zealand.

Moderna Inc, another front-runner in the vaccine race, told Reuters it would seek emergency FDA authorization to use its vaccine in high-risk groups if an interim assessment of its trial showed its vaccine was at least 70 percent effective.

Moderna, which made its protocols public on Thursday, said its first interim analysis of 53 infections is likely to come in November.

Some vaccine experts have said drugmakers should wait to reach their final analyses of more than 150 cases before seeking FDA approval. They note the speed at which vaccines are being developed for COVID-19, compressing what can be a decade-long process into months.

Relying on the more limited interim analyses could overstate a vaccine’s effectiveness simply because not enough trial participants fell ill, they have said. Moving more quickly through the trial process also means a drugmaker could miss potential side effects that could materialize if trials were given more time.

“These interim analyses have a flashing sign of short cuts,” said Eric Topol, director of the Scripps Research Translational Institute in La Jolla, California. “You miss safety issues and you may very well exaggerate the benefits.”

In addition to Pfizer and Moderna, Reuters reviewed the clinical trial protocols for vaccine candidates developed by AstraZeneca Plc and Johnson & Johnson.

AstraZeneca set its first interim analysis when about 40 coronavirus infections are reported among participants. Its U.S. trial is currently on hold after a patient fell ill. J&J’s first analysis would begin at 20 infections, according to the protocol of their large-scale trial due to begin on Sept. 21.

https://www.marketscreener.com/quote/stock/PFIZER-LIMITED-6493242/news/Pfizer-vaccine-trial-bets-on-early-win-against-coronavirus-documents-show-31316129/

In 12 U.S. states, at least 35% are obese – 2019 CDC data

Adult obesity is rising in the United States, with a greater impact on racial and ethnic minorities, a U.S. Centers for Disease Control (CDC) report showed, at a time when the health condition is seen causing heightened risk for severe COVID-19.

In 2019, at least 35% of the adult population were obese in 12 states, up from nine in 2018, based on data taken from a telephone survey by the CDC and the state health departments.

Alabama had the highest prevalence at 36.1%, followed by Alaska and Arizona, with Wyoming recording the lowest figures, with the health agency warning that obesity triples the odds of being hospitalized for COVID-19.

African American and Hispanic adults had higher prevalence than White adults and were more likely to suffer worst outcomes from COVID-19, the report, released on Thursday, said.

At 39.8%, Black adults suffered the most from the health condition, followed by Hispanic adults at 33.8% and 29.9% among non-Hispanic White adults.

Racial and ethnic minority groups have historically had fewer opportunities for economic, physical, and emotional health, and many of these factors are contributing to the higher level of obesity, the report said.

The U.S. health agency said college educated adults reported lower levels of obesity than people who did not graduate from college and young adults were half as likely to have obesity as middle-aged.

https://www.marketscreener.com/news/latest/In-12-U-S-states-at-least-35-are-obese-2019-CDC-data-shows–31316057/