Antibiotics May Dull Efficacy of Hormonal Birth Control

The combined use of broad-spectrum antibiotics and hormonal birth control was associated with a higher risk of unintended pregnancy, researchers found.

Individuals who used antibiotics while taking hormonal contraceptives — such as the pill, patch, or ring — were nearly seven times as likely to get pregnant (odds ratio 6.7, 95% CI 2.9-16.0), according to Jeffrey Aronson, DPhil, of Oxford University, and Robin Ferner, MD, of the University of Birmingham, both in England.

Enzyme-inducing medications, which have known effects on the efficacy of hormonal birth control, were associated with 13 times the risk of unintended pregnancy (OR 13.0, 95% CI 5.5-31.0), the team reported online in BMJ Evidence-Based Medicine.

The researchers suggested that unintended pregnancy may occur by a few different mechanisms, including the effects of antibiotics on increasing hepatic metabolism of hormones, altering gastrointestinal function, and changing physiochemical factors in the gut that may affect the absorption of synthetic estrogen and progesterone.

Ferner told MedPage Today that the findings should encourage physicians to tell their patients that “it’s safest to take extra precautions to avoid unintended pregnancy.”

“We don’t know from our data how many unplanned pregnancies occur as a result of broad-spectrum antibiotics,” he said in an email. “But for some women, even a 1:1,000 chance of an unintended pregnancy would be too much.”

The researchers recommended that individuals who do not wish to get pregnant either stop having sex, or use a condom in addition to hormonal birth control while taking antibiotics and for 7 days after completing the course.

Asked for her perspective, Carrie Cwiak, MD, MPH, director of the family planning division at Emory University School of Medicine in Atlanta, said that while the research suggests an association between unintended pregnancy and antibiotic use, “it doesn’t seem to fit with some of the studies early on.”

Cwiak added that some mechanisms of unintended pregnancy suggested by the investigators need further clarification, such as the possibility that antibiotic use might affect levels of ethinylestradiol — i.e., synthetic estrogen — in certain patients.

“Ethinylestradiol is in fact not the main driver of contraceptive effect in hormonal contraceptives,” Cwiak told MedPage Today. “It is the level of synthetic progesterone in the medication that you’re using that provides the majority of contraceptive effect.”

She noted that although the CDC does not recommend precautions for the combined use of hormonal birth control methods and broad-spectrum antibiotics, the study indicates an opportunity to further explore the interaction of these two medications. https://tpc.googlesyndication.com/safeframe/1-0-37/html/container.html

For the study, Aronson and Ferner conducted a database review of Yellow Card reports to the U.K.’s Medicines and Healthcare products Regulatory Agency, including all reports that mentioned unintended pregnancy.

The researchers looked at three different kinds of medications: non-enzyme-inducing antibiotics, enzyme-inducers, and commonly used control medicines, including ibuprofen and citalopram. Non-enzyme-inducing medications included amoxicillin, ampicillin, cephalexin, ciprofloxacin, erythromycin, metronidazole, nitrofurantoin, oxytetracycline, and trimethoprim.

The primary outcome of the study was unintended pregnancy. The researchers also assessed for congenital abnormalities, cardiac arrhythmias, and headaches, and looked at diarrhea as a potential confounding factor.

In the analysis of 173,073 spontaneous reports, the investigators found that patients who took enzyme-inducing medications had the highest rate of unintended pregnancy (119 per 100,000, 95% CI 81-156). The rate of unintended pregnancy was 62 per 100,000 among those who took antibiotics (95% CI 44-79), and 6 per 100,000 among those in the control group (95% CI 2-16).

The risk of congenital abnormalities was higher among individuals who took enzyme-inducing medications, but not among the cohort who took broad-spectrum antibiotics. Diarrhea was not a confounding factor.

Aronson and Ferner acknowledged that the research is limited based on the use of adverse reports, so the actual number of unintended pregnancies and combined users of hormonal contraceptives and antibiotics is thus unknown. In addition, it was not possible to calculate absolute risk.

Cwiak stated that although further research is needed about the drug interactions of antibiotics and hormonal birth control, it is important to emphasize the need to counsel patients to keep using their chosen contraceptive method. When taking the medications in question, dual protection is the safest choice, she noted.

“We hear too many negative messages about birth control overall, and the benefits by far outweigh the risks,” Cwiak said. “At the end of the day, our message has to be birth control positive.”

Disclosures

Aronson and Ferner reported that “they have both written widely about adverse drug reactions and interactions and have from time to time received fees for legal reports, payments for articles, and royalties on books that they have written on the subject.”

Primary Source

BMJ Evidence-Based Medicine

Source Reference: Aronson JK, Ferner RE “Analysis of reports of unintended pregnancies associated with the combined use of non-enzyme-inducing antibiotics and hormonal contraceptives” BMJ Evid Based Med 2020; DOI: 10.1136/bmjebm-2020-111363.

https://www.medpagetoday.com/obgyn/generalobgyn/88144

Coming COVID-19 vax wave seen generating $20B in sales next year

With leading COVID-19 vaccines moving into late-stage testing and rollouts possible in late 2020 or early 2021, analysts are starting to make predictions about what the market will look like—including Bernstein’s Ronny Gal, who’s projecting some big 2021 numbers.

In all, Gal predicts the market will be worth $20 billion next year. After 2021, it’s “hard to model” because little is known yet about the vaccine candidates, he wrote in a note to clients. The analyst predicts “six players” will compete in the field for years, with the market eventually dwindling down to down to $5 billion to $6 billion per year. 

So far, federal purchasing agreements “have largely covered the U.S.,” he wrote in a note to clients. The government has inked deals to buy enough doses to immunize three quarters of the country’s population, even if some of the candidates don’t pan out.  

If the FDA gives its first emergency use authorizations for all adults, vaccine supply will be limited during the first quarter of 2021, Gal wrote. But if the initial authorizations are more restrictive, and the agency requires six months of safety data, “then there will be effectively no supply bottleneck and the vaccination wave will peak mid-year, when ample supply is available,” the analyst wrote. 

Developed countries will be vaccinated “in parallel with the U.S. with similar pricing and availability trends,” Gal wrote. As vaccination rates in developed countries near 50%, Gal predicts demand will slow and doses will shift to developing countries.

If current capacity projections pan out, the analyst predicts enough supplies by the end of 2021 to “vaccinate everyone.” 

In a separate COVID-19 vaccine market analysis, Evercore ISI analyst Josh Schimmer recently predicted COVID-19 vaccine developers will split $100 billion in total revenues and $40 billion in total profits. His team sees Moderna supplying about 40% of the total market, followed by a 20% share for Novavax. Other companies will split the rest of the market, Schimmer wrote. 

But Moderna and Novavax are going up against the some of world’s largest vaccine and biopharma companies with their programs. Johnson & Johnson, Pfizer and AstraZeneca are all either in phase 3 testing or planning to run large studies soon.

https://www.fiercepharma.com/vaccines/coming-covid-19-vaccination-wave-will-generate-20b-sales-next-year-analyst

Indian vaccine maker eyes raising $1B for COVID-19 shot manufacturing, trial efforts

With the last three months of the year fast approaching, players in the global hunt for a COVID-19 vaccine are gearing up for what will likely be a busy final quarter. Now, one of the world’s largest vaccine makers is looking to raise a massive sum to boost its production of up to five candidates.

The Serum Institute of India (SII) is pursuing $1 billion in fundraising by September to support development of five COVID-19 vaccine candidates, including frontrunners from AstraZeneca and Novavax, the Economic Times of India reported.

Private-equity investors Blackstone and KKR are reportedly in talks to help fund SII plan’s through a special purpose vehicle to boost manufacturing of the vaccines and support pivotal clinical trials, the Times said.

A spokesperson for SII could not be reached for comment by press time.

A representative for KKR declined to comment, and a Blackstone spokeswoman said in an email the firm did not speculate on “market rumours.”

SII, the world’s largest producer of vaccines to developing nations, has inked two deals to produce and distribute leading vaccine candidates, including AstraZeneca and the University of Oxford’s adenovirus-based shot, and Novavax’s spike protein hopeful. The drugmaker is also developing two of its own candidates, as well as a fifth through an agreement with New York-based Codagenix, according to the Times.

In late May, SII and Novavax inked a licensing deal for the Maryland-based biotech’s COVID-19 candidate as part of its goal to produce 1 billion vaccine doses each year.

In tandem with that deal, Novavax shelled out $167 million for Czech manufacturer Praha Vaccines and a 150,000-square-foot, 150-employee facility that the partners are using to rapidly scale production of Novavax’s shot.

Then, in early June, AstraZeneca tapped SII in a licensing deal to produce 1 billion doses of its vaccine to low- and middle-income countries, with the goal of 400 million produced by the end of 2020. AstraZeneca has also signed a $750 million deal with the Coalition for Epidemic Preparedness Innovations and Gavi, the Vaccine Alliance to manufacture and distribute 300 million doses of Oxford’s vaccine before 2021.

The SII isn’t the only Indian drugmaker taking its place in the global hunt for a COVID-19 vaccine.

Last week, Hyderabad, India-based Biological E announced it was working with Johnson & Johnson on the pharma giant’s own recombinant DNA-based prospect. The Indian firm acquired a 39,000-square-foot facility from Akorn India that could add more than 165 million doses to its annual capacity to aid in that effort.

Akorn’s vaccine manufacturing site in Himachal Pradesh “may be able” to handle commercial production of J&J’s vaccine, Biological E said in a release. The site currently has capacity for 135 million doses per year with the ability to immediately expand by another 30 million, Biological E said.

https://www.fiercepharma.com/manufacturing/indian-vaccine-maker-looks-to-raise-1b-covid-19-vaccine-manufacturing-trial-efforts

Sanofi works with retailers, practices on safer flu shots amid pandemic

Americans might not be worried about the flu season right now, but experts are already focusing on how to distribute and administer as many vaccines as possible—and how to do it safely during a pandemic.

Leading flu vaccine manufacturer Sanofi has some ideas. The French drugmaker is working with retailers and large health practices on safer alternatives to traditional vaccine appointments. Think outdoor, curbside or walk-through clinics, which feature one-way foot traffic and minimize contact.

To put those ideas into practice, the company is working with a group that represents pharmacy chains nationwide, a spokesman said.

Amid the pandemic, flu vaccines will be “more important than ever” to reduce the burden on healthcare systems, Elaine O’Hara, Sanofi’s head of vaccines in North America, told reporters on a conference call Monday. Millions of Americans most at risk of severe COVID-19 are also at a high risk from flu, she added. The CDC recommends flu vaccines for people 6 months and older.

Besides producing and shipping vaccines, Sanofi has created a program called “adaptive vaccination solutions” for health practices and retailers to encourage safe vaccinations. Safety recommendations include administering shots curbside—a la COVID-19 diagnostic testing—or in outdoor tents. Encouraging patients to sign up and provide information ahead of time could also help; all they’d need to do for their appointment is walk up and receive the vaccine.

“We can likely expect to see more of these adaptive vaccination solutions in September as people seek out flu vaccination,” a spokesman said.

Meanwhile, Sanofi is in the process of shipping 80 million vaccine doses for the U.S. Globally, the drugmaker is producing 250 million flu vaccine doses this year. 

Aside from Sanofi’s 80 million flu vaccine doses, the U.S. is slated for 57 million doses from Seqirus and 50 million from GlaxoSmithKline, according to representatives from those companies. AstraZeneca plans to ship 8 million doses of the inhaled nasal flu vaccine FluMist. Altogether, flu vaccine makers aim to deliver a record-breaking total of nearly 200 million doses stateside.

Pharma companies aren’t alone in bolstering their vaccination efforts amid the pandemic. On Monday, Walgreens said flu vaccines are now available at nearly all of its 9,100 locations nationwide. People can get flu vaccines by walking into a location or setting up an appointment ahead of time, and they should expect enhanced cleaning, social distancing and COVID-19 symptom screening, the company said. 

Face coverings are required at CVS and Walgreens locations, and pharmacists at those companies will be wearing them as well. CVS said it’ll implement physical distancing at its pharmacies and require patients to answer COVID-19 screening questions. 

Ahead of the flu season, CDC chief Robert Redfield has raised red flags about the tough months ahead. With the Sars-CoV-2 and influenza viruses spreading at the same time, the country faces the prospect of “the worst fall, from a public health perspective, we’ve ever had,” Redfield told WebMD. He encouraged flu vaccination to help reduce the twin burden on the healthcare system.

But there are positive signs about the upcoming flu season from the Southern Hemisphere, Sanofi’s medical head for vaccines in North America, Michael Greenberg, told reporters. At the beginning of the year, there were “normal rates” of flu transmission, he said, but thanks to record vaccination rates and physical distancing to slow the spread of COVID-19, there’s been a “plummeting” of flu cases in the hemisphere.  

https://www.fiercepharma.com/vaccines/as-flu-vaccine-makers-ship-record-200m-doses-experts-stress-importance-immunizations-amid

Interferon Levels Could Be Biomarkers for COVID-19 Cytokine Storm

Shortly before COVID-19 patients’ conditions advance from moderate to severe, their levels of type I interferon (IFN) are present in the bloodstream drop. Because IFN is essential for antiviral immunity, its levels may serve as biomarkers that could allow physicians to begin more aggressive treatments before the situation becomes critical. It also offers the possibility of preventing disease progression by administering IFN therapy, according to a report in Science.

The simultaneous appearance of poor anti-viral immune responses and strong inflammatory responses in some patients with acute viral infections was quite surprising, one of the paper’s contributors, Darragh Duffy, Ph.D., immunologist, Institut Pasteur, told BioSpace.

After studying 50 COVID-19 patients with various levels of disease severity and 18 healthy controls, he and a total of 30 researchers from the Université de Paris, Institut Pasteur, Sorbonne Université and other notable institutions found that low levels of IFN, including IFN-α2 and IFN-β, occur before patients enter the critical stage of COVID-19.

“We saw lower levels in patients who went on to develop critical disease. Patient numbers in this group were low, however, so that finding needs replication,” Duffy stressed.

In the most severe cases, there was no detectable circulating IFN-β. In COVID-19 patients, inflammation was characterized by “increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling,” the paper reported. In contrast, the IFN response was high in mild-to-moderate patients.

These early findings “suggest that IFN administration could relieve patients’ IFN deficiencies and that adapted anti-inflammatory therapies targeting IL-6 or TNF-α merit further testing,” Duffy said.

This also means that by monitoring IFN in patients, physicians may be able to identify patients who are about to take a turn for the worse.

“The tests exist but need to be qualified and validated for clinical use,” Duffy said. “Our study wasn’t designed to address how far in advance the serious symptoms associated with IFN can be detected but, with advanced warning, you could more closely monitor patients at risk of developing severe disease.”

This research suggests that an IFN deficiency could be a hallmark of a severe stage of COVID-19 and could, therefore, provide the rationale for combined therapeutic approaches.

In reaching these conclusions, blood-based biomarkers were key. The team used the Simoa platform by Quanterix to quantify and profile relevant markers – notably IFN – in COVID-19 patients.

IFN-α is present in the blood at very low levels. “It would have been impossible to detect, much less, quantify, without the ultra-sensitivity of Simoa,” said Kevin Hrusovsky, CEO of Quanterix, and founder of Powering Precision Health, a nonprofit organization advancing research at the intersection of biomarker technology and healthcare.

Its collaborating members include leading innovators, scientists, physicians, medical professionals, advocates, government officials and regulators.

“Simoa is 1,000 times more sensitive than competing platforms. Such sensitivity enabled the research team to “sample patients via simple blood draws rather than more invasive approaches, and allowed them to demonstrate the feasibility of actually applying such a test in clinical settings,” Hrusovsky said.

If a therapy emerges based on these findings, it would, ideally, be administered to hospitalized patients just before they advance from moderate to severe disease. For context, “Approximately 20% of people with COVID-19 experience severe symptoms as a result of cytokine storms,” Hrusovsky added.

“While the team’s findings are preliminary, they demonstrate the utility of testing for the IFN-α response in the blood in the clinical setting. Healthcare workers could test for this and other inflammatory markers through blood tests upon admittance, identifying whether the patient is at a high risk of an immune reaction and, during their inpatient care, monitoring their response to the treatment,” he continued. 

“IFN is implicated in multiple diseases (both infection and autoimmunity) so it may have broader implications, but it is still too early to say,” Duffy added. The next step, he said, is to “confirm these observations with kinetic sampling, larger studies, and pre/post-treatment, which will – hopefully – provide strategies for clinical use.”

“Although COVID-19 has made headlines, it is not altogether unprecedented (as a disease),” Hrusovsky said. “It bears many similarities to viruses like SARS and MERS, which also are associated with respiratory complications. The bodies of research surrounding those viruses have been instrumental to this pandemic. They have provided us with an important starting point and source of comparison data. Similarly, this and the hundreds of other research studies being conducted around COVID-19 will be critical in the future, when we face the next viral threat. Because of work by PPH members like Dr. Duffy, we have even more knowledge in our collective arsenal to refer to in the years ahead.”

https://www.biospace.com/article/study-shows-interferon-levels-could-be-biomarkers-for-covid-19-cytokine-storm/

Merck to Build $1.3 Billion Research Hub in London

U.S.-based Merck, known as MSD in Europe to distinguish it from Germany’s Merck KGaA, Darmstadt, Germany, is moving ahead with its $1.3 billion research center in London. The plan was originally announced in 2017 as part of a pledge to support post-Brexit Britain. The project has been delayed a bit, some of that related to difficulties in finding space in London, and also because it wanted to be in the life sciences hub near the Francis Crick Institute in north London. Merck has a significant five-year neuroscience research-and-development deal with the Crick Institute.

The new research hub will be called the London Discovery Research Centre and is expected to open by 2025. Work is expected to begin late next year, and the site expects to create approximately 120 new jobs for researchers and technicians and employ about 800 people overall. The site is expected to be 25,000 square meters.

“We currently view the UK as a world leader in developing science, driven by the long-term emphasis on building a strong research and development infrastructure,” David Peacock, MSD managing director for UK and Ireland, told the Financial Times.

The new site is across from King’s Cross station. The deal has not been finalized yet, requiring the council for the London borough of Camden to sign off on it. And there are reports of at least one group that is protesting the move.

A group of brick buildings called Belgrove House are currently at the site and would need to be demolished for the research center to go in. A local activist who is anonymous but runs SaveBloomsbury.co.uk has called the plan “diabolical” and described the plans for the center’s structure a “monstrosity” inappropriate for the neighborhood.

The protester wrote, “Despite being situated in one of the most highly sensitive historic settings in London, the development is one of the ugliest and most inappropriate buildings proposed in recent times, rivaling the Town Hall Annexe itself for the title of ugliest building in Camden.”

If Camden’s council approves, Merck will begin construction late in 2021 and finish by 2025, which is five years after the date originally proposed. According to the Financial Times, the researchers at the site will run early-stage research and mostly focus on age-related diseases.

As the 2018 story out of the Crick Institute noted, a team of about 15 Merck chemists and pharmacologists have been based there while plans to build the site have dragged on. The Merck team’s research projects were independent from Crick research, but the team was fully integrated into the Crick scientific community.

In August 2019, researchers from Merck and Crick began a new collaboration to focus on the causes of Motore Neurone Disease. It was the first project out of the five-year collaboration. Motore Neurone Disease is better known as Amyotrophic Lateral Sclerosis (ALS). The project is led by Rickie Patani, a research group leader at Crick and UCL and a consultant neurologist at the National Hospital for Neurology and Neurosurgery.

At the time, Rickie said, “In the clinic, it’s devastating when I have to tell a patient they have Motor Neurone Disease. Often, the patient first walks in with mild weakness in a limb and then I see the disease progressing relentlessly with every visit. Within a year or two, they might be in a wheelchair and require breathing support. This disease destroys families, and I feel profoundly guilty that we still have no effective treatments to offer.”

He added, “Through fundamental research, we want to understand the basic biology underpinning the disease. Just knowing what’s happening can offer some comfort to patients, even when there aren’t treatments around the corner.”

https://www.biospace.com/article/merck-to-build-1-31-billion-research-hub-in-london/