Oxford-Sputnik V vaccine combo could be more effective

 When the efficacy of the Oxford/AstraZeneca vaccine was announced in late 2020, there was some confusion. The overall efficacy of the vaccine at stopping people developing symptomatic COVID-19, two weeks after the second dose, was 70%. But this wasn't the whole picture.

This figure was based on averaging the results from two groups. In one group, which was given two full doses, the vaccine was 62% effective at stopping people developing symptoms. But in the second group, a dosing error meant that volunteers received a half dose followed by a full one. This ended up being 90% protective against developing COVID-19.

This was intriguing. Why would giving people less of the vaccine lead to a more effective immune response? The answer to this may lie in the design of the vaccine, and could mean that there are ways to make this vaccine—and others that use the same design—more effective.

How the Oxford vaccine works

Vaccines work by exposing the immune system to recognisable parts—or "antigens"—of pathogens that cause disease, such as bacteria or viruses. The immune system then mounts a response. Immune cells called B cells make antibodies to destroy the pathogen. Sometimes T cells can also be called into action, which eliminate our own cells that have been infected with the pathogen.

Some B and T cells then remember the antigens for the future. At some future point, if the person is exposed to the pathogen, these long-lasting memory cells can quickly order more antibodies to be made to destroy the pathogen and attack infected cells.

In effect, the principle of vaccination is to "mimic" an infection, but in a controlled way so that immunity is generated without causing illness. After a few weeks, once T cells and B cells have been generated, the person vaccinated will be protected. For certain vaccines, this requires two doses, as in some people the first dose alone won't generate complete immunity. The booster dose ensures as many people as possible acquire protection.

In the case of the coronavirus vaccines, a number of methods are used to present the virus's antigens to the immune system. Some, such as the Sinopharm and Sinovac vaccines in China, simply present the body with a whole, inactivated version of the coronavirus. But others instead instruct the vaccinated person's own cells to produce a specific part of the coronavirus: the spike protein on its outer surface, which is a particularly recognisable antigen.

These vaccines do this by delivering the part of the coronavirus's genetic code that encodes the spike protein into the cells of the body, which then read the code and start making the protein. Some, such as the Pfizer/BioNTech and Moderna vaccines, deliver the code in the form of messenger RNA (mRNA). Others use a harmless virus to get the genetic code inside cells; the Oxford vaccine uses chimpanzee adenovirus, genetically altered so that it's unable to reproduce, called ChAdOx1. These are known as viral-vector vaccines.

How design could affect efficacy

It's not yet known why the reduced-dose regimen of the Oxford vaccine showed better efficacy in trials, but it could be down to the viral vector.

When a person is given a viral-vector vaccine, as well as generating an immune response against the coronavirus's spike protein, the immune system will also mount a response against the viral vector itself. This immune response may then destroy some of the booster dose when it is subsequently delivered, before it can have an effect. This has long been recognised as a problem.

However, a lower first dose might not allow for a strong anti-vector immune response to develop, which could leave the booster dose unscathed and lead to greater overall efficacy. If it turns out that this is the case, then future work will need to establish the optimum dosing regimen for generating the strongest immune response.

The Russian Sputnik V vaccine acknowledges that immunity to the viral vector could be a problem, but comes up with a different solution. It uses two different human adenoviruses—Ad26 and Ad5 (out of the 50 that affect humans) – for its two vaccine doses. This heterologous (or hybrid) vaccine, with different vectors for prime and booster vaccinations, is less likely to have one jab generate an immune response against the viral vector that then interferes with the other. The vaccine is therefore less likely to have a reduced efficacy.

The Gamaleya Center, the lab that made Sputnik V, said that after two doses the efficacy of the vaccine is over 90% (though it has yet to publish full results demonstrating this). This has now led to AstraZeneca testing a new hybrid vaccine schedule, comprising one dose of its vaccine and one of the Ad26-vector Sputnik V, to see if this makes the Oxford/AstraZeneca vaccine more effective.

https://medicalxpress.com/news/2021-01-coronavirus-combining-oxford-vaccine-russia.html

Kids highly likely to transmit coronavirus to others: study

 While children are less susceptible to illness with the new coronavirus, they are nearly 60% more likely than adults over 60 to infect other family members when they are sick, a new study shows.

The findings show the need to conduct COVID-19 vaccine safety and efficacy studies in children, according to co-senior study author Yang Yang, an associate professor of biostatistics and member of the Emerging Pathogens Institute at the University of Florida.

"We also need to take into account the potential high infectivity of children when we plan school reopenings and what prevention measures we need to take during active school sessions," Yang said in a university news release.

The researchers analyzed data from more than 27,000 households in Wuhan, China, that had confirmed cases of COVID-19 between Dec. 2, 2019 and April 18, 2020, a peak period of COVID-19 disease transmission in the city that was the first epicenter of the pandemic.

Previous research found that children shed SARS-CoV-2, the virus that causes COVID-19, at similar rates as adults. The higher infectivity of children in this study may be due to close contact with parents and other relatives caring for them, according to the authors of the study.

They noted that the overall contribution of child cases to household transmission of COVID-19 was still limited because infected children were isolated faster than infected adults.

The study also found that infants younger than 1 were significantly more likely to be infected with COVID-19 than children between the ages of 2 and 5. This may be due to a combination of their still-developing immune systems and their close contact with adults.

"It's unlikely there will be a vaccine for infants against COVID-19 in the near future, so we need to protect their caregivers," said study co-author Ira Longini, a professor of biostatistics at the University of Florida. "We may want to prioritize caregivers for COVID-19 vaccination to protect infants indirectly because we don't really know the long-term consequences of infection, especially in infants."

Among the other findings in the study:

• People who were asymptomatic during throughout their infection were 80% less infectious than people with symptoms, and presymptomatic people were about 40% more infectious than symptomatic ones.
• The secondary attack rate—the likelihood that a person with COVID-19 will infect another member of their household—was 15.6%, a rate similar to other respiratory pathogens.
• Older adults were more likely to become infected than younger household members, especially those under age 20.
• While children were less susceptible to COVID-19 infection than adults and they generally had less severe symptoms, they were just as likely to develop symptoms as adults.

"I recommend following CDC guidelines and taking extra caution when a household or family member is infected," Yang said. "This includes wearing masks if someone in the family has symptoms, especially when you need to be in close contact, good hand hygiene, surface cleaning and COVID-19 testing of asymptomatic members of the household, if possible."

The findings were published Jan. 18 in the journal Lancet Infectious Diseases.

https://medicalxpress.com/news/2021-01-kids-highly-transmit-coronavirus.html

Genetic testing's pitfalls for healthy patients

 Genetic testing can provide crucial information about what's causing a patient's problems and what lies ahead.

But for healthy patients? It's a lot tricker.

With the growing popularity of consumer genetic tests, patients are increasingly asking their doctors about whether a test could predict their vulnerability to certain conditions, such as cancer, dementia and heart disease. A case study published Monday in the Annals of Internal Medicine by researchers at Columbia University warns that doctors and patients alike should proceed carefully in understanding the context in which these tests provide useful information.

“Genetic testing was developed for diagnosing somebody who has a condition, or whose doctor suspects they have a condition,” said Ali Gharavi, MD, professor of medicine and chief of the Division of Nephrology at Columbia University College of Physicians and Surgeons and one of the article's authors. 

In that case, doctors start with a prior suspicion of a condition that can be confirmed, he told Fierce Healthcare.

But with a healthy patient, the probability of a currently undiagnosed disease is lower, which makes the probability of a false-positive result higher, he said.

As a result, physicians may need to do additional work to confirm a diagnosis. The amount of additional work required depends on the degree to which a given genetic variance has been positively correlated with a specific condition.

A relatively small number of genetic mutations are both well-studied and well-understood. Certain cancer mutations, for example, correlate strongly with the risk of developing breast cancer or ovarian cancer. However, a positive result on those tests doesn’t mean an individual has one of these cancers, or even that they definitively will get them. Instead, it may simply indicate they have a higher risk of developing that cancer.

With other genetic mutations, potential variations could be falsely correlated with a disease or they could occupy a gray area classified as a “variant of unknown significance.” Labs tend to use this classification for variants that require more study before they can be classified either as benign or malignant.

Gharavi says it’s important for physicians to take the consequences of a potential false-positive into account when helping patients make a decision on whether or not to undertake a given genetic test.

“It’s probably better to whittle things down to what you’re concerned about—if you’re concerned about Alzheimer’s and you conduct a test that scans the entire genome and come back with variants of unknown significance for heart disease and cancer, et cetera, then suddenly your anxiety level goes much higher.”

For patients, Gharavi recommends talking to your doctor about the conditions best suited to a genetic test and ensuring you understand beforehand what the potential consequences of a positive test might be. And if the test comes up negative, remember that it doesn’t mean you have no risk of contracting the disease in question.

For practitioners, Gharavi suggests bearing in mind that not all genetic tests have the same predictive capability. Understanding which tests are well-studied and correlate with specific diseases can help provide patients the education they need to decide which tests they really want, given their family history or other specific concerns.

Since research is ongoing, physicians should be aware that it can be a lot of information to stay on top of. “It’s all changing very quickly, so conferring with a genetic counselor or clinical geneticist also helps—somebody who’s really familiar with these tests,” Gharavi advises.

https://www.fiercehealthcare.com/hospitals/genetic-testing-presents-pitfalls-for-predicting-disease-healthy-patients

Hims & Hers goes public in $1.6B SPAC deal

 

• Consumer-facing digital health startup Hims & Hers on Wednesday completed its merger with special purpose acquisition company Oaktree Acquisition Corp., in a deal valuing the company at $1.6 billion.
• Hims & Hers received proceeds of almost $280 million as a result of the deal, which it plans to reinvest in driving geographic growth and new product lines.
• Beginning Thursday, Hims & Hers trades on the New York Stock Exchange under the symbol HIMS.

Wall Street has seen a flurry of digital health companies going public in recent months as the coronavirus pandemic continues to drive investor interest in the sector. Funding for digital health startups shattered records in 2020, with global equity funding hitting an all-time high of $26.5 billion last year.

Hims & Hers, which launched in November 2017, was originally geared toward addressing men's health issues such as erectile dysfunction and hair loss. In the past three years, the company added a women's health division, an online pharmacy and its own EHR.

Now, it operates as a telehealth platform connecting consumers nationwide to doctors in a variety of specialties, including mental health, sexual health, dermatology and primary care.

Hims & Hers is entirely cash-pay and doesn't contract with any insurance, though the company has said that could change in the future. Instead, members pay a subscription of around $20 a month for access to unlimited online consultations and a supply of generic medications.

Hims & Hers markets itself as a one-stop shop for consumers, allowing them to bypass the traditional in-person care delivery pathway. It can be more expensive than other telehealth offerings, but is still generally cheaper than the unbundled price of a doctor's visit and full-price prescription, according to SVB Leerink analyst Stephanie Davis.

The company has seen rapid growth. Since its launch a little more than three years ago, Hims & Hers has run more than 2 million telehealth visits and seen 100% compounded annual revenue growth, from $27 million in 2018 to $83 million in 2019 and an expected $138 million this year, per internal data.

Hims & Hers has more than doubled gross margins to 71%, with recurring revenue making up 91% of its top line. However, the company has yet to turn a profit, reporting a $69 million net loss in 2019, and doesn't expect that to change in the near-term as it reinvests in growth, according to financial documents filed with the SEC in December.

Beyond growing pains, Hims & Hers also faces additional risk as it looks to scale in the increasingly crowded and rapidly evolving virtual care market, elbowing against telehealth giants like Teladoc and Amwell and technology behemoths and retail pharmacies interested in the lucrative space, such as Amazon and CVS Health.

"We operate in highly competitive markets and face competition from large, well-established healthcare providers and more traditional retailers and pharmaceutical providers with significant resources," Hims & Hers said in the prospectus.

Additionally, the company noted it may not be successful in its nascent women's health and wellness initiatives. A substantial majority of its annual revenue is from male customers, so new and developing efforts to attract new female customers and retain existing ones could be challenging, according to the S-4.

The deal, approved Tuesday by Oaktree's shareholders, was first announced in October, closing in under three months. It values Hims & Hers at $1.6 billion, equal to 8.9 times estimated 2021 revenue, and 12.2 times estimated 2021 gross profit.

Of the $279.5 million in proceeds, about $204.5 million is cash from Oaktree Acquisition's trust account and $75 million is from private placement investors, including Franklin Templeton and other Oaktree clients. The San Francisco-based company's venture investors include McKesson Ventures, Founders Fund and IVP.

Hims & Hers' management and existing equity holders have also rolled between 90% and 100% of their equity into the combined venture, which will continue to be led by CEO and co-founder Andrew Dudum, along with much of its existing leadership team.

Merging with SPACs to go public as opposed to a traditional IPO has become an increasingly popular route for healthcare companies, as it generally allows founders and investors to retain more control with guaranteed access to capital. Another telemedicine company, SOC Telemed, went public in a similar deal in late July with special purpose acquisition company Healthcare Merger. Other healthcare companies using SPACs to go public in the fourth quarter include devicemaker Butterfly Network and medical documentation company AugMedix.

https://www.healthcaredive.com/news/hims-hers-goes-public-in-16b-spac-deal-1/593746/

ViiV: FDA OKs Cabenuva, 1st and only complete long-acting regimen for HIV

 ViiV Healthcare, the global specialist HIV company majority owned by GlaxoSmithKline plc (“GSK”), with Pfizer Inc. and Shionogi Limited as shareholders, today announced that the US Food and Drug Administration (FDA) approved Cabenuva, the first and only complete long-acting regimen for the treatment of HIV-1 infection in adults. Cabenuva is provided as a co-pack with two injectable medicines — ViiV Healthcare’s cabotegravir and Janssen’s rilpivirine — dosed once monthly, as an option to replace the current antiretroviral (ARV) regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per milliliter [mL]) on a stable regimen, with no history of treatment failure, and with no known or suspected resistance to either cabotegravir or rilpivirine. Prior to initiating treatment of Cabenuva, oral dosing of cabotegravir and rilpivirine should be administered for approximately one month to assess the tolerability of each therapy.

https://www.biospace.com/article/releases/viiv-healthcare-announces-fda-approval-of-cabenuva-cabotegravir-rilpivirine-the-first-and-only-complete-long-acting-regimen-for-hiv-treatment/

Genentech Earns Priority Review for Lung Disease Drug After Positive Data

 The U.S. Food and Drug Administration (FDA) has accepted Genentech’s supplemental New Drug Application (sNDA) and has granted Priority Review for the company’s unclassifiable interstitial lung disease (UILD) treatment Esbriet^® (pirfenidone). The FDA’s final decision on approval of the drug is expected by May 2021.

The recent sNDA accepted by the FDA was based on findings from a 24-week Phase II trial, the first randomized, placebo-controlled study to examine the effects of Esbriet in patients with UILD. Data from the trial were presented during a late-breaking abstract session at the 2019 European Respiratory Society’s annual meeting and were also published in The Lancet Respiratory Medicine.

In the multicenter trial, 253 patients with progressive fibrosing UILD were randomized to either 2403 mg pirfenidone (n=127) or placebo (n=126). Participants also presented with a percent predicted forced vital capacity (FVC) of 45% or higher and percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, a high-resolution computed tomography from the previous 12 months and more than 10% fibrosis on high-resolution CT.

Researchers used daily home spirometry to examine the mean change in FVC from baseline over a 24-week treatment period. Other endpoints in the study were the change in FVC, the proportion of patients who experienced a greater than 5% or more than 10% absolute or relative decline in percent-predicted FVC, change in percent predicted DLco, change in 6-minute walk distance (6MWD) as well as patient-reported outcomes.

The predicted median change in FVC over the 24-week period was -87.7 mL (Q1-Q3=-338.1-148.6) in patients randomized to Esbriet versus -157.1 mL (-370.9-70.1) in patients randomized to placebo. The predicted mean change in FVC, as measured by site spirometry, was significantly lower in patients assigned to Esbriet (treatment difference=95.3 mL; p=0.002). Treatment with Esbriet was associated with less loss of exercise capacity and lung function over the study period.

Additionally, the results for the 6MWD and DLco were “generally” in favor of Esbriet versus placebo. Common treatment-related and treatment-emergent adverse events included gastrointestinal disorders (47% for Esbriet vs. 26% for placebo), photosensitivity (8% vs. 2%), rash (10% vs. 7%), dizziness (8% vs. 3%), weight loss (8% vs. 1%) and fatigue (13% vs. 10%).

“Since its U.S. approval, Esbriet has become a standard of care for people living with idiopathic pulmonary fibrosis. However, significant unmet need remains in fibrotic lung diseases, including unclassifiable interstitial lung disease (UILD),” according to a statement made by Levi Garraway, M.D., Ph.D., Chief Medical Officer and head of Global Product Development at Roche. “We are working closely with the FDA in hopes of offering Esbriet to people with UILD, a rare and debilitating disease.”

Esbriet was approved in October 2014 for the treatment of idiopathic pulmonary fibrosis (IPF). Currently, the therapy is available for IPF treatment in more than 60 countries. Esbriet was obtained by Genentech in 2014 when Roche acquired InterMune, a Brisbane, Calif.-based company that developed the therapy, under an $8.3 billion merger deal.

Last year, Esbriet also received Orphan Drug Designation and Breakthrough Therapy Designation for UILD. The sNDA for Esbriet follows a legal battle, started in early 2019, that saw Genentech fighting to protect the drug from generic competition. Genentech went so far as filing 18 lawsuits over a few weeks to prevent other companies from selling their generic versions of the therapy for IPF.

https://www.biospace.com/article/genentech-earns-priority-review-for-lung-disease-drug-following-positive-clinical-data/

Servier and MiNA Partner to Create Entirely New Class of Drugs

 France-based Servier and U.K.-based MiNA Therapeutics are partnering on small activating RNA (saRNA) therapies to treat neurological diseases. saRNA is an entirely new class of drugs. They are small oligonucleotides, similar to siRNAs. This technology is MiNA’s focus, based on inventions from the company’s founder Pål Saetrom, which were assigned to MiNA by the Norwegian University of Science and Technology. The company has also in-licensed fundamental patents from UT Southwestern Medical Center that covers RNA activation therapeutics.

MiNA will leverage its saRNA platform to identify possible treatments to restore normal cell function in neurological diseases. Servier will handle preclinical and clinical development of potential candidates. Servier also will have the option for commercialization of any products coming out of the partnership.

Servier is paying MiNA an undisclosed payment up front and an exclusivity fee on specific neurological targets. MiNA is also up for various milestones and royalties. MiNA is eligible for up to 220 million euros ($268 million, U.S.) in upfront, development and commercial milestone payments for the first target. No specific neurological indications were disclosed.

“MiNA’s innovative approach to activate gene expression through small activating RNAs is an exciting opportunity to unlock potential for the treatment of genetically defined neurodegenerative diseases, for which there are currently limited treatment options,” said Ross Jeggo, Head of the Servier Neurology and Immuno-inflammation Therapeutic Area. “We are delighted to welcome the MiNA team and to combine their unique approach to restoring cellular function with Servier’s focus on treating neurological diseases.”

Small activating RNAs are short, double-stranded oligonucleotides. They selectively increase gene transcription. RNA activation (RNAa) was first described in 2006. In that study, saRNA that targeted the promoter region of a gene was found to activate transcription of the gene. Since then, research has shown that in mammals, saRNAs can activate a wide variety of genes.

MiNA’s pipeline currently consists of five compounds, three in the discovery stage for undisclosed metabolic, immuno-oncology and genetic targets. The other two programs are for the same drug, MTL-CEBPA, which are in Phase I/II trials, one with Bayer and Onyx Pharmaceuticals Nexavar (sorafenib) for hepatocellular carcinoma (HCC) and the other with Merck’s checkpoint inhibitor Keytruda (pembrolizumab) for advanced solid tumors.

The CEBPA gene encodes CCAAT/enhancer binding protein alpha, a transcription factor. This factor behaves as a master regulator of cell lineage determination and differentiation of myeloid cells, as well as other cell types. In the microenvironment of solid tumors, myeloid cells are often dysregulated. Restoring CEBPA expression in myeloid cells is believed to change immune cell populations in the tumor microenvironment and improve the effectiveness of cancer therapies.

In May 2020, MiNA presented topline data from the Phase Ib dose escalation and cohort expansion study, OUTREACH, of MTL-CEBPA and sorafenib in HCC. The trial hit the primary endpoints of safety and tolerability. Also, five patients experienced objective tumor responses, including two complete responses during the combination regimen.

“Working together with Servier, an established pharmaceutical leader in the treatment of CNS disorders, will enable us to expand the evaluation of our platform beyond our current liver-focused indications in an area of great unmet medical need,” said Robert Habib, chief executive officer of MiNA. “Following our first clinical proof-of-concept in cancer, this partnership in neurodegenerative disorders further demonstrates the potential of saRNAs as a promising treatment modality providing a new path to address previously undruggable targets.”

https://www.biospace.com/article/servier-and-mina-therapeutics-partner-on-small-activating-rna-for-neurological-diseases/