Idera Pharmaceuticals, Inc. (Nasdaq: IDRA; the “Company”) today is announcing that ILLUMINATE-301, the Company’s pivotal registration trial of tilsotolimod in combination with ipilimumab versus ipilimumab alone in patients with anti-PD-1 refractory advanced melanoma, did not meet its primary endpoint of objective response rate (ORR). Idera is evaluating its next steps regarding continuation of the trial toward its overall survival (OS) endpoint, which includes evaluating the full data set when it is available. The Company also plans to continue its ILLUMINATE-206 Phase 2 study of tilsotolimod in combination with ipilimumab and nivolumab in patients with microsatellite stable colorectal cancer (MSS-CRC).
ILLUMINATE-301 is a randomized, global, multi-center, open label Phase 3 trial comparing the efficacy of 8 mg intratumoral tilsotolimod in combination with 3 mg/kg ipilimumab versus 3 mg/kg ipilimumab alone in 481 patients with anti-PD-1 refractory advanced melanoma. The trial has a primary endpoint family of ORR per RECIST v1.1 and OS. Although the primary endpoint of ORR was not met, if the study continues and reaches a positive OS outcome, the Company would expect to discuss with regulatory authorities a potential path forward in this indication.
ILLUMINATE-301 Key Findings: Patients in the study were randomized and treated either with 8 mg of tilsotolimod in combination with ipilimumab or with ipilimumab alone. Topline results include:
ORR of 8.8% for the combination arm and 8.6% for ipilimumab alone.
Disease control rate (DCR, defined as stable disease or better) of 34.5% for the combination and 27.2% for ipilimumab alone.
Treatment-emergent adverse events (TEAEs) (Grade 3 and above) occurred in 61.1% of patients who received the combination vs. 55.1% of patients who received ipilimumab alone. Immune-related TEAEs (Grade 3 and above) were reported in 37.6% vs. 30.1%, respectively.
More detailed results from ILLUMINATE-301 may be submitted for future publication or presentation.
“We are surprised and disappointed that the response data from ILLUMINATE-301 do not lead us to an accelerated path to a new and much-needed treatment option for these patients,” stated Vincent Milano, Idera’s Chief Executive Officer. “We would like to extend our deepest gratitude to everyone involved in this study, especially the many courageous patients who participated and continue in follow up.”
Continued Mr. Milano, “Despite today’s news, we are continuing to explore tilsotolimod via our ongoing ILLUMINATE-206 study in order to understand its potential to lead to better outcomes for patients with MSS-CRC.”
SARS-CoV-2 is aerosolized. If a non-vaccinated person who is shedding the virus visits a vaccinated relative in a nursing home, he can easily spread the virus to all who reside in the facility.
As I have stated repeatedly, if we keep spreading around SARS-CoV-2, it may well mutate into a variant which evades the vaccines for coronavirus disease 2019 (COVID-19). According what recently went on in a Kentucky nursing home, the virus may well have done just that. According to WKYT: “The governor says a COVID-19 outbreak has been reported at a nursing home in eastern Kentucky. There are 41 cases reported, including five residents that have been hospitalized. Dr. Steven Stack says 30% of vaccinated individuals are symptomatic and 83% of the unvaccinated at the nursing home are showing symptoms.” According to Kentucky.com “85 percent of residents and 48 percent of staff opted to get a coronavirus vaccine.”
Initial reports are that this virus is not a known variant. I hope this outbreak is due to problems with the vaccine given nursing home residents and staff. If vaccine protocols for storage and reconstitution are not followed precisely, then the vaccines’ effectiveness will decrease. But baring that, this is very concerning news.
There are several take-home lessons. The first is that we should not be fully opening up our economy and relaxing public health measures. The recent updated guidance for nursing homes from the Centers for Disease Control and Prevention (CMS) should certainly be placed on hold. And as discussed in a recent article in Infection Control Today®, this guidance endangers the elderly. Herd immunity cannot be achieved in a nursing home. If one person is spreading the virus and one person is susceptible, viral transmission will occur. And this virus is aerosolized. Thus, if a non-vaccinated person who is shedding the virus visits a vaccinated relative, he can easily spread the virus to all who reside in the facility.
The initial reports appear to indicate the efficacy of the vaccine is diminished by this variant. Research has reported that the Pfizer and Moderna vaccines prevent symptoms in 95% of individuals and prevents hospitalizations in all who have been vaccinated. From the initial report, it appears that there is likely a very high infection rate in those who did not receive the vaccine. In vaccinated individuals there also appears to be protection, but nowhere near 100%. Unvaccinated residents were twice as likely to develop symptoms. It is reported that one vaccinated resident is hospitalized (1 in 71) with COVID-19, compared to 4 unvaccinated residents that are hospitalized (4 in 13).
The guidance that vaccinated individuals, even with the variants, will avoid hospitalizations does not appear to be valid. And we need to slow down the spread of this virus so we can slow down the mutation rates and our vaccine development can catch up with these new variants.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a potentially long incubation period and spreads opportunistically among those who are unaware they are infected. Asymptomatic COVID-19 cases are those that do not develop symptoms for the duration of infection, whereas presymptomatic cases develop symptoms later in the course of infection, but both are crucial drivers of transmission (1). Transmission without symptoms poses specific challenges for determining the infectious timeline and potential exposures. Early in the pandemic, most transmission was from undocumented cases, suggesting that spread was driven by people who were either asymptomatic or experiencing such mild disease that it was not recognized as COVID-19 (2). Contagious people without observable signs of illness make infection prevention efforts vulnerable to compliance with masking, distancing, hand hygiene, symptom screening, and ultimately, people staying home when possible. The lack of widespread testing in asymptomatic individuals further complicates COVID-19 mitigation and control efforts.
The true occurrence and transmission capacity of asymptomatic and presymptomatic infections are difficult to evaluate. Owing to insufficient surveillance testing (testing regardless of symptoms), presymptomatic cases lost to follow up, and unrecognized mild symptoms, symptomless cases are often undercounted or misclassified. It is virtually impossible to detect such cases without continuous community surveillance screening, which has not been widely implemented, or without effective contact tracing and testing. Beyond implementing general and often vague control measures, public health efforts have struggled to truly address symptomless transmission. Surveillance testing has predominantly been carried out in targeted populations such as long-term care facilities. Only certain industries, such as professional sports and entertainment, have implemented asymptomatic testing, but such data are not publicly available and these groups are not representative of the broader community. It is important to understand infectiousness and viral shedding, as well as the overall contribution of asymptomatic or presymptomatic cases to secondary cases.
The prevalence of symptomless cases is not precisely established. Early studies reported that asymptomatic cases accounted for 30 to 80% of infections (3), but more recent data point to a rate of asymptomatic cases between 17 and 30% (4). A recent systematic review of studies reporting SARS-CoV-2 diagnoses by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR, the standard molecular diagnostic test) and follow-up of symptoms found that the proportion of asymptomatic infections was 20% and that the rate of presymptomatic individuals could not be determined because of heterogeneity across studies (4). A limitation of such studies is measurement of asymptomatic status and selection bias. Often, large outbreaks driven by asymptomatic or presymptomatic transmission are restricted to specific populations or circumstances, such as in skilled nursing or long-term care facilities, where surveillance testing takes place (5). Because these are high-risk clinical environments, it is not surprising that symptomless transmission has been detected more frequently than in nonclinical settings, such as restaurants or offices, which lack access to testing or medically trained staff. The unknown prevalence of asymptomatic SARS-CoV-2 infections makes disease control and mitigation strategies inherently challenging.
Beyond assessing the prevalence of symptomless infections, it is vital to determine their risk for secondary transmission. Contact tracing is reliant on case identification, which generally involves testing of people with symptoms. This reliance on symptom-based testing, especially early in the pandemic, was also complicated by limited understanding of the full range of COVID-19 symptoms. The lack of surveillance testing makes analysis of secondary attack rates (the percentage of cases that result from one infected person within a defined group) for asymptomatic cases exceedingly difficult. In symptomatic COVID-19, infectiousness begins 2 days prior to symptom onset and for several days after, with reduced or undetectable viral shedding within the first week of symptom onset (5, 6). Viral shedding kinetics for asymptomatic COVID-19 is not well understood. Early in infection, individuals have similar viral loads regardless of eventual symptom severity, but asymptomatic cases have lower titers at peak replication, faster viral clearance, and thus a shorter infectious period (6).
Measuring the true impact of symptomless infections on transmission can be extremely confounding. Data on asymptomatic and presymptomatic cases who had close contacts but did not result in transmission are limited. Some studies found that asymptomatic cases were 42% less likely to transmit the virus, and observed lower secondary attack rates, whereas others have noted that regardless of a shorter infectious period, there is similar transmissibility for those with presymptomatic or asymptomatic COVID-19 in the first days of infection (6). Studies of presymptomatic transmission suggest that higher secondary attack rates are likely compared with asymptomatic cases (7). Moreover, analyses of contact tracing data indicated that at least 65% of transmission occurs prior to symptom onset (8). Another study found that only 12.6% of cases resulted from symptomless transmission (9). These discrepancies can be explained by several factors, including the misclassification of cases that were not followed up (4), but also that many are identified as a result of specific settings, such as superspreading events on cruise ships or in choir practice that result in rigorous investigations, and may not be representative of typical transmission events.
Determining the true transmission capability of asymptomatic and presymptomatic cases is inherently complex, but knowledge gaps should not detract from acknowledging their role in the spread of SARS-CoV-2. Those with symptoms appear to have higher secondary attack rates, but these cases are also more likely to present for testing and practice isolation because of obvious illness (10). The public health and infection prevention challenges rely on those without symptoms to self-quarantine and implement a suite of interventions, such as masking, social distancing, ventilation, and hand hygiene. However, emphasis on the degree of contagiousness rather than the knowledge that people without symptoms are generally contagious detracts from the public health threat that asymptomatic and presymptomatic infections pose and the need for continuous community-based surveillance and interventions.
The 2003 outbreak of the related SARS-CoV was eventually contained by using standard epidemiological approaches of isolating cases and tracing and quarantining contacts. This was effective because contagious patients could be easily identified through temperature and symptom screening. A major distinction from SARS-CoV is viral shedding of SARS-CoV-2 in the absence of observable clinical symptoms. Unlike SARS-CoV, SARS-CoV-2 viral loads are highest at symptom onset and up to a week after (6), which suggests substantial presymptomatic shedding. Therefore, people are likely contagious for a relatively long period and when they are unaware they have been infected or exposed. The minimum infectious dose required for transmission is also not known and likely varies depending on individual exposure and susceptibility. Although viral loads decline over the course of infection, the exact point at which someone stops being contagious is unclear, but probably occurs within 10 days of infection in most cases, provided symptoms are resolving.
Testing provides limited clarity on whether a person is likely to be contagious on the basis of estimated viral loads. Although people who have fully recovered from COVID-19 can continue to shed viral RNA and test positive by qRT-PCR in the absence of recoverable infectious SARS-CoV-2, as assessed by culture (1, 5, 6, 11–14), these cases have not been associated with new clusters of transmission (12, 13). qRT-PCR detects viral RNA but not infectious virus particles. PCR cycle thresholds can be used to estimate viral load in nasal swabs, but do not always directly correlate with the quantity of infectious virus shed in respiratory particles. These particles are highly heterogeneous depending on various factors, including where in the respiratory tract cells are secreting infectious virus, breathing rate, and symptoms such as coughing (15). Not all exhaled particles contain infectious virus, and the amount of time that virus remains infectious after exhalation in respiratory particles can vary substantially depending on environmental conditions such as temperature and humidity, as well as the quantity of infectious particles being shed. Assays that measure infectious titer must be performed in biosafety level 3 (BSL-3) containment, so this cannot be routinely measured in clinical settings. Furthermore, qRT-PCR and rapid antigen tests can be performed in hours or minutes, compared to several days for determining infectious titer. Viral loads determined by qRT-PCR are, at best, a crude measure of actual infectious virus shedding, so further research is needed to establish viral loads in asymptomatic and presymptomatic cases (see the figure).
The biological basis for transmission without symptoms is poorly understood, even though it is common for respiratory viruses, including “common cold” pathogens such as rhinoviruses and other coronaviruses, to be spread by both contact and inhalation. Symptomless transmission is influenced by the timing and magnitude of the host response to infection, which is a major determinant of pathogenicity. Delayed or reduced host antiviral immune responses are closely linked to COVID-19 severity, suggesting a relationship between host response and symptom onset. This includes suppressed interferon-induced cytokine expression, which is linked to symptoms. As a gateway between the body and the environment, the upper respiratory tract is regularly exposed to external antigens. Thus, the nasal mucosa is a niche immune site in which antiviral responses are modulated by external factors (such as temperature or humidity) and host susceptibility (mucus, receptor distribution, and host response to infection) and may explain why symptomless spread is common for respiratory viruses.
The titer of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the amount of viral RNA are generally lower in asymptomatic (A) than presymptomatic (Pre) COVID-19. There is likely to be a threshold at which a person becomes contagious, but this is not known. In presymptomatic patients, symptoms usually begin when viral load peaks, so there is a period of infectiousness when a person has no symptoms.
GRAPHIC: N. CARY/SCIENCE
With many contagious people experiencing no symptoms and in the absence of robust surveillance testing for asymptomatic or presymptomatic infections, it is critical to maximize efforts to reduce transmission risk in the community. Academic debates about the frequency of different transmission routes reframe exposure risk reduction as a dichotomy rather than a spectrum, confusing rather than informing guidance. Rather than targeting transmission by either inhalation or contact, infection prevention efforts should focus instead on the additive nature of risk reduction and the need for continued vigilance in community-based infection prevention measures, including masks, distancing, avoiding enclosed spaces, ventilation, hand hygiene, and disinfection.
Transmission without symptoms critically contributes to the unabated spread of SARS-CoV-2 and presents a considerable infection prevention challenge. Although asymptomatic individuals appear to be contagious for a shorter period of time and may pose a lower transmission risk, they still pose a substantial public health risk as they are more likely to be out in the community. It is unclear how vaccination will affect the number of asymptomatic cases, although preliminary data suggest that mass immunization will reduce infection overall, thus reducing transmission. For presymptomatic cases, research has shown that viral shedding is highest just before and for a few days after symptoms begin, which is a critical time to ensure that individuals who may not realize they have been exposed stay home when possible and practice risk reduction efforts when in the community. Until there is widespread implementation of robust surveillance and epidemiological measures that allow us to put out these smokeless fires, the COVID-19 pandemic cannot be fully extinguished.
-Improvement in mortality for each dose compared to placebo, while trending toward positive, was not statistically significant for the overall study population
- Significant improvement in mortality seen in U.S. study participants at both doses, and in the overall population when data from both treatment arms was pooled
- Expanded Access Program to allow eligible patients in the United States with COVID-19 associated ARDS to receive ruxolitinib will be discussed with the U.S. Food and Drug Administration
Given the urgent nature of the COVID-19 pandemic, Incyte plans to make ruxolitinib available to eligible patients in the United States at no cost via an Expanded Access Program (EAP) pending agreement with the U.S. Food and Drug Administration. The protocol will allow eligible patients with severe COVID-19 associated ARDS with disease severity requiring mechanical ventilation to receive ruxolitinib.
At present, there is ample commercial and clinical supply of ruxolitinib in the United States to meet the needs of U.S. patients receiving ruxolitinib in its approved indications and those participating in clinical trials or the COVID-19 EAP.
For more information about Incyte’s response to COVID-19, including information on the DEVENT study and EAP, visit: Incyte.com/COVID-19.
Amazon(AMZN) will expand its virtual health care pilot program to all of its U.S. employees and their families as well as other firms this summer, the company announced Wednesday, in a move that hit several stocks in the health care services sector. Amazon stock climbed.
The program, calledAmazon Care, was launched at its Seattle headquarters 18 months ago. It enables workers to connect with medical professionals via chat or video conference. and connect patients to medical professionals. In addition, Amazon Care can dispatch a medical professional to a patient's home for additional care.
Amazon said it's now expanding Amazon Care's virtual services from only Washington state employees and their families to those in all 50 states starting this summer. At that time, Amazon Care will expand its virtual care to include other companies nationwide.
Investors apparently fretted as Amazon now has its eye on targeting markets outside its employee base. The news hit shares of Teledoc Health (TDOC), American Well (AMWL), Rite Aid (RAD), CVS Health (CVS) and Walgreens Boots Alliance (WBA).
Shares of virtual health care company Teledoc lost 4.4%, closing at 190.10 on the stock market today. In addition, telemedicine company American Well dropped 4.5%, to 21.04. Drugstore chain Rite Aid fell 1.5% 26.97, while CVS Health slid 1.4% to 74.01. Walgreens skidded by 1.1% to 54.10. Meanwhile, Amazon stock climbed 1.4%, closing at 3,135.73.
A Growth Engine For Amazon Stock
If Amazon can deliver more efficient health care services, the potential is enormous for fueling its growth engine — and by extension Amazon stock. Health care now comprises nearly a fifth of the U.S. economy.
Amazon's last major health care move was its acquisition of PillPack in mid-2018. Amazon paid about $753 million for the online pharmacy, which delivers prescriptions presorted by the dose.
Amazon faces a health care industry that's primed for disruption once the coronavirus passes. Patients are weary of skyrocketing health care costs, while insurers balk at shelling out countless dollars for treatments.
Medical Care Within 60 Seconds
"Amazon Care enables employers to provide access to high quality medical care within 60 seconds for employees, including options for care around the clock through messaging or video," Amazon said in a blog post.
The service includes Covid-19 and flu testing, vaccinations, treatment of illnesses and injuries. Also, it includes preventive care, sexual health, prescription requests, refills, and delivery, it said.
Amazon has made many forays into the health care field over several years. The big unknown is just how far and deep the company will venture into the health care market and how much fuel that will bring to Amazon stock.
Late Tuesday, Baird analyst Colin Sebastian named Amazon a "Fresh Pick," saying it was "significantly undervalued, with a medium-term path to $5,000, based on robust fundamental trends in e-commerce, marketplace services and cloud."
He also estimates Amazon is quickly approaching 200 million subscribers to its Amazon Prime customer rewards program, "which means there are likely 400 million to 600 million people shopping with Amazon regularly and driving about 80% of the company's e-commerce volumes," he wrote in a note to clients.
Existing vaccines may protect against the Brazilian variant of the coronavirus, according to a University of Oxford study which also highlighted how a variant first found in South Africa poses the biggest headache for vaccine makers.
Coronavirus variants with specific mutations to the spike protein are of concern because scientists worry they will reduce the efficacy of vaccines, as well as immunity gained from prior infection.
The scientists used blood samples from people with antibodies generated by both COVID-19 infection and the Oxford/AstraZeneca and Pfizer/BioNTech vaccines that are being rolled out in Britain.
The data showed a nearly three-fold reduction in the level of virus neturalisation by antibodies generated by the vaccines for the P.1 Brazil variant - similar to the reduction seen with the variant first identified in Kent, Britain.
“These data suggest that natural- and vaccine-induced antibodies can still neutralise these variants, but at lower levels,” it said. “Importantly, the P1 ‘Brazilian’ strain may be less resistant to these antibodies than first feared.”
The variant first identified in South Africa triggered a much larger reduction in virus neutralisation, with a 9-fold reduction in Oxford/AstraZeneca’s vaccine, and a 7.6-fold reduction for Pfizer/BioNTech.
Last month, South Africa put use of AstraZeneca’s shot on hold after data showed it gave minimal protection against mild-to-moderate infection cause by the country’s dominant variant.
The authors of the study said that developing vaccines against the South Africa variant, known as B.1.351, should be the “greatest priority for vaccine developers globally”.
Andrew Pollard, chief investigator of the Oxford University vaccine trial, said the study provided “new insights that help us be prepared to respond to further challenges to our health from the pandemic virus, if we need to do so”.
The study was released on a pre-print server, and had not been peer-reviewed.
Johnson & Johnson is developing several next generation COVID-19 vaccines against the emerging variants of the coronavirus, Chief Executive Officer Alex Gorsky said on Thursday.
The drugmaker, which won the U.S. emergency use authorization of a one-shot vaccine last month, had previously said it was developing a second-generation vaccine that would target the variant first identified in South Africa. J&J is also working on a two-dose version of its vaccine.
“We could be in a situation where you could either need a booster to maintain the durability (of protection against the virus) or you might need to have a next derivative of the current vaccine to address these variants as they develop”, Gorsky said at a webinar by the Economic Club of New York.
