Did you know most of our generic drugs come from China?

Lynne Peterson is the Senior Writer for Trends-in-Medicine.

This is Part 2 of our 2-part Covid-19 Update, focusing on supplies, therapeutics, and the drug pipeline.

Medical supplies and drug shortages

Antibiotics: According to a 2019 estimate, 90% of the generic drugs Americans take come from either China or India. Of particular concern: no generic antibiotics are made in the U.S., and there haven’t been any plants making penicillin in the U.S. since 2004. This dependence on China and, to a lesser extent, India, has some experts — and some legislators — very concerned.

Disinfection: Xenex Disinfection Services has a $125,000 ultraviolet light robot for eradicating coronavirus from rooms and masks, and an analysis of the technology by the non-profit Texas Biomedical Research Institute said the device actually works. Texas Biomed estimated that the robot cleans surfaces in 2 minutes and N95 masks in 5 minutes.

Ventilators and related devices

  • ALung Technologies’ Hemolung, a respiratory assist system for reducing the need for invasive mechanical ventilation and intubation, was granted an EUA.
  • Baxter’s Oxiris filter set was granted an EUA to help reduce levels of inflammatory cytokines.
  • NASA’s Ventilator Intervention Technology Accessible Locally (VITAL), a high-pressure ventilator designed for Covid-19 patients, was granted an EUA.
  • Nvidia’s OP-Vent: The design for this low-cost (~$400), open-source ventilator — a device that can be manufactured from off-the-shelf parts — was made public.

Diagnosis of Covid-19

CT: In a study of 23 patients who were asymptomatic for Covid-19, published in the American Journal of Roentgenology, and who received an abdominopelvic CT for gastrointestinal symptoms found ground-glass opacities in the lower lungs of the patients, and 17 of those patients tested positive for Covid-19 on an RT-PCR test. The researchers suggested the findings should prompt radiologists identifying lung-base ground-glass opacities in abdominopelvic CTs to promptly alert the referring clinician that there is a possible Covid-19 infection.

Rapid Acceleration of Diagnostics (RADx) initiative: The National Institutes of Health (NIH) announced a $1.5 billion push (with stimulus funds) to develop Covid-19 diagnostics — not antibody tests. NIH issued a “national Covid-19 testing challenge,” urging scientists, inventors, and innovators to compete for a share of a $500 million pool earmarked for diagnostic development. Successful entrants will be matched with manufacturers and business experts who can help to scale up production quickly of any tests developed during the project.

In RADx, NIH will work closely with the FDA, CDC, and the Biomedical Advanced Research and Development Authority (BARDA). NIH Director Francis Collins, MD, PhD, said he hopes to harness “American ingenuity” to solve the problem of a simple, inexpensive, readily available Covid-19 test, one that can be scaled up quickly (by late summer or fall) so that millions of tests can be deployed weekly.

There are four phases to this challenge, which will be overseen by Bruce Tromberg, PhD, director of NIH’s National Institute of Biomedical Imaging and Bioengineering (NIBIB):

  1. Submissions, rather like a “Shark Tank” – and NIH expects about 100 applications to be submitted.
  2. Validation.
  3. Risk assessment.
  4. Clinical testing and regulatory approvals.

Among the Covid-19 diagnostic tests that recently got an EUA from the FDA are:

  • AIT Laboratories’ SARS-CoV-2 Test.
  • Altona Diagnostics’ RealStar SARS-CoV-2, real-time PCR kit for research use only.
  • Autobio Diagnostics’ Anti-SARS-CoV-2 Rapid Test.
  • Biocerna’s RT-PCR test, a modified version of Thermo Fisher Scientific’s TaqPath Covid-19 test.
  • GenoSensor’s GS Covid-19 RT-PCR kit.
  • Hologic’s Aptima SARS-CoV-2 test, a molecular test that runs on its Panther system, was submitted for an EUA.
  • KorvaLabs’ Curative-Korva SARS-CoV-2 Assay.
  • LabGenomics’ LabGun Covid-19 RT-PCR Kit.
  • MicroGenDX’ Covid-19 Key assay.
  • Nationwide Children’s Hospital’s SARS-CoV-2 assay.
  • Ortho Clinical Diagnostics’ VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack and Calibrators.
  • Rheonix’s Rheonix Covid-19 MDx Assay.
  • SD Biosensor’s Standard M nCoV Real-Time Detection kit.
  • Seasun Biomaterials’ U-TOP Covid-19 Detection Kit.
  • Ultimate Dx’s UDX SARS-CoV-2 Molecular Assay.

And, the European Medicines Agency (EMA) granted a CE-IVD Mark to some additional tests, including:

  • BAG Diagnostics’ ViroQ SARS-CoV-2 rapid PCR test.
  • JN Medsys’ ProTect Covid-19 RT-qPCR kit.
  • Vela Diagnostics’ ViroKey SARS-CoV-2 RT-PCR Test.

Tests on the horizon:

  • E25Bio is developing a Covid-19 antigen test that uses nasal swab from a patient, puts it into a solution, then exposes the solution to one end of a series of paper strips (rather like a home pregnancy test). The strips contain artificial antibodies specially designed to bind to coronavirus antigens. As the solution moves up the strip, any antigens that are present will bind to it and give a visual readout. The whole thing takes less than 30 minutes, and it doesn’t require special equipment or training. A company official said it could be priced as low as $10.

    But, before you get too excited about this, Alan Wells, MD, DMSc, the medical director of clinical laboratories at the University of Pittsburgh Medical Center, cautions, “It won’t work.” Why? He explained that antigen tests are good for bacterial diseases but not viruses, and the efficacy may depend on the ability to collect a good nasal swab. For example, the sensitivity of an antigen test for influenza has a sensitivity of 70%-80%, even with a good nasal swab.

  • Sanofi is partnering with Luminostics to develop a smartphone-based Covid-19 test.

Antibody (serology) testing

Demand for these tests has skyrocketed but so has the misunderstanding about what they can and cannot do. Basically, these tests can identify people who have antibodies to Covid-19, which means they were exposed to the virus, whether they got sick and recovered or were asymptomatic. Antibody positivity makes people potential donors for convalescent plasma, and it provides epidemiologists with a picture of the spread of the virus within the general population.

The problem is there is still no evidence that a person with antibodies has any immunity to SARS-CoV-2 or, if there is immunity, how long it lasts.

The FDA and NIH continue to remind people of this, but there remains a popular misconception about immunity related to a positive test. And, the specificity and sensitivity of the tests are still unclear. The White House proposed that, in some circumstances, two antibody tests be administered to the same person. And, the WHO warned against plans for proposed “immunity passports,” which would allow people who have recovered from the coronavirus to resume unrestricted travel and work.

Yet, there are a growing number of antibody tests getting either an EUA from the FDA or a CE Mark from the EMA, and there are more than 180 in development. The latest antibody tests include:

  • Abbott’s SARS-CoV-2 IgG antibody test, which claims 99% sensitivity and specificity – EUA and CE Mark.
  • Erba Mannheim’s ErbaLisa Covid-19 antibody Elisa detection kit — CE Mark.
  • Quest Diagnostics’ Covid-19 antibody test, which consumers can buy online for $119.
  • Quotient’s MosaiQ Covid-19 antibody microarray test, which claims 99.8% accuracy — CE Mark.
  • Roche’s Elecsys Anti-SARS-CoV-2 antibody test, which claims specificity >99.8% and sensitivity of 100% — EUA and CE Mark.
  • Siemens Healthineers’ fast total antibody test for SARS-CoV-2, which claims specificity and sensitivity of >99% — not yet approved.

The question is why any consumer would pay for any of these tests since there is no useable information beyond the ability to donate plasma.

Treatments

Gilead Sciences’ remdesivir, a direct-acting antiviral (an RNA polymerase inhibitor), was granted an EUA — not approval — for treating hospitalized Covid-19 patients. This is the first drug with an EAU for treating Covid-19 that has randomized trial data to back it up. Anthony Fauci, MD, Direcotr of the National Institute of Allergy and Infectious Diseases, called the results of that trial “quite good news,” adding, “This is really quite important. What it has proven is that a drug can block this virus.” He said remdesivir is now the “new standard of care” for all other trials.

In preliminary results from the 1,063-patient ACTT trial (at 47 sites in the U.S and 21 in Europe and Asia) sponsored by NIAID, remdesivir was shown to shorten the time to recovery from 15 days to 11 days, on average, a significant improvement versus placebo (P<0.001). However, it did not have a significant effect on mortality (8.0% versus 11.6%, P=0.059), the secondary endpoint, which means it failed on that endpoint, and describing it as a “trend toward a benefit” is inappropriate. And, those were the only trial results or details released.

Fauci compared remdesivir to AZT for HIV, saying, “When I was looking at these data with our team, it was reminiscent of 34 years ago in 1986 when we were struggling for drugs for HIV… and there were a lot of anecdotal reports…We did the first randomized trial with AZT… which had a modest effect… That was not the end game… but building on that… we had better drugs.”

Fauci said remdesivir is “opening the door” to other improved therapies. The next step for NIAID is going to be a trial of remdesivir with a monoclonal antibody — reportedly Lilly’s Olumiant (baricitinib), a JAK inhibitor. Fauci predicted, “As more investigators get involved, it will get better and better.”

Asked if remdesivir will change the vaccine timeline, Fauci said, “No.”

Asked about a negative study out of China, and published in The Lancet, which found no significant benefit to remdesivir, Fauci said that study was “underpowered… That was not an adequate study, and everyone in the field feels that way.”

The FDA put some specific conditions on the use of remdesivir:

  • Distribution has to be controlled by the government, with Gilead supplying remdesivir to authorized. distributors or directly to a U.S. government agency, who will distribute it to hospitals and other healthcare facilities, in collaboration with state/local authorities.
  • Patients must have suspected or laboratory confirmed Covid-19.
  • Patients must have severe disease, defined as blood oxygen saturation ≤94% on room air, the need for supplemental oxygen or mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
  • Remdesivir must be administered in an inpatient hospital setting. Remember, it is an IV drug.
  • Use must be accompanied by a Fact Sheet for healthcare providers and another one for patients and parents/caregivers.

Price: Gilead is donating 1.5 million doses to the government (enough to treat 140,000 patients). Beyond that, there is no word yet on how Gilead will price the drug. The Institute for Clinical and Economic Review (ICER) said remdesivir would be cost-effective at $4,460 per course of treatment.

Supply: The next question is whether Gilead can meet demand for remdesivir. The company hopes to have enough remdesivir to treat another 360,000 patients by October 2020 and 1 million patients by the end of 2020. While the company is considering possible licensing applications, it is concerned about not creating a shortage of the active pharmaceutical ingredients. And President Trump said the drug is not easy to make.

Distribution:The authorized distributor is AmerisourceBergen, but it is only the physical distributor. The Federal Emergency Management Administration (FEMA) said the Department of Health and Human Services (HHS) is making the decisions about where the drug goes. How HHS is choosing which hospitals get the drug is still unclear. There is an unconfirmed report that ~2 hospitals have gotten remdesivir. Massachusetts General Hospital is one of them. Mass Gen got enough remdesivir for ~170 patients, though it had 381 Covid-19 patients at the time, while other Boston hospitals with Covid-19 patients (e.g., Beth Israel Deaconess Medical Center with 248 cases and Boston Medical Center with 238 cases) didn’t get any. Likewise, Northwestern Medical Center, the University of California San Francisco, and the University of Michigan didn’t get any.

Outside the U.S., the demand is also going to be high, and Gilead will have to balance that with U.S. demand.

  • Japanese Prime Minister Shinzo Abe said remdesivir is expected to get a fast track review after approval elsewhere (i.e., the U.S.) to treat Covid-19.
  • The EMA started a rolling review of remdesivir.

Treatment duration: The open-label, Phase III SIMPLE trial compared a 10-day course of remdesivir treatment with a 5-day course, and in top-line results the shorter course was the winner:

  • Improvement in clinical status was comparable.
  • Time to improvement for 50% of patients was 10 days with the short course and 11 days with the longer course.
  • 60.0% of short-course patients were discharged from the hospital by Day 14 vs. 52.3% of longer course patients.
  • At Day 14, 64.5% of the short-course patients vs. 53.8% of longer course patients achieved clinical recovery.
  • Outside of Italy, overall mortality at Day 14 was 7% with both regimens, with 64% vs. 61% of patients discharged from the hospital.
  • In an exploratory analysis, patients who received remdesivir within 10 days of symptom onset had improved outcomes vs. patients treated >10 days after onset of symptoms. When data were pooled across treatment arms, by Day 14 62% of patients treated early were able to be discharged from the hospital vs. 49% of patients who were treated late.
  • No new safety signals were identified.
  • The most common adverse events with both regimens were nausea (10.0% vs. 8.6%), acute respiratory failure (6.0% vs. 10.7%). Grade ≥3 ALT elevations occurred in 7.3% of patients, with 3.0% discontinuing treatment as a result.

Convalescent plasma

There have been anecdotal reports of the efficacy of this therapy, but it has been used in 7,200 people in the past couple of months. Data on those patients are being analyzed, will be released in a couple of weeks, and should offer some useful insights, but it is not a randomized study.

The FDA issued guidance for healthcare providers and investigators on the administration and study of investigational convalescent plasma collected from people who have recovered from Covid-19, with recommendations on patient eligibility, donor eligibility/qualifications, labeling, recordkeeping, and more.

Johns Hopkins plans to start enrolling patients next week into two randomized clinical trials of convalescent plasma in the outpatient setting, with results expected in a couple of months:

  • A preventive study in nursing home patients to see if convalescent plasma will prevent them from catching Covid-19.
  • A treatment study in people with confirmed Covid-19 who are remaining at home to see if giving them convalescent plasma at home will prevent them from worsening to the point they need to be hospitalized.

Asked how many recovered Covid-19 patients would qualify to donate plasma, Arturo Casadevall, MD, PhD, chair of the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health, said, “The majority have high titers of antibodies… However, a small percentage have antibodies but not very high levels… And it depends on the antibody test used. They are not standardized very well. We are using an Elisa test developed at Mount Sinai.”

Hydroxychloroquine (HCQ)

President Trump is one of the few people still speaking out positively about HCQ, though he isn’t pushing it as hard as he used to. Some states are still stockpiling it. So, is it safe? Does it work? Two non-definitive but positive trials were reported recently.

A 568-patient retrospective Chinese study, available as a preprint on medRxiv.org, looked at critically ill Covid-19 patients who had severe acute respiratory distress syndrome (ARDS) despite antiviral and antibiotic therapy. Of the 568 patients, 48 also received HCQ (200 mg BID for 7-10 days).

  • Mortality (the primary endpoint) was 18.8% with HCQ versus 45.8% without it.
  • Length of stay before death was 15 days with HCQ and 8 days without it.
  • IL-6 levels were significantly lowered by the end of treatment with HCQ but not without it.
  • The researchers concluded that HCQ significantly decreased mortality in critically ill patients through attenuation of inflammatory cytokine storm and should be prescribed for treatment of critically ill Covid-19 patients.

A 1,061-patient retrospective analysis of HCQ in Marseille, France, in preprint, in which HCQ was combined with azithromycin, found that:

  • 91.7% had a good clinical outcome and virological cure within 10 days.
  • 4.3% of patients had a poor clinical outcome, and 8 died (0.75%). All the deaths were from respiratory failure, not cardiac toxicity.
  • Poor clinical outcome was associated with older age, severity at admission, and low HCQ serum concentration.
  • The researchers concluded that the combination of HCQ + azithromycin is safe and associated with a very low fatality rate.

The negative news: A report on 90 Covid-19 patients treated at a Boston hospital, published in JAMA Cardiology, found a potential for serious cardiac arrhythmias – significant QTc prolongation (>500 ms). One patient developed torsade de pointe when given HCQ + azithromycin.

Additional Developments

  • Roche’s Actemra (tocilizumab): This anti-IL-6R met the primary endpoint in the 129-patient French CORIMUNO-19 trial in hospitalized patients with moderate-to-severe Covid-19, with significantly fewer patients needing ventilation (mechanical or non-invasive) or dying by Day 14. The results have not yet been published. This drug makes sense because it is already used to treat cytokine storms in immunotherapy patients, and a key issue with Covid-19 is cytokine storm.
  • WHO announced the launch of Access to COVID-19 Tools Accelerator, a global project focused on developing and producing new treatments, vaccines, and tests for Covid-19, while ensuring global access to the products.

Other Drugs in Development

  • AbCellera and Lilly are collaborating on research for development of an antibody to treat Covid-19, and AbCellera got some help (up to $175.6 million) from the Canadian government’s Innovation, Science, and Economic Development Canada Strategic Innovation Fund.
  • BerGenBio’s bemcentinib, an oral selective AXL inhibitor – A 120-patient Phase II trial has started in the U.K. in hospitalized Covid-19 patients.
  • CAR T – Researchers at Duke-NUS Medical School in Singapore are studying whether there might be utility for CAR-T and/or TCR-T therapies in Covid-19.
  • Karyopharm Therapeutics’ Xpovio (selinexor) – The company announced the first patient was dosed with this cancer drug in a Phase II trial in severely ill Covid-19 patients.
  • Johnson & Johnson and Merck’s Pepcid (famotidine) – given IV at a dose 9-times the over-the-counter dose of this heartburn drug – is being tested in a clinical trial in New York City by Northwell Health.
  • Sarepta Therapeutics is initiating a discovery program to see if some of its antisense oligonucleotides can inhibit viral infection.

Vaccines

  • AstraZeneca is collaborating with Oxford University on the vaccine Oxford developed. Oxford took an existing chimp vaccine and engineered it to work for SARS-CoV-2, did efficacy studies in monkeys, and has now started a Phase I safety trial in healthy volunteers. The researchers predicted the vaccine could be ready by fall 2020.
  • Leukocare, ReiThera, and Univercells are collaborating on development of a novel adenoviral vector-based vaccine for Covid-19. They hope to launch a clinical trial this summer and begin manufacturing alongside clinical development.
  • Moderna, which has the lead in vaccine development and the support of NIAID, is advertising to fill a number of positions across Clinical, Quality, Technical Development, Drug Manufacturing, and Digital.
  • The Trump administration is working on a Manhattan Project-style initiative, Operation Warp Speed, to spur rapid development of a SARS-CoV-2 vaccine, with the aim of having a vaccine ready for use by the end of this year. The hope is that 3-4 of the 14 promising vaccines already in development will survive and be successful.

Lynne Peterson, Contributing Writing, Senior Writer for Trends-in-Medicine

Cat ID: 190

Topic ID: 79,190,254,930,570,574,190,926,192,927,151,928,925,934