BioNTech, Pfizer, and Fosun Pharma
Candidate: BNT162 ●●
Type: Potential first-in-class mRNA vaccine designed to induce immunity and prevent COVID-19 infection
Status: BioNTech and Pfizer said April 9 they intend to launch their first clinical trials for an mRNA COVID-19 vaccine as soon as the end of April, initially in the United States and Europe across multiple sites. The companies said they will advance multiple candidates.
Pfizer agreed to pay BioNTech $185 million upfront—including $72 million in cash and a $113 million equity investment—and up to $563 million in payments tied to achieving milestones. Pfizer will initially fund 100% of the development costs, and BioNTech will repay Pfizer its 50% share of these costs during commercialization of the vaccine.
The companies announced their up-to-$748 million COVID-19 vaccine development partnership in March, focusing on BNT162, the first treatment to emerge from BioNTech’s accelerated COVID-19-focused development program, “Project Lightspeed.”
The BioNTech-Pfizer partnership is worldwide except China, where BioNTech is partnering with Fosun Pharma to jointly develop BNT162. Fosun has agreed to make a $50 million equity investment, and pay BioNTech up to $85 million in additional upfront and milestone payments. The companies will share future gross profits from the sale of the vaccine in China.
Candidate: Vaccine for prevention of COVID-19 ●
Type: Recombinant Novel Coronavirus Disease Vaccine incorporating the Adenovirus Type 5 Vector (Ad5-nCoV)
Status: CanSino on April 9 said it and China’s Beijing Institute of Biotechnology, Academy of Military Medical Sciences, plan to initiate phase II clinical trial for Ad5-nCoV in China.
Last month, CanSino received approval from Chinese authorities to begin human trials of the vaccine, co-developed with China’s Beijing Institute of Biotechnology, Academy of Military Medical Sciences, and is looking for volunteers for the six-month Phase I study (ChiCTR2000030906). CanSino and the Academy are using Sartorius’ BIOSTAT® STR single-use bioreactor system for upstream preparation of the recombinant vaccine, Sartorius said March 25.
The vaccine candidate is the first novel coronavirus vaccine for COVID-19 to advance to Phase I in China. The company has cited results from animal studies showing that the vaccine candidate can induce strong immune response in animal models.
Chugai Pharmaceutical and Zhejiang Hisun Pharmaceutical
Candidate: Tocilizumab (Actemra® in the U.S.), alone and in combination with favipiravir (Avigan® in the U.S.) ●
Type: Humanized monoclonal antibody targeting interleukin-6
Status: Peking University First Hospital on March 16 registered an up-to-150 patient study assessing tocilizumab, marketed in China by Roche subsidiary Chugai Pharmaceutical, in combination with the Zhejiang Hisun Pharmaceutical-marketed drug favipiravir in adults with COVID-19 (ChiCTR2000030894). A 94-patient trial assessing Tocilizumab alone has been registered by The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) (ChiCTR2000029765).
Candidate: Leronlimab (PRO 140) ●
Type: Humanized IgG4 monoclonal antibody. Leronlimab is CytoDyn’s lead candidate, and is a CCR5 antagonist for patients who experience respiratory illness as a result of COVID-19 with potential for multiple therapeutic indications.
Status: CytoDyn on April 13 appointed its Chairman, Scott A. Kelly, MD, to the additional position of Chief Medical Officer and Head of Busines Development, a move it said would accelerate evaluation of leronlimab for COVID-19 and other indications.
Four days earlier, CytoDyn highlighted positive results from seven patients with severe COVID-19 after seven days of treatment with leronlimab: All seven showed “dramatic” immune restoration, especially in the CD8 T-lymphocyte population, and a “further dramatic” reduction in the critical cytokine storm cytokines IL-6 and TNF-alpha. At a “leading medical center in Southern California,” CytoDyn said, one severe COVID-19 patient was removed from external ventilation three days after treatment with leronlimab, and two moderate COVID-19 patients were removed from external oxygen support one day following leronlimab treatment,and discharged from the hospital. Based on these results, another four patients with moderate COVID-19 have been administered leronlimab and results are pending, CytoDyn said.
A day earlier, CytoDyn said Novant Health had begun enrollment of patients for a Phase II randomized clinical trial, assessing leronlimab in patients with mild-to-moderate indications—the second trial site in the nation and first in the Southeastern U.S. to do so. The first two COVID-19 patients had been treated with leronlimab in that study, CytoDyn said. In the U.K., CytoDyn is collaborating with the U.K.’s Department of Health to provide emergency access to leronlimab for severe and critically ill COVID-19 patients, with a formal request to be submitted soon to the Medicines and Healthcare Products Regulatory Agency (MHRA).
Enrollment is also underway in a second leronlimab study in COVID-19, a 390-patient Phase IIb/III trial in severely and critically ill COVID-19 patients. Patients are set to be administered leronlimab for two weeks, with the primary endpoint being the mortality rate at 28 days and a secondary endpoint of mortality rate at 14 days. The company will perform an interim analysis on the data from 50 patients.
CytoDyn also said it has treated 15 severely ill COVID-19 patients with leronlimab at four hospitals, under an emergency IND granted by the FDA (ten patients were treated in New York).
CytoDyn said April 2 eight of the severely ill COVID-19 patients treated with leronlimab showed “significant improvement” in immunologic biomarkers: “We continue to see increases in the profoundly decreased CD8 T-lymphocyte percentages by Day 3, normalization of CD4/CD8 ratios, and resolving cytokine production including reduced IL-6 correlating with patient improvement,” stated Bruce Patterson, MD, CEO and founder of IncellDx, a diagnostic partner and advisor to CytoDyn.
CytoDyn has initiated enrollment in a planned 75-patient Phase II trial for leronlimab treatment of COVID-19 patients with mild-to-moderate indications—and under the same IND is also proceeding with its second COVID-19 clinical trial, a planned 342-patient Phase IIb/III study in critically ill COVID-19 patients, with the primary endpoint being the mortality rate at 14 days.
CytoDyn and Longen China Group has said they will begin exploring leronlimab as a potential treatment for coronavirus as well as cancer.
Leronlimab has completed nine clinical trials in over 800 people, according to CytoDyn, including meeting its primary endpoints in a pivotal Phase III trial in combination with standard antiretroviral therapies in HIV-infected treatment-experienced patients. CytoDyn plans to file a BLA with the FDA in HIV during Q1 2020. Leronlimab has the FDA’s Fast Track designation as a combination therapy with highly active antiretroviral therapy (HAART) for HIV-infected patients, and for metastatic triple-negative breast cancer—for which CytoDyn saiod April 3 it has requested to meet with the FDA to discuss new clinical data in support of a Breakthrough Therapy designation from the agency.
Candidates: Antibodies bioengineered to fight COVID-19 ●
Type: Broadly neutralizing antibodies based on the company’s SuperHuman platform, which according to the company is the world’s most advanced computationally optimized human antibody library for antibody discovery.
Status: Distributed Bio’s CEO, president, and chairman Jacob Glanville, PhD, wrote April 2 that after nine weeks using its Tumbler technology, the company has generated thousands of extremely potent picomolar antibody binders that block known neutralizing ACE2 epitopes, blocking the SARS-CoV-2 from infecting human cells. “Hundreds of potent candidate therapeutic antibodies discovered that block the ACE2 receptor interaction with virus,” Distributed stated in a presentation.
A day earlier in a series of tweets, Glanville said the company’s approach was a “candidate cure” for COVID-19, and added: “We are trying to get this out by September but it will need funding and efficient GMP manufacturing.” That earned the company attention from news outlets as varied as Yahoo! Finance, Fox News Channel, and Radio New Zealand.
In March, Glanville told a South Korean outlet that the company is working to extract five SARS-CoV-2 antibodies and mutate them into 1 billion different types to see whether any of the antibodies bind to the virus that causes COVID-19.
If a potential antibody is identified this month, it could be mass produced in August or September, said Glanville, who gained fame after being featured in the Netflix docu-series “Pandemic: How to Prevent an Outbreak” in January.
Fujifilm Holdings and Zhejiang Hisun Pharmaceutical
Candidate: Favipiravir (marketed by Fujifilm as Avigan® and by Hisun in China as Favilavir) ●●
Type: Broad spectrum anti-viral agent that is designed to selectively and potently inhibit the RNA-dependent RNA polymerase (RdRp) of RNA viruses. Japan has approved Avigan for novel or re-emergent influenza and was previously used to treat Ebola patients in Guinea.
Status: Japan’s Prime Minister Shinzo Abe told reporters in March that his government will partner with other countries to launch trials of on COVID-19 patients and ramp up its production, with plans to pursue approval if it succeeds in clinical trials now underway at Fujita Health University Hospital in Aichi Prefecture and other institutions, according to NHK.
Zhang Xinmin, an official at China’s Science and Technology Ministry, told reporters March 17 that favipiravir produced positive results in clinical trials in Wuhan and Shenzhen involving 340 patients—including a shortening of the time after treatment that patients tested negative for COVID-19 from 11 days to four, and improved lung conditions in 91% of treated patients vs. 62% of untreated patients, as measured via x-rays. Fujifilm has responded with a statement stressing that Avigan remained under study and had not been approved.
Japan’s Health Minister Katsunobu Kato said his ministry would recommend Avigan, developed by Fujifilm-owned Toyama Chemical, for use as a coronavirus treatment after test dosages appeared effective in mild and asymptomatic cases at least two medical institutions. In China, the National Health Commission approved Hisun’s version of the drug as an investigational treatment for SARS-CoV-2.
Candidate: Remdesivir (GS-5734)
Type: Nucleotide prodrug
Status: Gilead has dramatically increased the patient populations of three Phase III trials of remdesivir now recruiting participants—from 600 to 1,600 moderate COVID-19 patients in one study (NCT04292730), and from 400 to 2,400 severe disease patients in the other (NCT04292899). The other study is in approximately 800 COVID-19 patients with a broad mix of symptoms, according to Gilead Chairman and CEO Daniel O’Day (up from 440 participants as listed on ClinicalTrials.gov, NCT04280705); that study was launched by the National Institute of Allergy and Infectious Diseases (NIAID;), and was highlighted March 22 on CBS’ “60 Minutes.”
The three are among seven trials assessing remdesivir’s safety and effectiveness, O’Day stated in an April 11 “open letter.”
On April 4, O’Day stated Gilead’s goal of producing more than 500,000 treatment courses by October, and more than 1 million treatment courses by the end of this year. O’Day said the company significantly increased its available supply of remdesivir to 1.5 million individual doses, including finished product ready for distribution as well as investigational medicine in the final stages of production.
“Depending on the optimal duration of treatment, which is something we are studying in clinical trials, this supply could equate to well over 140,000 treatment courses for patients,” O’Day wrote.
Gilead has launched two Phase III trials in the U.K. assessing remdesivir in patients with moderate to severe COVID-19 at an initial 15 sites, after receiving urgent public health research (UPHR) status from the Chief Medical Office.
On March 25, Gilead requested that the FDA rescind the orphan drug designation the company was granted for remdesivir in COVID, which confers seven years of marketing exclusivity, and said it will waive all benefits that accompany the designation. The company’s action followed criticism by Sen. Bernie Sanders, who accused Gilead of “profiteering” and benefiting from a “corporate giveaway” since the NIH is overseeing a clinical trial of the drug.
Three days earlier, Gilead said it was shifting how it allowed severely ill patients to access remdesivir, from individual compassionate use requests to expanded access programs, citing an “exponential increase” in demand. A 25-year-old New Jersey man was airlifted to the Hospital of the University of Pennsylvania to enter a clinical trial where the drug was being offered, his mother told The New York Times.
Rear Adm. Richard Childs, an assistant surgeon general and lung specialist at the NIH, told The Wall Street Journal in a report published March 13 that remdesivir showed a positive effect on 14 Americans who contracted SARS-CoV-2 aboard the Diamond Princess cruise ship, and received the drug during treatment at Japanese hospitals.
Remdesivir showed “no adverse events” when administered to the first American confirmed to be infected with SARS-CoV-2, members of the Washington State 2019-nCoV Case Investigation Team reported in a case study published in The New England Journal of Medicine.
Remdesivir is also under study in three U.S. trials: A study in 600 patients with moderate COVID-19 (NCT04292730), one in 400 severe disease patients (NCT04292899), and a 440-patient study launched by the National Institute of Allergy and Infectious Diseases (NIAID; NCT04280705). The NIAID study was highlighted March 22 on CBS’ “60 Minutes.” The segment by correspondent Bill Whittaker included comments by a 67-year-old patient, Carl Goldman.
Remdesivir and chloroquine phosphate were “highly effective in the control of 2019-nCoV infection in vitro,” a team of Chinese researchers reported in a study published February 4 in Cell Research.
Incyte and Novartis
Candidate: Jakafi® / Jakavi® (ruxolitinib)
Type: Janus kinase (JAK1/JAK2) inhibitor first approved by the FDA in 2011, with indications in polycythemia vera, myelofibrosis, and acute graft-versus-host disease. Marketed as Jakafi in the U.S. by Incyte, and as Jakavi outside the U.S. by Novartis.
Status: Incyte and Novartis said April 2 they planned to launch a Phase III clinical trial (RUXCOVID) to assess the efficacy and safety of Jakafi/Jakavi plus standard-of-care (SoC), compared to SoC therapy alone, in patients with COVID-19 associated cytokine storm.
In the U.S., Incyte added, it intends to begin an open-label emergency Expanded Access Program (EAP) that will allow eligible patients with severe COVID-19 associated cytokine storm to receive Jakafi while it is being studied for that indication. The company added that it is increasing manufacturing efforts to respond to anticipated supply needs related to its COVID-19 studies.
Outside the U.S., Novartis has established an international compassionate use program for eligible patients, and said it is working to manage the anticipated increase in COVID-19 related requests for Jakavi without interrupting access for patients using the drug for its authorized indications. Novartis cited other efforts to fight COVID-19, including its $20 million global fund to support communities impacted by the disease, and its commitment of 130 million doses of hydroxychloroquine to support pandemic response.
Inovio Pharmaceuticals and Beijing Advaccine Biotechnology
Candidate: INO-4800 ●
Type: DNA vaccine
Status: Inovio said April 6 the FDA accepted its IND application for INO-4800, paving the way for clinical testing of INO-4800 in healthy volunteers. A Phase I trial of INO-4800 will enroll up to 40 healthy adult volunteers in Philadelphia at the Perelman School of Medicine at the University of Pennsylvania, and Kansas City, MO, at the Center for Pharmaceutical Research), where screening of potential participants has already begun.
Last month, Inovio joined biologics CDMO Ology Bioservices on March 24 to announce that Ology was awarded an $11.9 million Department of Defense (DoD) contract to work with Inovio on DNA technology transfer to rapidly manufacture INO-4800 and deliver it to DoD for upcoming clinical trials.
On March 22, Inovio was among developers of COVID-19 drug and vaccine candidates highlighted March 22 on CBS’ “60 Minutes.”
Ten days earlier, Inovio said it received a $5 million grant from the Bill and Melinda Gates Foundation to accelerate testing and scale-up of CELLECTRA® 3PSP, a hand-held smart device for the intradermal delivery of INO-4800. Inovio is partnering with Beijing Advaccine Biotechnology on a Phase I trial in China in parallel with the company’s clinical development efforts in the U.S. to develop INO-4800 as a coronavirus treatment.
Inovio will develop INO-4800 through Phase I testing in the U.S., and has launched preclinical testing for clinical product manufacturing. INO-4800 development is also supported by a $9-million grant from the Coalition for Epidemic Preparedness Innovations (CEPI).
Janssen Pharmaceutical Cos. (J&J) and BARDA
Candidates: Lead vaccine candidate and two backups to prevent COVID-19 ●
Type: Not specified, but based on vaccine constructs created and tested by J&J with Beth Israel Deaconess Medical Center (BIDMC), part of Harvard Medical School, using Janssen’s AdVac® technology.
Status: Johnson & Johnson expects to start Phase I human trials by September for its lead COVID-19 vaccine candidate, and has expanded its vaccine R&D and clinical testing partnership between J&J’s Janssen Pharmaceutical Cos. and the Biomedical Advanced Research and Development Authority (BARDA) that is valued at over $1 billion.
J&J said it aims to have clinical data available by year’s end on the safety and efficacy of its lead COVID-19 vaccine candidate, an accelerated development and testing timeframe it said would allow vaccine availability for emergency use in early 2021. The company anticipates it can have the first batches of a COVID-19 vaccine available for FDA emergency use authorization in early 2021.
J&J plans to begin production at its own risk “imminently,” and has committed to bringing an “affordable” vaccine to the public on a not-for-profit basis for emergency pandemic use.
Candidate: mRNA-1273 ●●
Type: Novel lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding for a prefusion stabilized form of the Spike (S) protein.
Status: Moderna on March 29 said it was accelerating work on mRNA-1273 and was engaged in discussions for outside funding of such activities. CEO Stéphane Bancel detailed that acceleration a few days earlier during a Synbiobeta “town hall” presentation. He said a reason the SARS-CoV-2 vaccine development had been so fast was the work Moderna had done over the past two years in an existing collaboration with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) Dale and Betty Bumpers Vaccine Research Center (VRC) to develop a vaccine against MERS-CoV.
Moderna’s platform is based on injecting mRNA into cells to produce protein in human cells—an idea Bancel first viewed as crazy before realizing that making a human protein in a human cell is probably not going to be worse than making it in bacteria: “We don’t guess the biology—we use the biology of nature.”
Moderna was among developers of COVID-19 drug and vaccine candidates highlighted March 22 on CBS’ “60 Minutes.”
Also in March, Moderna disclosed in a regulatory filing that Bancel told Goldman Sachs representatives that while a commercially-available vaccine probably won’t be available for 12-18 months, a vaccine might be available in the fall of 2020 under emergency use authorization. He also said the Company was scaling up manufacturing capacity toward producing millions of doses per month, in the potential form of individual or multi-dose vials.
Moderna dosed the first patient in a Phase I open-label, dose-ranging trial of mRNA-1273 (NCT04283461) in males and non-pregnant females, 18 to 55 years old, occurring at Kaiser Permanente Washington Health Research Institute in Seattle. The 45-patient study will assess the safety and reactogenicity of a 2-dose vaccination schedule of mRNA-1273, given 28 days apart, across 3 dosages in healthy adults. The first batch of mRNA-1273 was shipped in February to the VRC, which partnered with Moderna in designing the vaccine.
Regeneron Pharmaceuticals and Sanofi
Candidate: Kevzara® (sarilumab)
Type: Interleukin-6 (IL-6) receptor antagonist approved by the FDA in 2017 to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.
Status: Regeneron Pharmaceuticals and Sanofi said March 30 they dosed the first ex-U.S. patient in the second multi-center, double-blind, Phase II/III trial (NCT04315298) conducted as part of the Kevzara COVID-19 program assessing Kevzara® (sarilumab) in severe COVID-19 patients. The 300-patient second trial will assess the safety and efficacy of adding a single intravenous dose of Kevzara to usual supportive care, compared to supportive care plus placebo.
On March 16, the companies said they had launched the first Phase II/Phase III clinical trial of Kevzara in the U.S. in severe COVID-19 patients. Up to 400 adults hospitalized with serious complications from COVID-19 will be assessed in that study, set to begin in medical centers in New York.
The global clinical program has been launched in Italy, Spain, Germany, France, Canada, Russia and the U.S. Regeneron leads clinical studies in the U.S., while Sanofi does so overseas.
Candidate: Actemra® (tocilizumab)
Type: Interleukin-6 (IL-6) receptor antagonist approved by the FDA in 2010, with indications in rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome.
Status: Genentech, a Member of the Roche Group, said March 23 it won formal FDA approval for a Phase III trial in collaboration with the Biomedical Advanced Research and Development Authority (BARDA) to assess Actemra to treat adults with severe COVID-19. “Our goal is to start the study as early as possible in April,” and complete it this summer, Levi Garraway, Roche’s chief medical officer, told McClatchy DC.
The randomized, double-blind, placebo-controlled trial, named COVACTA (NCT04320615), will evaluate the safety and efficacy of intravenous Actemra plus standard of care in hospitalized adults with severe COVID-19 pneumonia, compared to placebo plus standard of care. The trial will seek to enroll approximately 330 patients worldwide, including the U.S. The trial’s primary and secondary endpoints include clinical status, mortality, mechanical ventilation and intensive care unit (ICU) variables. Patients will be followed for 60 days post-randomization, and an interim analysis will be conducted to look for early evidence of efficacy, Genentech said.
The company also said it will provide 10,000 vials of Actemra to the U.S. Strategic National Stockpile for potential future use at the direction of the U.S. Department of Health and Human Services (HHS).
A Chinese research team in March published a study showing positive results for Actemra: 19 of 20 severe COVID-19 patients were discharged from hospital an average 13.5 days after treatment.
China’s National Health Commission earlier this month included Actemra in its 7th updated diagnosis and treatment plan for COVID-19, to treat patients with high levels of IL-6 and serious lung damage. Actemra is also under study as a COVID-19 treatment in three active Chinese clinical trials, according to the Chinese Clinical Trials Registry: A 188-patient study (ChiCTR2000029765), a 150-patient trial assessing Actemra in combination with favipiravir (ChiCTR2000030894); a 120-patient trial in combination with continuous renal replacement therapy (CRRT) (NCT04306705); a 100-patient trial in combination with intravenous immunoglobulin and CRRT (ChiCTR2000030442 ); and a 60-patient trial with JinYu Bio-Technology Co., which markets the drug as CMAB806 (ChiCTR2000030196).
In Italy, Actemra is the subject of an up-to-330-patient trial Phase II trial (TOCIVID-19; NCT04317092) and an up-to-30-patient Phase II trial (NCT04315480) designed to study the drug as a single 8mg/Kg dose in patients affected by severe pneumonia correlated to SARS-CoV2.
Sanofi, Pfizer, and various manufacturers
Candidates: Combination of Plaquenil® (hydroxychloroquine sulfate) and Zithromax® or Z-Pak (azithromycin); monotherapies Chloroquine phosphate (formerly Aralen®); Chloroquine hydrochloride (formerly Aralen Hydrochloride®); Zithromax (azithromycin); Zmax (azithromycin extended release) ●●●
Type: Plaquenil and the chloroquine treatments are antimalarial drugs; plaquanil has also been approved by the FDA for lupus erythematosus and rheumatoid arthritis. Chloroquine, for extraintestinal amebiasis. Zithromax and Zmax are antibacterials indicated for adults with acute bacterial sinusitis, and community-acquired pneumonia. Zithromax is also indicated for acute bacterial exacerbations of chronic obstructive pulmonary disease.
Status: President Trump on April 4 said the U.S. government will place 29 million doses of hydroxychloroquine into the Strategic National Stockpile to allow for use by COVID-19 patients—the latest action by his administration to promote use of that drug, alone and in combination with Zithromax (“I just hope that hydroxychloroquine wins, coupled with, perhaps, the Z-Pak”)—despite concerns expressed by Anthony Fauci, MD, Director of the NIH’s National Institute of Allergy and Infectious Diseases, that more data was needed on the safety and efficacy of the drugs.
Trump’s remarks came five days after the FDA on March 28 issued an emergency use authorization allowing healthcare providers to make available chloroquine phosphate or hydroxychloroquine sulfate to “patients for whom a clinical trial is not available, or participation is not feasible,” adding “FDA encourages the conduct and participation in randomized controlled clinical trials that may produce evidence concerning the effectiveness of these products in treating COVID-19.”
The University of Oxford plans to recruit 40,000 participants for a double-blind, randomized, trial assessing chloroquine phosphate or hydroxychloroquine sulfate compared with placebo (NCT04303507). The Population Research Institute is recuirting 1,500 participants for an open-label, parallel group, randomized controlled trial (NCT04324463).
Two other clinical trials are now recruiting healthcare workers as patients to assess hydroxychloroquine. One is an up-to-440-patient randomized study (NCT04331834) by the Barcelona Institute for Global Health; the other is an up-to-360 patient no-randomized study (NCT04333225) by Baylor Research Institute. Two other trials are being conducted in Australia, where the government of Prime Minister Scott Morrison on April 2 exempted hydroxychloroquine from the nation’s register of therapeutic goods, conditioned on the drug being imported, manufactured, or supplied via contract or arrangement with the health department.
Sanofi has offered French authorities “millions of doses” of Plaquenil, enough to treat up to 300,000 people. Sanofi obtained FDA approval for both Plaquenil (in 1955) and Aralen (in 1949), though the company has discontinued marketing brand-name Aralen. Pfizer gained FDA approval for Zithromax in 1991. All three drugs are marketed as generics by numerous companies worldwide. Among generic manufacturers, Mylan said in March it would restart production of hydroxychloroquine sulfate tablets at its West Virginia manufacturing facility while Teva Pharmaceutical Industries committed to donating more than 10 million doses by this month.
The combination of hydroxychloroquine and azithromycin has gained public attention for successful results in some studies. Notably, a study in press March 17 in the journal International Journal of Antimicrobial Agents was a 42-patient study in which 26 patients completed treatment with hydroxychloroquine, six with hydroxychloroquine and azithromycin, and 16 patients served as a control group receiving symptomatic treatment and antibiotics (six halted hydroxychloroquine treatment early).
According to the study, “100% of patients treated with hydroxychloroquine and azithromycin combination were virologicaly cured comparing with 57.1% in patients treated with hydroxychloroquine only, and 12.5% in the control group.” The study’s corresponding author, Professor Didier Raoult, MD, PhD, of l’Institut Hospitalo-Universitaire (IHU) Méditerranée Infection in Marseille—who discussed the results in a YouTube video posted March 17—has been appointed by the French government to research possible COVID-19 treatments.
A Chinese research team published positive results for hydroxychloroquine in COVID-19 patients, concluding March 18 in Cell Discovery that: “HCQ can efficiently inhibit SARS-CoV-2 infection in vitro. In combination with its anti-inflammatory function, we predict that the drug has a good potential to combat the disease. This possibility awaits confirmation by clinical trials.”
Another Chinese team concluded that chloroquine and Gilead Sciences’ Remdesivir were “highly effective in the control of 2019-nCoV infection in vitro,” according to a study published February 4 in the Nature-owned journal Cell Research that added: “They should be assessed in human patients suffering from the novel coronavirus disease.” Another Chinese team reported March 4 in Clinical Infectious Diseases that “Hydroxychloroquine was found to be more potent than chloroquine.”
However, neither the French nor Chinese studies were randomized clinical trials. The French investigators also acknowledged the “small sample size” in their conclusion—as cited by critics, along with the side effects of hydroxychloroquine. Critics also cite the death of a man after he and his wife ingested fish tank cleaner containing chloroquine phosphate; the death was disclosed March 23 by healthcare provider Banner Health, which added that his wife was in critical condition at a Banner hospital. Supporters of chloroquine phosphate have countered that the couple ingested a far higher dose than a doctor would have prescribed.
Other clinical trials of hydroxychloroquine for COVID-19 are underway in China vs. placebo (NCT04261517) and vs. AbbVie’s Kaletra (NCT04307693). While the ‘1517 study showed positive preliminary outcomes, its sample size was small (N=30, randomized 1:1 to treatment or placebo), and virological clearance rate was for placebo patients (93.3%) vs. hydroxychloroquine (86.7%). Radiological progression showed on 5 hydroxychloroquine patients (33.3) vs. 7 placebo patients (46.7%). A multi-nation trial comparing chloroquine with Kaletra in up to 3,040 patients (NCT04304053) was recruiting patients as of March 24.
University of Pittsburgh
Candidate: PittCoVacc, short for “Pittsburgh Coronavirus Vaccine” ●
Type: Microneedle array (MNA)-delivered recombinant protein subunit vaccine targeting SARS-CoV-2.
Status: Pitt researchers on April 1 published a study in the open access journal EBioMedicine detailing their development of PittCoVacc. Louis Falo, MD, PhD, and Andrea Gambotto, MD, were co-senior authors of the study, which reported that PittCoVac generated a surge of antibodies against SARS-CoV-2 within two weeks of MNA delivery when tested in mice.
The MNA is a fingertip-sized patch of 400 small needles made of sugar and protein pieces, designed to deliver the spike protein pieces into the skin, where the needles dissolve. The microneedle array can sit at room temperature until it is needed.
“MNA delivery of coronaviruses-S1 subunit vaccines is a promising immunization strategy against MERS-CoV and SARS-CoV-2 infection and can be adapted for other subunit vaccines against a broad range of infectious diseases,” the researchers concluded.
Pitt said its researchers are applying for an IND approval from the FDA, and aim to start a Phase I human clinical trial in the next few months.
Vir Biotechnology and Alnylam
Candidates: Small interfering RNA (siRNA) treatments for up to nine infectious disease targets—including three host factors required for SARS-CoV-2 infection. ●
Type: siRNA treatment(s) to be identified by Alnylam that target highly conserved regions of coronavirus RNAs. Alnylam has designed and synthesized over 350 siRNAs targeting all available SARS-CoV and SARS-CoV-2 genomes, which will be screened in in vitro potency assays, the companies said.
Status: Vir and Alnylam said April 2 they are again expanding their 2-1/2-year-old siRNA collaboration, agreeing to develop novel siRNAs for up to nine infectious disease targets. The companies agreed to advance up to three additional host factor-targeting candidates to treat SARS-CoV-2 and potentially other coronaviruses. The companies named two of the three targets, angiotensin converting enzyme-2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), adding that the third may emerge from Vir’s functional genomics work.
Potential coronavirus RNAi candidates will be discovered by Alnylam, with Vir leading development and commercialization. Alnylam will have the option to either share equally in any profits and losses associated with the development and commercialization of each coronavirus program—or instead earn development and commercialization milestones and royalties on net sales of any products resulting from the collaboration.
Another target for which a siRNA is to be developed is hepatitis B virus, the focus of the Vir-2218 (ALN-HBV02) program now in Phase I/II studies. The companies announced initial positive Phase I/II data for Vir-2218 in November 2019.
The companies launched their partnership in October 2017, initially agreeing to develop up to five novel siRNAs to treat infectious diseases, starting with Vir-2218, plus RNAi products for up to four additional infectious disease targets of Vir’s choosing. The companies expanded into coronavirus siRNAs on March 4, with Alnylam having designed and synthesized over 350 siRNAs targeting highly conserved regions of the SARS-CoV-2 genome.
Vir Biotechnology, Biogen, and NIAID (with WuXi Biologics and Xencor)
Candidates: Two versions of a human monoclonal antibody. ●
Types: Monoclonal antibody versions engineered through Vir’s platform and designed to neutralize SARS-CoV-2 live virus by binding to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1 (SARS). That, according to VIr, indicates that the epitope is highly conserved, and thus makes it harder for escape mutants to develop.
Each version has a half-life extending alteration to potentially extend the time over which the antibody provides protection.
One version has been developed with a second “vaccinal” mutation designed to increase short-term potency; the other version doesn’t have that mutation. The mutation allows the antibody to function both as a therapeutic and a vaccine, Vir says. The lead candidates are among additional antibodies identified by Vir that bind to different sites, and therefore could be used in combination with the lead development candidates.
Status: Vir Biotechnology on March 25 said it intended to move “as soon as possible” both versions of its lead antibody candidate into human Phase I/II trials, after two separate labs confirmed that the antibody neutralized SARS-CoV-2. The trial is expected to start within 3–5 months.
“The candidate could have implications for not only the current pandemic, but may have utility in the future both as a vaccine, and a therapeutic should other coronaviruses emerge,” Cowen analyst Phil Nadeau wrote.
To save development time, Vir said, it transferred the lead development candidate at-risk to WuXi Biologics and Biogen, both of which joined Vir in announcing COVID-19-focused collaborations in recent weeks. Vir announced its partnership with Biogen in March, and with WuXi the previous month. The WuXi partnership is a development and manufacturing collaboration to advance and produce human monoclonal antibodies to treat COVID-19. Should the antibodies receive regulatory approvals, WuXi Biologics has rights to commercialize therapies in Greater China and Vir, in all other markets worldwide.
Vir’s novel antibodies will have extended half lives through Xencor’s Xtend™ Fc technology, to which Vir has licensed non-exclusive rights under a technology license agreement announced March 25 by Xencor.
The company added that it is continuing to search for additional antibodies from survivors of SARS-CoV-2, SARS-CoV-1, and other coronaviruses.
Vir Biotechnology and GlaxoSmithKline (GSK)
Candidates: Antibodies, vaccines, and functional genomics products ●●
Type: Antiviral antibodies based on Vir’s proprietary monoclonal antibody platform technology; Vaccines based on GSK’s vaccine technologies; Functional genomics products based on genome-wide CRISPR screening of host targets
Status: GSK agreed to make a $250 million equity investment in Vir under an R&D collaboration designed to advance COVID-19 candidates into Phase II clinical trials later this year, the companies said April 6. The companies agreed to identify new anti-viral antibodies, and study existing ones, to prevent and treat COVID-19 and future coronaviruses.
GSK and Vir also agreed to research vaccines designed to prevent SARS-CoV-2 and other coronaviruses, as well as combine their expertise in CRISPR screening and artificial intelligence to identify products based on genome-wide CRISPR screening of host targets expressed in connection with exposure to SARS-CoV-2.