Candidate: Kaletra® (also marketed as Aluvia; lopinavir/ritonavir) ●
Type: HIV-1 protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children 14 days old and older.
Status: AbbVie on March 31 announced a $35 million donation to support COVID-19 relief efforts by healthcare systems and other groups.
A 44-patient trial (NCT04252885) delivered disappointing results, concluding that both Kaletra and Arbidol (umifenovir) “seems little benefit for improving the clinical outcome of mild/moderate COVID-19,” and that Kaletra might lead to more adverse events than Arbidol, researchers reported in a preprint posted March 23 on medRxiv—but cautioned that further verification was needed because of the small sample size.
Kaletra fared worse in a 199-patient Chinese study (ChiCTR2000029308) that was published March 18 in The New England Journal of Medicine: “In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care.”
In March, AbbVie waived patent rights to Kaletra after Israel issued a compulsory license for Kaletra as a treatment against SARS-CoV-2—while Mylan gave up its 180-day U.S. exclusivity for its generic version, allowing other drugmakers to make the antiviral should the HIV treatment prove effective against the SARS-CoV-2. AbbVie confirmed it was collaborating with health agencies and institutions globally to determine antiviral activity as well as efficacy and safety of Kaletra against COVID-19. The agencies include European health authorities, the FDA, the Centers for Disease Control and Prevention, the NIH, and the Biomedical Advanced Research and Development Authority (BARDA).
China’s National Health Commission in January authorized Kaletra to treat pneumonia caused by SARS-CoV-2. AbbVie donated RMB 10 million ($1.4 million) of Kaletra to Chinese authorities “as an experimental option to support this growing public health crisis.” And the Health Commission of Henan Province announced that three confirmed cases of patients diagnosed with new coronavirus infections recovered after taking Kaletra, a combination of ritonavir and lopinavir. Nucleic acid testing of more than 20 confirmed cases of patients infected with new coronavirus, admitted to hospitals in Zhejiang Province turned negative after taking Kaletra, according to Ascletis Pharma, which is evaluating a combination therapy of its own candidates ASC09 and ritonavir (See below).
Candidate: Soliris® (eculizumab)
Type: Complement inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).
Status: Alexion said March 24 it had discussed possible options to investigate Soliris in COVID-19 with global health authorities, in order to better understand the role of terminal complement inhibition in managing the severe pneumonia associated with the virus. Alexion added that it had provided Soliris as an experimental emergency treatment for a small number of patients with COVID-19 infection and severe pneumonia at the request of physicians, and in accordance with relevant national regulatory agencies.
Amgen and Adaptive Biotechnologies
Candidate: Antibodies targeting SARS-CoV-2 to potentially prevent or treat COVID-19 ●
Type: Fully-human neutralizing antibodies to be discovered and developed
Status: Amgen and Adaptive Biotechnologies said April 2 they will partner to discover and develop antibodies through a collaboration intended to combine Adaptive Bio’s immune medicine platform for identifying virus-neutralizing antibodies with Amgen’s expertise in immunology, antibody engineering, and novel antibody therapy development.
Adaptive Bio will use its high throughput platform to rapidly screen the B cell receptors from individuals who have recovered from COVID-19, enabling identification of tens of thousands of naturally occurring antibodies. Amgen will select, develop and manufacture antibodies designed to bind and neutralize SARS-CoV-2. Amgen subsidiary deCODE Genetics in Iceland will provide genetic insights from patients who were previously infected with COVID-19.
The companies said they will begin work immediately upon signing a Memorandum of Understanding whose terms were not disclosed, and will finalize financial details and terms “in the coming weeks.”
Type: Recombinant human angiotensin-converting enzyme 2 (rhACE2) developed to treat acute lung injury, acute respiratory distress syndrome, and pulmonary arterial hypertension.
APN01 is designed to imitate the human enzyme ACE2 so that the virus can no longer infect the cells, as SARS-CoV-2 binds to soluble ACE2/APN01 instead of ACE2 on the cell surface. APN01 is also designed to reduce harmful inflammatory reactions in the lungs and protects against acute lung injury/acute respiratory distress syndrome (ALI/ARDS).
Status: APEIRON said April 2 it received regulatory approvals in Austria, Germany, and Denmark to initiate a Phase II clinical trial of APN01 to treat COVID-19 (NCT04335136). The trial aims to compare APN01 to placebo in up to 200 severely infected COVID-19 patients at 10 sites. The first patients are expected to be dosed shortly, according to the company.
APN01 has been shown to be safe and well-tolerated in a total of 89 healthy volunteers and patients with pulmonary arterial hypertension (PAH) and ALI/ARDS in previously completed Phase I and Phase II clinical trials, APEIRON said.
In March, The First Affiliated Hospital of Guangzhou Medical University disclosed on ClincalTrials.gov that a planned open label, randomized, controlled, pilot clinical study of APN01 in patients with severe SARS-CoV-2 infection had been withdrawn without Chinese Center for Drug Evaluation (CDE) approval. No explanation has been given on the company’s website or on ClinicalTrials.gov. The trial was designed to obtain preliminary biologic, physiologic, and clinical data in patients with COVID-19 treated with rhACE2 or control patients, to help determine whether a subsequent Phase IIb trial is warranted.
Suzhou-based Angalpharma coordinated the Chinese clinical trial, with support from dMed Pharmaceutical, a CRO based in Shanghai.
Candidate: Ganovo® (danoprevir) ●
Type: Oral hepatitis C virus protease inhibitor
Status: Ascletis on March 24 trumpeted successful results from a Chinese clinical trial, the first such study of Ganovo in patients with COVID-19, assessing Ganovo compared with ritonavir (NCT04291729). The company stated that after 4- to 12-day treatment of Ganovo combined with ritonavir, all 11 patients with moderate COVID-19—two treatment-naïve, nine treatment-experienced—were discharged from the hospital. The first negative RT-PCR test occurred at a median of 2 days, with occurrences ranging from 1 to 8 days, and absorption in CT scans occurred at a median 3 days, ranging from 2 to 4 days. The trial was conducted at The Ninth Hospital of Nanchang. Ascletis announced the discharge of the study’s first three patients on February 26.
“Clinical findings suggest that danoprevir combined with ritonavir is a promising therapeutic option for COVID-19,” Ascletis stated.
In February, Ascletis said it was actively assisting “relevant medical institutions and medical researchers” in clinical trials assessing the combination of Ascletis’ ASC09 and ritonavir for COVID-19, following a request they made to the company. Ascletis applied in January to the National Medical Products Administration and its Drug Evaluation Center to include ritonavir and ASC09 fixed-dose combination into the national emergency channel.
ASC09 is in other Chinese clinical trials, including another study in combination with ritonavir (ChiCTR2000029603), and studies in combination with ritonavir compared with AbbVie’s Kaletra (lopinavir/ritonavir) (NCT04261907), and in combination with Tamiflu (oseltamivir) compared with ritonavir/Tamiflu and Tamiflu alone (NCT04261270). Tamiflu is distributed in the U.S. by Genentech, a member of the Roche Group, under license from Gilead Sciences.
Candidate: MultiStem® for acute respiratory distress syndrome (ARDS)
Type: Adult-derived “off-the-shelf” therapy under development for several neurological and cardiovascular diseases, as well as inflammatory, immune and related disorders. Developed from Multipotent Adult Progenitor Cells (MAPC®) obtained from the bone marrow of healthy, consenting adult donors.
Status: Athersys Founder, Chairman, and CEO Gil Van Bokkelen, PhD, told Ed Henry on his Fox News Channel program “America’s Newsroom” April 1 that the company was in active talks with the FDA about the design and implementation of a Phase III study of MultiStem “that will involve several hundred patients, that will be focused specifically on COVID-19 patients that are experiencing [ARDS].”
In March, Van Bokkelen told GEN the company was planning to launch the Phase III trial “as soon as possible.” The company has won the Biomedical Advanced Research and Development Authority (BARDA)’s designation as a “Highly Relevant” program for COVID-19 based on earlier positive results for MultiStem in ARDS, plus the FDA’s Fast Track designation for the MultiStem clinical program in ARDS—the only Fast Track designation for an ARDS treatment.
Bayer and numerous Chinese manufacturers
Candidate: Chloroquine phosphate (marketed by Bayer as Resochin®) ●
Type: Phosphate salt of chloroquine, a quinoline compound with antimalarial and anti-inflammatory properties. Resochin was discovered by Bayer and introduced into clinical practice in 1947 to treat malaria.
Status: German federal health minister Jens Spahn on April 3 told the newspaper Bild that he hoped Resochin will prove effective against COVID-19, while cautioning that further studies were needed. Chloroquine has “shown fairly good efficacy” according to Sun Yanrong, deputy head of the China National Center for Biotechnology Development under the Ministry of Science and Technology (MOST), the state-owned Xinhua news agency reported on February 17, following clinical trials in over 10 hospitals in Beijing, as well as in south China’s Guangdong Province and central China’s Hunan Province.
In March, researchers at the University of Queensland in Australia said they hoped to launch large-scale trials of chloroquine, as well as AbbVie’s Kaletra® (See above), after both drugs successfully treated patients with COVID-19. Chinese news outlet Shine reported that Bayer had donated about €1.5 million (about $1.7 million) in medicines and additional financial aid to the Chinese Red Cross to support prevention, diagnosis, treatment, and containment of COVID-19 in China. Bayer’s Kunming, China factory mobilized 50,000 disposable surgical masks and 10,000 R95 medical masks to donate to the Kunming Red Cross Society, in response to a call from the Yunnan Provincial Department of Commerce.
Chloroquine and remdesivir 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. After China’s National Health Commission included chloroquine phosphate in its latest treatment guidelines for COVID-19 pneumonia, eight Chinese companies sped up manufacturing and supply of the drug, Shanghai Daily reported February 20.
Celularity and Sorrento Therapeutics
Type: Allogeneic, off-the-shelf Natural Killer (NK) cell therapy developed from placental hematopoietic stem cells; also being developed in multiple myeloma, acute myeloid leukemia, glioblastoma multiforme and various blood and solid tumors.
Status: Celularity on April 2 won FDA clearance for its IND of CYNK-001 in adults with COVID-19, allowing the company to begin a Phase I/II trial of up to 86 patients. The IND followed high-profile efforts to promote CYNK-001, including a March 13 op-ed commentary by CEO Robert J. Hariri, MD, PhD, in The Wall Street Journal, and public support by President Donald Trump’s personal lawyer Rudy Giuliani, who invited Hariri onto his “Common Sense podcast: “Trials need to be EXPEDITED,” he tweeted on March 27.
In a February presentation, Celularity stated that its anti-COVID-19 construct had been generated within weeks, and that its DAR-T and DAR-NK cells “will soon be produced for anti-COVID-19 activity testing.” The companies in January launched a clinical and manufacturing collaboration designed to expand the therapeutic use of Celularity’s CYNK-001 to COVID-19. Sorrento and Celularity agreed to assess CYNK-001 as a potential novel therapy for coronaviruses, specifically SARS-CoV-2.
Sorrento—which owns 25% of Celularity—agreed to use current existing capacity in its cGMP cell therapy manufacturing facilities in San Diego to supplement Celularity’s new cGMP facility in Florham Park, NJ. Sorrento said it is already in contact with “leading” scientists and local Chinese experts to discuss clinical validation and logistics requirements for fast-tracking CYNK-001 in China.
Cobra Biologics and Karolinska Institutet
Candidate: DNA vaccine against COVID-19 ●
Type: Vaccine designed to deliver DNA to patient muscle to generate a viral antigen on which the immune system will react. The project will use Cobra’s 50L DNA suite in Sweden to support vaccine development by producing plasmid DNA in accordance with GMP.
Status: Cobra and Karolinska Institutet said March 30 they were awarded €3 million ($3.3 million) in emergency funding through the EU’s Horizon 2020 funding program for R&D and Phase I clinical trial testing of a DNA vaccine against COVID-19, as part of the OPENCORONA consortium. In addition to Karolinska Institutet, partners in the consortium also include Karolinska University Hospital, the Public Health Agency of Sweden (FoHM), IGEA, Adlego, and Giessen University.
Candidate: Vaccine ●●
Type: mRNA-based coronavirus treatment based on company’s vaccine platform
Status: CureVac on March 17 told reporters in a telephone briefing that it was committed to launching animal trials of its mRNA-based COVID-19 vaccine in April, and clinical trials in humans by early summer. The update came a day after the European Commission offered up to €80 million ($88 million) toward scaling up development and productions of the vaccine. The Coalition for Epidemic Preparedness Innovations (CEPI) awarded the company up to $8.3 million in January for accelerated vaccine development, manufacturing and clinical tests.
During the briefing and in a statement two days earlier, CureVac denied a report in the German newspaper Welt am Sonntag that the administration of President Donald Trump sought to lure German-based CureVac to the U.S. with funding to produce its vaccine exclusively for the U.S. market after then-CEO Dan Menichella visited the White House March 2 with other biopharma executives, while Germany’s government pressed for the company to stay in Tübingen and produce its vaccine for Germany and Europe.
U.S. ambassador to Germany, Richard Grenell denied the German news report via Twitter, but an unnamed German Health Ministry spokeswoman confirmed Germany’s interest in CureVac developing vaccines domestically in a statement to Reuters. Menichella resigned on March 11, and was succeeded by former CEO and founder Ingmar Hoerr, who just five days later took a temporary leave of absence for medical reasons “not caused by coronavirus,” the company said.
Eli Lilly and AbCellera
Candidates: Antibodies to treat and prevent COVID-19 ●
Type: Anti-SAR-CoV-2 Antibodies based on AbCellera’s rapid pandemic response platform
Status: Eli Lilly and AbCellera said March 13 that they will partner to co-develop the most promising of 500+ unique fully human antibody sequences identified in a blood sample from one of the first U.S. patients to recover from COVID-19.
AbCellera will tap into the expertise of the Dale and Betty Bumpers Vaccine Research Center of the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), which will identify the antibodies that bind the pandemic strain of SARS-CoV-2 the best. AbCellera and Lilly committed to equally share initial development costs towards a treatment, after which Lilly has agreed to oversee all further development, manufacturing and distribution. If successful, Lilly will work with global regulators to bring a treatment to patients.
Globally, Lilly has joined a cross-industry collaboration and the Bill & Melinda Gates Foundation to accelerate the development, manufacturing and delivery of vaccines, diagnostics and treatments for COVID-19. The consortium of 17 life sciences companies, announced by the Foundation March 25, plans to will work with regulators and the World Health Organization to ensure promising studies are quickly scaled to help people worldwide.
Candidate: TJM2 (TJ003234) ●
Type: Neutralizing antibody against human granulocyte-macrophage colony stimulating factor (GM-CSF)
Status: I-Mab said April 3 that the FDA cleared its IND to initiate clinical study of TJM2 as a treatment for cytokine release syndrome associated with severe illness caused by COVID-19. I-Mab also obtained central institutional review board (IRB) approval from the Western Institutional Review Board on the same day. The planned trial is a multi-center, randomized, double-blind, placebo-controlled, three-arm study designed to assess the safety, tolerability and efficacy of TJM2 in reducing the severity of complications as well as levels of multiple cytokines in patients with severe COVID-19.
I-Mab added that it submitted an IND application to South Korea’s Ministry of Food and Drug Safety for a similar study in severe COVID-19 patients in South Korea.
Candidate: XPOVIO® (selinexor)
Type: First-in-class, oral selective inhibitor of nuclear export (SINE), designed to block the cellular protein XPO1. Selinexor was granted FDA accelerated approval in July 2019 in combination with dexamethasone as a treatment for some adults with relapsed refractory multiple myeloma.
Status: Karyopharm said April 7 it will initiate a global randomized clinical trial evaluating low dose oral selinexor in hospitalized patients with severe COVID-19. The company noted that SINE compounds have been shown to disrupt the replication of multiple viruses in vitro and in vivo, and to mediate anti-inflammatory and anti-viral effects, including respiratory infections, in several animal models. Karyopharm cited a preprint study published March 20 in bioRxiv identifying SINE compounds as having the potential to interfere with key host protein interactions with SARS-CoV-2.
The company said it is still on track to submit a supplemental NDA to the FDA in combination with once-weekly Velcade® (bortezomib) and low-dose dexamethasone as a new second line treatment for patients with relapsed or refractory multiple myeloma, based on the BOSTON Phase III trial (NCT03110562).
Candidate: RYONCIL™ (Remestemcel-L)
Type: Allogeneic mesenchymal stem cell (MSC) product candidate, now under FDA priority review for treating pediatric steroid-refractory acute graft versus host disease (aGVHD), with a Prescription Drug User Fee Act (PDUFA) action date of September 30, 2020.
Status: Mesoblast said April 6 it received FDA clearance for its IND application to treat patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 with intravenous infusions of remestemcel-L, nearly a month after disclosing March 10 it was in active discussions with government and regulatory authorities, medical institutions and biopharma companies about assessing remestemcel-L in that indication.
The company has cited a clinical study published in February which reported that allogeneic MSCs cured or significantly improved functional outcomes in all seven treated patients with severe COVID-19 pneumonia. Mesoblast also cited post-hoc analyses of a study in 60 chronic obstructive pulmonary disease (COPD) patients submitted for presentation at a future conference, showing significantly reduced inflammatory biomarkers, and significantly improved pulmonary function in patients with elevated inflammatory biomarkers. The same inflammatory biomarkers are also elevated in COVID-19.
“Consequently, remestemcel-L could be an effective treatment to reduce the high mortality in patients with COVID-19 who are older, have elevated inflammation biomarkers, and develop moderate to severe ARDS,” Mesoblast CEO Silviu Itescu told GEN. “Clinical trials using remestemcel-L in ARDS associated with COVID-19 disease are expected to be initiated shortly.”
Candidates: Antiviral compounds ●
Status: Pfizer on March 13 restated earlier plans to develop its own antivirals against COVID-19 as well as collaborate with BioNTech on an mRNA vaccine to prevent the disease. The pharma giant also articulated five principles it said would govern its drug and vaccine development activity: Sharing tools and insights; creating “a SWAT team” of experts focused solely on fighting the pandemic; applying its drug development expertise; offering any excess manufacturing capacity to support other drug and vaccine developers; and building a “cross-industry rapid response team of scientists, clinicians and technicians” to improve response to future epidemics.
Earlier in March, Pfizer said it completed a preliminary assessment of antiviral compounds that were previously in development and that inhibited the replication of coronaviruses similar to the one causing COVID-19 in cultured cells. Pfizer said it was engaging with a third party to screen these compounds under an accelerated timeline and expected to have results back by the end of March.
“Toxicology studies would then need to be completed prior to any clinical development, but if successful, Pfizer hopes to be in the clinic by no later than the end of 2020,” the company added.
Candidate: Antibody cocktail therapy ●
Type: Combination of neutralizing monoclonal antibodies leveraging Regeneron’s monoclonal antibody discovery platform called VelocImmune®, part of the company’s VelociSuite™ technologies.
Status: Regeneron on March 17 announced making progress in developing an antibody cocktail therapy against COVID-19, saying that it isolated hundreds of virus-neutralizing, fully human antibodies from its VelocImmune mice, genetically-modified to have a human immune system—as well as antibodies from humans who have recovered from COVID-19. From these antibody candidates, Regeneron said, it will select the top two antibodies for a ‘cocktail’ treatment “based on potency and binding ability to the SARS-CoV-2 spike protein, as well as other desirable qualities.” Regeneron said it is working to produce hundreds of thousands of prophylactic doses per month by the end of summer, and smaller quantities for initial clinical testing at the start of the summer.
Regeneron has also said it is developing the combination of REGN3048 and REGN3051 as a COVID-19 treatment. The combination completed a 48-patient Phase I trial in MERS-CoV last year (NCT03301090). In February, The Biomedical Advanced Research and Development Authority (BARDA) said it was expanding upon an earlier partnership agreement with Regeneron to develop “multiple monoclonal antibodies that, individually or in combination, could be used to treat new treatments.”
On April 1, New York Gov. Andrew M. Cuomo announced that Regeneron created 500,000 test kits for state use at no charge. The first batch of test kits was delivered to the state on March 30, and the state will receive an ongoing delivery of 25,000 kits per day, Cuomo said.
The University of Hong Kong (HKU)
Candidate: Vaccine against COVID-19 ●
Type: Vaccine candidate based on the established flu-based DelNS1 live attenuated influenza virus (LAIV) platform, with the deletion of the key virulent element and immune antagonist, NS1, from the viral genome, adapted to express the surface protein of SARS-CoV-2. The vaccine uses flu vector to express a specific antigen to induce immunity targeting the critical element of the Receptor Binding Domain (RBD) of SARS-CoVs.
Status: On March 16, HKU’s State Key Laboratory for Emerging Infectious Diseases said it received an initial $620,000 from the Coalition for Epidemic Preparedness Innovations (CEPI) toward vaccine development. HKU researchers previously completed a proof-of-concept study testing their flu-based RBD vaccine system using a MERS-CoV animal infection model, and reported that vaccination with DelNS1-MERS-RBD LAIV provided full protection from pathogenic MERS-CoV. The team is currently conducting similar proof-of-concept studies in multiple animal models.
According to HKU, the vaccine candidate is one of five vaccine technologies by China’s Ministry of Science and Technology for further evaluation. HKU is partnering with Xiamen University to test the production of DelNS1-SARS-CoV2-RBD LAIV from eggs. The University is also collaborating with industrial partners in China—including Changchun-Baike, Hualan-Bio, Beijing Wantai, Sinovac, and CNBG China—to evaluate production of the vaccine candidate from MDCK cells.