Six months to the day that the World Health Organization (WHO) declared it a public health emergency, the SARS-CoV-2 virus, with its hideous red spikes, continues to taunt the world, hopping from host to host and haunting humans, many of whom wonder the same thing: What’s next?

There may be a plan, but the plan could change, depending on what the virus does. Finger-pointing, grappling over recommendations and predictions, arguing about masks and decisions to re-open businesses and schools safely – all of these things have dominated the global conversation. The nefarious nature of COVID-19 has created an anarchy of confusion rarely seen outside of war time.

But this is war. Scientists are working around the clock to knock this coronavirus back to the bat from whence it came and beyond. And they are working in record time.

Efforts to track this research began in late February with roughly 30 therapeutics and vaccines monitored by BioWorld. That grew to 433 by late May, then 588 by late June. Now, there are 672 – a one-month rise of 14%. Likewise, BioWorld MedTech has tracked 386 diagnostics that are available or in development for COVID-19. A total of 193 have the FDA’s emergency use authorization, up from 157 a month ago.

The exciting part is that some of the data are beginning to read out, and much of the results are encouraging. While biopharma financing opportunities are healthier than ever before, and the U.S. government’s Operation Warp Speed (OWS) and other efforts are accelerating the timeline to a vaccine, market enthusiasm for the sector has sent biopharma stocks surging well above where they were at the start of 2020.

Overall, however, as the world slowly recovers from the flatten-the-curve lockdowns, the virus is not dominating the biopharma news flow as it once did.

In June, about 22% of the licensings, collaborations and joint ventures were focused on COVID-19 therapeutics and vaccines, which was down from 28% in May. There were merely 17 clinical trial delays reported in June, and none in July, down from 248 in April and 60 in May. The pandemic accounted for only about 13% of the phase I through phase III news in June compared with 57% in April and 30% in May.

Still, several developers of COVID-19 therapeutics and vaccines continued to raise money in July, including Harbour Biomed, Adagio Therapeutics Inc. and Exevir Bio BV, which brought in $180 million collectively through venture capital rounds, and Allovir Inc., which priced a $276.25 million IPO.

July 30 marks the six-month anniversary of when WHO declared COVID-19 a public health emergency of international concern. It was declared a pandemic on March 11. The organization now reports that the virus is responsible for 16.78 million confirmed cases, a doubling within the last six weeks, and 661,244 deaths. The U.S., with 4.32 million cases and 148,640 deaths, accounts for 26% and 22% of the global totals, respectively.

Effective vaccines remain the holy grail, even if they are initially suboptimal. At one time, a COVID-19 vaccine was 18 months away, but simultaneous trials and manufacturing efforts, supported through government and private funding, has bumped that timeline up significantly. At this point, some companies are targeting late 2020 or early 2021 for delivery of the initial doses.

“There’s going to be more than one winner in the vaccine field,” said Anthony Fauci, director of the U.S. NIH’s National Institute of Allergy and Infectious Diseases, during the Biotechnology Innovation Organization’s annual convention in June, “because we’re going to need vaccines for the entire world. Billions and billions of doses.”

Speeding toward a vaccine

Of the 161 vaccines in development for COVID-19, those by Novavax Inc., Moderna Inc., Astrazeneca plc, Cansino Biologics Inc. and Biontech SE (in partnership with Pfizer Inc.) are the furthest along. All reported significant news in July.

  • Novavax received $1.6 billion in OWS funding and will deliver 100 million doses of NVX-CoV2373 by the end of 2020. The news sent its shares (NASDAQ:NVAX) up by 31.62%. A phase III trial with 30,000 people is set to begin this fall.
  • Moderna entered a phase III with mRNA-1273 after phase I/II data showed all 41 participants developed neutralizing antibodies at day 57. The company is targeting a regulatory filing in early 2021 and is on track to deliver at least 500 million doses annually. The U.S. Biomedical Advanced Research and Development Authority (BARDA) gave Moderna another $472 million to support the phase III, bringing total funding to $955 million. Notably, the U.S. government began collaborating with Moderna in mid-January and the vaccine entered a phase I trial 62 days later. “There is no doubt that that’s the world indoor record,” Fauci said. “I’ve never seen anything go that fast.”
  • Astrazeneca’s phase I/II data showed AZD-1222 (formerly ChAdOx1) demonstrated a fourfold increase in antibodies in 95% of participants and T-cell responses were markedly increased. It signed a $174 million contract with Emergent Biosolutions Inc. in July, and the company expects to provide millions of doses by the end of the year after having received $1.2 billion through OWS.
  • Cansino’s Ad5-nCoV adenoviral vector vaccine demonstrated antibody responses at 38 days post immunization in 95% of those in the high-dose group and 91% in the low-dose group. The vaccine also demonstrated T-cell responses in 90% and 88%, respectively, without serious adverse reactions, in the 508-subject phase II trial. Next step is a global phase III trial.
  • Biontech and Pfizer received FDA fast track designation for both BNT-162b1 and BNT-162b2, and they selected the latter for the phase II/III randomized study with 30,000 participants. Preclinical and phase I/II data showed both candidates elicited strong CD4 and CD8 T-cell responses, but BNT-162b2, which encodes a full-length spike glycoprotein, had a better tolerability profile. Also in July, OWS agreed to pay $1.95 billion for the first 100 million doses. The companies expect to seek market access as early as October 2020.

According to a research note from RBC Capital Markets analyst Brian Abrahams, “mRNA-based vaccines have demonstrated relatively higher neutralizing antibody levels, and adenoviral vector-based vaccines have shown benefit in safety with fewer side effects – which strikes an interesting balance of efficacy/safety, though we believe large, randomized trials will be needed to determine the levels of immune responses needed for protection against COVID-19.”

During a webinar July 24 hosted by Evercore ISI analyst Josh Schimmer, immunologist Michael Farzan of The Scripps Research Institute touted subunit vaccines because they “have a much greater range of adjuvants that they can be using to boost the immune response” and “the proteins can be made in almost every country and almost every city,” something that is not true for adenovirus or mRNA vaccines. Subunits are “established technology with fewer surprises,” he said.

Aside from the Novavax vaccine, the most advanced subunit vaccines hail from Clover Biopharmaceuticals Inc. and Sanofi SA, both of which are partnered with Glaxosmithkline plc. Clover’s SCB-2019 is in a phase I trial with results expected in August. The company received $66 million from the Coalition for Epidemic Preparedness Innovations in July. Sanofi’s adjuvanted recombinant subunit vaccine is supported by BARDA and is expected to enter a phase I trial in the coming months. Sinovac Biotech Ltd. also has moved its Coronavac vaccine, which uses an adjuvant from Dynavax Technologies Inc., into a phase III trial in Brazil.

Adenoviral vaccines include Johnson & Johnson’s Ad26.CoV2-S, set to enter the clinic this summer, as well as the candidates from Cansino, Astrazeneca and Vaxart Inc., which also plans to move into a phase I this year. Moderna and Biontech both have mRNA vaccines, as does Arcturus Therapeutics Holdings Inc. with ARCT-021, which was expected to enter a phase I/II trial in July, and Curevac AG with CVnCoV, which moved into a phase I in June. Glaxosmithkline recently acquired a 10% stake in Curevac for about $164 million.

Of the vaccine data presented in July, the most advanced candidates appear to be sufficient in terms of keeping healthy people out of the hospital, but less significant in terms of protecting people absolutely from infection, Farzan said.

“As it is for both therapies and vaccines, you can overwhelm it with numbers,” he said. Vaccine boosters will likely be needed at first. “You don’t want to deeply breathe near the mouth of somebody who is sick no matter how vaccinated you are.”

Live attenuated vaccines, such as the one developed by Codagenix Inc., are also an option. The company is moving into a phase I study this fall with Codavax-COVID, using a human challenge model that involves deliberately infecting healthy volunteers. Data are expected by the end of 2020. In addition, inactivated viral vaccines are advancing, such as one from Sinopharm subsidiary, Wuhan Institute of Biological Products. It entered a phase III trial in Abu Dhabi in July.

Regardless of when a vaccine is available, researchers say they rarely protect everyone. Most current COVID-19 trials are being done in young, healthy volunteers, while testing in the elderly and those with pre-existing conditions are saved for the phase III trials. Moderna and Biontech both dosed the first volunteers in their pivotal trials on July 27.

Many vaccines in development, Farzan said, are attempting to prevent the virus from entering the lower respiratory tract where it leads to pneumonia and hospitalizations, but they may not be as effective in keeping the virus out of the upper respiratory tract, where it would symptomatically become a bad cold.

Nevertheless, “I think it’s nearly inevitable that most of these get approved,” Farzan said. Later improvements to the vaccines and a field of therapeutics can help address any viral breakthroughs.

As of July 30, there were 37 vaccine candidates in clinical trials vs. 30 at the end of June. Seven are in phase II or later trials compared with four last month. There are currently 108 potential COVID-19 vaccines in preclinical trials and at least 15 others in the discovery stage.

Filling the gap with therapeutics

With a total of 511 therapeutics in development for COVID-19, Gilead Sciences Inc.’s remdesivir is at the forefront. In addition to holding emergency use authorization in the U.S., it was granted conditional marketing authorization by the European Commission in July. Clinical data reported during the month showed a 62% reduction in the risk of mortality vs. standard of care.

Several other candidates in late-stage development for COVID-19 include options from Regeneron Pharmaceuticals Inc., which signed a significant government deal in July, and Octapharma USA Inc., Calcimedica Inc., Synairgen plc and Glenmark Pharmaceuticals Ltd., all of which reported positive data during the month.

  • Regeneron received $450 million through BARDA and the U.S. Department of Defense to manufacture its phase III monoclonal antibody REGN-CoV2, providing 70,000 to 300,000 doses by this fall at the latest.
  • Octapharma’s Octagam 10%, an intravenous immunoglobulin treatment, has demonstrated it reduces inflammation and points to an increase in survival, according to top-line phase III results.
  • Calcimedica’s Auxora (CM-4620-IE) showed in a phase II trial a median time to recovery for 19 patients of five days vs. 12 days for nine patients treated with standard of care (SOC) alone, and 18% of those receiving Auxora required mechanical ventilation vs. 50% of the SOC patients.
  • Synairgen’s SNG-001 (interferon-beta-1a) reduced the odds of patients in the drug-treatment arm developing severe disease, either requiring ventilation or leading to death, by a statistically significant 79% vs. the placebo group. In response to the phase II data, the company’s stock (London:SNG) surged 552% in early trading.
  • Glenmark’s favipiravir demonstrated in a randomized phase III trial conducted in India that 69.8% of treated mild to moderate COVID-19 patients achieved clinical cure vs. 44.9% of those in the control arm, and it also showed a 28.6% faster viral clearance in the overall study population. Favipiravir was approved for the indication in India in June, prior to the results.

Despite the flurry of encouraging data, some negative news for interleukin-6 inhibitors arrived in July. Regeneron’s IL-6 antibody, Kevzara (sarilumab), did not meet its primary composite endpoint in hospitalized COVID-19 infection and the U.S.-based phase II/III trial was stopped. Likewise, Genentech Inc. reported July 29 that its phase III Covacta trial missed the primary endpoint of improved clinical status (p=0.36) with its IL-6 inhibitor, tocilizumab (Actemra), in those with COVID-19-associated pneumonia. It also missed a key secondary endpoint of reduced mortality (19.7% for Actemra vs. 19.4% for placebo).

The disappointments follow reports in June that both chloroquine/hydroxychloroquine and lopinavir/ritonavir (Abbvie Inc.) showed no benefit in late-stage trials.

Following positive data of dexamethasone in June, demonstrating a one-third reduction in deaths in COVID-19 patients on ventilators, published data in July indicated little benefit in patients who are 70 or older, Abrahams wrote. “Unfortunately, and perhaps not surprisingly,” he said, “the most vulnerable individuals in society may continue to have the least amount of options to blunt poor outcomes.”

Of the 511 therapeutics in development, 106 are in phase II/III trials or later, which is up from 97 in June and 57 in May. Regardless of the near-term outcomes, there will likely be an ongoing need for COVID-19 research.

“The thing that we don’t yet fully appreciate,” Fauci noted, “is what are the long-term, durable, negative effects of the infection.”

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