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Drug Development

C&EN’s Year in Pharma 2020

The pandemic thrust the drug industry into the global spotlight

by Lisa M. Jarvis
December 6, 2020 | A version of this story appeared in Volume 98, Issue 47

Credit: C&EN

Infectious disease experts for years had warned that a pathogen would one day bring the world to its knees. In 2020, their nightmare scenario became reality. By the end of November, nearly 63 million people around the globe had contracted COVID-19; the respiratory infection had caused more than 1.4 million deaths.

The pandemic put the importance of the pharmaceutical industry in stark relief. Safety measures like masks, hand washing, and lockdowns can slow the virus’s spread—and, in the countries with highly coordinated efforts, even contain it for periods. But it quickly became evident that to return to anything resembling normal, the world would need diagnostics, drugs, and vaccines.

Thus, for a stretch of the spring, many drug developers dropped everything else to turn their attention to tackling the virus. Technology that had been percolating for years, like messenger RNA and rapid antibody development, became the backbone of some of the first COVID-19 drugs and vaccines in testing. The public suddenly became aware of the complexity of drug manufacturing, the fallibility of clinical trial design, and the tricky nature of immunity.

At some point, the pharmaceutical industry widened its lens again. The sector didn’t return entirely to its prepandemic state, but business continued. Big firms got back to buying smaller ones; a wave of start-ups formed; and somehow the US Food and Drug Administration found time to approve new drugs.

With that backdrop, we bring you some of the big stories of 2020. We’ve typically called this feature Year in Pharma, but it’s fair to say 2020 will go down in the books as the year of pharma.



mRNA vaccines took center stage

The pandemic pressure cooker puts the hyped technology to the ultimate test

by Ryan Cross


Credit: AP
Moderna enrolled 30,000 people in its Phase 3 vaccine study this year.

A year ago, you wouldn’t have expected your friends and neighbors to be asking you for the latest gossip about messenger RNA. The nascent technology, which can be used as either therapy or vaccine, was hyped in the biotech industry, but it never loomed large in the public sphere. Fast-forward to late 2020, and promising data on mRNA vaccines for COVID-19 are making the front pages of every major news outlet.

The COVID-19 pandemic has put mRNA vaccines in the spotlight and likely shaved years off the technology’s development. At the beginning of 2020, the mRNA company Moderna had enrolled only about 1,500 people across its many clinical trials. If the vaccines are authorized for use, next year more than 1 billion people could get an mRNA vaccine developed by Moderna or a competing shot jointly developed by Pfizer and the German firm BioNTech.

“I think it would be the best outcome we could have hoped for,” says Michael Haydock, an analyst at Informa Pharma Intelligence. “It is a completely unproven technology, and yet they are the two vaccines that are likely to make it on the market first.”

Once the first mRNA vaccine gets licensed, and if it turns out to be safe and effective, then everything will be much, much easier in the future.
Norbert Pardi, mRNA vaccine scientist, University of Pennsylvania

Never before in biotech history has a new technology debuted with the potential to shape so many people’s lives. The first generation of products based on new technologies—gene therapies, cell therapies, and RNA interference drugs, to name a few—is typically designed to treat rare diseases. That’s because it is usually easier to test a new technology in a small group with a well-defined disease.

mRNA loyalists are hopeful that a successful COVID-19 vaccine will catapult the technology to instant stardom.

“Once the first mRNA vaccine gets licensed, and if it turns out to be safe and effective, then everything will be much, much easier in the future,” says Norbert Pardi, an mRNA vaccine scientist at the University of Pennsylvania. “This will be a huge step forward for the field.”

Moderna has long touted mRNA as the ideal technology for rapid vaccine development. To induce immunity, traditional vaccines often use whole viruses or viral proteins, which must be painstakingly grown in vats of cells. mRNA vaccines, in contrast, outsource production of viral proteins to cells in our bodies. Moderna encoded the genetic instructions for the SARS-CoV-2 spike protein in mRNA strands, which it manufactures synthetically.

In theory, the process is quick and easy. But like any potentially disruptive technology, mRNA has had its doubters. “Until now, many companies didn’t believe that mRNA would have its day,” says Lior Zangi, an associate professor at the Icahn School of Medicine at Mount Sinai. “Now it has lived up to its promise.”

mRNA vaccines aren’t out of the woods yet. Moderna and Pfizer haven’t published full data sets from their trials, leaving many questions about the ultimate impact their vaccines will make on the pandemic. The low temperatures required for their storage could hamper distribution. Scientists warn that we must remain vigilant for rare, but severe, side effects that could potentially arise once millions of people get an mRNA vaccine for the first time. And although the immune responses in the trials looked good, we don’t know how long they will last.

Still, excitement for the potential of mRNA vaccines to slow the pandemic is palpable. “Up until this year, investment in infectious disease vaccines has really been falling behind,” says Michael Kinch, director of the Center for Research Innovation in Biotechnology at Washington University in St. Louis. “Hopefully the pandemic will wake the world up.”


Mergers & Acquisitions

Pharma M&A moderated, but ticket prices did not

Even with a drop, dealmaking was robust in 2020, and oncology assets still demanded high prices

by Lisa M. Jarvis


After the barn burner of 2019, which brought a 10-year peak in mergers and acquisitions, dealmaking in the pharmaceutical industry moderated in 2020. But the pandemic could not stop deals from happening, nor could it dampen competition for the hottest assets.

Glenn Hunzinger, US pharma and life sciences leader at the advisory firm PwC, says the pandemic meant dealmaking among big drug companies slowed for about 3–4 months “as people tried to look inward, get their business in order,” and figure out how to hold the intense meetings that occur in the run-up to an acquisition. But activity bounced back by the third quarter, and to date, the industry has initiated roughly $70 billion in deals, Hunzinger says. He expects to see more bolt-on buys as the year winds down and for the tenor of dealmaking to remain about the same in 2021.

For the purchases that did happen, competition was high. “The deal sizes are jaw dropping,” says Brad Loncar, CEO of Loncar Investments. Take, for example, Gilead Sciences’ acquisition of Immunomedics, a biotech firm focused on antibody-drug conjugates (ADCs). Gilead had been under pressure to prop up its revenue, and after completing nearly a dozen smaller oncology deals over the previous 2 years, it spent $21 billion on the New Jersey–based biotech.

The clear driver was Trodelvy, an ADC approved by the US Food and Drug Administration in April to treat people with triple-negative breast cancer but with potential in other types of tumors. Investors think the drug could one day bring in $4 billion annually.

Still, “$21 billion for one drug?” Loncar asks. The other large, pricey deal of the year was Bristol Myers Squibb’s $13 billion purchase of cardiovascular disease-focused MyoKardia. Those high numbers reflect the competition for mature assets and the cheap price of debt, Loncar says. With interest rates near zero, it is practically free for companies to borrow cash for deals.

“There’s a lot of capital chasing very few companies,” Hunzinger says. Another reason for the high price tags, he says, is that biotech firms have many choices for where they get their next influx of cash. An acquisition could be the answer, but if the price being offered isn’t appealing, start-ups also have an easy time finding support for going public. “A lot of these biotech companies have alternatives if they want to tap into the capital market,” Hunzinger says.

Like in years past, oncology-focused biotech firms with late-stage or newly approved drugs were in high demand. But while the past focus was on immuno-oncology assets, this year brought a new darling: ADCs. In addition to Gilead, several other big companies—most notably Merck & Co. and AstraZeneca—purchased or took stakes in ADC-focused companies.

“ADC technology has finally arrived,” Loncar says. “In previous years—and actually previous decades—there had been some one-off successes, but the science of ADCs has improved so much.”

Big-ticket bolt-ons

Cheap capital and limited inventory meant drug companies paid dearly for the companies they acquired in 2020.

Datea Acquirer Target Value ($ billions) Aim of deal
January Eli Lilly and Company Dermira $1.10

Expand its late-stage portfolio with lebrikizumab, an IL-13 antibody in development for atopic dermatitis.

March Gilead Sciences Forty Seven 4.9

Obtain the antibody magrolimab, a midstage cancer immunotherapy that blocks CD47

May Alexion Pharmaceuticals Portola Pharmaceuticals 1.4

Diversify its rare-disease portfolio with Andexxa, a drug that reverses the effects of factor Xa inhibitors.

August Sanofi Principia Biopharma 3.7

Acquire small-molecule BTK inhibitors for immune diseases and multiple sclerosis.

August Johnson & Johnson Momenta Pharmaceuticals 6.5

Expand its immune disease portfolio with the late-stage anti-FcRn antibody nipocalimab.

August Nestlé Aimmune Therapeutics 2.6

Own the peanut-allergy drug Palforzia.

September Gilead Sciences Immunomedics 21

Expand its cancer portfolio into solid tumors with the antibody-drug conjugate Trodelvy.

September Illumina Grail 8

Reintegrate liquid biopsy technology that was spun out of Illumina in 2016.

October Bristol Myers Squibb MyoKardia 13.1

Boost its cardiovascular disease portfolio with mavacamten, a small-molecule allosteric modulator of myosin that has completed Phase 3 studies.

October Bayer Asklepios BioPharmaceutical 4

Become a leader in cell and gene therapies.

November Merck & Co. VelosBio 2.8

Get the ROR1-targeted antibody-drug conjugate VLS-101, in midstage clinical trials for blood cancers and solid tumors.

November Novo Nordisk Emisphere Technologies 1.8

Add an oral drug delivery platform for small and large molecules.

Datea: January

Acquirer: Eli Lilly and Company

Target: Dermira

Value: $1.10 billion

Aim of deal: Expand its late-stage portfolio with lebrikizumab, an IL-13 antibody in development for atopic dermatitis.

Datea: March

Acquirer: Gilead Sciences

Target: Forty Seven

Value: $4.9 billion

Aim of deal: Obtain the antibody magrolimab, a midstage cancer immunotherapy that blocks CD47

Datea: May

Acquirer: Alexion Pharmaceuticals

Target: Portola Pharmaceuticals

Value: $1.4 billion

Aim of deal: Diversify its rare-disease portfolio with Andexxa, a drug that reverses the effects of factor Xa inhibitors.

Datea: August

Acquirer: Sanofi

Target: Principia Biopharma

Value: $3.7 billion

Aim of deal: Acquire small-molecule BTK inhibitors for immune diseases and multiple sclerosis.

Datea: August

Acquirer: Johnson & Johnson

Target: Momenta Pharmaceuticals

Value: $6.5 billion

Aim of deal: Expand its immune disease portfolio with the late-stage anti-FcRn antibody nipocalimab.

Datea: August

Acquirer: Nestlé

Target: Aimmune Therapeutics

Value: $2.6 billion

Aim of deal: Own the peanut-allergy drug Palforzia.

Datea: September

Acquirer: Gilead Sciences

Target: Immunomedics

Value: $21 billion

Aim of deal: Expand its cancer portfolio into solid tumors with the antibody-drug conjugate Trodelvy.

Datea: September

Acquirer: Illumina

Target: Grail

Value: $8 billion

Aim of deal: Reintegrate liquid biopsy technology that was spun out of Illumina in 2016.

Datea: October

Acquirer: Bristol Myers Squibb

Target: MyoKardia

Value: $13.1 billion

Aim of deal: Boost its cardiovascular disease portfolio with mavacamten, a small-molecule allosteric modulator of myosin that has completed Phase 3 studies.

Datea: October

Acquirer: Bayer

Target: Asklepios BioPharmaceutical

Value: $4 billion

Aim of deal: Become a leader in cell and gene therapies.

Datea: November

Acquirer: Merck & Co.

Target: VelosBio

Value: $2.8 billion

Aim of deal: Get the ROR1-targeted antibody-drug conjugate VLS-101, in midstage clinical trials for blood cancers and solid tumors.

Datea: November

Acquirer: Novo Nordisk

Target: Emisphere Technologies

Value: $1.8 billion

Aim of deal: Add an oral drug delivery platform for small and large molecules.

Sources: Companies.
a Month the deal was announced.



Anthony Fauci inspired and infuriated in equal measure

America’s top infectious disease official has been a polarizing figure during the COVID-19 pandemic

by Megha Satyanarayana


Credit: Donuts Delite/Facebook

Few doctors can inspire both a sitting president to spit nails and a bakery owner to put their face on doughnuts. But such is the reach of Anthony Fauci, the longtime director of the US National Institute of Allergy and Infectious Diseases.

Fauci, an immunologist and infectious disease expert, has become a household name during the COVID-19 pandemic by doing nothing more than preaching caution, whether by telling Americans to wear face masks or by reminding US government officials they need to wait for solid data before proclaiming any treatment or vaccine the definitive end of SARS-CoV-2, the virus that causes COVID-19.

“I know we’re living in a charged political environment,” Fauci said at a November event in Washington, DC, during several record-breaking days of coronavirus infections in the US. “We just continue to do our job to foster public health but also to do the science,” he continued, noting that such work would bring benefits like COVID-19 vaccines.

That Fauci has become the government’s loudest voice about public health and science is a function of a few things, says Scott Becker, CEO of the Association of Public Health Laboratories. The administration of President Donald J. Trump failed to offer a federal strategy for addressing the pandemic and often disagreed with public health officials. Meanwhile, the Centers for Disease Control and Prevention, which historically guided public health response, was frequently silent.

Fauci wasn’t saying anything particularly controversial, Becker says, but because he was mostly alone, he became a target.

He was and is our hero in this.
Scott Becker, CEO, Association of Public Health Laboratories

“He was and is our hero in this because he was consistently trying to give these very practical messages. But at times he was out there on his own doing this without the entire machinery of the federal government behind him,” Becker says. “Without a national strategy, it meant chaos.”

Fauci’s caution extended to drug and vaccine safety. When AstraZeneca halted one of its vaccine trials after a participant fell ill, Fauci called it an unfortunate event and a necessary pause. When studies of hydroxychloroquine, an antimalarial drug hyped by Trump early in the pandemic, failed to work in treating COVID-19, Fauci hailed the rigor of the science.

Fauci is plainspoken, which earns him praise as a science communicator, especially from other scientists. But that quality means he is in danger of being held up as a foil to the president and his followers rather than a scientist speaking clearly, says Vinay Prasad, an oncologist at the University of California, San Francisco, who has been outspoken about cancer clinical trials.

“In a well-functioning system, a public health official that tells you about what you should do to stay safe and keep your community safe—they are as forgettable as any scientist,” Prasad says. “In any normal world, a guy like that would never be a polarizing figure.”

It’s not the first time Fauci has found himself in the flames of an outbreak response. During the height of the AIDS epidemic, he was the target of a protest by AIDS activists demanding a seat at the drug development table and frustrated that Fauci wasn’t moving fast enough. But Fauci listened, got the activists involved, and eventually built long-standing relationships with some of them.

Any feuding between science and politics might soon simmer down. President-Elect Joe Biden has spoken repeatedly of trusting science and scientists in the US approach to managing the coronavirus pandemic. Biden and Vice President Elect Kamala Harris have created a COVID-19 task force helmed by researchers and public policy experts. Come Jan. 20, Fauci, who tries to remind people of the neutrality of his position when he says that he has served under six presidents, will serve, not forgettably but perhaps more harmoniously, under a seventh.



Biotech start-ups launched in spite of the pandemic

Notable start-ups in 2020 include new firms tackling coronaviruses and brain diseases

by Ryan Cross


Cash for coronaviruses

Adagio Therapeutics

Adagio Therapeutics, a spin-off from the designer antibody company Adimab, launched with $50 million to develop a broadly neutralizing antibody therapy that targets multiple betacoronaviruses, including SARS-CoV-2, the virus that causes COVID-19. The start-up already has 7,000 vials of its experimental drug ready for clinical trials in January 2021.

Atea Pharmaceuticals

Atea Pharmaceuticals raised $215 million in May to repurpose a hepatitis C drug to treat SARS-CoV-2 infections. In October, Roche partnered with Atea to develop the drug, an RNA-dependent RNA polymerase inhibitor, which is now in a Phase 2 clinical trial of people hospitalized with mild COVID-19.

ExeVir Bio

ExeVir Bio launched with $27 million in July to develop a single-domain camelid antibody that targets SARS-CoV-2 and SARS-CoV-1, the virus that causes severe acute respiratory syndrome. The company is a spin-off from the Flanders Institute for Biotechnology in Ghent, Belgium, and the antibody came from a llama named Winter.

When US labs began shutting down in March, some biotech observers worried that the pandemic would hurt the booming biotech start-up scene. Although it’s too early to know COVID-19’s long-term effects on the industry, one thing is clear: the novel coronavirus did not bring biotech start-up launches to a grinding halt.

North of 100 start-ups focusing on drug discovery and development launched with their series A funding—the company’s first formal round of funding—between January and October, according to C&EN’s count. Cell therapy and gene therapy start-ups continued to launch with large financings. New small-molecule firms took aim at drug-resistant tumors and innate immune system proteins like inflammasomes. Companies with new takes on gene editing, microbiome therapies, and protein engineering made strong showings too.

One notable trend in 2020 was investment in firms with fresh ideas for treating brain diseases. Multiple start-ups launched drug discovery programs for targets implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease. Big pharma firms have started taking note of the new approaches as well. Bristol Myers Squibb and Merck & Co. both established drug discovery partnerships with start-ups working on ALS and FTD.

Drugs that treat COVID-19 also made an appearance in biotech financings. At least a dozen start-ups raised funds for antivirals, anti-inflammatory drugs, and vaccines for COVID-19. Three of the most notable include Adagio Therapeutics, Atea Pharmaceuticals, and ExeVir Bio.

New brains on the block

Neuroscience-focused start-ups had a strong showing in 2020. These are some of the notable companies that emerged with big plans to tackle brain disease with small molecules, gene therapies, and more.

Company Money raised ($ millions) Focus
Taysha Gene Therapiesa $125

Gene therapy for 18 genetic central nervous system diseases, including Angelman syndrome, GM2 gangliosidosis, and Rett syndrome

Praxis Precision Medicines 110

Small molecules and antisense oligonucleotides for genetic epilepsies as well as mood, movement, and pain disorders

AavantiBio 107

Gene therapy for Friedreich's ataxia

Nura Bio 73

Small-molecule NAD hydrolase SARM1 inhibitors to prevent axon degeneration

Aspen Neuroscience 70

Personalized neuron replacement therapy derived from induced pluripotent stem cells for Parkinson's disease

Prilenia Therapeutics 62.5

Pridopidine, a small-molecule σ1 receptor agonist for amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and other neurodegenerative disorders

Nine Square Therapeutics 50

Small molecules for amyotrophic lateral sclerosis, dyskinesias, essential tremor, and Parkinson's disease

QurAlis 42

Small molecules and antisense oligonucleotides to restore autophagy and target TDP-43 for amyotrophic lateral sclerosis

Nitrome Biosciences 38

Small molecules targeting enzymes called nitrases for Parkinson's disease

Tranquis Therapeutics 30

Small molecules to restore the myeloid immune cell metabolic pathway for amyotrophic lateral sclerosis and frontotemporal dementia

Libra Therapeutics 29

Small molecules to boost autophagy for amyotrophic lateral sclerosis and frontotemporal dementia

Redpin Therapeutics 15.5

Chemogenetic (small-molecule-controlled) gene therapy for epilepsy and pain

Company: Taysha Gene Therapiesa

Money raised: $125 million

Focus: Gene therapy for 18 genetic central nervous system diseases, including Angelman syndrome, GM2 gangliosidosis, and Rett syndrome

Company: Praxis Precision Medicines

Money raised: $110 million

Focus: Small molecules and antisense oligonucleotides for genetic epilepsies as well as mood, movement, and pain disorders

Company: AavantiBio

Money raised: $107 million

Focus: Gene therapy for Friedreich's ataxia

Company: Nura Bio

Money raised: $73 million

Focus: Small-molecule NAD hydrolase SARM1 inhibitors to prevent axon degeneration

Company: Aspen Neuroscience

Money raised: $70 million

Focus: Personalized neuron replacement therapy derived from induced pluripotent stem cells for Parkinson's disease

Company: Prilenia Therapeutics

Money raised: $62.5 million

Focus: Pridopidine, a small-molecule σ1 receptor agonist for amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and other neurodegenerative disorders

Company: Nine Square Therapeutics

Money raised: $50 million

Focus: Small molecules for amyotrophic lateral sclerosis, dyskinesias, essential tremor, and Parkinson's disease

Company: QurAlis

Money raised: $42 million

Focus: Small molecules and antisense oligonucleotides to restore autophagy and target TDP-43 for amyotrophic lateral sclerosis

Company: Nitrome Biosciences

Money raised: $38 million

Focus: Small molecules targeting enzymes called nitrases for Parkinson's disease

Company: Tranquis Therapeutics

Money raised: $30 million

Focus: Small molecules to restore the myeloid immune cell metabolic pathway for amyotrophic lateral sclerosis and frontotemporal dementia

Company: Libra Therapeutics

Money raised: $29 million

Focus: Small molecules to boost autophagy for amyotrophic lateral sclerosis and frontotemporal dementia

Company: Redpin Therapeutics

Money raised: $15.5 million

Focus: Chemogenetic (small-molecule-controlled) gene therapy for epilepsy and pain

Source: Companies.
a Total includes multiple fundraising rounds.


Pharmaceutical Chemicals

Contract manufacturing came forward

Drug and vaccine development this year shone a light on the key role played by service firms

by Rick Mullin


Credit: Flamma
Technicians working at Flamma, an Italian contract manufacturer that will produce two intermediates for Gilead Sciences' remdesivir

Regulators and the public alike learned a lot about the arcane mechanisms of the pharmaceutical supply chain in 2020 as the world monitored the development of therapies and vaccines that might bring life back to normal. A key discovery: outsourcing does not always mean offshoring. Far from it.

Production costs have pushed generic-drug manufacturing to low-cost Asia over the last 20 years, but drugmakers have also increased their reliance on drug-ingredient firms close to home for their more cutting-edge therapies.

A group of US and European pharmaceutical chemical companies has evolved since the 1990s into a full-service industry, now global, offering development and manufacture of active pharmaceutical ingredients (APIs), finished-dose drug production, and new technologies like cell and gene therapy. These contract development and manufacturing organizations (CDMOs) have acquired customers’ plants as big pharma gravitates toward exiting large-scale manufacturing.

CDMOs also provide essential services to the small biotech ventures at the forefront of drug discovery. That critical role has shown up in headlines all year as companies, anxious to secure adequate manufacturing capacity, put in place the infrastructure required to quickly meet demand for the COVID-19 drugs and vaccines in development.

We have been doing a lot of work with the federal government and other governments to explain where the CDMO market is now and how it is working.
Gil Roth, president, Pharma and Biopharma Outsourcing Association

“People are coming to understand that when company X puts out a press release saying it can manufacture 1 billion doses of a vaccine by 2021, that it actually has commitments with contract manufacturers to make 1 billion doses by 2021,” says Gil Roth, president of the Pharma and Biopharma Outsourcing Association, a trade group representing pharmaceutical manufacturing and research service firms. “We do a lot of work with the federal government and other governments to explain where the CDMO market is and how it is working.” Awareness is increasing, Roth says.

He says the emergent pairing of API manufacturing with finished-dose formulations in a single provider has prepared the CDMO sector for the opportunities and challenges created by the pandemic.

Industry consultant James Bruno sees these full-service firms taking over the traditional role of pharmaceutical manufacturing. Drug companies will develop the technology, he says, but that technology will go to contractors such as Thermo Fisher Scientific and Lonza for turning into actual drugs and vaccines.

Service firms have signed on throughout the year with COVID-19 vaccine makers. Catalent, for example, is working with AstraZeneca and the University of Oxford on their jointly developed vaccine. Catalent and Lonza will manufacture for Moderna, a vaccine front-runner. Smaller service firms, such as Flamma, a family-owned Italian company contracted to manufacture two intermediates for Gilead Sciences’ remdesivir, have been tapped to rapidly ramp up production of COVID-19 therapies.

Europe’s contract manufacturing sector is running at near full capacity, and expansion projects are rampant. Carbogen Amcis announced it will spend $110 million on an API facility in Switzerland and an injectable-drug plant in France. Another Swiss firm, Dottikon, says it plans to invest $660 million over 10 years to boost API production, citing the reshoring of production from Asia.

Beyond the pandemic response, industry watchers foresee a major role for CDMOs in emerging fields of pharmaceutical research, and service firms are taking their positions. Catalent and Thermo Fisher, for example, have added cell and gene therapy to their offerings through recent acquisitions. Lonza opened a cell and gene therapy facility in Texas in 2018.

Capacity anxiety will outlast the crunch to meet demand for COVID-19 drugs and vaccines, according to Peter Bigelow, president of xCell Strategic Consulting and a former CDMO executive. “There are so many clinical trials going on,” Bigelow says of cell and gene therapy, comparing the expectations and uncertainty to the biotech industry in the 1980s. “If someone had a crystal ball on success rate, it would be helpful.”


Drug Development

Aducanumab: A fate undecided

Despite halted trials and shaky data, Biogen is asking the FDA to approve its controversial Alzheimer’s drug

by Megha Satyanarayana


Credit: Biogen
Biogen’s aducanumab can lower levels of amyloid (red) in the brains of people with early-stage Alzheimer’s. But data on cognitive benefits are thin. Left, pretreatment. Right, after 54 weeks of the drug.

Few drug development tales have had the twists and turns of aducanumab, Biogen’s antibody treatment for Alzheimer’s disease. And as 2020 comes to a close, Biogen’s highly anticipated drug sits under a dangling sword. In a November hearing with a US Food and Drug Administration advisory panel, the agency’s statisticians panned the company’s analysis of clinical data, and external reviewers seemed unconvinced the drug is effective. The FDA has until March 2021 to make a ruling.

This latest chapter comes after a tumultuous year and a half for aducanumab, which binds to protein fragments called amyloid-β that accumulate in the brains of people with Alzheimer’s. Biogen halted Phase 3 trials of the treatment in early 2019 after an independent data monitoring committee said the drug was unlikely to prove effective. The company turned around a few months later and applied for FDA approval based on a larger data set—one that suggested high doses of the drug provided some benefit in memory and other cognitive markers.

More is at stake than the possibility of the first meaningful treatment for a disease that is becoming more prevalent. A rejection by the FDA could be the last gasp for the amyloid hypothesis of Alzheimer’s disease—the notion that amyloid-β plaques, and the neuronal death they cause, are the root of the illness. Already, many other amyloid-targeting therapies have failed, and research hasn’t yielded many new ideas. The Alzheimer’s pipeline is otherwise thin.

Going into the meeting, Biogen officials had reason to be confident. FDA documents released ahead of the event were supportive, recognizing the need for new treatments for Alzheimer’s as well as the novelty of aducanumab, which addresses the underlying cause of the disease. Billy Dunn, director of the FDA’s Office of Neuroscience, said during the hearing that the results of one of Biogen’s trials were “highly persuasive.”

But then the daylong meeting turned.

External reviewers criticized the statistical analysis of the trial that Biogen heralded as evidence its treatment works. They voiced concerns that the trial was inadvertently unblinded when people had to be treated for side effects. Another reviewer said there was no correlation between a reduction in amyloid clumps and long-term reduction in symptoms.

It’s not clear what the FDA will do, says Maria Teresa Ferretti, an Alzheimer’s disease researcher and the chief scientific officer of the Women’s Brain Project. The agency typically follows its advisers, she says, but on occasion it has approved drugs that had similarly disastrous advisory committee meetings.

It surprised everybody that Biogen didn’t give up.
Maria Teresa Ferretti, chief scientific officer, Women’s Brain Project

That the aducanumab story is still being written is a testament to a growing dilemma, Ferretti says.

As the world population ages, the number of people with Alzheimer’s is growing. About 5.8 million people aged 65 and older in the US are living with it, and by 2050, that number is expected to grow to at least 14 million. The disease and other dementias will cost the country $305 billion this year, according to the Alzheimer’s Association. With no surefire treatments, the FDA knows the situation is dire, Ferretti says. This desperation might be a reason the agency decided to proceed with the hearing in spite of the confusing data.

“It was absolutely exceptional,” she says. “It surprised everybody that Biogen didn’t give up.” Despite the negative tone of the hearing, Ferretti says, just the possibility of improvements in memory and quality of life could sway the FDA to approve the drug.


Infectious disease

The UK RECOVERY trial: An ambitious test of COVID-19 treatments

Although it’s not perfect, experts say it’s a well-designed and well-executed trial improving clinical practice around the world

by Megha Satyanarayana


Credit: Newscom/John Super/Xinhua
The UK RECOVERY trial, which is testing several treatments for COVID-19, including dexamethasone, has been praised for its simplicity and scope but criticized for a lack of transparency.

In March, with a plethora of treatment choices but little data to show whether they actually worked against COVID-19, researchers in the UK began a massive clinical trial. Called RECOVERY (Randomised Evaluation of COVID-19 Therapy), the trial has enrolled more than 14,000 people hospitalized with COVID-19. Its goal is to answer, as systematically as possible, what medicines will be effective in the fight against the respiratory disease.

RECOVERY, which clinicians hope will ultimately enroll 20,000 people, will be one of the largest drug trials for COVID-19, testing both older drugs used for other diseases and new ones invented amid the pandemic. As results from the trial are released and clinical practice changes almost instantaneously, experts say the enormous effort has been invaluable.

In a short period of time, this relatively low-budget, very simple study has given us tremendous insight into what works to treat COVID.
Vinay Prasad, oncologist, University of California, San Francisco

“In a short period of time, this relatively low-budget, very simple study has given us tremendous insight into what works to treat COVID,” says Vinay Prasad, a University of California, San Francisco, oncologist who studies clinical trial design.

In its first 3 months, the trial revealed that the steroid dexamethasone could reduce mortality in seriously ill people with COVID-19. Researchers and clinicians consider this result the most meaningful, and most definitive, for any drug tested so far for the disease. The trial also revealed that neither an HIV drug nor the antimalarial hydroxychloroquine, the treatment championed by US president Donald J. Trump, works at all.

RECOVERY is a randomized, controlled trial, a standard that Prasad and others have said is sorely lacking in COVID-19 clinical trials. For example, only one of the many late-stage trials for remdesivir, an antiviral that was eventually approved by the US Food and Drug Administration for use in people hospitalized with the infection, included a placebo arm.

Anyone in the UK who is hospitalized with COVID-19 can agree to participate in the trial by filling out a short form. The person is immediately sorted into one of the treatment arms or the control arm, which is the standard treatment at the time at that hospital. This sort of trial doesn’t assume that a treatment will be beneficial, Prasad says, and is designed to make sure that potentially harmful treatments are given to the fewest people.

“The whole purpose of the study is what’s the least number of people we can expose to the bad pill before we figure out which one’s a good pill,” he says.

In the study, treatments that fail or succeed can easily be replaced without having to revise the trial design. With answers in hand about dexamethasone and hydroxychloroquine, researchers have cycled in new treatments, including convalescent plasma, aspirin, and an antibody therapy from Regeneron Pharmaceuticals. And tracking all this is easy, Prasad says, because hospitals in the UK’s National Health Service use the same medical records platform.

The trial is not without flaws. Other scientists have criticized the organizers of the trial for releasing results without detailed data and for a lack of diversity in the demographics of the trial participants.

While criticisms of “science by press release” are understandable, Prasad says, RECOVERY’s leaders had already made public how they would analyze their data and what their protocols were. He points to industry-sponsored trials that release even fewer details ahead of time. RECOVERY may not be perfect, he says, but he’s hard pressed to improve on it under the constraints of the pandemic.

“It represents what everyone should have aspired to do, and the best you could do in a short time period,” Prasad says. When asked if there was anything he would have changed about the study, he says, after a moment’s thought, “I don’t have too many criticisms. I give them a lot of credit.”


Drug Development

Small pharma and biotech firms dominated 2020 drug approvals

Experts say the lack of big pharma approvals points to problems with R&D

by Megha Satyanarayana


The US Food and Drug Administration had approved 47 new molecular entities by early December, on pace to match or best the 48 drugs that got the green light in 2019. The agency also approved a handful of novel biologics and vaccines. Those new products arrived despite the constant stream of diagnostics, drugs, and vaccines in development for COVID-19 that the FDA was evaluating for emergency use.

The volume of approvals has been high for several years, but that pace belies a troubling trend, says Bernard Munos, a senior fellow at the think tank FasterCures. Most of this year’s approved treatments were discovered by smaller pharmaceutical and biotech companies rather than the big drug companies that spend billions of dollars each year on R&D. For decades, he says, the output of the 13 largest companies has been fairly flat, despite massive year-over-year increases in R&D spending.

That several big pharma companies didn’t get a drug approved this year—or bought in the ones that did get a green light—calls into question the sustainability of their business models, Munos adds.

Here are some of the standout approvals of 2020.

Genentech and Roche


Evrysdi (risdiplam) is the first oral medication for spinal muscular atrophy, a rare disease that leads to gradual loss of motor function. The small molecule acts on the messenger RNA of the SMN2 (survival of motor neuron 2) gene to encourage proper RNA splicing, leading to the formation of the normal protein that is missing in children with the disease.

Regeneron Pharmaceuticals


Inmazeb is the long-awaited first approved treatment for Ebola virus disease. It is made of three antibodies that target different regions of the glycoprotein that dots the surface of the highly contagious and deadly Zaire ebolavirus. This binding neutralizes the virus’s ability to infect. Inmazeb was tested during the 2018 outbreak of Ebola disease in regions of the Democratic Republic of the Congo, where it was able to clear virus from the blood in infected people 12 days earlier than a similar drug called ZMapp.

AstraZeneca and Merck & Co.


Koselugo (selumetinib) is the first treatment for a rare genetic disease called neurofibromatosis, which emerges in early childhood and causes small tumors to grow all over a person’s nerves. The tumors are often benign, but a subclass called plexiform neurofibromas can become malignant. The small-molecule MEK1/2 inhibitor treats the malignant tumors that have become inoperable.

Aimmune Therapeutics


Palforzia is the first treatment approved for peanut allergies in a nonemergency situation. People with peanut allergies take an increasing dose of the powder, which is made of ground peanuts that have been roasted and had the fat removed; over time, the powder should desensitize the immune response to the food. Peanut allergy is one of the most common food allergies in the US, affecting about 1 million children.



Tazverik, the brand name for tazemetostat, is the first approved drug that works by modifying epigenetic pathways The small molecule blocks a mutated form of the methyltransferase EZH2, an enzyme that helps tune the activity of genes by tacking methyl groups onto histones. Mutations in EZH2 have been linked to several cancers; so far, the drug is approved to treat epithelioid sarcoma and follicular lymphoma.

Gilead Sciences


Veklury, the brand name for remdesivir, was approved to treat people hospitalized for COVID-19. The antiviral, which was originally developed to treat Ebola, stops viral replication by mimicking one of the genetic building blocks of SARS-CoV-2, the virus that causes COVID-19. This action makes it impossible for the virus to replicate. Remdesivir was granted a broader emergency use authorization for treating COVID-19 in April before being fully approved for a narrower subset of COVID-19 patients in October.



IPO window remained wide open

The pandemic did not slow companies’ efforts to go public

by Lisa M. Jarvis


Cash flood
Biotech companies wanting to go public found significant support in 2020.
Source: Ladenburg Thalmann.
a As of Oct. 20, 2020.

Despite—or perhaps because of—the global pandemic, biotech companies tapped into public markets with vigor in 2020. The year brought a surge in initial public offerings (IPOs) for a wide range of companies, many still working to put their first drug into the clinic.

“2020—despite the challenges surrounding the pandemic and our nation’s reckoning with social and political ills, as well—did not skip a beat in terms of biotech funding,” Nina Kjellson, general partner at the early-stage venture capital firm Canaan Partners, says in an email to C&EN. The “rising tide of overall healthcare investment,” alongside a steady pace of positive life sciences news, “kept the IPO window wide open,” she says.

Brad Loncar, CEO of life sciences–focused Loncar Investments, points to the public’s newfound understanding of the importance of developing drugs and vaccines. “The pandemic has opened the world’s eye to how vital biotech is to society,” he says. When stocks started to rebound from their sharp decline in March, when the outbreak was prompting global shutdowns, the biotech sector was one of the first to benefit, he says.

“This is the easiest year ever to take a biotech company public,” Loncar says. “We’re almost running out of biotech companies to go public.”

Indeed, by October, 75 biotech firms had completed an IPO, raising nearly $14 billion, according to the investment bank Ladenburg Thalmann. The bank notes that the financing window, or the period of time when conditions are right for taking a company public, has been open since October 2012—the longest in decades.

An increasing number of the IPOs are from biotech firms that have yet to put a drug into the clinic. Not long ago, taking a preclinical-stage company public was taboo, Loncar says. “Now, it’s totally normal.”

The comfort with these very young firms reflects increasing confidence in science. In the past, Loncar points out, it was harder to judge whether an early-stage drug would survive the clinical trial gauntlet. “You can make a much stronger call today on a preclinical company on the scientific merits than you could have 5–10 years ago,” he says.

The question now is whether the window will remain open in 2021. Kjellson says the infatuation with innovation will remain, while concerns over dramatic health-care or drug pricing reforms have abated now that the US election is settled. All signs “suggest the IPO market’s going to be just fine headed into the new year, with a roster of high-quality companies to come,” she says.



Rapid antibody development came of age

Lilly and Regeneron pushed timelines to their limits, but the impact of their COVID-19 antibodies remains to be seen

by Ryan Cross


Drugs take years to develop, usually more than a decade, according to one oft-cited statistic from the Tufts Center for the Study of Drug Development. But at Eli Lilly and Company, the urgency of the COVID-19 pandemic shrank that timeline to about 8 months.

In November, the US Food and Drug Administration granted Lilly’s antibody therapy bamlanivimab emergency use authorization (EUA) for treating certain COVID-19 cases. It’s not a full-fledged approval for the drug, which is designed to prevent the virus from infecting cells, but it is the first authorization for any therapy discovered and developed during the pandemic specifically for SARS-CoV-2 infections. A similar therapy, a cocktail of two antibodies, from Regeneron Pharmaceuticals has also moved at a pandemic pace.

Both companies spent just a few months on the discovery and preclinical development of their antibodies, which were isolated from human plasma samples and from genetically engineered mice immunized with viral proteins. Their initial clinical trials began in June; within 2 months, both were in larger, Phase 3 studies. Lilly and Regeneron were granted limited EUAs for the antibodies in November.

“About 4 months for clinical studies is unheard of,” says Janice Reichert, executive director of the Antibody Society, a trade organization. “It is crazy fast.”

A tale of two companies

Regeneron Pharmaceuticals and Eli Lilly and Company raced to discover and develop new antibody therapies for treating COVID-19 in under a year.

Feb. 4

  • Regeneron Pharmaceuticals immunizes mice to make antibodies that target the SARS-CoV-2 spike protein.

Feb. 25

  • AbCellera Biologics begins looking for antibodies in convalescent plasma from an individual who recovered from COVID-19.

Mar. 12

  • Eli Lilly and Company partners with AbCellera to develop an antibody to treat COVID-19.

Jun. 1

  • Lilly begins Phase 1 clinical studies.

Jun. 11

  • Regeneron begins Phase 1 clinical studies.

Jul. 6

  • Regeneron begins Phase 3 clinical studies.

Aug. 3

  • Lilly begins Phase 3 clinical studies.

Sep. 16

  • Lilly reports that preliminary data on 452 people in a Phase 2 study suggest that its antibody reduces the rate of hospitalization in people with mild to moderate disease.

Sep. 29

  • Regeneron reports that preliminary data from the first 275 participants in a trial suggest that its antibodies reduce viral loads.

Oct. 7

  • Lilly and Regeneron say they have filed for emergency use authorization (EUA).

Oct. 13

  • Lilly’s antibody trial is paused due to safety concerns.

Oct. 14

  • A different antibody therapy developed by Regeneron, Inmazeb, becomes the first drug approved by the US Food and Drug Administration for treating Ebola virus infections. It was discovered with the same technology used for its COVID-19 antibodies.

Nov. 9

  • Lilly’s COVID-19 antibody, bamlanivimab, gets EUA from the FDA.

Nov. 21

  • Regeneron’s COVID-19 antibody cocktail, containing casirivimab and imdevimab, gets EUA from the FDA.

Regeneron tried its hand at rapid antibody development during the 2014 Ebola virus outbreak. Although the firm developed a triple-antibody cocktail in under a year, it was not able to test it in a large clinical study until a subsequent outbreak that began in 2018. The FDA approved the drug this October.

Researchers say the speed this time around comes from the convergence of maturing technologies. For instance, scientists have devised multiple methods for isolating individual B cells that make antibodies against a particular target, like the SARS-CoV-2 spike protein. Faster and cheaper DNA sequencing and synthesis allow scientists to easily identify and produce hundreds of antibodies, which are tested head to head in the lab to find the ones that are most effective at neutralizing the virus.

“All of these things have been percolating for the last 4 or 5 years,” says Robert Carnahan, associate director of the Vanderbilt Vaccine Center. “Everyone knew we could go fast, but necessity is the mother of invention.” His group discovered two antibodies that AstraZeneca is now testing in Phase 3 clinical trials.

Reichert’s organization and the Chinese Antibody Society have tallied more than 120 academic and company programs developing antibodies that target the SARS-CoV-2 spike protein, including more than a dozen in clinical trials. “I don’t want to overstate the case, but it seems like just about anybody can make an antibody,” Reichert says. “There are so many, I kind of got tired of counting them.”

But it is too soon to know whether any of these antibodies will be successful. Neither the Lilly nor the Regeneron therapy helped people hospitalized with severe COVID-19, and the focus now is on testing their drugs in mild and moderate cases. Lilly’s and Regeneron’s EUAs were granted on the basis of data suggesting that the antibodies lower the chance of hospitalization in high-risk individuals recently diagnosed with mild to moderate infections.

There are also obstacles to adoption. The drugs are expensive, and Lilly and Regeneron have limited capacity to make them—factors that could diminish their global impact.

Experts are hesitant to say whether the rapid speed will be replicated outside the pandemic. “Nonetheless, it totally resets expectations for what is possible, although not necessarily what is desirable if you have more time,” Reichert says.



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