The BioPharma Dive Outlook on 2021

Biopharma dealmakers had tempered their excitement heading into last year. After 2019 brought an unprecedented amount of activity, the odds of having another record-breaking stretch — especially so soon — looked slim. They also felt that with the upcoming U.S. presidential election and its potential impact on drug policy, some companies would take a wait-and-see approach to deals.

What they hadn't planned for was dealmaking grinding to a halt as a once-in-a-century pandemic took hold.

The lull lasted about two to three months in the spring, according to experts who spoke to BioPharma Dive. By June, deal negotiations were churning again. Business development teams got used to virtual meetings, and rubbing elbows online rather than at conferences. Some even noticed an unusually high appetite for mergers and acquisitions once companies got their bearings.

"Our M&A group for the last couple months has been redlining," said Barbara Borden, co-chair of the M&A practice at Cooley.

A big run at the end of the year — including a $39 billion acquisition from AstraZeneca — wasn't enough to offset the slower pace at the start, though. Ernst & Young tallied $159 billion worth of life sciences dealmaking in 2020, well below the $200 billion that's become the annual standard as of late. PwC found the number of deals fell too, down 2% compared to 2019.

Still, dealmakers see the uptick in the back half of 2020 as a good sign, and expect a more complete rebound this year.

There are potential obstacles, however. Young biotechs are having an easy time raising cash, and so may not be as open to deals with big pharma companies, many of which are in need of new products.

Political and regulatory headwinds could come into play as well. Stuart Cable, global chair of M&A at the law firm Goodwin, said he'll be keeping a close eye on antitrust issues like the ones Roche ran into while acquiring the gene therapy developer Spark Therapeutics.

"The trend I'm most concerned about for 2021 is less about whether big pharma is buying, and more about whether we're going to get these deals approved," Cable said.

Below are five more trends experts think will shape biotech and pharma company dealmaking in the months to come.

Private equity adds competition

Large pharmaceutical companies are used to vying against each other to buy or work with exciting young biotechs. But looking ahead, they may find more competition from private equity firms.

These investors have, over the past decade, shown a greater interest in healthcare. In one of the more recent and high-profile examples, reports surfaced KKR had formally approached Walgreens Boots Alliance with what could have been the largest leveraged buyout in history.

Drug development has come up on their radar as well. Last April, Blackstone made one of the biggest private financings of a biotech company, with a $2 billion investment in Alnylam Pharmaceuticals. Then in July, the firm secured $4.6 billion in what it claims to be the largest-ever private equity fund for life sciences investing.

"Big private equity like KKR, Bain, they are all entering this industry with some force," Cable said.

Cable doesn't think private equity is likely to place massive bets on biotech just yet. But for deals valued in the range of $2 billion or less, he expects "an increasing trend of private equity competing with big pharma, particularly for late-stage companies and commercial companies."

To that latter point, Amag Pharmaceuticals, a women's health company with three marketed products, was in October bought out for roughly $650 million by a specialty pharmaceuticals company with ties to the private equity firm Apollo Global Management.

Big pharmas refine their pitches

Private equity isn't the only potential roadblock for big pharma buyers.

Biotech companies have been raising exceptionally large amounts of money from both venture capitalists and public investors. Data from Pitchbook and SVB Leerink show that venture deals in this space came close to $25 billion last year, an increase of more than 50% from 2019. Biotechs also conducted a record-breaking number of initial public offerings in 2020, with at least 31 raking in $200 million or more, according to data compiled by BioPharma Dive.

While the influx of cash does create new biotechs, and consequently more targets, it can also allow these companies to operate longer without needing to entertain a deal with a larger drug company.

"The principal argument that big pharma makes is: 'We'll give you plenty of money to develop your drug.' Well, guess what, there's plenty of money elsewhere," Cable said.

"Their competition," Cable added, "for the most part is not necessarily one another. It's not like it's Pfizer against Bristol Myers Squibb, or Merck against Sanofi. Their competition is continuing independence."

Buyers therefore may have to adjust how they work with and court biotechs.

That was the case for Gilead, which last year deployed tens of billions of dollars in pursuit of becoming a leader in cancer drug development. Gilead's chief financial officer recently detailed to BioPharma Dive how, to get certain deals done, his team had to be open to less conventional terms.

In the race for innovative drugs, buyers will need to "get in very early to make some strategic bets and stay ahead of potential competition or disruption," said Varun Budhiraja, a principal in the M&A practice at Deloitte.

"A lot of those bear hugs are converting into deals over time," he added.

Premiums stay sky-high

An added consequence of stiff competition and well-funded biotechs is having to shell out larger sums of money to lock down deals.

Last year alone saw Portola Pharmaceuticals, Aimmune Therapeutics and Immunomedics each sell at more than double their respective market values. According to EY, publicly traded biopharmas bought at a 74% premium, on average, in 2020.

"It's a great time to sell," noted Arda Ural, EY's Health Sciences and Wellness leader for the American markets.

Big pharmas, with their internal research and development lagging, have grown accustomed to paying these steep premiums to access new drugs and technologies. However, that doesn't mean price can't complicate deals.

"Boards get uncomfortable if premiums are too low; buyers get uncomfortable if premiums are too high, because of criticisms," said Borden from Cooley. "So it can have a psychological impact on whether people are willing to transact or not."

Still, for the largest drugmakers, price doesn't seem to be standing in the way if the deal is right.

"I don't have an upper bound," Pfizer CEO Albert Bourla told investors Tuesday at the J.P. Morgan Healthcare Conference. "We have the ability to basically do everything that exists out there, if we wanted to."

Neuroscience commands more attention

For years, the attention of biopharma dealmakers has centered on a select few areas of drug development — cancer, rare and immune diseases, as well as technologies like cell and gene therapy. Now, another area is gaining traction.

Big pharma had largely pulled back from research into the brain and central nervous system because so many drugs ended in failure. But in recent years, a better understanding of these systems has brought reasons for optimism in diseases like ALS, depression and movement disorders, in turn reigniting the interest of acquirers.

"The shift that I'm seeing the most is that more companies are going into CNS," said Marya Postner, head of the life sciences partnering practice at Cooley.

Postner said companies fighting neurodegenerative conditions such as Parkinson's disease and Alzheimer's disease are especially in demand. Indeed, last summer saw Biogen wager $560 million up front and potentially more than $1 billion total on some experimental treatments for Parkinson's. Then, in December, Eli Lilly agreed to spend nearly $900 million to buy Prevail Therapeutics, a gene therapy company with clinical-stage programs targeting inherited forms of Parkinson's and dementia.

Public and private investments are giving rise to more of these brain-focused biotechs, too. Just this week, Atalanta Therapeutics, a company trying to treat neurodegenerative disorders by silencing genes, launched with $110 million in funding from the venture capital firm F-Prime Capital. Atalanta already has collaborations in place with Biogen and Roche.

Blank-check companies stick around

Another neuroscience biotech that recently made headlines was Cerevel Therapeutics, a spin out from Pfizer and Bain Capital.

Like many biotechs, Cereval hit the public markets last year. But it did so in an unusual way. Rather than go through the typically arduous process of running an initial public offering, Cerevel merged with a blank-check company — more formally known as a SPAC, or special purpose acquisition company.

SPACs are essentially shell companies with one main purpose: to raise lots of money through an IPO, then use that money to merge with a promising company in a particular industry. In Cerevel's case, it raised $445 million in net proceeds by combining with Arya Sciences Acquisition Corp II, a SPAC sponsored by Perceptive Advisors.

Cerevel wasn't alone, either. In October, Panacea Acquisition announced a merger with the cancer drug startup Nuvation Bio. And this month, the Celgene spin out Celularity raised $372 million by combining with GX Acquisition.

Several other SPACs are still out there, looking for biotechs to merge with. And they typically have a two-year lifespan, meaning they will likely stick around as a vehicle for biotechs to go public at least through 2021, according to Ural from EY.

"We expect SPACs to continue to be on fire," said Lisa Haddad, co-chair of the public M&A and corporate governance practice at Goodwin.

Clinical trials are the proving ground for new and experimental medicines. Strong results can lead to regulatory approvals and change how diseases are treated, while weaker findings can dash hopes and close down testing. For biotech and pharmaceutical companies, clinical trial results are also the currency by which they convince investors, raise money and strike deals.

As the coronavirus pandemic worsens in the U.S. and in other countries around the world, the stakes are higher than ever for a number of clinical trials this year. Success from vaccines, antibody drugs and antivirals could help save lives and make COVID-19 a more manageable disease.

Important tests also await for drugs for depression, hemophilia, lung cancer and a rare disease called alpha-1 antitrypsin deficiency. As the first six months of 2020 unfold, keep an eye on these 10 clinical trials:

Three years ago, the Food and Drug Administration granted a landmark approval to the first gene therapy for an inherited disease, clearing a blindness treatment called Luxturna.

Since then, the regulator has approved one more gene therapy, the spinal muscular atrophy treatment Zolgensma, and given a green light for dozens of biotech and pharmaceutical companies to start clinical testing on others. Genetic medicines for a range of diseases, including hemophilia, sickle cell and several muscular dystrophies, appear in reach, and new science is galvanizing research. 

But, entering 2021, the gene therapy field faces major questions after a series of regulatory and clinical setbacks have shaded optimism. "The ups and downs of adolescence are on full display" analysts at Piper Sandler wrote in September, summing up the state of gene therapy research.

Here are five questions facing scientists, drugmakers and investors this year. How they're answered will matter greatly to the patients and families holding out hope for one-time disease treatments. 

Are recent high-profile setbacks a warning sign? 

The FDA was widely expected last year to approve a closely watched gene therapy for hemophilia A, the more common type of the blood disease. Instead, the agency in August surprisingly rejected the treatment, called Roctavian, and asked its developer, BioMarin Pharmaceutical, to gather more data. 

The next day, Audentes Therapeutics reported news came a third clinical trial participant had died after receiving the biotech's experimental gene therapy for a rare neuromuscular disease. The tragedy brought flashbacks to past safety scares in gene therapy, although the current wave of treatments being tested have generally appeared safe. 

A little less than five months later, the gene therapy field is grappling with two more setbacks. UniQure is exploring whether a study volunteer's liver cancer was caused by its gene therapy for hemophilia B. And Sarepta, one of the sector's top developers, faces significant doubts about its top treatment for Duchenne muscular dystrophy after disclosing a key study missed one of its main goals. 

In each case, the drugmakers involved offered explanations and reasons for optimism. BioMarin still expects to obtain an approval; Audentes' trial is now cleared by the FDA to resume testing; UniQure thinks it's unlikely the cancer case is linked to treatment; and Sarepta argued its negative data were the product of unlucky study design. 

But taken together, the developments are powerful reminders of both the stakes and uncertainty still facing gene therapy.

All four events also highlighted lingering worries about one-time genetic treatment. In rejecting Roctavian, for example, the FDA seemed to be concerned the impressive benefit hemophilia patients initially experienced may wane over time. The deaths in Audentes' study, meanwhile, renewed warnings about extremely high doses of gene therapy. Researchers have long watched for evidence that replacing or altering genes may cause cancer to develop in rare instances, particularly after four infants developed leukemia in a gene therapy study in the early 2000s. And Sarepta's negative findings were surprising because early signs of dramatic biological benefit that didn't seem to translate into clear-cut functional gains for all patients.

Experts are still confident gene therapy can deliver on its promise. Bu recent events suggest getting there may take a bit longer than some expected. 

Has the FDA raised its bar?

"The process is the product," is an often-used cliche about gene therapy, which are complex treatments with exacting manufacturing standards. 

Most of the roughly 60,000 pages in Spark Therapeutics' application for approval of Luxturna, for instance, involved what's known in the industry as "chemistry, manufacturing and controls." 

The therapeutic basis for gene therapy, by contrast, is much clearer for many of the rare, monogenic diseases that developers are targeting. If mutations in a single gene lead to disease, replacing or otherwise fixing that gene should have a large benefit. 

"Genetic medicine is not industrialized serendipity," said Gbola Amusa, an analyst at Chardan, contrasting gene therapy with chemical-based drugs. "It often is an engineering question."

In 2020, the FDA gave ample notice that it's watching gene (and cell) therapy manufacturing closely. Sarepta, Voyager Therapeutics, Iovance Biotherapeutics and Bluebird bio were all forced to revise their development timelines after the agency asked for new details about production processes. 

"The FDA is saying to companies that you've got to up your standards," Amusa added. 

For their part, FDA officials have indicated the spate of data requests are a product of the sharply higher numbers of companies advancing through clinical testing.

Are gene editing stocks overheated?

While setbacks have piled up for therapies that seek to replace genes, 2020 was a "transformative year" for therapies designed to edit them, according to Geulah Livshits, an analyst at Chardan. 

CRISPR gene editing, already widely recognized as a scientific breakthrough, gained further prestige with the awarding of the Nobel Prize in Chemistry to two early pioneers, Jennifer Doudna and Emmanuelle Charpentier. 

But the year also brought important progress from early biotech adopters. Editas Medicine and Intellia Therapeutics, for example, notched CRISPR firsts with use of the editing technology inside the human body.

And CRISPR Therapeutics and partner Vertex showed their experimental therapy, which uses CRISPR to edit stem cells, worked exceptionally well in the first 10 patients with either sickle cell disease or beta thalassemia treated in two early studies. 

The data are the most concrete sign yet that CRISPR's clinical use can live up to its laboratory promise. While all three companies' therapies are still in early stages, their advances have ginned up substantial investor enthusiasm.

Together, the market value of CRISPR Therapeutics, Editas and Intellia totals nearly $25 billion. Beam Therapeutics, a startup that uses a more precise form of gene editing, is worth nearly $6 billion. 

"Gene therapy will have a big role to play," said John Evans, Beam's CEO. "But I do think in the last year or so there's a growing realization that, when possible, you'd probably rather edit than add an extra gene." 

Clinical tests will prove that out but, until then, the large upswing in share price for gene editing companies may not be sustainable as valuations creep higher and higher. Some of the recent run-up, for instance, appears driven by money flowing from generalist investors through exchange-trade funds, rather than from investors experienced in handicapping preclinical- or early clinical-stage companies.

"They're overdue for some type of rationalization," predicted Brad Loncar, CEO of Loncar Investments, adding that many companies are targeting similar diseases, most commonly sickle cell and beta thalassemia. 

Can a wave of new startups develop better tools?

Tasked with replacing faulty genes with functional ones, scientists for the most part have turned to two types of viruses to safely shuttle genetic instructions into cells. Adeno-associated viruses, or AAVs, are typically used for infused treatments, while researchers working on cells extracted from patients generally opt for lentiviruses. 

Each virus class has advantages, but also notable drawbacks. AAVs, for instance, can trigger pre-existing immune defenses in some people, making those individuals ineligible or poor candidates for gene therapy. Lentiviruses, by contrast, are known to integrate their DNA directly into the genomes of cells they infect — a useful attribute in some regards but limiting in others. 

Over decades of gene therapy research, scientists have found ways to tweak and modify these viral vectors to better suit their needs, but the basic tools are the same. Jim Wilson, a gene therapy pioneer who ran the study that led to the death of teenager Jesse Gelsinger in 1999, told attendees at a STAT conference last fall that he's "somewhat disappointed" by slow progress in viral vector research. 

And as more and more gene therapies enter clinical testing, the limitations of current viral vectors have become more apparent. 

The pace of research might be picking up, however. Recently, a number of companies aiming to build better delivery tools have launched, including Harvard University spinout Dyno Therapeutics and 4D Molecular Therapeutics, which recently raised $222 million in an initial public offering. 

Larger companies are interested, too. Roche, Sarepta and Novartis have all partnered with Dyno, for example. 

In gene editing, meanwhile, researchers are developing new ways to cut DNA, while Beam and others are advancing different editing approaches altogether. 

Will large drugmaker bets bear fruit? 

Billions of dollars have flowed from pharmaceutical companies into gene therapy over the past few years, leaving few large multinational drugmakers without a research presence. 

2020 was no different, with sizable acquisitions inked by Bayer and Eli Lilly, as well as an array of smaller investments from Pfizer, Novartis, Johnson & Johnson, Biogen, and UCB. And CSL Behring, best known for its blood plasma products, spent nearly half a billion dollars to buy UniQure's most advanced gene therapy, a treatment for hemophilia B. 

Over the past three years, there's been at least $30 billion spent on biotechs involved in gene or cell therapy. (Four deals account for the majority of that value.)

All of that dealmaking, while following promising and compelling science, is ultimately a bet that one-time genetic treatments can be scaled up and commercialized into a lucrative business. 

Many of the acquired companies are working on therapies for very rare disorders affecting hundreds or thousands of people. A handful, however, are taking aim at more prevalent conditions, starting with still relatively uncommon diseases like hemophilia to ones affecting millions of people like Parkinson's. 

"For gene therapy to meet our lofty expectations — not just for investors, but for society — it has to make the leap from these ultra-rare diseases," said Loncar.

Commercially, the track record for the few therapies on the market in the U.S. is mixed. Luxturna, now owned by Roche, is a niche product. Zolgensma has broader use and earned Novartis about $1 billion in the year and a half it's been commercially available. 

Two cell therapies from Novartis and Gilead, meanwhile, have struggled to gain traction.

Gene therapy's biggest commercial test yet was supposed to come this year, with the expected approval of BioMarin's Roctavian in hemophilia A. The FDA's surprise rejection could mean a yearslong delay in the U.S., but the challenges of pricing, reimbursement and patient access in gene therapy remain dauntingly large.

Few government agencies were as front and center in the public eye last year as the Food and Drug Administration, which came under immense pressure to authorize unproven drugs as the world grappled with the pandemic and conducted high-stakes reviews of two coronavirus vaccines.

As COVID-19 cases continue to soar in the U.S., most of those pressures haven't gone away. But the inauguration next week of Joseph Biden as president will almost certainly bring new management to the agency, a change that can often result in policy shifts both subtle and far-reaching.

There will also be new faces at the FDA's parent agency, the Department of Health Human Services, which has battled FDA leadership at several points during the Trump administration. Even now, with days left to Trump's term in office, HHS officials are reportedly attempting to ram through several new policies that impact the FDA.

The pace and frequency of drug approvals, meanwhile, has quickened in recent years, prompting some to question whether reviewers are showing enough caution. Depending on who's appointed commissioner, the Biden administration could pull the reins somewhat.

"I think after so many years of faster, faster, faster, we're going to see a little bit of a pendulum shift," Remy Brim, co-lead of the health and life sciences practice at lobbying firm BGR Group, said Dec. 14 during the virtual Biopharma Congress sponsored by Prevision Policy.

"FDA, especially under Democratic administrations, really feels that a product is not safe and effective until it's shown it's safe and effective," Brim said. "It doesn't necessarily take the stance that a six -month or a one-year delay is detrimental."

Here are five issues before the FDA that will define its first year under a Biden administration:

Who will Biden nominate to be commissioner?

The FDA commissioners under President Donald Trump, Scott Gottlieb and Stephen Hahn, have been relatively steady leaders. Even though Hahn yielded to pressure from Trump to grant some controversial coronavirus drug authorizations, he became a fierce defender of the agency's review process for vaccines developed by Moderna and partners Pfizer and BioNTech.

While Hahn offers continuity amid the pandemic, the Biden administration is almost certain to appoint a new commissioner. The appearance of David Kessler, an FDA commissioner under Presidents George H.W. Bush and Bill Clinton, on the Biden transition team raised eyebrows. Two other Obama administration-era FDA officials, Luciano Borio and Lisa Barclay, are also members of the team.

Kessler, however, is reportedly out of the running for a FDA commissioner appointment, according to BioCentury.

Other names that have emerged include Gottlieb and two former commissioners, Margaret Hamburg and Mark McClellan. From within the agency, Amy Abernethy, the principal deputy commissioner whose name surfaced the last time there was a vacancy, has also been mentioned, as has a past holder of Abernethy's post, Joshua Sharfstein, now at Johns Hopkins University.

In a Nov. 16 note to clients, Cowen analyst Rick Weissenstein wrote Sharfstein's continued involvement in agency issues since leaving a decade ago makes him the best nomination for the sector. "We see a pick like Sharfstein as the best possible outcome as it would mean continuity at the FDA and maintain a positive environment for drug developers," he wrote.

A heavy coronavirus workload

Authorizing two coronavirus vaccines in two weeks last December was a monumental task, but the job isn't done. Three more vaccines could soon have late-stage study results supportive of authorizations, too, while testing continues for new experimental antivirals and antibodies that aim to help infected patients stay alive and out of the hospital.

If the latest vaccines succeed in the clinic, the FDA would likely convene an advisory committee meeting for each one as it did with the Pfizer and BioNTech and Moderna vaccines, a time-consuming task that is nonetheless considered important for building public trust.

Meanwhile, drugmakers that developed coronavirus treatments now cleared for emergency use, including Regeneron and Eli Lilly, may seek to convert their authorizations into full approvals.

The job of reviewing all of them will be made more complicated by the companies' efforts to expand the populations in which they can be used. Both the Regeneron and Lilly antibody drugs were authorized after results in comparatively small numbers of patients. Data from larger groups could change the conclusions of the drugs' effectiveness and pose thorny questions for reviewers.

Powerful examples in adapting clinical trial design

The massive trials to push coronavirus vaccines through from design to emergency authorization in less than a year, and a separate one to quickly evaluate treatments of hospitalized patients, have proven that big studies do not necessarily need to be multi-year affairs. The RECOVERY trial in the U.K., in particular, showed how a simple trial asking only one or two urgent public health questions can yield answers within weeks or a few months. The U.S. government's COVE trial, which tested Moderna's vaccine, did something similar.

The public health emergency of 2020 no doubt inspired agency reviewers to be more flexible about clinical trial design and the speed at which they were conducted. While normal times won't bring the same pressure, the experience could have lessons for regulators' oversight of trials in the future.

Particularly in cancer and rare diseases, the FDA has shown that it's willing to work with drug developers to design trials that can determine whether or not treatments work in short order. RECOVERY and COVE point toward a way to do the same for broader public health questions, and the agency may need to consider how the study of new drugs for major conditions like diabetes or cardiovascular disease could be sped up.

Regulating a wave of genetic medicines

The FDA's surprise rejection of BioMarin Pharmaceutical's hemophilia gene therapy Roctavian, along with scrutiny of manufacturing processes for other gene therapy developers, has led some to argue the FDA has raised standards. But Wilson Bryan, head of the agency's gene therapy review center, has argued the tough oversight is tied to "an increase in activity in the field."

Roctavian's rejection was unexpected, as two previous gene therapies, Roche's Luxturna and Novartis' Zolgensma, had largely non-controversial approvals. (The clearance for the latter, however, was marred by a post-approval data manipulation scandal.)

The FDA's concern, according to BioMarin, was that early data from later-stage testing showed a somewhat weaker treatment effect than a smaller, early study, raising questions about the durability of Roctavian's benefit. And in hemophilia, patients have many existing drug options available to them, which may have changed the agency's risk-benefit calculation.

"What does unmet need mean, when you have a gene therapy versus other products on the market?" Brim said at the Biopharma Congress session. "Once a patient takes [a gene therapy], they can't untake it."

More than 1,000 Investigational New Drug applications for gene therapies have already been submitted to the FDA, according to Bryan, meaning the demands on the agency will only grow with time.

PDUFA VII

The laws authorizing the user fees that partially fund FDA drug reviews — known in shorthand as PDUFA — sunset every five years, requiring Congress to pass a new one to sustain the program. The current edition is set to expire Sept. 30, 2022, so work is already underway to set the agenda for the seventh iteration of the law.

In the past, reauthorization of the PDUFA program has forced the agency to set firmer deadlines for drug approval decisions and has created expedited approval pathways such as the Breakthrough Therapy designation. The laws can also become a vehicle for Congress to achieve changes within the agency, which has been under the microscope during the coronavirus pandemic.

"How FDA handles itself on COVID is going to play into what type of policy riders we're going to see," Brim said.

A chief FDA request has been for more resources to beef up the staffing in its gene and cell therapy division. The agency, meanwhile, may be called upon to expand its work on new models of clinical trials, such as adaptive studies, that can shorten the amount of time experimental drugs spend in development.

Drugmakers could also seek to streamline the manufacturing paperwork involved in expedited review pathways to further shorten timelines.

While the COVID-19 pandemic has disrupted the Food and Drug Administration's review of new drugs, the agency's main office still managed to approve 53 medicines last year, near a record high set in 2018. 

That total doesn't include some biologic drugs products, nor does it count the emergency use authorizations for two coronavirus vaccines issued by the FDA last month — reviews that consumed much of regulator's time and attention. 

Coronavirus vaccines will still be a major focus in 2021, with several others near completion of late-stage testing. But the agency has a full plate of drug reviews, too, and will soon make one of the most important decisions in its recent history: whether to approve Biogen's controversial Alzheimer's treatment aducanumab. 

Decisions on a heart failure drug, a new Duchenne muscular dystrophy medicine and a cancer cell therapy are expected before the end of March as well. 

The following five drugs are listed in order of the currently scheduled date by which the FDA has agreed to make a decision on approval.

Merck & Co. and Bayer's vericiguat for heart failure

Editor's note: The FDA approved vericigaut on Jan. 20. 

In spite of an array of medicines, the prognosis for heart failure patients remains poor, with one estimate putting median survival at just over two years following hospitalization. Nonetheless, few new drugs have been shown to improve on existing regimens, with Novartis' Entresto, approved in 2015, a notable exception. 

Merck and Bayer, though, have submitted vericiguat for use in people whose hearts have weakened to the point where they can pump no more than 45% of the blood in the left ventricle, compared to 55% or more in a healthy heart. A pivotal trial showed that, when added to normal treatment for recently hospitalized patients, vericiguat can reduce the risk of another hospitalization or death by 10%. When the data was examined closely, however, the drug did not have any effect on cardiovascular death.

The FDA is expected to decide on approval by Jan. 20.

Entresto is already approved for these patients, but because only 15% of the patients in the vericiguat trial also received Novartis' drug, physicians may need more data to support using the drugs in combination.

Cowen analyst Steve Scala, commenting on the vericiguat results when they were released last March, argued the drug will likely be used in only the most severe patients, a small share of the estimated 3 million people who would be eligible.

Sarepta's casimersen for Duchenne muscular dystrophy

Casimersen has so far avoided the controversy that accompanied FDA approvals of Sarepta's first two drugs, Exondys 51 and Vyondys 53.

By now, FDA reviewers should be familiar with Sarepta's approach of using a drug to prevent translation of a disease-causing genetic mutation, which is how Exondys and Vyondys work to treat Duchenne. In clinical studies, casimersen stimulated greater production of a key muscle-building protein called dystrophin, levels of which reached about 2% of normal after treatment compared with less than 1% of normal at baseline.

Exondys and Vyondys were approved on similarly modest benefits, so unless the FDA review turns up a previously unidentified safety issue, casimersen looks likely to gain approval. The FDA didn't convene an advisory committee to review the drug, which will be sold as Amondys 45 if cleared. 

Each drug is targeted to specific, genetically defined subsets of Duchenne patients who are likely to benefit from treatment. An estimated 8% of Duchenne patients would be eligible for casimersen, according to Sarepta. 

A decision on casimersen, which is expected by Feb. 25, is one of two big early-year catalysts for Sarepta. Long-term data for the biotech's Duchenne gene therapy are anticipated within weeks — an event investors are watching closely as it could be used in a wider range of patients than Sarepta's other three drugs. 

Regeneron's Libtayo for lung cancer

Regeneron is a latecomer to immunotherapy, having won the first approval for its drug Libtayo years after multiple rival medicines were already well established.

Sales to date have been modest, totaling roughly $251 million for the first nine months of 2020. But they could ramp up considerably with two new approval decisions expected this quarter — the most notable being in frontline lung cancer, one of the most competitive segments of oncology. 

Immunotherapies have changed the way many lung cancer patients are treated. A combination of Merck & Co.'s Keytruda and chemotherapy, for instance, is now standard treatment for a majority of people newly diagnosed with advanced non-small cell lung cancer, the most common form of the disease. 

Regeneron hopes to play a role too, and an approval for Libtayo monotherapy by the FDA's Feb. 28 decision date would put the biotech company in the mix with Merck, Roche, Bristol Myers Squibb and several others. Importantly for Regeneron, an approval would also help its plans to study different drug combinations. 

Regeneron has presented Libtayo results which Wall Street analysts found comparable to Keytruda monotherapy. The company also has an ongoing Phase 3 trial testing combinations of its drug with either chemotherapy or Bristol Myers' Yervoy against Keytruda head-to-head.

Results from that study are expected this year. Other tests combining Libtayo with cell therapies and oncolytic viruses are underway as well. 

Biogen's aducanumab for Alzheimer's

Editor's note: Biogen announced on Jan. 29 the FDA extended its review of aducanumab by three months. The new date by which the FDA expects to make its decision is June 7.

The FDA is facing a no-win decision on Biogen's Alzheimer's treatment aducanumab. After collaborating with the company on review of its approval application in spite of mixed and controversial data, a panel of outside advisers voted decisively against the drug's benefit-risk profile. 

Now, if FDA follows the advisory committee's advice, it risks disappointing the patients, families and advocates who have pushed for new Alzheimer's therapies. If regulators ignore the committee, they risk damaging their reputation as independent arbiters of safety and effectiveness.

How the agency chooses will have enormous consequences, not least of which will be the ripple effects on Alzheimer's research. Many drugs that work similarly to aducanumab, which blocks the accumulation of a protein called amyloid beta in the brains of Alzheimer's patients, have failed previously. 

While most Wall Street analysts doubt the FDA will approve the drug, some are holding out the possibility of a surprise by the decision deadline of March 7. 

"There are two reasons that FDA could go against the recommendation," Stifel analyst Paul Matteis wrote in a Dec. 17 note to clients. "[First], FDA briefing documents were overwhelmingly positive, and [second] one thing that's clear is FDA believes aducanumab is safe, even in the community setting."

Bristol Myers Squibb and Bluebird bio's ide-cel for multiple myeloma

Rights to ide-cel, a cancer cell therapy, were acquired by Bristol Myers in its $74 billion takeover of Celgene two years ago. In their deal negotiations, the companies agreed to link U.S. approval of ide-cel and two other experimental drugs to a type of tradable security that promised Celgene shareholders an additional $6 billion. 

The much-scrutinized security is now void, after the FDA did not reach a decision on one of the other medicines by a Dec. 31, 2020, deadline set by Bristol Myers and Celgene. 

But ide-cel remains a critically important product for Bristol Myers and Bluebid bio and, if approved, would be the first cancer cell therapy cleared for use in multiple myeloma. Clinical trial results showed ide-cel to be a strongly potent treatment, eliminating or reducing patients' cancers in more than three quarters of study participants. While ide-cel causes significant side effects — severe in a small percentage of people — the treatment is expected to be approved by the FDA's target decision date of March 27, 2021.

Getting to this point, however, has taken longer than the companies originally expected. Last May, the FDA unexpectedly refused to accept the company's approval application, requesting more information on manufacturing. The notice, and the resulting time Bristol Myers and Bluebird needed to gather the additional information and resubmit its application, cost them several months.

From a business perspective, the delay could lessen the time Bristol Myers and Bluebird have without other cell therapy competition in multiple myeloma. A rival therapy being developed by Johnson & Johnson has looked similarly effective in clinical testing and should soon be under FDA review as well.

Other types of multiple myeloma treatments, including a kind of dual-targeting antibody drug, are quickly emerging, too.