C&EN’s Year in Pharma 2019 – Chemical & Engineering News

Vaping deaths. Drug shortages. Contaminated medicines. Opioids.

These are some of the biggest issues that the US Food and Drug Administration has dealt with in 2019, a year that saw one commissioner resign, one acting commissioner reassigned, and a new head nominated.

Stephen M. Hahn is expected to be confirmed as the FDA’s new commissioner in the next few weeks. In addition to these public health issues, he will have to deal with a pharmaceutical and biotech industry that wants fewer barriers to getting drugs to market and a public fed up with high drug prices. Hahn would be the fifth person to lead the agency since President Donald J. Trump took office in 2017.

Hahn would replace Scott Gottlieb, who took office in May 2017 and resigned roughly 2 years later. Gottlieb was known for his strong public and personal stances on issues like smoking and opioids. He sang the praises of e-cigarettes as a way to prevent cigarette-related illnesses but later backtracked on his support as large numbers of teens and young adults started vaping and getting sick. Gottlieb proposed reexamining the efficacy of opioid painkillers as a first step toward potentially changing the way they are regulated and even pulling some off shelves.

Between Gottlieb and Hahn was Norman E. “Ned” Sharpless, who spent approximately 7 months as acting head while Trump considered a replacement. Sharpless followed suit on Gottlieb’s efforts to regulate the vaping industry, proposing guidance that would end flavored e-cigarettes and suggesting that several chemicals found in the devices be added to a list of harmful chemicals in tobacco products. Brett Giroir served briefly as interim commissioner after Hahn was nominated and Sharpless was reassigned to the National Cancer Institute.

It’s not clear if Hahn, who Trump nominated at the last possible legal minute, will also follow in Gottlieb’s footsteps or forge an entirely different path.

His nomination was generally met with accolades.

“He seems to understand what his responsibility is, what his challenge is, and I think people are willing to give him the benefit of the doubt,” says Bernard Munos, who spoke to C&EN before the confirmation hearings. Munos is a senior fellow at FasterCures, a think tank trying to bring drugs to market more quickly.

The revolving door at the top of the agency might look troublesome, Munos says, but the agency’s day-to-day work will likely not change, at least as it relates to drug approvals.

“It used to be seen, back 15 years ago, as an impediment to innovation. Today, it’s widely recognized as a catalyst for innovation,” Munos says about the FDA.

Hahn is a radiation oncologist and in that role has been part of dozens of studies testing the efficacy of various cancer treatments. He also has leadership and crisis experience: he steered the University of Texas MD Anderson Cancer Center out of financial and legal trouble, and while he was at the University of Pennsylvania, he took responsibility for shoddy treatment of veterans with cancer.

The commissioner’s office has seen a lot of turnover since Trump took office. Depending on Trump’s reelection success, Hahn may not have a lot of time to realize his agenda, no matter how ambitious it might be.

In June, the drug industry held its breath as a cancer clinician took the stage at a major oncology conference and unveiled the first results on AMG 510, a small molecule that blocks a mutant form of KRAS. That data set represented the culmination of 30 years spent chasing KRAS, which is the most commonly mutated gene in cancer that until now has been impossible to drug.

AMG 510, discovered by chemists at Amgen, is one of four compounds in the clinic that directly inhibit KRAS G12C, a mutant form of the protein found in some 13% of lung cancers and 3% of colon cancers. Mirati Therapeutics, Eli Lilly and Company, and Johnson & Johnson have also begun human studies of KRAS G12C inhibitors.

Throughout the year, Amgen and Mirati offered early looks at how their drugs work in a few dozen patients with various tumors. Oncologists, drug developers, and industry watchers alike carefully analyze each report to try to understand the activity of this new class of compounds. Preliminary data unveiled at the June conference and elsewhere suggest that KRAS G12C inhibitors cause tumors to shrink in people with lung cancer but on their own might not be enough to overcome colon cancer.

The biggest open questions are how long the early effects will last and whether the benefits of the drugs can be extended if they are combined with other cancer therapies. KRAS is a central node in a complex signaling network, and many researchers worry that cancer cells will quickly shift their dependence to a new protein.

And while everyone in the field is excited to see the long-sought clinical milestone, veteran KRAS researchers also are cautious to set expectations for the impact of the drugs and the road ahead.

“This is the start of a journey,” says Frank McCormick, a professor at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center and a central figure in the RAS field, which inclues KRAS and its family members HRAS and NRAS. “People may be disappointed initially by the relapse rates, but combination therapy, better dosing, and an understanding of these drugs will push out their benefits significantly.” Getting to that point could take years, McCormick cautions, but “over time, RAS inhibitors will definitely have a place—and will provide major clinical benefit.”

And even if this first wave of drugs targeting KRAS G12C is effective, that still leaves a large swath of cancers driven by other KRAS mutations—around 85% of them, points out Darryl McConnell, research head for Boehringer Ingelheim’s site in Vienna, who is leading an effort to drug KRAS. “I’ve got this pie chart in my head starting with G12D and V and C, but also G13D, G12R/A, and Q61H—we need to drug all of those,” McConnell says. “There’s still a massive amount of work before we are finished with KRAS.”

Two years ago, Timothy Yu was not a seasoned drug developer. The Boston Children’s Hospital geneticist planned on devoting his career to diagnosing genetic diseases, not treating them.

That all changed with a young girl named Mila Makovec.

Yu’s team pinpointed the root cause of Mila’s neurological condition: a genetic mutation that no one had ever seen before. Yu then realized that an antisense oligonucleotide—a short stretch of synthetic DNA—could potentially cover up the offending mutation and treat her disease.

What followed was an unprecedented sprint to design, test, and manufacture a custom drug that was ultimately approved for injection into Mila—all in the span of 10 months. It’s what the field is calling an N-of-1 therapy, and it shattered records for speed and personalization in drug development.

“Tim Yu showed that someone who has never done an antisense oligonucleotide experiment in their life can rapidly develop a customized drug and treat a patient,” says Arthur Krieg, chief scientific officer of the oligonucleotide company Checkmate Pharmaceuticals. “That’s the huge breakthrough that the field has been waiting for. It’s like the first time someone ran a 4-minute mile,” he adds.

And this breakthrough won’t be the last.

Indeed, Yu is spearheading several more N-of-1 oligonucleotide treatments for rare neurological diseases, including two that may be ready for injection this year or early next. “We’ve been contacted by hundreds of families,” Yu says. He can’t help them all, but his work is invigorating several others to pursue N-of-1 therapies.

For instance, this summer, Columbia University physician Neil Shneider began giving an N-of-1 oligonucleotide to Jaci Hermstad, a woman with a rare form of amyotrophic lateral sclerosis. Although it wasn’t designed just for her—it could help other people with the same mutation—the US Food and Drug Administration approved its use just for Hermstad.

Rohan Seth, an engineer in San Francisco, founded the Lydian Accelerator to develop a custom oligonucleotide for his daughter, Lydia, who was born with a rare genetic form of epilepsy. Seth hopes to create a blueprint based on his experience that other families trying to make N-of-1 therapies can use.

And Rich Horgan, a recent graduate of Harvard Business School, founded a nonprofit called Cure Rare Disease to develop customized CRISPR gene-editing therapies for his younger brother, Terry, and other people with rare forms of muscular dystrophy that oligonucleotides can’t help.

“That so many parents and families are deciding to go it alone shows that the system isn’t working for everybody,” Yu says. “It clearly speaks to this huge, pent-up, unmet need.”

At its annual meeting in October, the Oligonucleotide Therapeutics Society formed a task force to create guidelines for N-of-1 projects. A small number of universities and medical centers are laying foundations for their own N-of-1 oligonucleotide programs. And at least one biotech start-up is quietly working on a business plan to provide the full gamut of services, from genetic diagnosis to N-of-1 drug design.

Many economic, ethical, and regulatory hurdles remain, but Yu showed that N-of-1 drug development is possible. “It is the start of something that will become much more common,” Krieg says. “And the question in my mind isn’t whether there will be tens or hundreds more, but how long will it take us until there are thousands and tens of thousands of Milas?”

CRISPR gene editing has barely graced the clinic. This year, it was tested in a handful of humans in clinical trials for cancer, HIV, and sickle cell disease. And although drug companies have only just begun to offer the first evidence that CRISPR works in humans, scientists are still racing to discover and design new versions.

The classic form of the gene editor that debuted in 2012, CRISPR-Cas9, is like a pair of molecular scissors. It cuts DNA to turn genes on or off. Tools called base editors, which were published in 2016 and 2017 and are often compared to pencils, can change a single nucleotide—or letter—of DNA into another. Although base editors have been hailed as CRISPR 2.0, they can make only 4 of the 12 possible letter-to-letter changes.

Now we have a new system known as prime editing. It can make all 12 letter-to-letter changes, as well as add or remove short stretches of DNA. Call it CRISPR 3.0.

Prime editing was just the latest in a series of gene-editing innovations published this year. In February, Jennifer Doudna’s lab at the University of California, Berkeley, published a detailed study on a genetically and structurally distinct CRISPR enzyme called CasX, which makes staggered breaks during its cutting of the DNA double helix. That could provide an extra foothold for inserting new DNA sequences into the genome. A start-up, Scribe Therapeutics, is engineering improved versions of CasX for gene editing.

This summer, two labs—one led by Samuel Sternberg at Columbia University and another led by Feng Zhang at Broad Institute of MIT and Harvard—separately described how bacteria use Cas proteins to precisely insert a mobile segment of a DNA called a transposon. They also showed that they could hijack the system to insert a new strand of DNA into a programmable location. Both groups have filed patents on their systems, although they’ve been tested only in bacteria so far.

Then, in October, Broad Institute scientist David Liu, whose lab also invented base editors, debuted his prime editors. The tools are a molecular mash-up of a modified Cas9 protein and a reverse transcriptase enzyme. Cas9 looks to one arm of a guide-RNA molecule to determine where to go in the genome, and the reverse transcriptase reads another arm of the guide RNA to determine what change to make—whether that is swapping one letter for another or adding or removing DNA.

Liu compares prime editors to a search-and-replace function on a computer. And before he even published the paper, he formed a new company, Prime Medicine, to commercialize the technology. Prime has already licensed prime editors to Beam Therapeutics, a company that Liu cofounded to develop medicines with base editors.

And beyond gene editing, several start-ups—Korro Bio, Navega Therapeutics, and Shape Therapeutics—launched this year to develop therapies that edit RNA, the short-lived cousin to DNA. The approach provides a new strategy for treating conditions like chronic pain and inflammation, and it alleviates some concerns about the long-term safety of editing DNA.

New tools yield new intellectual property, which can form the basis of new gene-editing start-ups. But more broadly, tools such as prime editing give biologists yet another way to edit genomes and bring them one step closer to changing DNA in any way they please.

After a bumper crop of 59 new drug approvals in 2018, 2019 looked to be a reset year for the US Food and Drug Administration. As of Nov. 25, 41 new therapies had found their way to the market, some offering first-in-class treatment and others launching into an already-competitive landscape.

While 2019 is shaping up to be a more average year for the number of approvals, the small-molecule drugs and biologics that have been approved so far tackle several underserved diseases and add to patient options for others, says Bernard Munos, senior fellow at the think tank FasterCures. About 25% of the drugs are intended to treat neurological disorders, including Parkinson’s disease and spinal muscular atrophy. And another 25%, including an antibody-drug conjugate, treat various cancers.

The breadth of diseases treated and the types of drugs approved signify the FDA’s commitment to innovation, Munos says. “FDA has worked very hard to become a partner in innovation, to really push companies, to encourage companies to be bolder,” he says.

Here are some of the standout approvals of 2019:

Pretomanid

TB Alliance

Pretomanid

Pretomanid was approved in August as part of a combination treatment to combat tuberculosis, which according to the nonprofit TB Alliance is now the deadliest infectious disease in the world. The nitroimidazole antibacterial, developed by the nonprofit, is used with two existing TB treatments. It’s the second drug approved as part of a special program within the 21st Century Cures Act devoted to new treatments for infectious diseases.

Trikafta

Vertex Pharmaceuticals

Ivacaftor

Tezacaftor

Elexacaftor

Trikafta

Trikafta is a triple therapy for cystic fibrosis (CF), a rare genetic disease in which a misfolded ion transporter can’t get to the surface of lung cells, leading to mucus buildup in the lungs. Two of the three drugs in Trikafta, elexacaftor and tezacaftor, help chaperone the ion transporter to the cell surface, and the remaining drug, ivacaftor, helps keep the ion channel open longer than normal. The therapy, approved in October, is expected to help up to 90% of people with CF.

Zolgensma

Novartis

Zolgensma is a gene therapy approved in May for treating spinal muscular atrophy (SMA), a neurodegenerative disease caused by mutations in a gene called survival motor neuron 1 (SMN1). The onetime injection of a virus carrying a normal version of the gene was widely anticipated by families affected by SMA, but Zolgensma has also been mired in controversy over preclinical data manipulation as well as its price—more than $2 million for the single dose.

Zulresso

Sage Therapeutics

Brexanolone

Zulresso, approved in March, is the first drug to be cleared by the FDA specifically to treat postpartum depression, which affects one in nine women who give birth in the US. The active ingredient, brexanolone, works on GABA receptors in the brain. Zulresso is administered intravenously, and because it comes with a risk of losing consciousness, a new mom has to be monitored during the infusion, which takes about 2.5 days.

CORRECTION
The story on new drug approvals was updated on Dec. 4, 2019, to clarify that Zulresso is administered in a hospital because it can cause loss of consciousness, not because it is administered intravenously.