Today, I offer a third prediction—this one in the realm of drug development: RNA-based therapies will shine as never before.
If 2017 was the year of DNA—a time of gene therapy breakthroughs and of the continued refinement of the gene editing tool CRISPR—then 2018, I foretell, will be the year of DNA’s kissing cousin: RNA, or ribonucleic acid.
Molecular biology’s famous “Central Dogma” states that DNA, the living computer code that makes up our genes, is first transcribed into RNA, which is then translated into specific proteins, which ultimately do the 24/7 work of the body and form its many structures. (There are some exceptions to the rule, as certain tumor viruses demonstrate—see the sad, heroic tale of Nobel laureate Howard Martin Temin, who had the effrontery to challenge said dogma.) But while single-stranded RNA has never shared top billing on the biological marquee with its elegant, gyring, double-stranded relative, it just might hold the answer to some remarkable cures. That’s because, in theory, thanks to that single wisp of intermediate code, the genes implicated in many diseases should be easier to quiet.
One way to shut down the communication link is through a snippet of RNA called “antisense”—which binds to the messenger RNA (a “sense”-making strip of nucleic acids) that is transcribed by a given stretch of DNA. In short, when antisense RNA matches up with and binds to messenger RNA (mRNA), or to a precursor strand called pre-mRNA, it stops the latter from conveying the instructions for making proteins. (There’s also a separate, related, strategy called RNA interference, or RNAi, which typically relies on one of two types of tiny RNA molecules—either small (or short) interfering RNA or microRNA—to silence genes. The journal Nature Reviews Genetics has a terrific animated video explainer here.)
The notion that antisense oligonucleotides might inhibit the progression of genetic diseases or tumor-causing viruses dates back to the late 1970s, when legendary molecular biologist Paul Zamecnik and colleague Mary Stephenson demonstrated the method’s viability against the Rous sarcoma virus. And it’s been one of those ideas that has excited—and taunted—researchers and drug developers ever since: one that, at the same time, is brilliantly intuitive and agonizingly hard to make work.
Though hailed as “a new therapeutic principle” in 1990, it nonetheless took another eight years for the FDA to approve the first antisense drug, fomivirsen—for the treatment of AIDS-related retinitis caused by human cytomegalovirus. The next antisense agent to earn approval didn’t get that nod until a decade and a half later, in 2013. That was for mipomersen, a medicine used to treat familial hypercholesterolemia, a hereditary condition that causes massive increases in LDL cholesterol. The hope was that antisense oligos for everything from cancer to HIV would roll off the pharmaceutical assembly line—but despite a generation of valiant effort, the successes on this front have been meager.
Now, it looks like the tide may at last be turning. In recent months, there have been promising results in RNA-targeting drugs for some rare neurological disorders.
And the reports from one early (Phase 1/2a) clinical trial of an antisense oligonucleotide called IONIS-HTTRx, made by California biotech Ionis Pharmaceuticals, suggest that this approach might one day stop Huntington’s disease—a cruel, progressive, and ultimately fatal neurodegenerative disorder. Huntington’s is caused by an inherited mutation in a gene called HTT, which encodes for a toxic protein that destroys brain neurons—damage that, over time, can severely limit a person’s ability to walk, talk, swallow, or even think clearly. As with functional genes, the aberrant Huntington’s gene sends its protein-coding instructions by way of a messenger: RNA. And in the recent randomized study—which was designed to assess the safety and tolerability of various doses in volunteers from Canada, Germany, and the UK—IONIS-HTTRx appeared to substantially block the gene’s pernicious message from getting through. The experimental drug, according to reports, sharply reduced the cell-killing protein in the subjects’ nervous systems and apparently had no major side effects. (The results have yet to be published.)
The gene-silencing strategy, in the form of RNA interference, has also showed promise against an uncommon neurodegenerative disease called hereditary ATTR amyloidosis, as Sy wrote about in Fortune’s year-end Investor’s Guide. Alnylam Pharmaceuticals, based in Cambridge, Mass., has so far spent 15 years developing patisiran, an investigational RNAi drug for hATTR—and this past November, at a scientific meeting in Europe, the company presented Phase 3 trial results that appeared to blow the research community away. The FDA, for its part, seems excited, too; shortly after the study presentation, it granted patisiran “Breakthrough Therapy Designation” status—a promise that the agency will expedite its review of the drug if and when it’s submitted for approval.
Human biology, of course, has a way of teasing and fooling those who try to solve its mysteries—so the latest upbeat findings may be yet another false harbinger of success. Nonetheless, I’d bet on this trend in 2018 and beyond. It just makes good antisense.
|Clifton Leaf, Editor in Chief, FORTUNE|
Digital health upstart Quartet raises $40 million. There is a somewhat inexplicable disconnect between how people—and the medical system itself—approach physical versus mental health, sometimes siloing two facets of the human body which are actually inextricably linked. Coordination across these sphere in health care can be difficult; but startup Quartet is trying to change that with a tech-savvy platform to connect these different kinds of medical professionals for patient care. The firm announced Thursday that it’s raised another $40 million in a Series C funding round, bringing its total haul to $87 million. It’s also added some heavy hitters like F-Prime Capital executive partner Carl Byers and Anthem vet Ken Goulet. “Making collaboration between primary care physicians and behavioral health specialists work is a must if we are ever going to improve the overall health of our country,” said Quartet founder and CEO Arun Gupta in a statement. “The bridge between mental and physical health is being built with technology leading the charge.”
StartUp Health raises $19.3 million. Speaking health startups—StartUp Health, which is investing in a slew of new medical tech, digital health, and other upstart health care firms across a bevy of medical “moon shots,” has raised $19.3 million in a funding round led by Ping An Global Voyager Fund, GuideWell, Masimo Corporation, and joined by others. “StartUp Health has created a health moonshot factory which brings us early access to the innovators transforming health on a global level. Together, we will be able to speed up innovation cycles and make a significant impact on people’s lives,” said Ping An Chief Innovation Officer Jonathan Larsen in a statement.
Allergan to cut jobs. Botox maker Allergan is sharpening the ax to lop off more than 1,000 jobs in a restructuring meant to save the firm $300 million to $400 million this year. Allergan shares have tumbled more than 21% in the past 12 months and the company is bracing for more competition from generic drugs. (CNBC)
Sanofi’s dengue vaccine woes in the Philippines persist. The Philippines has hit the pause button on a widespread vaccination program using French pharma giant Sanofi’s pioneering dengue vaccine Dengvaxia, and fined the company a small but symbolic $2,000 for the problems that have propped in the program so far. The company recently said that the vaccine can actually make dengue worse in certain people who have never been infected before, and has said it will cooperate with Philippines authorities. (Reuters)
THE BIG PICTURE
Philip Morris says the future is smokeless. Is it serious? Tobacco giant Philip Morris has made its name and fortune by being one of the dominant players in the tobacco product and cigarette market. Now, the company is saying its long-term goal is a “smoke-free” future and to stop selling cigarettes altogether. That’s a major shift for the company and underscores its ambitions to move into vaping products that heat, rather than burn, tobacco. But anti-smoking advocates remain skeptical, asking why Philip Morris won’t support public health initiatives endorsed by experts, such as higher tobacco taxes and graphic warnings on cigarette packaging. (USA Today)
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The China Trade War Has Already Begun, by Alan Murray
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|Produced by Sy Mukherjee|