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PETRI DISH PERSPECTIVES

Episode 23: Alnylam

October 02, 2025 • Manead Khin • Season 1 • Episode 23

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What if you could silence disease at its genetic root? That was the bold promise behind RNA interference (RNAi), one of the most groundbreaking scientific discoveries of the 21st century.

In this episode, we dive into the story of Alnylam Pharmaceuticals, from its founding by a powerhouse team of Nobel laureates, pioneering scientists, and biotech visionaries, to its transformation into the world’s first RNAi therapeutics company. We explore the challenges of turning a fragile lab discovery into medicine, the blockbuster drugs that redefined rare disease treatment, and the people who made it all possible.

Whether you’re a biotech enthusiast, a student of innovation, or just curious about how cutting-edge science becomes lifesaving therapy, this episode will take you inside the revolution that gave rise to RNAi medicines.

🎧 Listen now, stay curious, and don’t forget to subscribe for new episodes every Thursday!

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Intro

Hello and welcome to Petri Dish Perspectives: Biotech Unleashed, the podcast where we geek out about science and the companies shaping the future of healthcare. I’m your host, Manead, and I’m a PhD scientist by training, biotech storyteller by choice. With every new episode released on Thursday, my goal is to deliver digestible pieces of information on healthcare companies under 30 mins.

Today we’re diving into the story of Alnylam Pharmaceuticals, a company that took a Nobel Prize–winning discovery and built an entirely new class of medicines around it.

Why listen to this episode? If you’ve ever wondered how a biotech can survive two decades of skepticism, massive cash burn, and clinical failures before finally breaking through with billion-dollar products this is the episode for you. Pay special attention to the science of RNA interference, or RNAi, and how Alnylam turned what many thought was just a laboratory curiosity into life-saving drugs.

Quick disclaimer, I give full credit to the original articles cited in the references in the transcript!

Grab a coffee or tea, settle in, and let’s jump in!

Segment 1: Founding Story & The RNAi Revolution

The story of Alnylam starts not with a business plan, but with a spark of science.

In the late 1990s, two scientists Andrew Fire and Craig Mello were studying worms, C. elegans, of all things. In 1998, they published a paper showing that short double-stranded RNAs could silence genes in a sequence-specific way. This process, which they called RNA interference, or RNAi, was unlike anything researchers had seen before. It was precise, potent, and universal across species. The discovery was so powerful that by 2006, Fire and Mello were awarded the Nobel Prize in Physiology or Medicine.

Suddenly, labs everywhere were asking: if we can “turn off” any gene at will, could this become a new way to make medicines?

In 2002, a group of visionaries decided to try. They founded Alnylam Pharmaceuticals in Cambridge, Massachusetts. The founders were a mix of Nobel-caliber academics and seasoned biotech entrepreneurs:

Let’s start with Phillip Sharp, the intellectual heavyweight of the group. Sharp was already a legend by the time Alnylam came into existence. An MIT professor, Sharp had earned the Nobel Prize in Physiology or Medicine in 1993 for discovering RNA splicing. Basically, that our genes are cut up and re-stitched like film reels before they’re turned into proteins. This revelation transformed molecular biology and gave Sharp unparalleled credibility in the world of RNA science. When the RNA interference (RNAi) breakthrough surfaced in 1998, Sharp immediately grasped its potential. He wasn’t just a great scientist; he was also a believer in turning discovery into medicine, having co-founded Biogen years earlier. His role at Alnylam was to provide not just scientific gravitas, but also the credibility needed to attract investors and talent.
Then there was Paul Schimmel, another MIT professor and one of the great pioneers of RNA biology. Schimmel’s claim to fame was decoding the role of aminoacyl-tRNA synthetases, enzymes that are essential in translating the genetic code into proteins. While this may sound esoteric, it’s actually one of the most fundamental processes of life. Schimmel had co-founded multiple biotech companies before Alnylam, including Cubist Pharmaceuticals. He had the rare combination of deep scientific chops and entrepreneurial instincts. Schimmel brought with him a reputation as someone who could bridge academia and industry, a key ingredient for a company trying to commercialize an unproven technology like RNAi.
Next is David Bartel, a quieter but equally essential presence. A professor at the Whitehead Institute at MIT, Bartel had been at the cutting edge of RNA interference research almost from the start. His lab was one of the first to show how small RNAs/microRNAs could regulate gene expression in plants and animals. Bartel represented the young, rising generation of RNA scientists. At Alnylam, his knowledge of the biology gave the company an intellectual edge and helped guide its earliest decisions on which targets and diseases might be approachable with RNAi.
And finally, John Maraganore, who became the driving force as Alnylam’s founding CEO. Maraganore wasn’t just another scientist, he was a scientist turned dealmaker. With a PhD in biochemistry and molecular biology, he had worked at companies like Biogen, Millennium, and Millennium’s spinouts, where he learned the art of biotech business. By the early 2000s, he had both scientific credibility and boardroom savvy. When he took the reins at Alnylam, his mission was to transform a promising but fragile idea, RNAi therapeutics into a viable business. Over the next two decades, Maraganore would become the face of Alnylam, steering it through financial hurdles, scientific setbacks, and, eventually, to historic drug approvals.

The early idea was simple but revolutionary: take this elegant, natural gene-silencing mechanism and turn it into drugs. But there was a catch: RNAi was fragile, unstable, and easily degraded in the body. Delivering RNA into human cells without causing chaos seemed like science fiction. Yet, the founders believed that if they could solve this one problem, they’d open the door to an entirely new class of therapeutics.

It was a moonshot, and they knew it. But Cambridge was the right place for moonshots.

Segment 2: The Science of RNAi

So how does RNAi actually work?

Inside our cells, genes are expressed through messenger RNA, the “middle step” between DNA and proteins. Messenger RNA, or mRNA, tells the cell which proteins to make, like an instruction sheet.

RNA interference hijacks this process. When short double-stranded RNAs, called siRNAs, are introduced into the cell, the cell’s natural machinery loads them into a protein complex known as RISC, the RNA-induced silencing complex. RISC then uses the siRNA as a guide, seeking out any matching messenger RNA and slicing it up. Without its messenger, the protein can’t be made.

This is gene silencing at the post-transcriptional level before the protein even exists. Unlike drugs that block proteins after they’re made, or antibodies that target proteins outside the cell, RNAi stops the problem at the root.

It’s elegant. It’s programmable. In theory, you could design an siRNA for any gene whether it’s a rogue protein in cancer, an enzyme driving a rare disease, or even a viral genome. That universality made scientists dream of RNAi as a “platform” for dozens, even hundreds, of new medicines.

But the challenge was enormous. Naked RNA injected into the bloodstream is destroyed almost instantly by enzymes. Worse, early attempts often triggered dangerous immune responses. RNAi looked beautiful in a petri dish but in people? That was another matter.

Alnylam’s entire first decade was about answering that question: how do you safely deliver siRNA into human tissues? That was the key to turning Nobel Prize science into a therapy.

Segment 3: Struggles, Breakthroughs & the IPO

From the start, Alnylam leaned on partnerships to survive. Merck, Roche, and Novartis all poured hundreds of millions into alliances, hoping to get early access to RNAi therapies. For a time, RNAi was the hottest thing in biotech.

But then reality hit. By the late 2000s, delivery problems remained unsolved. Several big pharma partners, including Roche and Novartis, walked away. Investors began to wonder if RNAi was destined to remain a lab tool rather than a medicine. Reporters labeled Alnylam a cash-burning machine with lots of promises but no products.

Yet Alnylam held on. In 2004, it had gone public, raising about $35 million in one of the early biotech IPOs of that era. Alnylam Pharmaceuticals' IPO price was $6.00 per share on May 27, 2004. The IPO itself was gutsy; Alnylam had no clinical-stage products, just the promise of a platform. Investors were essentially betting on an idea. For years afterward, the stock swung between euphoria and despair, sometimes doubling on good preclinical news, sometimes crashing when partnerships dissolved.

John Maraganore became the company’s chief storyteller. He believed and convinced others to believe that RNAi would eventually deliver. He kept raising money, recruiting talent, and pushing the science forward, even as the valley of death grew deeper.

The turning point came around 2010–2012, when Alnylam’s scientists made key advances in delivery technology. They discovered that attaching siRNAs to GalNAc sugars, which bind to receptors on liver cells, allowed for precise and efficient targeting of the liver, an organ central to many genetic diseases. For the first time, RNAi could reliably reach human cells in vivo.

With that, clinical trials began to show real promise. The disease they chose first was hereditary transthyretin amyloidosis, or hATTR, a rare, devastating condition caused by misfolded proteins that damage nerves and the heart. In 2012, the first patient data came back: RNAi was lowering disease-causing proteins in the blood. Suddenly, after a decade of doubt, the dream was alive again.

Segment 4: Blockbuster Drugs & Breakthroughs

Alnylam’s first major triumph was Onpattro (patisiran), approved in 2018. It was the first-ever RNAi therapeutic. For patients with hATTR amyloidosis, who previously had no effective treatments, Onpattro was life-changing. Delivered via lipid nanoparticles, it silenced the transthyretin gene and slowed or reversed disease progression. For the biotech world, it was a milestone: proof that RNAi could become real medicine.

But Alnylam didn’t stop there. In 2019, the company scored again with Givlaari (givosiran), for acute hepatic porphyria. This ultra-rare disease causes debilitating pain attacks and carries high mortality. Givlaari worked by silencing a liver enzyme that drives toxic metabolite buildup. Patients who once lived in fear of unpredictable attacks finally had hope.

Next came Oxlumo (lumasiran) in 2020, for primary hyperoxaluria type 1 a genetic disease that causes dangerous kidney stones and renal failure. By shutting down a key enzyme in oxalate production, Oxlumo directly attacked the cause of the disease, not just the symptoms.

And in 2022, Alnylam launched Amvuttra (vutrisiran), a next-generation therapy for hATTR. Unlike Onpattro, which requires IV infusions, Amvuttra is injected under the skin just once every three months. The convenience factor massively expanded the market and solidified Alnylam’s leadership in RNAi for amyloidosis.

These weren’t just rare-disease wins. Collectively, they proved a platform could generate multiple first-in-class drugs, across different diseases, all built on the same RNAi backbone. For investors, it validated two decades of patience. For patients, it offered therapies where none had existed. And for science, it cemented RNAi as a new therapeutic pillar.

Regeneron and Alnylam have two major collaborations: a partnership initiated in March 2018 to find RNAi therapeutics for nonalcoholic steatohepatitis (NASH) (a liver disease) and a larger, "blockbuster" collaboration announced in April 2019 to develop RNAi drugs for eye and central nervous system (CNS) diseases. The 2019 deal included a significant upfront payment and equity investment from Regeneron, and it leverages Alnylam's RNAi technology along with Regeneron's genetics and discovery expertise.

Segment 5: People Who Made Their Mark

If one name defines Alnylam, it’s John Maraganore, the company’s founding CEO. A PhD scientist turned biotech executive, Maraganore steered Alnylam from its earliest days through nearly two decades of turbulence. His relentless advocacy for RNAi, ability to raise billions in capital, and talent for building partnerships were critical.

Maraganore became known as one of biotech’s great storytellers selling a vision long before the data caught up. Without his persistence, it’s unlikely Alnylam would have survived to see RNAi reach the clinic. When he stepped down in 2021, it marked the end of an era, but his legacy remains baked into the DNA of the company.

Segment 6: Lessons from Alnylam

What lessons can we draw from Alnylam’s journey?

First, stick with the science. RNAi was messy, complicated, and doubted for years, but the company’s long-term commitment paid off.

Second, delivery is everything. Biology breakthroughs only matter if you can deliver them safely to patients. Alnylam’s innovations in delivery unlocked the whole field.

And third, vision attracts capital. Even when the science was unproven, Alnylam’s bold pitch attracted investors and partners. Without that, survival would’ve been impossible.

Segment 7: What’s Next for Alnylam?

Looking ahead, Alnylam is expanding beyond rare diseases. The company is testing RNAi therapies for common conditions like hypertension and high cholesterol. One of its most closely watched programs is inclisiran, a cholesterol-lowering siRNA partnered with Novartis, which could reach millions of patients worldwide.

They’re also exploring CNS delivery, gene editing synergies, and even RNAi combinations with other therapeutic modalities. The vision is no longer just to prove RNAi works, it's to make it a mainstream, widely used therapeutic platform.

For Alnylam, the next chapter is about scale. Can they move from rare, ultra-orphan diseases to common global conditions? If they succeed, RNAi could stand alongside small molecules, biologics, and cell/gene therapies as a foundational pillar of modern medicine.

By the time the episode was recorded, Alnylam’s stock price sits at $457.91, a whopping 76x jump from an initial IPO share price in 2004. And, their market cap is close to $60B. According to Glassdoor, an Alnylam PhD salary varies by role, but typical base salaries for scientific positions with a PhD can range from approximately $120,000 to over $150,000 annually for Scientist and Principal Scientist roles. Alnylam Pharmaceuticals is headquartered at 675 West Kendall Street in Cambridge, Massachusetts, serving as the company's global hub for strategic and administrative functions. The company also maintains a manufacturing facility in Norton, Massachusetts, along with numerous other offices in North America, Europe, and Asia.

Closing

Alnylam’s story is a case study in persistence, vision, and scientific conviction. From the Nobel Prize discovery of RNA interference to the first patient treated with Onpattro, the company spent nearly 20 years chasing what many thought was impossible.

Today, Alnylam is proof that sometimes the boldest scientific bets, the ones that seem most impractical in the beginning, can change the future of medicine.

References

Manead Khin

Host