MK-0616: The 2023 Molecule of the Year
We asked the global drug discovery community to nominate and vote on their favorite molecule from 2023, and the results are in! The 2023 winner, with the most votes between ten molecules, is Merck’s oral macrocyclic peptide inhibitor of PCSK9, MK-0616, derived from mRNA display technology and shown to have clinical efficacy. Herein, we highlight what makes MK-0616 so impressive to the drug discovery community.
The First Oral PCSK9 Inhibitor and First mRNA Display-Derived Macrocyclic Peptide to Demonstrate Clinical Efficacy
Merck’s macrocyclic PCSK9 protein–protein interaction (PPI) inhibitor, MK-0616, is a once-daily LDL-cholesterol-lowering “small” molecule that has demonstrated antibody-like efficacy as an oral agent in the clinic. The program highlights numerous technical achievements at the forefront of modern drug discovery, from mRNA display screening to the use of lipidic permeation enhancer formulations, and will set a standard for modern “classics in drug discovery” for some time. The sheer ingenuity and impact of this molecule is best encapsulated in the reflections of Dr. Christie Ballantyne, first author of the Ph. II clinical trial, who stated, “I was told early on that developing an oral PCSK9 inhibitor is impossible. But the technology keeps advancing. It’s very exciting to see the tremendous advances in understanding the pathways and finding ways to make a challenging target like PCSK9 treatable with a once-daily pill.”
Notably, the discovery of MK-0616 was enabled by mRNA display technology that was invented in 1997 by Richard Roberts and Jack Szostak to identify cyclic peptide starting points. To execute the screen, Merck collaborated with Ra Pharmaceuticals, a Cambridge biotech specializing in peptide chemistry that was co-founded by its SAB Chair, Szostak. While limited details are available on the screen itself, the approach is likely similar to the puromycin-based ExtremeDiversity™ approach used by Ra Pharmaceuticals in the discovery of zilucoplan. Subsequent lead optimization efforts were accelerated by key institutional strengths in structure-based drug design and innovative medicinal chemistry efforts.
In a Ph. II trial, MK-0616 reduced LDL-C levels by 61% from baseline with a low oral dose of 30 mg QD, a reduction comparable to evolocumab, alirocumab, and inclisiran (NCT05261126). In humans, the targeted 80% reduction of free PCSK9 for 12 h was achieved at a 10 mg oral dose, with an estimated human bioavailability of 2%, and a half-life of 35–43 h at 10–35 mg (PO). Virtually complete efficacy was achieved by week 2, with the response being maintained throughout the 8-week dosing period, and with no serious adverse events reported. Ph. III trials have been initiated to evaluate the efficacy and safety of MK-0616 in adults with hypercholesterolemia (NCT05952856), and in reducing major adverse cardiovascular events in participants at high cardiovascular risk (NCT06008756). In all, MK-0616 is strongly positioned to become the first approved oral PCSK9 inhibitor.
This drug discovery campaign, leading to the first PCSK9-targeting small molecule to demonstrate clinical efficacy in humans, is a tour de force from Merck, highlighting not only technical sophistication but also the organizational commitment and project championship needed from drug hunters. At every stage of this drug discovery project, one can imagine all the ways the project could have broken down based on the investment needed by multiple groups to advance – from the application of mRNA display technology with external partnership to the “optimization for the impossible” medicinal chemistry, to the heroic synthetic chemistry needed to enable clinical supply, to the clinical use of lipidic permeation enhancers, to the commercial decision to advance an oral PCSK9 molecule. A lack of buy-in from any department – from chemistry to pharmacology, clinical development to commercial – would have stalled or killed this program. Reaching clinical proof-of-concept with an oral, cell-impermeable, bRo5 macrocyclic peptide PCSK9 protein-protein interaction inhibitor continues to bolster Merck’s reputation for scientific leadership and organizational excellence.
Given these remarkable achievements, against nearly impossible odds, it is no wonder that the drug discovery community has recognized Merck’s MK-0616 as the 2023 Molecule of the Year. Congratulations to all of the drug hunters involved!
The Votes and Runners-Up
#1: MK-0616 (Merck, Rahway, NJ — 25%)
Out of ten contenders, MK-0616 garnered a quarter of all votes and stands out even with an impressive cohort of competitive nominees for 2023!
#2: RMC-6291 (Revolution Medicines, Redwood City, CA — 21%)
The runner-up is RMC-6291, a molecular glue that uses a novel tri-complex mechanism to selectively target the active, GTP-bound signaling, or “ON” state of KRAS G12C. While an increasing number of follow-on KRAS inhibitors are emerging with similar mechanisms of action to sotorasib and adagrasib, Revolution Medicines’ natural product-derived G12C inhibitor is representative of a completely novel approach that could become a strong addition to the clinical toolbox for KRAS, but also serves as proof-of-concept for a new class of small molecule therapeutics entirely. RMC-6291 is currently being evaluated in a Ph. I/Ib dose escalation and expansion trial in patients with advanced KRAS G12C-expressing solid tumors (NCT05462717) and preliminary data suggests it exhibits clinically meaningful activity and is generally well-tolerated.
#3: VX-548 (Vertex, San Diego, CA — 19%)
In 3rd place is Vertex’s VX-548, a potential first-in-class, exquisitely selective, oral NaV1.8 inhibitor that recently captured headlines for its positive Ph. III data (NCT05558410, NCT05553366, NCT05661734) in moderate-to-severe acute pain treatment and positive Ph. II data in pain from diabetic peripheral neuropathy (DPN) (NCT05660538). The FDA has granted VX-548 Breakthrough Therapy and Fast Track designations, and based on the promising clinical results, Vertex has decided to file an NDA by mid-2024 for the treatment of moderate-to-severe acute pain.
#4: KT-474 (Kymera Therapeutics, Watertown, MA / Sanofi, NJ — 15%)
In 4th place is Kymera’s KT-474, a CRBN-based IRAK4 degrader with promising clinical activity in moderate to severe atopic dermatitis (AD) or hidradenitis suppurativa (HS) patients. Notably, Kymera’s partner, Sanofi, initiated a Ph. II study of KT-474 in HS (NCT06028230) and has also started a Ph. II trial in AD (NCT06058156). KT-474 is a remarkable example of an orally bioavailable molecule in the bRo5 space and is the first oral degrader to demonstrate activity in clinical trials for the treatment of a non-oncology indication.
#5: lirafugratinib (RLY-4008) (Relay Therapeutics, MA / D. E. Shaw Research, NY — 6%)
In 5th place is lirafugratinib (RLY-4008), the first isoform-selective FGFR2 inhibitor with kinetic selectivity rationalized by molecular dynamics from Relay Therapeutics and their collaborators at D. E. Shaw Research. In early reports from the ongoing first-in-human ReFocus Ph. I/II study, data confirms the high isoform-selectivity observed preclinically, with encouraging efficacy and broad mutational coverage, setting it up as a potential best-in-class FGFR2 inhibitor with a significant likelihood of reaching approval for intrahepatic cholangiocarcinoma.
Why MK-0616 is Interesting to Drug Hunters
We asked the drug discovery community what they found most impressive and scientifically notable about MK-0616 and here’s some of what was said:
“MK-0616 expands the limits of what seems possible for a PPI inhibitor. Tour de force!” Tim Clackson, President and CEO at IDRx
“Synthetic complexity was required to solve a specific problem!” Matt Lucas, VP of Chemistry at Third Harmonic Bio
“Orally bioavailable macrocyclic peptide targeting a therapeutically important target.” Rick Ewing, VP, Head of Chemistry at Rapafusyn
“Its properties are way beyond the rule of 5, but it’s so potent that even with such a small %F, the dose required is still reasonably small. It flies in the face of a lot of rules that drug hunters have stuck to for decades.” Cameron Hanna, Principal Scientist at Unnatural Products
“Impressive and unusual entropy-driven design strategies and smart use of formulation to obtain oral bioavailability for such a molecule that is arguably stretching the BRO5 space.” Anh Tran, Principal Scientist at Amgen
“Oral delivery of what is ultimately a large peptide!” Klemens Hoegenauer, Associate Director at Novartis
“It is a truly innovative molecule which has proved the potential of macrocyclic peptide as an oral drug as well as the prospective capability of mRNA display in drug discovery.” Seong Heon Kim, SEVP, Head of Drug Discovery at Hyundai Pharm
“I'm always impressed by orally active "large" molecules.” Clint James, Director at Paraza Pharma
“The WHOLE story of MK-0616 is just insane!” Anonymous
“First proof-of-concept for the discovery technique and exceptional molecule.” Anonymous
“The tour de force effort is amazing!” Joel Walker, Principal Scientist at Amgen
“Great example of an oral macrocyclic peptide!” Xavier Fradera, Senior Principal Scientist at Blueprint
“The size and complexity of the molecule, as well as the ability to achieve oral bioavailability and efficacy with such a large molecule.” Anonymous
“It's the proof-of-concept for mRNA display to produce compelling clinical candidates and highlights the growing prominence of peptides as therapeutics.” Dorothy Wai, Postdoctoral Research Fellow at Monash University
“The first example of a new modality to address protein–protein interactions.” Stefania Colarusso, Principal Research Investigator at IRBM
We’ll be covering more on the science behind the discovery, development, and impact of MK-0616 as more details about this fascinating molecule emerge. Sign up for our newsletter so you don’t miss the next part when it releases!
