The front runners in the game of drug delivery include small-molecule and large-molecule drugs, but there is another class that lands right in between peptides.

Several companies, including Rhythm Pharmaceuticals (Boston, MA), Kalos Therapeutics (San Diego, CA), Aileron Therapeutics (Cambridge, MA), and Bicycle Therapeutics (Cambridge, MA) have emerged as prominent players in the peptide arena.

Let’s review the differences between the drug classes and explain where peptides fit into the picture. Then we’ll take a spectator’s interest in the companies and products leading the charge in peptide therapeutics.

Small molecule drugs are chemically synthesized, which means they are made by a series of chemical reactions in the lab. They are typically taken as a pill or capsule. The pill or capsule dissolves in the gastrointestinal tract, and the active ingredient is easily absorbed into the bloodstream via the intestinal wall. The molecules that make up these drugs are so tiny they are able to penetrate cell membranes and get inside cells. In contrast, large molecule drugs — protein-based therapeutics known as biologics — are made by living cells. They must be administered via injection because they will be destroyed by digestive enzymes in the gastrointestinal tract if given orally. Their large size, anywhere from 50 to 1,000 times larger than a typical small molecule drug, makes it impossible for them to penetrate cells. On the flip side, large molecules are highly specific for their target — typically a cell-surface receptor outside the cell. The FDA defines a peptide therapeutic as a chain of amino acids (the building blocks of proteins) containing 40 amino acids or less and regulates them as small molecules. Peptide therapeutics are similar to small molecule drugs in that they can be synthesized in the lab using a peptide synthesis machine — a machine that links amino acids together in a specified order. Peptides also share key characteristics with large-molecule drugs, including sensitivity to digestive enzymes, delivery by injection, and high specificity for their target.

Examples of peptide drugs on the market today include glucagon-like peptide-1 (GLP-1) receptor activators, such as Byetta (AstraZeneca; Cambridge, England), Victoza (Novo Nordisk; Bagsvaerd, Denmark), and Trulicity (Eli Lilly; Indianapolis, Indiana). These peptide drugs work by interacting with a receptor on the surface of pancreatic beta cells and stimulating insulin release for diabetes.

Rhythm Pharmaceuticals (Boston, MA) conducted clinical studies of their anti-obesity peptide drug setmelanotide (Imcivree). Designated as a breakthrough therapy by the FDA, clinical trial results in rare genetic forms of obesity were promising, helping to attract $41 million from key investors, including Pfizer venture Investments and Third Rock ventures to fund Phase III. The FDA initially approved Setmelanotide in November 2020 for chronic weight management.

Setmelanotide works by activating the melanocortin-4 receptor (MC4R), a receptor present on the surface of cells in the hypothalamus of the brain, a region involved in regulating both appetite and satiety. Mutations in MC4R that result in reduced activation are the most common genetic cause of obesity and account for approximately 6-8 percent of obesity cases.

Kalos Therapeutics (San Diego, CA) has a peptide drug in development based on a straightforward observation. Despite the constant activity, heart muscles don’t get bigger, and cancers of the heart are extremely rare. At least part of the reason for this is a peptide known as atrial natriuretic peptide (ANP), which is produced in the heart. It helps control cell growth and division, ensuring that the heart doesn’t get too big for the chest. Since cancer is caused by out-of-control cell growth and division, a connection was made: perhaps these peptides could play a role in controlling tumor growth.

Kalos Therapeutics has identified a portion of ANP and is synthesizing and testing it as a potential anti-cancer agent. Dubbed KTH-22, the agent is cytostatic, meaning it halts the growth and division of cancer cells, but does not directly kill them as a cytotoxic (toxic to cells) agent would. KTH-22 is in preclinical research, with data supporting its use in treating pancreatic and ovarian cancers.

Most peptide therapeutics do not penetrate cell membranes. Designing peptides that could enter cells would indeed endow them with the best characteristics of both large and small-molecule therapies. Aileron Therapeutics (Cambridge, MA) and Bicycle Therapeutics (Cambridge, U.K.) are aiming to do just that.

Aileron Therapeutics is developing “stapled peptides.” These peptides are synthesized according to an optimized amino acid sequence. Next, a chemical linker connects two amino acids within the chain, creating a folded or “stapled” version of the peptide. These stapled peptides still recognize their target protein, are more stable, and are better able to penetrate cell membranes than the linear versions.

Aileron’s leading stapled peptide candidate, ALRN6924, activates p53, a protein that triggers cell death in cancer cells but is inactivated in a range of malignancies. ALRN-6924 is in Phase II/ Ib clinical studies for lymphoma. The company is pursuing the development of stapled peptides in various therapeutic areas, including inflammation and endocrine and metabolic diseases.

Bicycle Therapeutics also uses chemically-linked peptides to increase stability, target interaction, and penetrate cells. Their peptides are formed — using a chemical linker — into the shape of a bicycle.

Bicycle’s lead candidate, BT1718, is a “bicycle drug conjugate” — a bicyclic peptide with a toxic drug attached. The peptide targets a protein called “membrane type 1 matrix metalloproteinase” (MT1MMP), which is overexpressed in many tumors. BT1718 delivers its toxic payload to tumors overexpressing MT1-MMP. BT1718 is now in Phase I stage 2 clinical studies for solid tumors.

Already capable of affecting a range of therapeutic targets with high specificity, continued peptide design and delivery innovations should make this class of drugs a vital player.

The realm of peptide therapeutics is rapidly evolving, bridging the gap between small and large-molecule drugs. With companies like Rhythm Pharmaceuticals, Kalos Therapeutics, Aileron Therapeutics, and Bicycle Therapeutics at the forefront, the potential of peptides in addressing various medical conditions, from obesity to cancer, is becoming increasingly evident. As these companies continue to innovate and refine their approaches, the future of peptide drugs looks promising. Their unique characteristics, combined with the advantages of both small and large-molecule drugs, position them as a significant contender in the pharmaceutical landscape.

1. WHAT ARE THE PRIMARY DIFFERENCES BETWEEN SMALL-MOLECULE DRUGS, LARGE-MOLECULE DRUGS, AND PEPTIDES?

Small molecule drugs are chemically synthesized and can penetrate cell membranes, while large molecule drugs are protein-based, made by living cells, and cannot penetrate cells. Peptides fall in between, sharing characteristics with both.

2. HOW DOES SETMELANOTIDE, DEVELOPED BY RHYTHM PHARMACEUTICALS, FUNCTION?

Setmelanotide activates the melanocortin-4 receptor (MC4R) in the hypothalamus, regulating appetite and satiety. Mutations in MC4R can lead to obesity.

3. WHAT UNIQUE OBSERVATION LED KALOS THERAPEUTICS TO DEVELOP AN ANTI-CANCER PEPTIDE DRUG?

The rarity of heart cancers and the heart muscle’s controlled growth led to the discovery of the atrial natriuretic peptide (ANP), which controls cell growth and division. This peptide’s potential in controlling tumor cell growth is being explored.

4. HOW ARE AILERON THERAPEUTICS AND BICYCLE THERAPEUTICS ENHANCING THE ABILITY OF PEPTIDES TO PENETRATE CELL MEMBRANES?

Aileron is developing “stapled peptides” that are more stable and can better penetrate cell membranes. Bicycle Therapeutics uses chemically-linked peptides formed into a bicycle shape to increase stability and penetration.

5. WHY ARE PEPTIDE THERAPEUTICS CONSIDERED A VITAL PLAYER IN THE FUTURE OF DRUG DEVELOPMENT?

Peptide therapeutics combine the benefits of both small and large-molecule drugs, offering high specificity and the potential to target a wide range of therapeutic areas. With ongoing peptide design and delivery innovations, their significance in the pharmaceutical industry is set to grow.