From Poisons To Pills: Peptides

Posted February 10th, 2017 by Ros Deegan, in From The Trenches, Portfolio news, Science & Medicine, Translational research

This blog was written by Ros Deegan, CBO of Bicycle Therapeutics, as part of the From The Trenches feature of LifeSciVC.

When a taxi driver finds out the name of my company, I am inevitably asked, “What does Bicycle Therapeutics do?”

It’s not a question that came up when I worked at Trevena. My taxi driver would move straight on to discussing the weather or soccer or the news of the day. However, the word ‘Bicycle’ makes my world seemingly accessible to life beyond the biotech bubble.

Three days of back-to-back partnering meetings are easier to negotiate than a single taxi challenge. How can I stop the driver’s eyes glazing over at the mere mention of ‘bicyclic peptides’ when even Pharma sometimes struggles to look beyond antibodies and small molecules? Yet peptides are my passion as well as my paycheck so I would like to share my excitement about the future of peptide drug discovery with you. And with my curious taxi driver.

Join two or more amino acids together and you’ve got a peptide. Keep adding amino acids and eventually you’ve got a protein (although the size transition from peptide to protein is somewhat arbitrary). Biting animals, which are a bit of a theme for me, illustrate the importance of peptides. Snakes, spiders and scorpions use venom peptides to immobilize or kill their prey by targeting the muscular, cardiovascular and immune systems. Some creatures use peptides for defense, inducing inflammation and pain in aggressors. Parasites use peptides to prevent immune responses, produce local anesthetics to avoid detection and inject anticoagulant peptides to prevent their host’s blood from clotting.

Peptide compounds sourced from venom have been evaluated for many different therapeutic activities including chemotherapy, immunosuppression, analgesia, antiarrhythmia and antibiotic effects. There have been notable successes, including Byetta for diabetes and Captopril for hypertension.

Outside of venom, peptides mediate many other biological processes. Well known peptides include oxytocin, the so-called ‘cuddle hormone’, which is released when people snuggle up or bond socially. There are also opioid peptides that act on the same receptor class as heroin to create a natural high.

Yet despite the identification of pioneering peptide compounds – such as insulin – at the start of the modern era of drug discovery, drug developers rapidly shifted attention to small molecules because of the more convenient oral route of administration and ease of production. Prospective analyses of the types of compounds most likely to be successful in drug discovery led to broad generalizations, including a preference for small sized drugs. These biases ruled out all but the smallest peptides.

However, many of the more tantalizing drug targets are members of large families that share structural elements. Small molecules struggle to differentiate between one family member and the next, which has led to many clinical failures as a result of unwanted side-effects.

A lifting of the size cap allows for many additional points of target engagement, which in turn enables much higher selectivity between family members. And so, in the latter part of the 20th century, a new class of therapeutics with a very different size emerged.

Antibodies show exquisite selectivity for their molecular targets and typically require administration by injection. Increased interest in large molecules (antibodies and other biologics) has been supported by a regulatory trend towards more stringent safety standards and a lower tolerance for off-target side effects. The success of this new class of therapeutics shows the importance of understanding patient needs: injections are not a barrier to the treatment of serious diseases.

The rise of biologics has opened the door to further opportunities for peptide therapeutics. Peptides combine many of the benefits of both large and small molecules. With apologies to the late Muhammad Ali, our mantra is that peptides target like antibodies, perform like small molecules and excrete like peptides.

Peptides show the same exquisite targeting and selectivity associated with antibodies but in a small molecule package with rapid tissue penetration, low risk of activating an immune response, straightforward manufacturing and the opportunity for alternative routes of administration beyond injectables. Peptides are typically excreted through the kidney, bypassing the potential liver toxicity that may be seen with small molecules and antibodies. Based on their strong, selective binding, peptides offer the potential for low dose administration without major side effects. This translates into a reasonably high probability of regulatory approval (circa 20%) from the commencement of clinical trials.

Despite all these notable benefits, peptides have not received the same level of resourcing as small molecules and biologics. Nevertheless, peptide drugs continue to receive approval. Indeed, recent technological advances are sparking additional interest. In my view, the future success of peptide therapeutics lies in finding opportunities that play to peptides’ natural characteristics, and leveraging new technologies to optimize those characteristics.

Turning a weakness into a strength

The most commonly cited weakness of peptides as therapeutics is their low biological stability and concomitant short half-life. Yes, most peptides degrade in human serum within one hour. Yet human whole body blood circulates in under one minute. Given their high volume of distribution compared to antibodies – and associated rapid tissue penetration – sufficient concentrations of peptide drugs do reach their target long before the peptides break down, thus ensuring reliable activity.

It’s also worth remembering that for many indications a short half-life agent is exactly what the physician is looking for. This is particularly true in oncology. In chemotherapy, the predominant determinant of efficacy is cell killing and not a prolonged duration of effect. And when harnessing the immune system to attack cancer there is a fine line between efficacy and overstimulation, requiring treatments with the power on, power off attributes of a sprinter versus the persistent power of a marathon runner.

Antibodies and their very long systemic exposure are one of the key modalities in oncology development, both as a vehicle to deliver cytotoxics (antibody drug conjugates or ADCs) and in immuno-oncology. However, after billions of dollars of investment over the past 20 years, we still only have two approved ADCs (Adcetris and Kadcyla) due to the challenge of reaching an acceptable therapeutic index given prolonged exposure of normal tissue to toxin. Substantially less investment has gone into targeted delivery of radionuclides. Yet there has been some success using peptides as the delivery vector (peptide receptor radionuclide therapy).

Although antibodies have shown great promise in immuno-oncology, we are now seeing the challenge of prolonged activity with increasingly apparent toxicities reported in scientific journals and in the mainstream media.  The short half-life of peptides may be a desirable attribute in this context. We should remember that most natural peptides exert their biological function by acting as a signal. And stopping the signal is just as important as the signal itself. Peptide drug development may also provide access to the ‘accelerator’ as well as the ‘brake’ in the immune system, going after co-stimulatory T-cell targets in addition to checkpoint inhibitors.

New Peptide Technologies

There are many new technologies, including cyclization, that are enabling the peptide drugs of the future. Two emerging areas of focus are peptides as pills, and accessing intracellular targets as well as cell surface receptors.

Peptides as pills

Due to their low gastric stability, most peptide therapeutics cannot be taken orally. In effect, the body can’t tell the difference between a steak and a peptide. There are some exceptions to this, such as cyclosporine, which is stable on ingestion. The existence of unusually stable peptides, such as cyclosporine, demonstrates the potential for orally available peptides and there are various chemical strategies now being employed to optimize oral absorption. Formulation and permeability enhancers will also play a role. A peptide pill for oral administration is currently being developed by Enteris Biopharma. The coating of this pill protects the peptide from digestion, whilst its excipients protect the peptide against peptidases and facilitate uptake through the intestinal wall.

Intracellular targets

Peptides cannot typically penetrate a cell wall because they have too many polar atoms and are generally hydrophilic. They are, therefore, incompatible with the hydrophobic interior of the membrane. However, in recent years, technologies have been invented for the insertion of membrane permeability elements, including so-called ‘cell-penetrating peptides’ such as penetratin. The potential for peptides to target intracellular processes is an exciting area, and requires additional understanding of the biology involved in both the passive diffusion and active transport of drugs across cell membranes. Aileron is one of the pioneers in this area, targeting intracellular protein-protein interactions mediated by p53.

More than 100 peptide-based drugs are on the market today. An additional 100-plus peptide drugs are currently in clinical development. And around 500 therapeutic peptides are in preclinical development. In 2012 the FDA approved six new peptides, five of which also received European approval.

The continued challenge of specificity for small molecules, the new toxicity challenge of combining multiple long exposure biologics, and the advances being made in peptide manipulation and formulation have convinced me that the first half of the 21st century is a great time to be a peptide discovery company. If a peptide specialist like Bicycle Therapeutics breaks through to become a globally-recognized company, the taxi challenge will disappear.

But for now, I’ll go with the answer from my most recent driver. After 10 minutes of pitching peptides he replied, ‘You’re trying to cure cancer.’ And then we went back to talking about the weather.

Thanks to Paul Beswick, Pamela Esposito, Kevin Lee, Peter Park, Michael Skynner and Dan Teufel for reading drafts of this post.


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