Despite decades of effort, oral delivery of peptide, protein and antibody drugs remains a major pharmaceutical challenge, with only a handful of products on the market.
That is particularly disappointing as biologics are also the fastest growing segment of the pharma market, tripling in value from $36bn to $163bn between 2001 and 2012, thanks to their high specificity for drug targets. Their specificity derives from their structural complexity, which is also the reason they are so challenging to formulate and deliver.
At the moment, biologics are generally delivered by intravenous or subcutaneous injection, which is effective but not desirable for patients, particularly for chronic conditions. Other routes of delivery such as transdermal, intranasal, inhalation and oral administration are under investigation, but oral delivery is generally considered the optimal route.
However, while convenient for patients, there are a host of challenges which make this route of administration challenging for large-molecule drugs. Foremost among these is enzymatic and pH-dependent degradation of drugs in the stomach and intestines, the low permeability of epithelial cells that line the gastrointestinal (GI) tract and the intrinsic instability of these compounds.
That means that proteins and peptides typically have extremely low bioavailability in the range of around 0-2% when taken by mouth. As a result, it is estimated that upwards of 100 projects focusing on oral delivery of peptides and proteins have ended in failure, despite myriad strategies aimed at increasing the bioavailability of drugs, overcoming acid and enzymatic degradation and enhancing the permeability of the gut lining.
Proteins and peptides typically have extremely low bioavailability in the range around 0-2% when taken by mouth
The technologies used to allow oral dosing of large molecules generally fit into one or more of the following categories: enzyme inhibitors; absorption or permeation enhancers; adhesive polymers that stick to the gut lining; and carrier molecules.
Drugs based on peptides – being generally smaller than proteins and antibodies – have been the most accessible area for oral delivery and account for all the drugs that are already on the market. Some peptides – such as transplant rejection drug cyclosporine and diuretic hormone desmopressin acetate – are simple enough to be amenable to standard oral formulation technologies and so have been available for years.
Among a newer generation of orally-delivered peptides is Ironwood Pharma’s peptide drug Linzess/Constella (linaclotide) – which debuted in 2012 for constipation associated with irritable bowel syndrome. This product however has the advantage of targeting receptors within the stomach which means that aside from some protection from the harsh environment in the gut it does not require a sophisticated delivery system that can help it cross over into the bloodstream.
Insulin in a pill
Insulin has long been the most popular target for oral delivery as it needs to be injected every day and – even with new self-injector pens – can be burdensome for patients. The only alternative to injections of the hormone at the moment is Mannkind’s inhaled insulin Afrezza – partnered with Sanofi – which has not gained much momentum yet in the marketplace with sales running at a few million dollars a quarter.
Oral insulin that could be taken alongside meals is considered to be the best option for patients, as the insulin would pass directly into the portal circulation running between the liver and the GI tract, allowing it to work more efficiently.
In fact, diabetes is thought to be the single largest area for oral delivery of biologics, with a number of groups working on oral insulin as well as analogues of glucagon – like peptide-1 (GLP-1), a hormone that works independently of insulin to stimulate glucose release.
Now, after a number of failed projects, some progress does seem to be happening. Novo Nordisk and Merrion are working on an oral formulation of insulin based on the latter’s GIPET technology, an absorption enhancer designed to help large molecules cross from the GI tract into the blood, and recently entered their candidate into phase IIa trials.
GIPET uses oral formulations based on proprietary combinations of excipients which increase the permeability of the GI tract lining, boosting the bioavailability of compounds by 10 times or more. The oral insulin – called NN1953 – is currently in phase I trials.
Novo Nordisk is also working with another specialist on oral delivery for protein drugs – Emisphere Technologies – that has applied its Eligen technology to develop an oral version of semaglutide, a GLP-1 agonist that recently completed a phase II study. The two companies are now discussing with regulators how to take the project into phase III.
The Eligen technology uses excipient carrier molecules to enable drug molecules of all sizes to cross cell membranes via a passive transport system. Once the drug leaves the GI lumen and reaches the intracellular space the carrier and active drug dissociate, leaving the drug to enter the circulation while the inert carrier is excreted.
Other companies developing oral insulins include Diabetology Ltd which has taken a product called Capsulin based on Proxima Concepts’ Axcess aromatic alcohol-based absorption enhancer technology in trials, as well as Israeli company Oramed whose ORMD-0801 candidate is in phase II. Oramed – whose technology relies on encapsulating the peptide or protein and delivering it alongside enzyme inhibitors and permeation enhancers – has also recently started clinical trials of an oral GLP-1 agonist.
Other drug advances
There are examples of developments outside diabetes as well. Cara Therapeutics has a chronic pain treatment based on a peptide that is rendered orally bioavailable using Enteris Biopharma’s Peptelligence platform, which combines a permeation enhancer and a calcium chelator (citric acid) to encourage the active ingredient to pass between the cells lining the GI tract.
Meanwhile, Chiasma remains committed to the development of an oral form of the peptide drug octreotide – a growth hormone inhibitor used to treat acromegaly – despite Roche’s decision to hand back rights to the drug last year. The Octreolin formulation is based on Chiasma’s Transient Permeability Enhancer (TPE) system which combines excipients to form an oily suspension of solid hydrophilic particles in a hydrophobic medium, which protects the active drug while allowing it to permeate through the gut wall.
Taking a slightly different tack, companies such as Google-partnered Entrega are looking at the use of nanoparticles – tiny wafers stacked within a pill that carry the drug substance. When the tablet dissolves in the stomach, the thin wafers attach to the lining of the small intestine, staying there while the payload is gradually absorbed. The technology came to prominence after Google announced it was using it to develop a pill that would deliver magnetic nanoparticles that would seek out early signs of cancer.
Antibody challenge
For really large molecules like antibodies the challenges for oral delivery are even more profound. However, as they can be engineered to have a long half-life in the body there is a greater likelihood that they can be delivered using less frequent injections, sometimes as rarely as once a quarter for example, which makes the drive to oral delivery less pressing.
Nevertheless some companies are taking up the challenge – albeit mainly for indications where the antibody target resides in the GI tract. Among these are Avaxia Biologics, which is developing an anti-tumour necrosis factor (TNF) antibody for inflammatory bowel disease and UK-based VH Squared, which has an early-stage programme ongoing looking at using single-chain antibodies in GI infections and immune-mediated diseases.
One exception is Applied Molecular Transport, which is based at Johnson & Johnson’s bioincubator in South San Francisco and has developed a protein scaffolding technology that harnesses a mechanism used by microorganisms to penetrate cells in the gut. While still in its infancy, preliminary research suggests the approach could allow large molecules to enter the blood stream.
Similarly, Rani Therapeutics recently signed an agreement with Novartis to evaluate oral delivery of a number of biologics using a ‘robotic pill’. The capsules are loaded with tiny needles made of a widely-used pharma excipient that penetrate the wall of the intestine to deliver their payload, pushed by a balloon that self-inflates in response to the conditions in the intestine. As the intestines don’t have sharp pain receptors the delivery goes unnoticed by the patient and – according to the company – the lesion caused in the lining of the GI tract is quickly resolved.
Novartis has agreed to an 18–24 month feasibility study to explore the application of the robot pill to its current portfolio of biologics.
Nevertheless, it is somewhat remarkable that so many oral delivery projects for biologics have failed to progress beyond early to mid-stage clinical trials and in some ways the picture looks little changed from 10 or even 20 years ago – a plethora of small and start-up companies and few big pharma names.
There does seem to be some financial momentum building behind these companies however, with an estimated $1bn in venture funding in the last 10 years, and there is a vast amount of activity in reported scientific discoveries and patent awards.
All eyes will now be on the performance of the first marketed products – such as Linzess, Octreolin and Ostora. If successful, that could encourage more companies to invest in the development phase for oral delivery technologies that will help free patients from invasive injectable treatments.