If we set aside the COVID-19 pandemic for a second, non-communicable diseases are still the big game for clinical-stage biotechs. These diseases, which include heart disease and cancer, are collectively responsible for nearly 70% of all deaths worldwide, according to the WHO.
The rise of these diseases has been driven by four risk factors – tobacco use, alcohol abuse, inadequate exercise and poor diet.
NCDs present a challenge for health systems around the world and the prevention and control of them is, therefore, a primary focus for drug development companies.
One of the lesser-known NCDs is idiopathic pulmonary fibrosis (IPF), a fatal disease for which, prior to 2011, there was no pharmaceutical treatment at all.
In this feature:
- Tackling a disease with dire outcomes
- How can monoclonal antibodies help?
- What is an i-body?
- Reaching the body's receptors
- Economic drivers for tackling fibrosis
- The COVID connection
Tackling a disease with dire outcomes
IPF is a thickening and scarring of the lung tissue. Risk factors include smoking, asthma, pollution and other environmental or genetic factors.
“When there is an injury to any organ or any tissue it creates an immune or inflammatory response,” AdAlta CEO Tim Oldham said.
"From there, you get a scarring response to heal damaged tissue. This can cause a lack of plasticity and flexibility in the skin. That wound healing process can become out of control, and if it happens in the lungs, kidneys, liver, it can destroy the normal organ function.”
IPF affects about 500,000 people globally and it is diagnosed in around 12 in 100,000 people annually.
Men are more commonly affected than women, the typical age range for sufferers is 60 to 70, and the cause is unknown (which is where ‘idiopathic’ comes in).
IPF has a poor prognosis, with an average life expectancy of four years following diagnosis.
How can monoclonal antibodies help?
Antibody drugs revolutionised the pharmaceutical industry when they first appeared in 1986, because they confirmed greater specificity and selectivity relative to small molecules than could be achieved before.
Scientists were able to access a raft of new targets for a disease that small molecules had not been able to address.
The problem with these antibodies was their size. Antibodies are large molecules – an antibody is 1,000 times bigger than a small molecule like aspirin.
“They’re great but are inhibited by their size, so there are many targets they’ve been unable to address,” said Oldham. "As a result, people have been looking for drug discovery platforms that perform similarly to an antibody but are much smaller than an antibody.”
“Antibodies are structured so there is a constant part, which engages with your immune system, and then there is a small part of the antibody that confers the specificity,” said Oldham.
“At first, scientists tried to break up the traditional monoclonal antibody to isolate that hyper-variable region.
“This works to a certain extent but you’re creating something that’s not found in nature and is therefore not as stable.”
What is an i-body?
Enter the i-body, a marvel of molecular biology that can be applied in many different diseases and is used as a building block in many different drug formats.
The i-body came about when it was discovered that there were similar antibodies in the animal world, which could be adapted for use in humans. In AdAlta’s case, shark antibodies have been used, but in other cases, they come from cameloid family – llamas, alpacas and camels have a similar system.
“We found a human protein that exists in nature that mimics the size and shape of a shark backbone and then we used biotechnology techniques to engineer in the variable binding groups," Oldham said.
“From this, we evolved a single domain antibody that is 10% of the size of a human antibody – this is much closer to something already found in nature, so it’s going to be inherently more stable.
AdAlta has a library of 10 billion variants of these small-format, single domain antibodies – i-bodies – that mimic the properties of the shark immune system, and can screen against a variety of targets that traditional antibodies have not worked well against.
“Our vision as a company is to use them to create novel therapeutics against unmet diseases of many different kinds.”
Reaching the body's receptors
G Protein Coupled Receptors (GPCRs) are found in the membranes of cells. They perceive many extracellular signals and tell the cell how to respond to what is going on around it.
“These GPCRs have implications for multiple different biochemical pathways within a cell,” Oldham said. "But because they are buried within a cell membrane, it’s harder for a traditional monoclonal antibody to reach them.
“And because they’re implicated in these multiple signalling pathways, you may want to switch off one of those pathways and not the others. The i-body is advantaged to address these targets, which are implicated in all sorts of diseases.”
One of these GPCRs is involved in fibrotic diseases, and AdAlta has discovered how to optimise an i-body to target this GPCR, and hence fibrosis.
“We found an i-body that binds to this specific receptor," said Oldham. “It is specifically selected so that it has advanced anti-fibrotic properties, but we’ve dialled back some of the other things that that receptor also does when we engage it – things like mobilising stem cells from your bone marrow while you receive treatment.
“Like anything in medicine, if it isn’t broken you don’t try to fix it, so you don’t want to be doing something that isn’t necessary to treat the disease if you don’t have to.”
By engaging the GPCR, AdAlta is bringing a novel mode of action to the fibrosis treatment space, which means the treatment acts on a different biochemical pathway to other drugs, which are competing for the same pathway.
“That’s important for us because there’s an opportunity to use our drug in combination with all of the others,” said Oldham. "Most physicians today agree that fibrosis is going to be treated by multiple therapies in combination, much like cancer.”
Economic drivers for targeting fibrosis
IPF affects 200,000 patients each year in the US, a similar number in the rest of the world and a growing number in countries like India and China, where there is poorer air quality and high rates of smoking.
The most pressing unmet need for clinicians targeting IPF is the absence of a drug that can halt or even reverse fibrosis, as opposed to one that merely slows its progression.
And it doesn’t stop at the lungs – fibrosis can affect almost any organ in the body, with devastating results. The mechanism is likely to be common across all organ systems, so AdAlta is betting that the clinical pathway for this treatment for IPF will also be useful for a range of other fibrosis indications.
“We would be looking at fibrosis in other organ systems, and we already have some good preclinical data in kidney fibrosis and in age-related macular degeneration, which causes fibrosis of the eye," said Oldham. “They are additional markets.”
Existing drugs on the market for IPF alone generate sales of $3 billion annually, but, according to Oldham, are sub-optimal, and may present side effects that can result in patients needing to cease therapy.
“The current drugs slow the rate of progression, give you a marginal improvement in life expectancy but not much and they’re toxic, so many people can’t tolerate the gastrointestinal side effects and nausea. One of them causes photo sensitivity, so you burn easily in sunlight,” he said.
“We’re talking about a progressive degenerative disease that will ultimately kill you.”
The COVID connection
The clinical pathway used to combat fibrosis may be used in the longer-term fight against COVID-19.
The acute respiratory distress syndrome caused by COVID-19 can result in scarring of the lungs and heart.
“We don’t know yet whether it’s going to be progressive like IPF,” said Oldham. “But we expect a significant incidence in fibrotic respiratory disease because of COVID infections.
“We’re following a couple of studies to see how the COVID-induced fibrosis space plays out.”