To understand 4D pharma PLC (LON:DDDD), it is first worth trying to get your head around the technology that has spawned drug candidates in cancer, gastrointestinal and respiratory ailments and autoimmune disease.
Working in the emerging area of the human microbiome (the bacteria that reside mainly in the gut), 4D has developed Live Biotherapeutics — products that contain live organisms such as human commensal bacteria.
The approach focuses on single strains to assess specific mechanisms of action targeting a defined disease pathway.
Even variations between different strains of bacteria of the same species are assessed and exploited.
4D’s chief executive, Duncan Peyton, says superficially identical bacteria can sometimes differ up to 20% in their gene content, and therefore may have highly different functional profiles.
Attractive safety profiles
Toxicity has always been a major impediment to the success of new drugs.
In developing its Live Biotherapeutics, 4D has isolated bacteria from healthy human donors which are expected to have “highly attractive safety profiles”.
“A lot of the safety issues encountered in novel drug development are due to the off-target effects,” explains Peyton.
“As bacteria derived from the human gut, and which are restricted to the gut following administration, we first approached Live Biotherapeutics from that angle – the potential to create safe and efficacious drugs.”
Early studies assessed the impact of these Live Biotherapeutics on the immune system.
While early programmes investigated ways to suppress the immune system, one strain, now known as MRx0518, was found to be a significant stimulator of it.
That was an important breakthrough, particularly in this era of immuno-oncology, where the body’s defences are used to battle and beat the disease.
Now in the early phase of clinical development, MRx0518 is being trialled as a single therapy for solid tumours and pancreatic cancer.
Sexier, to the lay investor at least, will be its collaboration with Merck & Co. trialling 4D’s breakthrough with the American giant’s blockbuster checkpoint inhibitor Keytruda.
Checkpoint inhibitors are big business. By 2022 sales are expected to be around US$25bn a year, while Keytruda alone generated revenues of US$11.1bn in 2019, up 55%.
But this class of drug, which works to unmask cancer to the immune system, currently has its limitations.
First, the likes of Keytruda work for probably only 30% of the population. When they do work, they work exceptionally well.
Sadly, over time the effect can wane.
MRx0518 is being trialled to assess its potential to work synergistically with Keytruda to reengage the immune system.
How is it doing?
In its full-year results statement, the company listed the publication of the first proof-of-concept data for MRx0518 in last-line cancers and the journey towards a listing on NASDAQ as highlights of 2020.
The live biotherapeutics specialist ended the year with cash and cash equivalents of £8.8mln, up from £3.8mln at the end of 2019.
Revenue rose to £534,000 in 2020 from £211,000 in 2019 while research & development (R&D) costs were cut back to £22.0mln from £26.5mln the year before.
The loss before tax was little changed at £30.3mln versus a loss of £29.4mln the previous year.
In August 2020, 4D said its lead drug candidate, MRx0518, when used alongside Merck & Co’s Keytruda “far exceeded” expectations in an early-stage clinical study. The combination was used to treat 12 ‘end of line’ patients with either advanced metastatic renal cell carcinoma or metastatic non-small cell lung cancer.
Five people, or 42% of the group, experienced a clinically meaningful benefit from the two drugs. This was well ahead of the success threshold of 10% agreed at the outset of the phase I/II trial.
Three patients enjoyed what’s called a partial response to the combination with tumour shrinkage of 30% or greater; in the other two the disease remained stable.
The median duration of treatment for the five patients experiencing the clinical benefit from the regimen was 13.2 months at the time of the announcement.
The treatment itself was well tolerated with no serious adverse effects.
Professor Jaap Verweij, a leading cancer expert from the Netherlands and an advisor to 4D who has carried out more than 150 early-stage trials of this kind, called the results “extremely encouraging”.
This latest data came from the first group of a two-stage trial. Group B will recruit 30 people per tumour type.
Checkpoint inhibitors such as Merck’s Keytruda, which works to unmask cancer to the immune system, currently have their limitations. They work for probably only 30% of the population. When they do work, they work exceptionally well. Sadly, over time the effect can wane.
MRx0518 has been developed to work synergistically with Keytruda to reengage the immune system.
In February 2020, 4D signed a clinical trial collaboration and supply agreement with Merck KGaA, and Pfizer Inc. Later this year it will start a clinical trial of BAVENCIO, a drug for advanced or metastatic urothelial carcinoma developed by Merck and Pfizer, in combination with UK group’s MRx0518.
"With this second clinical trial collaboration for MRx0518 with a leading immune checkpoint inhibitor, 4D is able to evaluate MRx0518 in a new combination and earlier treatment setting,” said CEO Peyton.
What the boss says: Duncan Peyton, the chief executive officer
"4D has made significant progress leading the field in the development of Live Biotherapeutics, and made great strides from a corporate perspective."
“In addition to the data we have generated in the field of oncology, we completed our merger with Longevity and obtained a NASDAQ listing which, together with a concurrent fundraise, provides 4D with approximately US$40 million of additional capital and a solid financial footing moving forward. This puts 4D pharma in a strong position to capitalise on multiple data readouts from our ongoing trials in asthma and oncology as well as facilitating the move into the clinic with our Parkinson's disease programme," Peyton added.