Sue Pearson Ph.D. Freelance Writer GEN
Biotechnology Rolls on Despite Brexit Uncertainty
There were a number of new technologies discussed at the recent BioTrinity conference organized by OBN, the UK’s largest biotech networking group. The meeting brought home the point that despite Brexit fears, UK biotechs still have a great deal to offer investors and big pharma in terms of in-licensing, partnering, and acquisition opportunities.
One firm disclosing good news at the conference, was Elasmogen. The Aberdeen-based company, in partnership with Canada’s Feldan Therapeutics, announced a new research collaboration with Amgen. The partnership combines the capabilities of Feldan’s Shuttle peptide-based delivery method and Elasmogen’s soloMER™ fully humanized, single chain biologics to develop and deliver binding domains for two of Amgen’s intracellular targets.
According to Caroline Barelle, Ph.D., CEO at Elasmogen, “Amgen is a company I have always admired for being forward thinking so we are pleased to be working with them alongside Feldan to produce small, stable soloMERs for use in the intracellular world. Many biologics are too large to deliver in any other way than through a needle or infusion. Our aim is to use our soloMER technology, for example, to deliver biologics to the eye in a topical form making biologics that are as flexible in their use as small molecules.”
According to Dr. Barelle soloMERs are therapeutic single-domain biologics derived from VNARs (variable new-antigen receptors), which are part of the adaptive immune system in sharks. They have inherently high affinity for target and are only 11 kDa. Yet, they have four binding loops that can bind to hidden epitopes. They are site specific and can be used in ocular and digestive disorders to bind to extracellular and intracellular targets.
The technology is being used by partners such as Merck to develop reagents to target hidden epitopes and by Almac to produce drug conjugates to target cancers. Elasmogen also has an Innovate UK grant to explore using bi-functional reformatting of anti-inflammatory and anti-autoimmune soloMERs, which are currently in preclinical development to treat ocular diseases.
“soloMERs are not true IgGs and because they are derived from sharks there is a size benefit, as well as an IP benefit to using them instead of conventional monoclonal antibody therapeutics,” adds Dr. Barelle.
She went on to discuss the clinical candidates being developed for treating uveitis (ELN21 and ELN22) and presented evidence which showed that in rabbit models where a contact lens is used to administer the soloMER at the front of the eye, more than 300 nM reached the back of the eye.
“Our results show that we can achieve therapeutic doses to the back of the eye and the potency of our ELN22 product is equivalent to Humira therefore creating the potential to treat uveitis but with a topical application instead of injection,” noted Dr. Barelle.
The company, which is looking for Series A investment to fund its ocular clinical development programs further, had more good news with Dr. Barelle being awarded runner up in the Perfect Pitch competition at BioTrinity where ten emerging R&D companies pitched their technology in front of a panel of experienced investors. Mike Karim, CEO of Oxford Endovascular, was named the winner of this years’ competition.
Small Is Beautiful
Like Elasmogen, another company developing small, high-affinity biologics is Cambridge firm Avacta. It confirmed at the conference that a patent protecting its affimer technology has been accepted in China, which the firm believes adds further strength to their global intellectual property position. Alastair Smith, Ph.D., CEO, explained the technology saying: “We have developed affimers that are based on the naturally occurring human protease inhibitor Stefin A. These are 12-14 kDa molecules with no cysteines or any post-translational modifications and a large binding surface obtained via two nine amino acids loops. We select for specific affimers using in-vitro phage display.”
According to Dr. Smith, because affimers are around 10 times smaller than antibodies, they can penetrate tissues more readily and can be used as bispecific molecules to bind to different druggable targets.
The company has several partnerships and Dr. Smith mentioned recent collaborations with Moderna to enable delivery of mRNA therapeutics and another with Glythera to produce drug conjugates using affimers with Glythera’s PermaLink™ conjugation chemistry. Dr. Smith also presented data on their in-house immune-oncology preclinical development program which showed that affimers targeting PD-L1 demonstrated efficacy in competitive ELISA assays and CT26 mouse models.
Mastering Stem Cells
Michael Stein, Ph.D., CEO and chairman of Oxstem, also a Perfect Pitch finalist, presented his firm’s combined stem cell and small-molecule drug screening approach.
“In many cancers, stem cells are resistant to drugs so if we can turn those endogenous stem cells back on in brain, heart and eye for example, we could stimulate healthy new cell growth and cellular processes to allow cells to become receptive to treatment. What we are doing is looking for compounds that activate those stem cells’ master switches,” explained Dr. Stein.
According to Dr. Stein, Oxstem, which is based across five departments at the University of Oxford, including the university hospitals, has access to human tissues which they culture and phenotypically screen.
“Using cells derived from human tissue we grow stem cells like yoghurt in suspension,” said Dr. Stein. “These cells have hundreds of developmental pathways and we select for specific stem cell populations using fluorescence activated cell sorting (FACS). We then screen these selected stem cells with a library of small molecules, followed again by FACS to determine the effects they have on stem cell populations to try and find those compounds that activate stem cells.”
The company raised £16.9 million in 2016, in the UK’s largest seed funding round. Dr. Stein says the firm will be spinning out four companies, Oxstem oncology, neurology, ocular, and cardiology to perform screens in these different therapeutic areas. The company is also looking for series A funding and strategic partners to further this work.”
Another firm at BioTrinity that discussed their promising use of stem cells as a regenerative therapy was Rexgenero. The UK-based firm manufactures stem- cell therapies at its manufacturing site in Spain and its lead product, an autologous bone marrow-derived mononuclear cell (BM-MNC) therapy known as REX-001, is in Phase III trials to treat some of the serious complications caused by Critical Limb Ischemia (CLI).
Joe Dupere, Ph.D., CEO at Rexgenero, points out that “25 percent of CLI patients are likely to have an amputation within one year of diagnosis because treatment options are limited for complications such as ischaemia and leg ulcers. With an ageing population and the rise of type 2 diabetes which can cause CLI, this is going to be a growing problem.”
According to Dr. Dupere, it takes 20 minutes to obtain BM-MNCs and eight hours to manufacture the therapy in an automated process at their manufacturing facility in Spain and the resulting REX-001 has 48 hours of shelf-life. The therapy is injected directly via a catheter into the artery in a hospital setting and has the advantage that it is administered to the vessels directly where it is needed. This kickstarts blood vessel regeneration and stimulates regrowth of tissue to alleviate ischaemia and heal ulcers.
Dr. Dupere presented results of one of two Phase II clinical trials in which 60 CLI patients were treated with REX-001.
“Twelve months after treatment with a single infusion, two thirds of patients with CLI showed regrowth and after six months these same patients had complete healing,” he said. “To date, approximately 150 CLI patients have been treated with a single infusion of REX-001 in our different clinical trials and over 70 percent of the patients improved at least one clinical grade.”
Using this cell therapy could save up to 20,000 euros in treatment costs and improve patient’s quality of life, said Dr. Dupere. REX-001 has been approved by the EMA to be used in two confirmatory double-blind placebo controlled Phase III trials of patients with diabetes and CLI, which began in 2017.
“The results we are having with REX-001 shows it is the best in class for this type of cell therapy and we believe it has a high probability of success in Phase III trials,” he noted. “We hope to achieve marketing authorization for this product which has a broad treatment application and could be used to treat up to two million patients every year.”