Making the (pre)clinical rounds
September 2018
by Jeffrey Bouley  |  Email the author

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There is often a surfeit of news in our inboxes at DDNews with regard to published research, but only so much room and so many writers to cover it all. So, as we do sometimes, we are going to try to fit in a little extra by giving you a quick roundup of some of the more notable offerings lately in the journals, this time with a preclinical twist and covering the range from oncology to endocrinology and pulmonology to neurology.
 
ArQule publishes data for ARQ 531 in hematological cancer
BURLINGTON, Mass.—ArQule Inc. announced mid-August the publication of preclinical study data for ARQ 531, the company’s reversible inhibitor of both wild-type and C481S-mutant Bruton’s tyrosine kinase (BTK). ARQ 531 is meant to treat B cell malignancies—in particular, relapsed or refractory chronic lymphocytic leukemia (CLL). The studies were published in Cancer Discovery under the title “The BTK Inhibitor ARQ 531 Targets Ibrutinib Resistant CLL and Richter’s Transformation,” and were conducted in collaboration with researchers at Ohio State University. The data reportedly demonstrate efficacy in in-vitro and in-vivo hematologic malignancy models that recapitulate the most common mechanisms of resistance to irreversible BTK inhibitors, including ibrutinib.
 
Among the highlights of the paper is a discussion of the differentiated crystal structure and biochemical profile of ARQ 531, which is said to elucidate a mechanism of BTK inhibition that is not dependent on the specific amino acid residue at position 481. In addition, the recombinant BTK biochemical assays of ARQ 531 and ibrutinib show similar inhibition for wild type BTK though ibrutinib demonstrated dramatically lower inhibition, binding affinity and residence time for mutant BTK.
 
“Relapsed and refractory patients that develop resistance to ibrutinib have poor outcomes and limited treatment options,” said Dr. Brian Schwartz, chief medical officer and head of research and development at ArQule. “ARQ 531 was rationally designed and selected to address this unmet need by inhibiting both wild type and mutant BTK. The published crystal structure and biochemistry clearly demonstrate the mechanism by which ARQ 531 maintains binding and inhibition of mutant BTK in conditions where ibrutinib cannot.”
 
Other findings regarding ARQ 531 included that the drug:
  • Exhibited dose-dependent toxicity in human primary CLL cells (mutant and wild type)
  • Inhibited CLL cell migration in vitro
  • Established superiority to ibrutinib in an engraftment murine model of CLL
  • Showed activity against other B cell signaling pathways
  • Demonstrated efficacy in a murine model of Richter’s transformation.
“The inhibition profile of ARQ 531 may confer distinct advantages over ibrutinib, potentially expanding the patient population beyond those with a C481S mutation who may benefit from treatment,” said Dr. John Byrd, the Warren Brown Chair of Leukemia Research at Ohio State University. “Targeting multiple kinases in the B cell activation pathway may provide more durable responses to treatment while also delaying the emergence of treatment resistance.”
 
Dr. Jennifer Woyach, an associate professor of medicine at the university, added: “I am particularly encouraged by the CLL mouse model data which established the superior efficacy of ARQ 531 compared to ibrutinib, and the efficacy of ARQ 531 in the model of Richter’s transformation, as this is an extremely aggressive disease with very few treatment options.”
 
Apitope announces publication of Graves’ disease data
HASSELT, Belgium & CHEPSTOW, U.K.— Apitope, a clinical-stage biotech company developing potential first-in-class antigen-specific immunotherapies targeting autoimmune diseases, recently announced the publication of its preclinical Graves’ disease data in Endocrinology under the title “Immunotherapy with apitopes blocks the immune response to thyroid stimulating hormone receptor in HLA-DR transgenic mice.”
 
The paper reports the results from a series of studies to identify peptides that can be used to treat the abnormal immune response to the thyroid-stimulating hormone receptor (TSHR) in Graves’ disease patients and reportedly shows that a mixture of two immunodominant apitopes—which are the company’s highly specific and proprietary collection of peptide-based therapeutics—was sufficient to suppress both the abnormal T cell and antibody response to TSHR in HLA-DR transgenic mice. Tolerance induction was not disrupted by current drug treatments for Graves’ disease.
“The data shows that immunotherapy with apitopes is a suitable approach to be investigated for the treatment of Graves’ disease and demonstrate the potential to be the first disease-modifying treatment, as well as the first innovative therapy for Graves’ disease in more than 60 years,” said Dr. Keith Martin, CEO of Apitope.
 
Prof. David Wraith, chief scientific officer of the company, added: “I am excited to see these data published, because it provides further evidence of the broad applicability of the Apitope platform to identify peptide apitopes to treat a wide range of autoimmune diseases.”
 
MRx0004 protects against airway inflammation in severe asthma
LEEDS, U.K.—On Aug. 14, 4D pharma plc announced the publication of a paper demonstrating that MRx0004, a live biotherapeutic derived from the human gut microbiome, might prove useful in protecting against airway inflammation by reducing both neutrophilic and eosinophilic infiltration in a mouse model of severe asthma.
 
The paper “Bifidobacterium breve MRx0004 protects against airway inflammation in a severe asthma model by suppressing both neutrophil and eosinophil lung infiltration” was published in Scientific Reports.
 
MRx0004 is a strain of Bifidobacterium breve isolated from the gut microbiome of a healthy human, and it was tested prophylactically and therapeutically in a house dust mite mouse model of severe asthma. A strong reduction of neutrophil and eosinophil infiltration was observed in lung bronchoalveolar lavage fluid following MRx0004 treatment. Furthermore, MRx0004 reportedly had a striking effect on lung histopathology, with a strong reduction of both peribronchiolar and perivascular inflammatory infiltrate.
 
“These data provide further evidence that live biotherapeutics have the potential to change the way we treat disease,” said Alex Stevenson, chief scientific officer of 4D pharma. “Using MRx0004, we have demonstrated superior efficacy to biologics in a severe and steroid-resistant model of asthma.”
 
Auris confirms dose-dependent effects of betahistine in vertigo model
ZUG, Switzerland—July saw Auris Medical, a clinical-stage company dedicated to developing therapeutics that address important unmet medical needs in neurotology and mental health supportive care, announce the publication of an article confirming dose-dependent effects of betahistine and their relationship to bioavailability in a cat model of surgery-induced acute vertigo. The peer-reviewed article, “Betahistine treatment in a cat model of vestibular pathology: pharmacokinetic and pharmacodynamic approaches,” was published in Frontiers in Neurology.
 
The article presents the outcomes of a study with betahistine in a previously established model of acute loss of vestibular function in cats following the unilateral sectioning of the vestibular nerve (neurectomy). The study demonstrated that daily oral administration of betahistine 2 mg/kg resulted in faster improvement of acute symptoms than with betahistine 0.2 mg/kg. In addition, unlike the lower dose, betahistine 2 mg/kg also accelerated significantly the recovery process; further, it was associated with a significant increase of the histaminergic activity of the tuberomamillary nuclei in the hypothalamus and substantially higher bioavailability in blood plasma.
 
“We are very excited about the evidence from this study that confirms the benefits of increasing betahistine’s bioavailability,” said Thomas Meyer, Auris Medical’s founder, chairman and CEO. “This finding provides further support for our approach of using intranasal delivery of betahistine for treating acute vertigo. As previously reported, intranasal administration to healthy volunteers resulted in a 20- to 40-fold higher bioavailability compared with oral administration.”
Code: E091814

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