EIF2B1

Denali Therapeutics disclosed further disappointing data for its experimental amyotrophic lateral sclerosis (ALS) treatment DNL343 in a securities filing Wednesday.While the eIF2B agonist had missed the primary efficacy endpoint of Regimen G — part of the Phase II/III HEALEY ALS Platform Trial — Denali had been hoping that an analysis of neurofilament light (Nfl), a biomarker of neuronal damage, would show some degree of DNL343 activity. But Denali revealed in an update this week that its candidate "did not demonstrate a treatment effect" on Nfl over the 24-week, double-blind period of Regimen G, which had randomised 186 patients with ALS to receive DNL343, while 139 individuals were given placebo.DNL343 had a similar lack of efficacy in patients who received an additional 28 weeks of treatment in the open-label active treatment extension cohort; Denali plans to discontinue the extension study. The company said it is assessing "potential future development opportunities" for the candidate, and will present the full data from Regimen G at a future medical meeting.ALS stumbles The biomarker results are the latest in a series of clinical setbacks for Denali's ALS aspirations. The topline Regimen G results, shared in January, showed that DNL343 did not significantly slow disease progression over placebo, as measured by ALS Functional Rating Scale-Revised (ALSFRS-R) — nor did it lead to statistically significant improvements in muscle strength or respiratory function.Last year, the biotech revealed that a separate ALS programme, its Sanofi-partnered RIPK1 inhibitor DNL788, had missed the ALSFRS-R primary endpoint in the Phase II HIMALAYA study. Shares in Denali dipped about 3% on Thursday.

From left: Terray CEO Jacob Berlin, Ph.D and CFO a Terray Therapeutics and Calico Life Sciences struck a research and development collaboration focused on the development of small-molecule therapeutics for age-related diseases. From left: Terray CEO Jacob Berlin, Ph.D and CFO and COO Eli Berlin/courtesy Terray Therapeutics Terray Therapeutics and Calico Life Sciences struck a research and development collaboration Wednesday focused on the development of small-molecule therapeutics for age-related diseases. The multi-target partnership will pair Terray’s tNova drug discovery and development platform with Calico’s target biology experience. The two companies intend to identify novel therapeutics for people impacted by diseases of aging, including cancer. The potential targets will be identified by Terray’s tNova platform, an engine the company noted is capable of billions of measurements made with “massive scale and precision.” Once the targets are identified, Calico, an Alphabet company, will then undertake responsibility for clinical development and potential commercialization. Terray launched earlier this year with $60 million. Terray’s internal programs are aimed at immunology where the company has identified a number of selective molecules. Currently, the internal programs are in the preclinical stage. The tNova platform generates precise chemical datasets that work alongside artificial intelligence to systematically map biochemical interactions between small molecules and the causes of different diseases. Researchers are then able to rapidly assess the potential efficacy in preclinical research in order to drive them into the clinic. Jacob Berlin, Ph.D., chief executive officer at Terray, told BioSpace the tNova platform is capable of measuring the interaction of small molecules and targets of interest in a matter of minutes. This allows the research team to refine their exploratory work for affinity and selectivity and hone in on the most promising approaches. At its core, Berlin said the issue in drug discovery isn’t an algorithm problem, it’s a data problem. To solve that, Terray built the platform to make the tests and iterate them in unsurpassed scale and precision. The platform is designed to power computational learning and reveal new interactions as quickly as possible. It relies on libraries built on reusable chips about the size of a nickel. Each chip holds 32 million different compounds to create the world’s densest microarray technology. “It’s not about compressing timelines but solving problems that can’t be solved with other technologies. We’ve seen the platform deliver starting points and solutions where others cannot,” he said. In a brief statement, Jonathan W. Lewis, Calico’s chief business officer, said the collaboration will allow for the discovery of first-in-class therapeutics against age-related diseases. The number of targets included in this collaboration was not disclosed. Berlin did note Calico is picking the targets in age-related disease and bringing them to Terray for assessment. Once the assessment is complete, Terray will then return the information to Calico, which will then begin development programs, Berlin said. Terray’s process can shave months off the average industry timeline for optimization and delivery into animal models, Berlin noted. Terray will receive an undisclosed upfront payment from Calico and be eligible for milestone payments, as well as royalties on any sales. “Our combined expertise will leverage the scale, precision, and speed of our tNova platform to rapidly discover and advance therapeutics for patients. We’re tackling some really interesting age-related diseases and we have an opportunity to transform people’s health,” Berlin said. Since its launch, California-based Calico has focused on the development of products and technologies that can extend and control one’s lifespan, as well as target age-related diseases, such as cancer and neurodegeneration. The company has forged a number of collaborations, including one with AbbVie valued at more than $1 billion . One asset that sprang from that partnership is ABBV-CLS-7262, which is being assessed in the HEALEY ALS Platform Trial. ABBV-CLS-7262 targets eIF2B, which is a key regulator of the integrated stress response, a pathway activated in people with ALS.

Bristol Myers Squibb (BMS) has opted-in to an exclusive global license for Evotec’s neurodegenerative drug EVT8683. The deal is the first programme to emerge from the two companies’ collaboration in neurodegeneration, which was initiated in 2016. Evotec originally signed the collaboration deal with Celgene, which was subsequently acquired by BMS in 2019. EVT8683 is a small molecule targeting a key cellular stress response which has the potential to deliver disease-modifying treatments for several neurodegenerative diseases. The EVT8683 programme originates from a phenotypic screen conducted by Evotec using its IPSC (induced pluripotent stem cell) drug discovery platform. Under the terms of the deal, Evotec has received an option payment of $20 m and is eligible to earn up to $250m in milestone payments. Cord Dohrmann, chief scientific officer of Evotec, commented: “We are very excited to bring a first drug candidate which originated from Evotec’s iPSC discovery platform into the clinic. EVT8683 is targeting a highly promising mechanism of the cellular stress response and has already demonstrated a very compelling pre-clinical efficacy and safety profile. Richard Hargreaves, senior vice president of BMS’s Neuroscience Thematic Research Centre, added: “Targeting one of the mechanisms which may play a key role within neurodegeneration makes us hopeful that our further development of the program may result in providing treatments for many people suffering from these devastating neurological disorders. Based on Evotec’s scientific expertise and seamless integration, we are delighted to continue development of this clinical candidate.”