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AstraZeneca is bolstering its rare disease pipeline with a deal to buy Amolyt Pharma, a biotech company in late-stage development with a therapy designed to treat a rare hormone deficiency whose only FDA-approved treatment will soon cease production. According to deal terms announced Thursday, AstraZeneca is paying Amolyt shareholders $800 million up front. Another $250 million is tied to the achievement of a regulatory milestone that was not disclosed. Considering that the drug is in Phase 3 testing, that milestone could be a regulatory approval. Lyon, France-based Amolyt is developing a therapy for hypoparathyroidism, a disease in which the parathyroid glands do not produce enough parathyroid hormone. This hormone is important for regulating calcium and phosphate levels in the blood. Disease symptoms include tingling or burning sensations in the fingertips and toes, muscle aches or cramps, muscle twitching or spasms, and fatigue. Hypoparathyroidism disproportionately affects women. Calcium and vitamin D supplements can help, but at high doses, calcium supplements can lead to gastrointestinal problems such as constipation. When supplements alone aren’t enough to manage hypoparathyroidism, the only FDA-approved therapy is Natpara, an engineered version of parathyroid hormone sold by Takeda Pharmaceutical. Amolyt could bring patients a different way to manage hypoparathyroidism. The biotech’s drug candidate, eneboparatide, is a peptide designed to bind to PTH receptor 1, the receptor that native parathyroid hormone binds to. In Phase 2 results reported in 2022, Amolyt said its drug led to normal calcium levels in the blood as well the potential to eliminate the need for daily calcium and vitamin D supplements. Furthermore, the drug preserved bone mineral density, which is important for patients at higher risk of developing bone problems such as osteopenia or osteoporosis. The market need for new hypoparathyroidism treatments is becoming urgent. Takeda’s Natpara (Natpara outside of the U.S.) has had a rocky commercialization history since its FDA approval in 2015. In 2019, the FDA issued a recall due to potential contamination from tiny rubber particles from the cartridge housing the injectable product. Takeda’s efforts to resolve the problem to the FDA’s satisfaction have been unsuccessful. In late 2022, Takeda said it planned to discontinue manufacturing of Natpara/Natpar by the end of 2024. After that, the company said it would supply the remaining doses of the drug until inventory is depleted or the product is expired. The Amolyt acquisition brings AstraZeneca into a group of companies vying to fill the hypoparathyroidism treatment need that will be left when Takeda’s drug is no longer available. Extend Biosciences is in Phase 1 testing with a drug derived from parathyroid hormone. MBX Biosciences has reached Phase 2 testing with a peptide drug. Both drug candidates are injectable. Septerna is developing an oral drug for hypoparathyroidism. Last year, the South San Francisco-based startup raised $150 million in financing to advance the small molecule to Phase 1 testing. Amolyt last raised money in early 2023, a €130 million (about $138 million) Series C financing to support its pipeline. Besides the hypoparathyroidism program, that pipeline includes AZP-3813, a potential treatment for acromegaly, a disease in which the body produces too much growth hormone. Phase 1 testing began last summer. Amolyt has said it expects preliminary data in the first half of 2024. AstraZeneca expects to complete the Amolyt acquisition by the end of the third quarter of this year. When the deal closes, Amolyt will become part of Alexion, AstraZeneca Rare Disease, the pharmaceutical giant’s Boston-based rare disease division. AstraZeneca said the acquisition will enable it to expand its rare disease research into endocrinology. “Chronic hypoparathyroid patients face a significant need for an alternative to current supportive therapies, which do not address the underlying hormone deficiency,” Marc Dunoyer, CEO of Alexion, AstraZeneca Rare Disease, said in a prepared statement. “As leaders in rare disease, Alexion is uniquely positioned to drive the late-stage development and global commercialization of eneboparatide, which has the potential to lessen the often debilitating impact of low parathyroid hormone and avoid the risks of high-dose calcium supplementation.”

Gut bacteria and a diet rich in the amino acid tryptophan can play a protective role against pathogenic E. coli, which can cause severe stomach upset, cramps, fever, intestinal bleeding and renal failure. Gut bacteria and a diet rich in the amino acid tryptophan can play a protective role against pathogenic E. coli, which can cause severe stomach upset, cramps, fever, intestinal bleeding and renal failure, according to a study published March 13 in Nature. The research reveals how dietary tryptophan -- an amino acid found mostly in animal products, nuts, seeds, whole grains and legumes -- can be broken down by gut bacteria into small molecules called metabolites. It turns out a few of these metabolites can bind to a receptor on gut epithelial (surface) cells, triggering a pathway that ultimately reduces the production of proteins that E. coli use to attach to the gut lining where they cause infection. When E. coli fail to attach and colonize the gut, the pathogen benignly moves through and passes out of the body. The research describes a previously unknown role in the gut for a receptor, DRD2. DRD2 has otherwise been known as a dopamine (neurotransmitter) receptor in the central and peripheral nervous systems. "It's actually two completely different areas that this receptor could play a role in, which was not appreciated prior to our findings," said Pamela Chang, associate professor of immunology in the College of Veterinary Medicine and of chemical biology in the College of Arts and Sciences. "We essentially think that DRD2 is moonlighting in the gut as a microbial metabolite sensor, and then its downstream effect is to help protect against infection." Samantha Scott, a postdoctoral researcher in Chang's lab, is first author of the study, "Dopamine Receptor D2 Confers Colonization Resistance via Microbial Metabolites." Now that Chang, Scott and colleagues have identified a specific pathway to help prevent E. coli infection, they may now begin studying the DRD2 receptor and components of its downstream pathway for therapeutic targets. In the study, the researchers used mice infected with Citrobacter rodentium, a bacterium that closely resembles E. coli, since certain pathogenic E. coli don't infect mice. Through experiments, the researchers identified that there was less pathogen and inflammation (a sign of an active immune system and infection) after mice were fed a tryptophan-supplemented diet. Then, to show that gut bacteria were having an effect, they gave the mice antibiotics to deplete microbes in the gut, and found that the mice were infected by C. rodentium in spite of eating a tryptophan diet, confirming that protection from tryptophan was dependent on the gut bacteria. Then, using mass spectrometry, they ran a screen to find the chemical identities of tryptophan metabolites in a gut sample, and identified three such metabolites that were significantly increased when given a tryptophan diet. Again, based on pathogen levels and inflammation, when these three metabolites alone were fed to the mice, they had the same protective effect as giving the mice a full tryptophan diet. Switching gears, the researchers used bioinformatics to find which proteins (and receptors) might bind to the tryptophan metabolites, and from a long list they identified three related receptors within the same family of dopamine receptors. Using a human intestinal cell line in the lab, they were able to isolate receptor DRD2 as the one that had the protective effect against infection in the presence of tryptophan metabolites. Having identified the metabolites and the receptor, they analyzed the downstream pathway of DRD2 in human gut epithelial cells. Ultimately, they found that when the DRD2 pathway was activated, the host's ability to produce an actin regulatory protein was compromised. C. rodentium (and E. coli) require actin to attach themselves to gut epithelial cells, where they colonize and inject virulence factors and toxins into the cells that cause symptoms. But without actin polymerization they can't attach and the pathogen passes through and clears. The experiments revealed a new role of dopamine receptor DRD2 in the gut that controls actin proteins and affects a previously unknown pathway for preventing a pathogenic bacteria's ability to colonize the gut. Jingjing Fu, a former postdoctoral researcher in Chang's lab, is a co-author. The study was supported by the Arnold and Mabel Beckman Foundation, a President's Council of Cornell Women Affinito-Stewart Grant, the National Institutes of Health and a Cornell Institute of Host-Microbe Interactions and Disease Postdoctoral Fellowship.

Immuron proceeding to Phase 3 registration strategy with the FDA Travelan® topline clinical trial results demonstrate protective efficacy with single daily dose 36.4% protective efficacy against Enterotoxigenic Escherichia coli (ETEC) induced moderate to severe diarrhea was observed in the Travelan® group compared to the placebo group (primary endpoint) 66.7% protective efficacy against ETEC induced severe diarrhea was observed in the Travelan® group compared to the placebo group (secondary endpoint) 83.3% statistically significant reduction in the number of subjects in the Travelan® group requiring early antibiotic treatment post challenge compared to the placebo (secondary endpoint) 100% of the subjects requiring IV fluids post challenge were in the placebo (secondary endpoint) 55.6% reduction in the number of subjects experiencing adverse events associated with the ETEC challenge observed in the Travelan® group compared to the placebo group (secondary endpoint) Phase 2 clinical study data supports the excellent safety and tolerability pro Travelan® MELBOURNE, Australia, March 07, 2024 (GLOBE NEWSWIRE) -- Immuron Limited (ASX: IMC; NASDAQ: IMRN), an Australian based and globally integrated biopharmaceutical company is pleased to announce the interim topline results confirming that a single daily dose of Travelan® is effective in prevention of moderate to severe diarrhea following challenge with enterotoxigenic Escherichia coli (ETEC). Immuron was awarded AU $4.8 (USD $3.43) million funding by the U.S. Department of Defense (ASX Announcement 12 January 2022) to perform a randomized double-blind placebo-controlled phase 2 controlled human infection model (CHIM) study to assist with evaluating a dosing regimen that is most suited to deployed US troops visiting developing countries. Healthy volunteers were recruited and randomly assigned to receive a single daily oral dose of 1200 mg of Travelan® or placebo. Dosing commenced 2 days prior to challenge with ETEC strain H10407 and continued for 7 days. ClinicalTrials.gov Identifier: NCT05933525. This interim analysis summarizes the data for a total of 60 subjects who have completed the inpatient challenge component of this current clinical study. Last patients last visits are anticipated to commence in April this year and final clinical study report will be completed in H2 2024. Having demonstrated protective efficacy in two published clinical studies (Otto et al., 2011), this Phase 2 study was designed to compare the preventative effects of once daily dosing to the current standard recommended treatment of three times daily dosing. To learn more about Phase 2 study design, read: U.S. Food and Drug Administration Step 3: Clinical Research IMM-124E (Travelan®) will be the first product developed with Immuron’s platform technology to proceed into Phase 3 clinical trials. The underlying nature of Immuron’s platform technology enables the development of medicines across a large range of infectious diseases. The platform can be used to block viruses or bacteria at mucosal surfaces such as the Gastrointestinal tract and neutralize the toxins they produce. More information on Immuron’s platform technology can be found below. Travelan® demonstrated clinical efficacy in preventing ETEC-attributable diarrhea in two previous CHIM studies (Table 1). These studies showed dosing 400 mg three times daily, resulted in 76.7% (p=0.007) to 90.9% (p=0.0005) protection (Otto et al., 2011). This trial demonstrated protective efficacy* with once daily dosing even though the attack rate for this study was much lower than planned. The intended attack rate (percentage of subjects with ETEC-induced moderate- severe diarrhea) for this study was approximately 70%. The attack rate for the Placebo group of this study was only 37% (Table 2). Given the lower than planned attack rate, this current study is underpowered to appropriately detect a significant difference in moderate to severe ETEC attributed diarrhea in the Placebo group compared to the Treatment group. This makes the demonstration of protective efficacy and reduction in adverse events and diarrheal symptoms particularly noteworthy. The company will now proceed to hold an end of Phase 2 meeting with the U.S Food and Drug Administration to discuss the pivotal Phase 3 registration strategy and planned clinical trials including recommended dosing to support a Biologics License Application (BLA) for Travelan® as a prophylactic medicine for Travelers’ Diarrhea. A preventative treatment that defends against infectious enteric diseases is a high priority objective for the U.S. Military. Immuron is in the process of exploring non-dilutive funding opportunities for these Phase 3 clinical trials. Topline results: Travelan®, a first-in-class, oral antibody therapy, dosed once daily resulted in a reduction ETEC-induced moderate-severe diarrhea compared to placebo. ETEC-induced moderate to severe diarrhea was reduced by 36.4% in the Travelan® group compared to the placebo group Protective efficacy of once daily dosing shown to be approx. 50% as effective as the current recommended three times daily dosing regimen; this is a strong result given the lower than expected attack rate 66.7% protective efficacy against ETEC induced severe diarrhea was observed in the Travelan® group compared to the placebo group Statistically significant reduction of 83.3% in the subjects in the Travelan® group requiring early antibiotic treatment post challenge compared to the placebo For the subjects requiring intravenous rehydration post challenge 100% were in the placebo group and none were in the Travelan® group 55.6% reduction in the number of subjects experiencing adverse events post the ETEC challenge was observed in the Travelan® group compared to the Placebo group Studies using the CHIM for a variety of different enteric pathogens suggest the greatest protection may be against more severe disease and in studies where the disease appears to be predominately mild, which appears to be the case in this study, the efficacy estimates can be lower than anticipated. Table 1: Summary of current clinical study data Event post challenge Travelan® n = 30 n (%) Placebo n = 30 n (%) Reduction in AEs or Symptoms (%) P value Primary Endpoint Number (n) of subjects with ETEC-induced moderate- severe diarrhea 7 (23.3%) 11 (36.7%) NA 0.399 Protective efficacy [%]1 95% 2-sided Confidence Interval2 36.4%* (-79.8%, 79.1%) Secondary Endpoints - Safety and tolerability Number of subjects with an adverse event (AE) 95% 2-sided Confidence Interval2 4 (13.3%) (-3.8%, 37.1%) 9 (30.0%) 55.6% 0.1172 Number of subjects with (AEs) fever, nausea, anorexia, or abdominal pain/cramps rated as moderate to severe 95% 2-sided Confidence Interval2 3 (10.0%) (-5.2%, 31.9%) 7 (23.3%) 57.1% 0.1659 Secondary Endpoints – Degree to which a participant experiences diarrheal symptoms Number of subjects who experienced severe diarrhea 95% 2-sided Confidence Interval2 1 (3.3%) (-5.8%, 19.2%) 3 (10.0%) 66.7% 0.3006 Number of subjects requiring early antibiotic treatment 95% 2-sided Confidence Interval2 1 (3.3%) (1.0%, 32.4%) 6 (20.0%) 83.3% 0.0444 Number of subjects requiring IV fluids 95% 2-sided Confidence Interval2 0 (-0.7%, 20.7%) 3 (10.0%) 100.0% 0.0756 1 Fishers exact test and binomial distribution 2 Chi-square test AE = Adverse event associated with the ETEC challenge * Intent-to-treat analysis set defined as randomized subjects who received study medication and were challenged Table 2: Comparison of clinical study data attack rates Event post challenge Otto3 Study 1 Placebo n = 15 n (%) Otto3 Study 2 Placebo n = 14 n (%) Current Travelan® Study n = 30 n (%) Number (n) of subjects with ETEC-induced moderate- severe diarrhea 11 (73%) 12 (86%) 11 (37%) 3Otto et al., 2011 Immuron is investigating the impact of the lower than expected attack rate. Immuron has filed a provisional patent application with the U.S. Patent Office including results from this trial. This release has been authorized by the directors of Immuron Limited. COMPANY CONTACT: Steven Lydeamore Chief Executive Officer steve@immuron.com About Immuron Immuron Limited (ASX: IMC, NASDAQ: IMRN), is an Australian biopharmaceutical company focused on developing and commercializing orally delivered targeted polyclonal antibodies for the treatment of infectious diseases. For more information visit: and Subscribe for Immuron News: Here