Progress towards new treatments for tuberculosis

Boosting the body's own disease-fighting immune pathway could provide answers in the desperate search for new treatments for tuberculosis.

Tuberculosis still represents an enormous global disease burden and is one of the top 10 causes of death worldwide.

Led by WEHI's Dr. Michael Stutz and Professor Marc Pellegrini and published in Immunity, the study uncovered how cells infected with tuberculosis bacteria can die, and that using new medicines to enhance particular forms of cell death decreased the severity of the disease in a preclinical model.

Fighting antibiotic resistance

Tuberculosis is caused by bacteria that infect the lungs, spreading from person to person through the air. A challenge in the fight against tuberculosis is that the bacteria that cause the disease have developed resistance to most antibiotic treatments, leading to a need for new treatment approaches.

Tuberculosis bacteria grow within immune cells in the lungs. One of the ways that cells protect against these 'intracellular' pathogens is to undergo a form of cell death called apoptosis—destroying the cell as well as the microbes within it.

Using preclinical models, researchers sequentially deleted key apoptosis effectors, to demonstrate their roles in controlling tuberculosis infections. This demonstrated that a proportion of tuberculosis-infected cells could die by apoptosis—opening up new opportunities for controlling the disease.

Using host-directed therapies to reduce disease burden

Dr. Stutz said researchers then tested new drugs that force cells to die. This revealed that a drug-like compound that inhibits cell death-regulatory proteins called IAPs could promote death of the infected cells.

"When we treated our infection models with this compound, we were able to significantly reduce the amount of tuberculosis disease," he said.

"The longer the treatment was used, the greater the reduction of disease."

The research team was able to replicate these results using various different IAP inhibitors.

"Excitingly, many of these compounds are already in clinical trials for other types of diseases and have proven to be safe and well-tolerated by patients," Dr. Stutz said.

"We predict that if these compounds were progressed for treating tuberculosis, they would be most effective if used alongside existing antibiotic treatments."

Opening the door to new treatment methods

Professor Marc Pellegrini said until now, antibiotics were the only treatment for tuberculosis, which were limited in their application due to increasing antibiotic resistance.

"Unlike antibiotics, which directly kill bacteria, IAP inhibitors kill the cells that the tuberculosis bacteria need to survive," he said.

"The beauty of using a host-directed therapy is that it doesn't directly target the microbe, it targets a host process. By targeting the host rather than the microbe, the chances of resistance developing are incredibly low."

The team hope the research will lead to better treatments for tuberculosis.

"This research increases our understanding of the types of immune responses that are beneficial to us, and this is an important step towards new treatments for tuberculosis, very few of which have been developed in the last 40 years," Dr. Stutz said.

"We have demonstrated that host-directed therapies are viable for infections such as tuberculosis, which is particularly important in the era of extensive antibiotic resistance."

https://www.sciencedirect.com/science/article/abs/pii/S1074761321002533?via%3Dihub

Oral Transglutaminase 2 Inhibitor Beneficial in Celiac Disease

For patients with celiac disease, treatment with a selective oral transglutaminase 2 inhibitor (ZED1227) attenuates gluten-induced duodenal mucosal damage, according to a study published in the July 1 issue of the New England Journal of Medicine.

Detlef Schuppan, M.D., Ph.D., from the Johannes Gutenberg University in Mainz, Germany, and colleagues conducted a proof-of-concept trial of a six-week treatment with ZED1227 at three dose levels versus placebo among adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point of attenuation of gluten-induced mucosal damage was assessed among 35, 39, 38, and 30 patients assigned to 10-mg, 50-mg, and 100-mg ZED1227 and placebo, respectively.

The researchers found that at all three dose levels, ZED1227 treatment attenuated gluten-induced duodenal mucosal injury. From baseline to week six, the mean ratio of villus height to crypt depth estimated difference from placebo was 0.44, 0.49, and 0.48 in the 10-, 50-, and 100-mg groups, respectively. For the change in intraepithelial lymphocyte density, the estimated differences from placebo were −2.7, −4.2, and −9.6 cells per 100 epithelial cells, respectively, for 10-, 50-, and 100-mg ZED1227. Symptom and quality-of-life scores may have been improved with use of the 100-mg dose.

"Although this trial is very encouraging, whether treatment with ZED1227, and more generally transglutaminase 2 inhibition, in patients with celiac disease will be efficient in real life and during long-term gluten exposure remains to be determined," writes the author of an accompanying editorial.

https://www.medchemexpress.com/zed-1227.html

Oral Transglutaminase 2 Inhibitor Beneficial in Celiac Disease  

Bayer Wins Approval for CKD Drug ......

The U.S. Food and Drug Administration (FDA) greenlit Bayer’s Kerendia (finerenone) to reduce the progression of chronic kidney disease associated with type 2 diabetes. The first nonsteroidal mineralocorticoid receptor antagonist (MRA) is approved for adults with chronic kidney disease associated with type 2 diabetes. 

Kerendia was explicitly approved to reduce the risk of kidney failure, heart attack, heart failure hospitalization, and cardiovascular death in adult patients with chronic kidney disease associated with type 2 diabetes. Although there are guideline directed therapies for CKD, many patients with chronic kidney disease associated with type 2 diabetes are at risk for disease progression and cardiovascular events. 

Amit Sharma, Vice President of Cardiovascular and Renal at Bayer, expressed excitement at bringing this new treatment for patients with CKD associated with type 2 diabetes. 

Kerendia acts by blocking the overactivation of the mineralocorticoid receptor, which contributes to fibrosis and inflammation. Those can then contribute to permanent structural kidney damage. 

“Chronic kidney disease associated with type 2 diabetes can have such a debilitating impact on patients’ lives. Unfortunately, this disease is far reaching, as up to 40 percent of all patients with type 2 diabetes develop chronic kidney disease,” Kevin Longino, chief executive officer of the National Kidney Foundation and a kidney transplant patient, said in a statement. “It is important for physicians and patients to have new treatment options that can slow chronic kidney disease progression.”

The FDA approved Kerendia based on data from the Phase III FIDELIO-DKD study. The trial demonstrated positive kidney and cardiovascular outcomes in patients with CKD associated with type 2 diabetes. 

Trial findings were published in the New England Journal of Medicine in 2020. Type 2 diabetes is the leading cause of end-stage kidney disease, when patients may need dialysis or a kidney transplant to stay alive. It is estimated that about 40% of all type 2 diabetes patients will develop chronic kidney disease. 

George Bakris, the lead study investigator for the FIDELIO-DKD study, said the patient populations included in the Phase IIII study were at risk of disease progression despite being on the current standard of care treatment to control blood pressure and blood glucose. The approval of Kerendia provides physicians with a treatment option that can give kidney protection, he said. 

Bayer expects Kerendia to be available for patients by the end of the month. The company is seeking approval in Europe. Kerendia was approved under both Fast Track and Priority Review designations. 

https://en.wikipedia.org/wiki/Finerenone

Drug could be promising new option against eczema

In continuation of my update on Upadacitinib

 

 

A pill called upadacitinib, already approved for treating rheumatoid arthritis, might also ease another common immunological condition—eczema.

In two phase 3 clinical trials, patients with moderate to severe eczema showed rapid and significant improvements after taking the drug, said researchers at Mount Sinai in New York City.

The clinical trials were funded by the dug's maker, AbbVie Inc., and included nearly 1,700 patients with the inflammatory skin condition.

"The results of these trials ... were so incredible that by week 16, most patients with moderate to severe atopic dermatitis [eczema] either had a 90% disease clearance, or even 100% disease clearance," study first author Dr. Emma Guttman-Yassky said in a Mount Sinai news release. She's professor and chair of the department of dermatology at Mount Sinai's Icahn School of Medicine, in New York City.

"We achieved extremely high clearance rates that are bringing us closer to the amazing clearance rates that we see in psoriasis," Guttman-Yassky noted.

According to the National Eczema Association, "people with eczema tend to have an over-reactive immune system that when triggered by a substance outside or inside the body, responds by producing inflammation. It is this inflammation that causes the red, itchy and painful skin symptoms common to most types of eczema."

Eczema affects more that 31 million American adults and between 10 to 20% of children, the study authors noted.

The two new clinical trials involved a total of almost 1,700 patients and took place between 2018 and 2020.

Besides the rapid disease clearance noted in patients, "the itch improvements already started to be significant within days from the beginning of the trials, and the maximum clinical efficacy was obtained early, at week 4, and maintained to week 16," Guttman-Yassky said.

The drug was well tolerated by patients who received the two highest doses of the drug—15 milligrams and 30 milligrams—and no significant safety risks were seen, she added.

Upadacitinib is already approved and marketed for use against rheumatoid arthritis under the brand name Rinvoq. It works by blocking what are known as multiple cytokine-signaling pathways—parts of the immune system that can malfunction and cause eczema.

According to Guttman-Yassky, other eczema therapies exist, but most come with certain drawbacks.

While injectable biologic drugs are highly successful in treating eczema patients who don't respond to or can't use topical creams, their use cannot be stopped and restarted at will, because the potential creation of anti-drug antibodies will shorten the half-life of the drugs, she explained.

However, "patients were able to start and restart [upadacitinib] at any time, allowing for flexibility, which cannot be achieved with biologics," Guttman-Yassky, said. "And, biologics, which are injectable agents that target specific lymphocytes that are 'misbehaving' or are up-regulated in atopic dermatitis, do not suppress the entire immune system as other immunosuppressants tend to do."

Dr. Michele Green is a dermatologist at Lenox Hill Hospital in New York City who wasn't involved in the new study.

She called the findings "important."

Upadacitinib is the first drug in its class "to be effectively used for patients with significant improvement of pruritus [itch] within several days of treatment and clearance of their disease within several weeks," Green noted.

"It is also significant since adolescents were included in this study and I believe an oral treatment is much more appealing to treating adolescents than current injectable biologics," she added.

 

 https://pubchem.ncbi.nlm.nih.gov/compound/Upadacitinib#section=2D-Structure