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Upcoming Phase 2a Trial To Test Oral Desidustat In Sickle Cell Disease

Zydus Lifesciences is launching a proof-of-concept Phase 2a clinical trial to evaluate the safety and efficacy of its oral candidate desidustat in people with sickle cell disease (SCD). The study is the result of a collaboration with the Indian Council of Medical Research (ICMR).

"Public-private partnerships in the healthcare sector is essential to deliver novel [drugs] to achieve the goals of the National Sickle Cell Anaemia Elimination Mission," Pankaj Patel, chairman of Zydus, said in a company press release. "The initiation of this study reaffirms hope for the 20 million sickle cell-affected patients in the country for a high potential novel treatment."

Desidustat is approved in India under the name Oxemia for treating people with anemia, or a shortage of red blood cells, associated with chronic kidney disease (CKD).

"Desidustat was invented in India, and patients with sickle cell disease need therapies in addition to the currently available drug, hydroxyurea," said Rajiv Bahl, MD, PhD, the secretary of the Government of India's department of health research and the director general at ICMR.

In SCD, mutations in the HBB gene give rise to a faulty version of hemoglobin, the protein that carries oxygen in red blood cells. As a result, red blood cells adopt a sickle-like shape, leading to their premature destruction and anemia. The misshapen and rigid cells can also block blood flow, causing episodes of severe pain called vaso-occlusive crises (VOCs).

According to India's National Health Mission, there are about 20 million people with SCD in the country, with an estimated 50,000 children born with sickle cell anemia, the most common type of SCD, each year. The National Sickle Cell Anaemia Elimination Mission was initiated to put an end to SCD as a public health problem in India before 2047.

Studying oral desidustat for sickle cell disease

Hydroxyurea, an oral medication approved to reduce the frequency of VOCs and lessen the need for blood transfusions, is a standard treatment for people with SCD. It's believed to work by increasing levels of fetal hemoglobin, an alternative version of hemoglobin made in early fetal development, but not after birth. Hydroxyurea is not universally effective, however, and is associated with side effects like low levels of immune neutrophils and clotting-promoting platelets, according to Zydus. And while blood transfusions provide a source of healthy red blood cells, they can be expensive and inaccessible to many. They can also trigger adverse immune responses, red blood cell destruction, and iron overload.

Desidustat, developed by Zydus, stimulates the production of erythropoietin (EPO), a signaling molecule mainly secreted by the kidneys in response to low blood oxygen levels, activating the production of red blood cells in bone marrow.

Phase 2 trial data showed desidustat increased hemoglobin levels in a dose-dependent manner in people with anemia secondary to CKD. The therapy was also not inferior to standard treatments for patients undergoing dialysis and those not having dialysis in Phase 3 studies. Dialysis is a procedure that helps the body remove extra fluid and waste products from the blood when the kidneys are unable to.

The new multicenter, proof-of-concept Phase 2a trial (CTRI/2024/06/068363) will evaluate oral tablets of desidustat against a placebo in SCD patients.

The study's primary goal is to assess the proportion of patients with a hemoglobin response, defined as an increase in hemoglobin of at least 1 g/dL after four and eight weeks. Key secondary goals include changes in hemoglobin levels and percentage of sickle hemoglobin, along with the proportion of patients needing blood transfusions or experiencing VOCs.

The trial will be co-funded and co-monitored by ICMR's Indian National Clinical Trial and Education Network (INTENT).

"This collaboration reflects our commitment to advancing clinical research in India through strategic public-private partnerships," Bahl said. "Our vision is to ensure that India continues to lead in the development of innovative and affordable healthcare solutions."

Oral AND017 Granted Orphan Drug Status For SCD

The U.S. Food and Drug Administration has granted orphan drug status to Kind Pharmaceuticals' investigational oral small molecule AND017 to treat sickle cell disease (SCD).

This designation is granted to potential treatments for rare diseases, or those affecting fewer than 200,000 people in the U.S. It provides incentives like tax credits for clinical trials, exemption from certain fees, and seven years of market exclusivity if an approval is ultimately granted.

"The FDA's granting of ODD [orphan drug designation] for AND017 underscores the urgent medical need for new therapies, particularly oral drugs to safely and effectively treat patients with SCD," Dong Liu, PhD, Kind's founder, chairman, and CEO, said in a company press release.

SCD results from mutations in the gene coding for hemoglobin, a protein that carries oxygen in red blood cells. The mutated protein causes red blood cells to take on a sickle-like shape. These misshapen red blood cells block small blood vessels, leading to organ damage and painful episodes known as vaso-occlusive crises. They are also prone to break down easily, causing anemia.

AND017 inhibits an oxygen-sensitive enzyme called hypoxia-inducible factor prolyl hydroxylase (HIF-PH). This tricks the body into thinking that oxygen levels are falling below normal levels, which signals the bone marrow to produce more red blood cells.

Better safety, efficacy

In preclinical studies, AND017 appeared to be safe and work as intended. For Gang Huang, PhD, a professor at the University of Texas Health San Antonio who was involved in those studies, AND017 "might not only provide a novel oral treatment with unique mechanism of action, but also an obvious better safety and efficacy profile."

"Hydroxyurea and L-glutamine [marketed as Endari] are the limited FDA-approved oral treatments for SCD," Huang said. "I am eager to see how a compound with such unbelievable preclinical safety and efficacy data will translate to real world SCD patients."

Because AND017 triggers the production of red blood cells, it is also being developed to treat anemia due to other conditions, including chronic kidney disease, cancer, myelodysplastic syndrome, and beta-thalassemia, another disease marked by reduced levels of hemoglobin.

AND017 has been tested in two Phase 1 studies in healthy volunteers: one in Australia (NCT04751539) that evaluated multiple doses of the therapy a single time or once daily for 10 days, and another in China (NCT04712500), which examined whether the oral therapy can be taken with food.

In the Australian study, AND017 showed safe, predictable behavior in the body across single and multiple doses, with elimination half-lives (the time taken for its levels to halve) from 10.1 to 19.7 hours. In the study in China, food did not affect the levels of AND017, indicating the treatment can be taken with or without food.

Two Phase 2 studies (NCT05035641 and NCT05265325) have also investigated it in people with chronic kidney disease at sites in the U.S. And China. In both studies, treatment with AND017 increased or maintained the levels of hemoglobin in the blood and was well tolerated.

National Summit Focuses On Sickle Cell

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By Genoa BarrowOBSERVER Senior Staff Writer

Sickle cell disease continues to get national attention. In observance of September as Sickle Cell Awareness month, the U.S. Department of Health and Human Services hosted its first Sickle Cell Disease Summit late last month.

The event, held in person in Washington D.C. And livestreamed, featured remarks from sickle cell warriors, health providers, lawmakers and other stakeholders. The theme of the summit was "Empowered and Thriving SCD Warriors and Communities" and is part of HHS's commemoration of Sickle Cell Awareness Month.

Hosts called the summit an opportunity to connect the SCD community with new audiences around a shared vision of accelerating advancements in SCD care, research, and quality of life.

Opening remarks came from HHS Secretary Xavier Becerra.

"No one with SCD should have to fight stigma and bias to access the lifesaving care they need," Becerra said. "Today's summit unites experts and warriors with lived experience, all with one goal: to secure a quality life for everyone affected by this disease and ultimately end the power and hold of SCD."

Panel discussions included "Gradually, then Suddenly: The History and Current State of SCD Therapies," "Meeting Warriors Where They Are: Advancements in Access to Care" and "Reproductive Health and Sickle Cell." The latter featured "Deadpool & Wolverine" actress Wunmi Mosaku, who shared her personal journey with in vitro fertilization for the first time publicly. She and her husband, both Nigerian, have the sickle cell trait, or SCT. She knew her status, but her husband only found out for sure through genetic counseling in 2020. According to the Centers for Disease Control and Prevention, if both parents have SCT, there is a 25% chance that a baby born to them will have SCD. There's also a 25% chance that the child won't have SCD or SCT.

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"We were a little naive and we thought maybe we should take this opportunity to really do our homework. We learned so much," said Mosaku, who appears in the new Ryan Coogler horror film "Sinners."

Armed with new knowledge, the couple decided to undergo IVF with genetic testing.

"I just felt like there was so much I didn't know and until we knew we both had the trait, then people in my community kind of talked to me about what it's like to be a carrier or to have the disease," Mosaku said.

The actress thanks sickle cell "warriors" for educating her.

"I am indebted to you," said Mosaku, who gave birth to a daughter in 2023. "My family is indebted to you because I felt like I was able to make an informed decision."

Mary Brown, president and CEO of California's Sickle Cell Disease Foundation, participated on a panel titled "State and Private Sector Innovations in Sickle Cell Care." Brown spoke of learning how to advocate and push for better resources and creating 12 adult Sickle Cell Centers of Excellence, also known as Networking California for Sickle Cell Care, or NCSCC.

"People in California were dying way too early," she said. "And frankly I was a little tired of going to funerals. I was also tired of sitting in [rooms] with a lot of well-intentioned people who talked about resolutions, but never any action. We came to this place where we had to get something done."

Sickle cell has been in the spotlight of late. Gov. Gavin Newsom recently signed Assembly Bill 107, the Budget Act of 2024, which includes a one-time appropriation of $5 million to the California Department of Public Health to continue funding the NCSCC clinics.

Brown calls the allocation "crucial."

"California stands as a national leader in advancing sickle cell disease care, with initiatives like Networking California for Sickle Cell Care setting a gold standard," Brown said in a joint statement with NCSCC co-founder Dr. Diane Nugent.

"This funding represents a significant stride toward ensuring that every person affected by sickle cell disease receives the highest standard of care and support they deserve," Dr. Nugent added.

One day after the sickle cell summit, the pharmaceutical company Pfizer voluntarily withdrew the sickle cell disease treatment Oxbryta from worldwide markets, stating "clinical data that now indicates the overall benefit no longer outweighs the risk in the approved sickle cell patient population."

Dr. Clarice Reid receives the prestigious Assistant Secretary for Health's Exceptional Service Medallion during the summit for her contributions to public health and her tireless advocacy for the warrior and research communities. Photo Courtesy U.S. Department of Health and Human Services

The move, Dr. Nugent said, exacerbates "an already limited supply of treatment options."

"While Pfizer's announcement marks a setback in the SCD treatment landscape, it also highlights the urgent – and ongoing – need to meaningfully address systemic inequities affecting the SCD community," she continued.

Networking California for Sickle Cell Care provides specialized care to SCD patients, aiming to improve their disease management, reduce emergency room visits, and enhance their overall well-being through proactive, patient-centered treatment plans. The group has vowed to fill the gap left by this treatment withdrawal with comprehensive care options.

"People with this disease don't want anything more than anyone else," Brown said. "They want to live high-quality lives. They want to be able to do what they want to do."

Editor's note: To read stories from Senior Staff Writer Genoa Barrow's award-winning series, "Painfully Aware: Understanding Sickle Cell and Its Impact on the African American Community," visit SacObserver.Com.

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