Sanofi advances a new treatment for a rare, platelet-destroying disease

An oral treatment developed by the French pharma giant Sanofi raised platelet counts and reduced bleeding episodes in patients with a rare autoimmune disorder that causes the body to attack and destroy its own blood-clotting platelets.

In a randomized, Phase 3 study, the Sanofi drug, called rilzabrutinib, achieved an improved platelet response in 65% of participants with persistent or chronic immune thrombocytopenia (ITP) compared to 33% of participants on a placebo. A durable platelet response was reported in 23% of the rilzabrutinib group compared to no patients in the control arm. The drug also showed reductions in bleeding episodes and improvements in fatigue.

Rilzabrutinib is a bruton's kinase (Btk) inhibitor, a type of drug that is approved for use in treating forms of blood cancer. But rilzabrutinib appears to be safer and better tolerated than existing medicines in the class, said David Kuter, a physician and director of hematology at Massachusetts General Hospital, and an investigator in the Sanofi study.

Many patients with severe ITP receive transient benefits from currently available treatments or don't respond at all. The durability of platelet responses seen with rilzabrutinib, he added, could help establish the drug as a new standard treatment, Kuter added.

Sanofi has submitted rilzabrutinib to regulators in the U.S. and Europe, with a decision on a potential U.S. approval expected next August.

A Novo Nordisk pill seems to reduce severe sickle cell pain crises

An oral drug from Novo Nordisk appeared to improve the oxygen-carrying capacity of red blood cells and reduced the frequency of severe pain crises experienced by patients with sickle cell disease. The Phase 2 study results, if confirmed in a larger study, could lead to a new way of treating the debilitating blood disease that mostly affects people of African descent, including Black Americans.

Sixty participants entered the study experiencing an average of 3.3 severe pain crises per year. After one year in the study, the annualized rate of pain crises fell to just over one for participants treated with Novo's once-daily pill, called etavopivat, compared to just under two for participants on a placebo.

Statistically, etavopivat reduced the occurrence of pain crises by 46% compared to a placebo, although the improvement did not reach statistical significance. Etavopivat also increased levels of hemoglobin, the protein that helps red blood cells carrying oxygen and improved a measure of fatigue, both relative to placebo. Headaches, stomach discomfort, and elevated liver enzymes were the most commonly reported side effects.

Etavopivat belongs to a class of drugs that activate an enzyme called pyruvate kinase that red blood cells use to convert sugars into energy. The drug improves the health of red blood cells and slows their destruction.

"These results are encouraging," said Julie Kanter, a physician and director of the adult sickle cell program at the University of Alabama at Birmingham. Kanter was an investigator in the etavopivat study, and sees the drug, if eventually approved, as having the potential to become a standard treatment for the disease, alongside mainstay medicines like hydroxyurea.

Novo is conducting a larger Phase 3 study of etavopivat in sickle cell disease with results expected in 2026. Agios Pharmaceuticals is developing a similar drug, called mitapivat, also in a late-stage clinical trial.

The regulatory bar in the U.S. for the approval of new drugs to treat sickle cell disease has likely been raised after the recent market withdrawal of Oxbrytra, a sickle cell drug from Pfizer, due to safety concerns. With Oxbryta, the FDA loosened its standard and granted approval based on an improvement in hemoglobin, alone.

Kanter said she would like to see drugmakers design studies in sickle cell disease that use patient-reported outcomes, including but not solely focused on severe pain crises, as a more meaningful measure of overall patient benefit.

Assessing a drug based only on the frequency of severe pain crises that sends a person to the hospital is hard to standardize because individuals have different levels of pain tolerance or access to medicine and hospitals to treat pain, Kanter said.

Beam's CRISPR therapy for sickle cell yields consistent results with more patients

In more sickle cell news, seven patients treated with a CRISPR-based therapy from Beam Therapeutics have all produced more than 60% fetal hemoglobin, a healthy, normally functioning form of the oxygen-carrying molecule. Corresponding levels of sickled, or disease-causing, hemoglobin in the blood of all seven patients fell below 40%, Beam reported today.

No patients have reported severe pain crises since treatment with the Beam therapy, called BEAM-101, although follow-up time remains relatively short.

The updated study results are consistent with an analysis conducted on four patients that was reported in November.

BEAM-101 uses a newer, gentler form of CRISPR, called base editing. Base editing only "nicks" DNA and changes a single letter, rather than breaking an entire gene. The base-editing approach could lead to healthier cells and higher levels of fetal hemoglobin, compared to an older version of CRISPR used by Vertex Pharmaceuticals in its approved treatment, called Casgevy.

As previously reported, a participant in the Beam study died due to respiratory failure that was caused by the toxic chemotherapy regimen required to prepare the bone marrow before BEAM-101 can be administered.

Fertility preservation for sickle cell patients can be safe, but comes with extra considerations

Many sickle cell patients with severe disease wrestle with a heart-wrenching dilemma : potentially curative therapies carry the risk of infertility due to the treatment regimens that precede these therapies. New research presented at ASH underscores that, in the hands of experienced health care providers, fertility preservation before curative therapy is a viable option for patients — provided that they have access to the procedure.

Researchers reviewed medical records on sickle cell patients across five treatment centers who sought oocyte cryopreservation, in which a doctor uses hormones to coax ovaries to release immature eggs, or oocytes, which are then extracted and frozen. Out of 45 patients, 36 needed only a single cycle, while five needed at least two cycles of hormones because of a low cell yield the first time.

The researchers also saw that, in general, patients needed higher levels of the hormone gonadotropin to stimulate their ovaries compared to other young adults undergoing the procedure, and yet the ovaries of those with sickle cell still responded less to the hormone. But the number of oocytes retrieved and preserved was comparable between people with and without the disease.

Nearly half of the cryopreservation cycles were associated with a complication, including 19 cases of pain crises after oocytes were retrieved. Researchers found that having a complication was significantly more likely among patients who'd had at least three pain crises the year before.

"We can make this a safe procedure, and not to say that there won't be complications such as pain and repeat cycles," said Marti Goldenberg, a pediatric hematologist at Johns Hopkins and the study's first author. "This can be a great option for patients, as long as they're counseled."

A greater challenge, she added, is that only 21 states have laws requiring insurers to cover fertility services. More sickle cell patients are likely to seek these services with the advent of gene therapies from Vertex and CRISPR Therapeutics as well as Bluebird Bio. Vertex filed a lawsuit against the U.S. government earlier this year to allow the company to pay for fertility preservation services for people receiving its therapy, a step that currently risks violating federal law.

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