SAN DIEGO —The 65th annual meeting of the American Society of Hematology got a dramatic introduction. On Friday, as researchers and doctors arrived here, the Food and Drug Administration approved two gene therapies for sickle cell disease, an inherited condition that for several years now has been a regular focus on the conference.
“ASH 2023 is going to be marked by these two FDA approvals,” said Alexis Leonard, a hematologist and assistant faculty member at St. Jude Children’s Research Hospital. “This is 10 years’ worth of clinical trial work and 30 years of basic science culminating in what happened yesterday.”
Both Vertex Pharmaceuticals and Bluebird bio, respectively makers of the two therapies, are at ASH with updated data for their treatments, which will soon be available in the U.S. for people with sickle cell aged 12 years or older. For Bluebird, it’s the seventh year running that it has presented sickle cell data here.
While the approval news may be the biggest headline, there are many other studies of note, including one of CAR-T therapy in autoimmune disease and another highlighting the difference between the trial setting and the real world.
CAR-T’s next use case
Could CAR-T cell therapy’s next application be in treating autoimmune disease? A small academic study in Germany is offering clues.
An initial slice of data, from the first five study participants, drew attention to the question last year. At ASH on Saturday, researchers led by Fabian Mueller of the Bavarian Cancer Research Institute presented new results from 15 patients with lupus or two other autoimmune diseases.
Their findings suggest CAR-T therapy, currently used for blood cancers like leukemia and lymphoma, could treat those immune conditions, too.
“All [patients] remain in complete remission since we have treated them with CD19 CAR-T cells,” said Mueller, at an ASH press conference Saturday. “At least for now, it’s a lasting remission.”
In a related statement, he shared how the first lupus patient treated with CAR-T in the trial was so sick at the time that she wasn’t expected to live much longer than a month. Now she’s running five days a week, he said.
The rationale for using CAR-T in autoimmune diseases has to do with how the treatments work. They consist of a patient’s own immune cells, engineered to target a protein called CD19 that’s typically found on the surface of B cell cancers. But it appears these souped-up cells can also destroy misfiring B cells that are responsible for the immune attack that inflammatory diseases like lupus inflict on the body.
So far, the 15 patients in the study have been followed for a median of 15 months after their CAR-T infusions. All are doing well and have stopped taking immunosuppressive drugs. Two-thirds experienced a mild form of cytokine release syndrome, an immune side effect of CAR-T therapy, but there were no serious treatment-related adverse events.
Mueller and his fellow researchers are hopeful their findings could lead to an alternative treatment to autologous stem cell transplant in people with life-threatening autoimmune diseases.
“Of course we need longer follow-up to establish how effective the treatment is going to be in the long run,” said Mueller.
There are signs drugmakers are paying attention. A group of biotechnology companies are exploring whether a special type of immune cell called Tregs could be used for autoimmune cell therapies. And earlier this month, CRISPR Therapeutics, in a research pivot, said it was planning to test one of its experimental CAR-T therapies in lupus.
One potential hurdle? An investigation by the FDA into the possible risk of T cell malignancies in people who received CAR-T therapies for cancer. While the agency believes the benefits outweigh the risks, that balance might be different in autoimmune diseases.
Efficacy versus effectiveness
Randomized clinical trials are the most powerful tool drug researchers have. Matching two groups of patients, assigning one an experimental therapy and the other a placebo or known treatment, can produce convincing answers about which medicines work and which don’t.
But as controlled experiments, they don’t always mirror patients’ reality. For instance, researchers might exclude certain people from a trial, such as those who are sicker, or only enroll people from a specific demographic group.
Alissa Visram, a doctor at the Ottawa Hospital Research Institute in Canada, set out to study this issue, comparing the “efficacy” of multiple myeloma drug regimens in clinical trials to the “effectiveness” they actually had in the real world.
“The criteria for clinical trial eligibility are often quite stringent, so the results are not always generalizable,” Visram said in a statement about research that will be presented at ASH Sunday.
Their findings are sobering. Among nearly 4,000 people with the blood cancer who were treated in Ontario, Canada, between 2007 and 2020, outcomes were markedly worse for six standard drug regimens than the respective marks in Phase 3 studies.
Median progression-free survival, a measure of how long until a person’s disease progresses or death, was between three and 18 months shorter in the real world than in trials, depending on the regimen. Median overall survival was at least 19 months shorter outside of clinical testing across the six treatments.
“Understanding the effectiveness of treatments is important for policymakers who regulate the use of drugs, but also for patients and clinicians to make informed treatment decisions,” said Visram at a press conference held by ASH.
A seventh regimen, Bristol Myers Squibb’s Pomalyst with the steroid dexamethasone, actually performed better in the real world than in trials, Visram and her colleagues found.
“We think that this is because this was the only regimen where the prior treatment exposures were comparable between the real world and trial controls,” Visram said at the press conference.
They didn’t design their research, which relied on public health records, to determine what caused the “efficacy-effectiveness” gap, but noted that, on average, people included in their real world analysis were older and had more comorbidities than those who were in the comparator trials.
Sickle cell’s social media mentions
People with sickle cell disease routinely face obstacles to receiving proper care, particularly during the acute pain crises they experience. Managing such crises can require emergency room treatment and strong painkillers like opioids, which doctors may misconstrue as drug seeking or be hesitant to prescribe.
To document some of those barriers, researchers at Pfizer turned to social media, parsing more than 45,000 posts on platforms such as Instagram and TikTok for conversations related to sickle cell.
Their findings may not be surprising, but the researchers describe their study as an innovative way to capture patients’ voices in a format where people are more likely to be candid.
“If you were to ask patients about their sickle cell disease care in the clinic, it is likely you would get a filtered response,” Oliver Shastri, a rare disease team lead at Pfizer who led the research, said in an ASH statement.
Shastri and his colleagues worked with data analysts to mine social media posts by U.K. users for key search terms such as the disease name, treatments and hashtags, results from which they organized using a computer algorithm. They then validated and contextualized the resulting output manually.
Many of the posts showed patients experienced “a lack of empathy from healthcare providers” and discrimination in seeking care. Patient posts also expressed a sense that their symptoms were dismissed or underestimated by physicians.
“Social media listening offers a novel and quantifiable method of capturing the patient’s digital voice, where traditionally gathering these insights was limited by geography or the high burden of administration,” Shastri said in the statement.
Pfizer sells one drug, Oxbryta, for sickle cell disease and is developing another, data for which was presented Saturday at ASH.
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- Source: https://www.biopharmadive.com/news/ash-2023-car-t-autoimmune-multiple-myeloma-real-world/702082/