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ASH Gene Therapy Highlights in Hemophilia, TDT: Vertex Pharmaceuticals, CSL Behring, and More

Stock photo of red blood cells

NEW YORK – Drugmakers and researchers at the American Society of Hematology's annual meeting in San Diego reported data on gene therapies for various genetic blood disorders. Below are brief reports on data readouts from the conference.

Vertex Pharmaceuticals' Casgevy

More than 90 percent of patients with transfusion-dependent beta thalassemia (TDT) who received a single infusion of Vertex Pharmaceuticals and CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) have achieved transfusion independence.

Casgevy involves editing patients' autologous CD34-positive hematopoietic stem cells ex vivo with CRISPR-Cas9 to alter the BCL11A gene. The genetic alteration aims to increase production of fetal hemoglobin, a protein that carries oxygen and the adult form of which is dysfunctional in patients with TDT.

The UK Medicines and Healthcare Products Regulatory Agency last month granted Vertex conditional marketing authorization for Casgevy as a treatment for sickle cell disease and TDT. In the US, it has earned approval from the US Food and Drug Administration for the sickle cell indication, but the agency isn't expected to issue a decision on the TDT indication until March 30, 2024.

The analysis presented at the meeting is based on 52 TDT patients who received the gene-editing therapy within Vertex's ongoing pivotal Phase III CLIMB THAL-111 trial. Of 35 patients with at least 16 months of follow-up data, 91 percent achieved transfusion independence, maintaining a weighted average hemoglobin of at least 9 grams per deciliter without red blood cell transfusion for at least a year. Patients on average stopped transfusions 35.2 days after infusion with Casgevy and remained transfusion independent for 22.5 months.

Prior to treatment with Casgevy, patients on average had 37.1 red blood cell transfusions per year. For the three patients who did not achieve 12 consecutive months of transfusion independence, two were transfusion-free for 7.3 months and 4 months, and the other experienced a nearly 84 percent reduction in annualized red blood cell transfusion volume. 

On average, patients' total hemoglobin after three months was 11.4 grams per deciliter, with at least 12 grams per deciliter after six months.

The proportion of edited BCL11A genes was stable in bone marrow and peripheral blood cells. "It was sustained over time, suggesting a long-term, meaningful benefit after the exa-cel [treatment]," said Franco Locatelli, head of the pediatric hematology and oncology department at IRCCS Bambino Gesù Children's Hospital in Rome.

All patients had at least one adverse event, and 88.5 percent of patients had adverse events of grade 3 or higher. The most common issues were febrile neutropenia, headache, and stomatitis.

Two patients had serious adverse events due to Casgevy, specifically headache, hemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, and idiopathic pneumonia syndrome, all of which resolved. There were no deaths, trial discontinuations, or malignancies.

Pfizer's giroctocogene fitelparvovec

A single infusion of Pfizer's giroctocogene fitelparvovec nearly eliminated bleeding episodes in patients with severe hemophilia A, also known as classical hemophilia, a rare bleeding disorder caused by mutations in the F8 gene and a lack of the FVIII blood-clotting protein it encodes.

Giroctocogene fitelparvovec, a gene therapy developed under a collaboration between Pfizer and Sangamo Therapeutics, is designed to treat the condition by delivering modified F8 complementary DNA with an adeno-associated virus serotype 6 vector, which aims to enable synthesis of functional endogenous FVIII proteins. With the gene therapy, Pfizer is hoping to boost patients' FVIII activity into the mild to normal ranges, defined as between 5 percent and 40 percent of factor activity in the blood or more than 50 percent, respectively.

Investigators at the meeting presented follow-up data from the ongoing Phase I/II Alta trial in which patients with severe hemophilia A received the gene therapy at one of four ascending doses. Although 11 patients participated in the trial, the analysis focused on the five patients in the highest-dose cohort.

The average annualized total bleeding rate was zero for the first year after treatment and 1.4 during the four-year follow-up period, and no patients in the highest-dose cohort resumed prophylaxis. The median annualized total bleeding rate during this time was zero, with three patients having no bleeds and multiple bleeds in one patient. The patient who experienced bleeds had 25 bleeds throughout the follow-up period.

Investigators observed increased FVIII activity in patients on the highest dose of the gene therapy, with an average of 26.6 percent FVIII activity for the four patients who had data four years post-treatment. One patient sustained normal FVIII activity into year four, while most others experienced a decline in activity but had maintained FVIII in at least the mild range as of their last follow-up visit. The patient who reported multiple bleeds had low FVIII activity.

The fifth patient in the highest-dose cohort left the study after three years, which was the original follow-up period in the trial but was amended to four years, according to Jeremy Rupon, who leads clinical research at Pfizer. At three years, that patient had mild FVIII activity.

"Additional follow-up is required to further assess the durability and efficacy of this treatment," Rupon said, noting that there's an ongoing Phase III trial, dubbed Affine, in which the gene therapy is being tested in patients with moderately severe to severe hemophilia A.

The most common treatment-related adverse events among the five patients who received the highest dose were elevated liver enzymes and infusion-related reactions, including pyrexia and tachycardia. One patient reported a serious treatment-related adverse event, hypotension and fever, which fully resolved. That patient was the first patient treated in the highest-dose cohort, and investigators have since modified the treatment protocol to include pretreatment with Tylenol (acetaminophen) and Benadryl (diphenhydramine), Rupon said.

No patients developed a confirmed inhibitor to FVIII, and none had thrombotic events or developed liver masses.

CSL Behring's Hemgenix (etranacogene dezaparvovec)

In an analysis of patients three years after treatment with CSL Behring's gene therapy Hemgenix (etranacogene dezaparvovec) for severe or moderately severe hemophilia B, investigators said the drug demonstrated sustained bleeding protection over time.

The one-time gene therapy Hemgenix, which uses an adeno-associated virus type 5 vector to deliver a functional version of the FIX Padua R338L transgene, has been approved in multiple countries, including in the US and UK — although the treatment's cost-effectiveness is in question in the UK. It's often referred to as the most expensive drug in the world, priced at $3.5 million.

In this latest three-year follow-up analysis of 52 out of 54 patients enrolled in the company's ongoing pivotal Phase III trial, dubbed HOPE-B, investigators found that the average annualized bleeding rate during months seven through 36 post-treatment was reduced by 64 percent compared to the six months prior to treatment.

There were 136 total bleeds during the six-month lead-in period, which decreased to 55 during the first year, 48 during the second year, and 37 during the third year after infusion. The median number of bleeds per patient decreased from two during the lead-in period and remained stable at zero bleeds through year three.

Three years after treatment, 87 percent of participants were in the mild or normal range for FIX activity, with one-third of patients observed at between 40 percent to 100 percent and nearly half of patients between 12 percent and 40 percent. Of the patients who were not in that range, one patient did not respond to the gene therapy and another patient, who had a severe infusion-related reaction, did not receive the full dose. The other four patients had missing data because they died or had a liver transplant, or due to other issues, said Steven Pipe, a professor of pediatrics and pathology at the University of Michigan.

Patients' mean endogenous FIX activity level was 41.5 percent in the first year, 36.7 percent in the second year, and 38.6 percent in the third year.

Nearly half, or 46.3 percent, of patients received no FIX infusions over the three-year period post-treatment, and 94.4 percent remained free of continuous FIX prophylaxis at the three-year mark. Seventy percent of patients received no FIX infusions during the second year and three-quarters received no FIX infusions during the third year after treatment.

All patients experienced at least one treatment-emergent adverse event, three-quarters of which were categorized as mild, 19 percent were moderate, and 4 percent were severe. Increases in alanine transaminase were the most common adverse events. There were no serious adverse events that were linked to the treatment, and no FIX inhibitors or thrombotic events were detected in the trial. One patient died from urinary tract infection-related sepsis and one patient developed hepatocellular carcinoma, but neither of these adverse events were related to the gene therapy.

St. Jude's scAAV2/8-LP1-hFIXco

A gene therapy developed and manufactured by St. Jude Children's Research Hospital in Memphis, Tennessee, succeeded in lowering the annualized bleeding rate in patients with severe hemophilia B and sustaining that reduction over the long term, according to a small study of patients tracked for more than 10 years.

St. Jude's scAAV2/8-LP1-hFIXco is designed to deliver a copy of the wild-type FIX gene with a self-complementary adeno-associated virus. Researchers previously reported that a single infusion of the gene therapy led to an increase in FIX expression in 10 adults with the severe and rare bleeding disorder.

Hemophilia B is caused by a mutation in the FIX gene that leads to insufficient production of a protein of the same name that supports blood clotting.

The study, which was launched in 2009, now has a median of 10.7 years of follow-up efficacy and safety data from these patients. At this meeting, researchers reported that, over the long term, expression of the FIX transgene remained stable, with an average FIX activity of 1.7 percent, 2.3 percent, and 4.9 percent across the three dose-escalation cohorts in the study.

The average annualized bleeding rate over the decade-long follow-up period was 1.95 after receiving the gene therapy, compared to 16.5 prior to receiving it. The six patients in the highest-dose group experienced an average annualized bleeding rate of 1.2. Five of the 10 patients are off of prophylaxis.

There were two malignancies: a non-mucinous lung adenocarcinoma in situ of the lung discovered five years after treatment and deemed unrelated to the gene therapy; and an adenocarcinoma of the prostate discovered 12 years post-infusion, which investigators are still tracking, though they think it is unlikely to be related to the gene therapy.

Investigators did not observe FIX inhibitors, thrombosis, or persistent transaminitis, and there were no patient deaths.

"The findings support further evaluation of this approach for other monogenic conditions," said Ulrike Reiss, director of the hemophilia treatment center at St. Jude. There are no plans to dose new patients with this specific gene therapy, but Reiss said researchers are planning an international clinical trial with a modified version in low- and middle-income countries.