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Impact Of Recombinant Replacement Therapy Detailed In Genetic Clotting Disorder

A recombinant replacement for the ADAMTS13 protein (Adzynma) missing in congenital thrombotic thrombocytopenic purpura (TTP) restored levels and reduced acute TTP events, according to interim trial data that led to FDA approval.

For the primary endpoint, no acute TTP events occurred among patients getting prophylactic ADAMTS13 compared with one case on standard therapy with plasma-derived products (mean annualized event rate 0.05) over 6 months, reported Marie Scully, MD, of University College London Hospitals, and colleagues in the New England Journal of Medicine.

Thrombocytopenia, the most common disease manifestation, was also less common with recombinant ADAMTS13 (annualized event rate 0.74 vs 1.73).

With just 30 of the randomized 48 patients having finished the trial by the time of the interim analysis and given the rarity of congenital TTP, the trial did not have sufficient power to enable statistical hypothesis testing, the researchers cautioned. They could only calculate 95% confidence intervals unadjusted for multiplicity, the width of which "should not be used to infer definitive treatment effects," they wrote.

Nevertheless, these data led to FDA approval in November 2023 for recombinant ADAMTS13 as prophylactic or on-demand enzyme replacement therapy for the extremely rare, chronic disorder that causes clotting in the small blood vessels throughout the body and can lead to severe bleeding episodes, strokes, and organ damage.

Scully's group suggested that "prophylaxis with recombinant ADAMTS13 may allow the treatment landscape for congenital TTP to evolve toward preventing long-term organ damage by minimizing the formation of platelet-rich microthrombi."

Its apparently more acceptable side-effect profile and higher average ADAMTS13 activity levels (mean 101% vs 19% with standard therapy) seen in the trial "may, in clinical practice, help expand patient access to long-term prophylaxis," they added.

ADAMTS13 replacement through prophylactic or on-demand infusions of fresh-frozen plasma, plasma treated with a solvent-detergent process, or ADAMTS13-containing plasma-derived factor VIII/von Willebrand factor concentrates relies on donor plasma given as lengthy in-hospital infusions and carries the potential for severe and treatment-limiting allergic reactions to plasma.

"Patients appreciate it -- it's much much easier for them," Spero R. Cataland, MD, of the Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute in Columbus, told MedPage Today. It's minutes versus hours for infusion, "and side effects are much better on this recombinant."

Severe adverse events occurred in 7% of patients receiving recombinant ADAMTS13 compared with 14% on standard therapy. The most common adverse events of any severity were headache, migraine, nasopharyngitis, and diarrhea.

Their phase III trial enrolled patients in two cohorts. A total of 48 patients were randomized in a crossover design to thromboprophylaxis with weekly or every-other-week IV recombinant ADAMTS13 (40 IU/kg) or investigator's choice of standard therapy with plasma-derived products. After 6 months, they switched to the other treatment for another 6 months, followed by 6 months when everyone received recombinant ADAMTS13.

An on-demand cohort of five patients who enrolled during an acute congenital TTP event were eligible to join the prophylactic cohort after resolution of the initial event, which three did.

At the interim analysis, 32 patients had completed the trial in the prophylactic cohort (all adults and adolescents) and another 14 patients (including eight younger than 12 years of age) were still underway in the trial. One adult discontinued due to a severe allergic reaction to prophylaxis with standard therapy; a second stopped after their diagnosis was confirmed as immune-mediated TTP. The trial protocol called for enrollment of only congenital TTP as confirmed by molecular genetic testing and ADAMTS13 activity of less than 10%.

Given that the disease affects only one or two persons per million, "those numbers are actually pretty good, all things considered," Cataland noted.

For the primary outcome endpoint, acute TTP events were defined as a drop in platelets by at least 50% from baseline or to a level less than 100,000 platelets/mL and either a doubling in lactate dehydrogenase or rise to more than two times the upper limit of normal. While an objective and laboratory-based definition, it was "probably conservative as compared with clinical practice and existing literature," Scully's group noted.

Among the secondary endpoints, two subacute TTP events occurred in patients while on recombinant ADAMTS13 compared with five occurring in four patients on standard therapy (raw mean annualized event rate 0.07 vs 0.25).

"When these patients have episodes, their platelet counts are dropping because they are consuming their platelets to form clots throughout the body," Cataland said. "So when you see a high platelet count, that's a good thing."

The researchers acknowledged the risk of immunogenicity with the enzyme replacement but noted no neutralizing antibodies in any patient during 12 months of prophylactic use.

"Historically, an important consideration with recombinant hematologic products has been the development of inhibitors against the product, such as factor VIII," they wrote. "Given these findings and the results reported here, the overall immunogenic potential for ADAMTS13 replacement in patients with congenital TTP appears to be low."

No other safety concerns emerged with recombinant ADAMTS13.

The trial's open-label design was a limitation, albeit "necessary because the substantial differences in volume between recombinant ADAMTS13 and standard therapy could not be masked," the researchers wrote. Another limitation was the lack of data on pediatric patients, for whom limited data were available because of age-staggered enrollment.

Importantly, "owing to the rarity of congenital TTP, limited available data on the natural history of the disorder, and lack of data from controlled clinical trials, our trial did not have sufficient power to detect differences between comparator groups," Scully and team wrote.

In announcing approval, drugmaker Takeda had noted that a continuation study of both the prophylactic and on-demand cohorts supported approval, although these data have not yet been published. Follow-up is planned for a total duration of approximately 6 years for a maximum of approximately 77 participants.

Disclosures

The trial was supported by Takeda Development Center Americas and Baxalta Innovations, a Takeda company.

Scully disclosed relationships with Alexion Pharmaceuticals, Octapharma USA, Sanofi US Services, and Takeda Oncology.

Cataland disclosed consulting for Takeda.

Primary Source

New England Journal of Medicine

Source Reference: Scully M, et al "Recombinant ADAMTS13 in congenital thrombotic thrombocytopenic purpura" N Engl J Med 2024; DOI: 10.1056/NEJMoa2314793.

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US Approves Gene Therapy Treatment For Hemophilia

Pfizer's Beqvez, which is given as a single intravenous infusion, was shown in a clinical trial of 45 people to be better at preventing bleeding among adults with moderate to severe hemophilia B, compared to regular infusions of a protein that promotes clotting (SPENCER PLATT)

Pharmaceutical giant Pfizer has received US approval for a gene therapy against a form of hemophilia, a rare and inherited blood clotting disorder, the company said Friday.

Beqvez, which is given as a single intravenous infusion, was shown in a clinical trial of 45 people to be better at preventing bleeding among adults with moderate to severe hemophilia B compared to regular infusions of a protein that promotes clotting, called protein factor IX (FIX).

The current standard of care is cumbersome, requiring infusions up to several times per week.

"Many people with hemophilia B struggle with the commitment and lifestyle disruption of regular FIX infusions, as well as spontaneous bleeding episodes, which can lead to painful joint damage and mobility issues," said Adam Cuker, director of the University of Pennsylvania's Comprehensive Hemophilia and Thrombosis Program, in a Pfizer statement.

"A one-time treatment with BEQVEZ has the potential to be transformative for appropriate patients by reducing both the medical and treatment burden over the long term."

The therapy was generally well tolerated but a common side effect was elevated liver enzymes, a sign of liver inflammation that wasn't accompanied by outward symptoms. Still, patients are advised to avoid alcohol for up to a year following their treatment, to prevent liver damage.

Patients will be followed up to gather more data for up to 15 years.

Pfizer's genetic therapy targets hemophilia B, the second most common form of the condition, which primarily affects males. More than 38,000 people worldwide live with hemophilia B, according to the World Federation of Hemophilia.

It works by infecting the body with a virus, modified to be harmless, which delivers a functional copy of the factor IX gene to liver cells, instructing them to produce the protein that promotes clotting that the patient otherwise lacks.

It received approval by Canada in January and is awaiting review by the European Medicines Agency.

It comes with a hefty list price of $3.5 million. But a Pfizer spokesperson said that the cost for people with insurance would likely be less. By comparison, the annual cost of the current treatment "may be more than $600,000 and as high as $1.1 million," whereas Beqvez is a one-time dose.

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FDA Green Lights Pfizer's Gene Therapy For Rare Bleeding Disorder Hemophilia

Friday, the FDA approved Pfizer Inc's (NYSE:PFE) Beqvez (fidanacogene elaparvovec-dzkt) for moderate to severe hemophilia B in adult patients who currently use factor IX (FIX) prophylaxis therapy or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes, and do not have neutralizing antibodies to adeno-associated virus serotype Rh74var capsid.

Beqvez is a one-time treatment designed to enable hemophilia B patients to produce FIX themselves rather than the current standard of care, which requires regular intravenous infusions of FIX that are often administered multiple times a week or multiple times a month.

Hemophilia B is a rare genetic bleeding disorder that prevents normal blood clotting because of a deficiency in FIX that causes those with the disease to bleed more frequently and longer than others.

The approval is based on the BENEGENE-2 Phase 3A study, which showed that a single dose of Pfizer's therapy helped eliminate bleeding in 60% of patients compared to 29% in the prophylaxis arm.

A median annualized bleeding rate (ABR) of zero (range of 0 to 19) was observed during the efficacy evaluation period compared to the prophylaxis arm, in which a median ABR of 1.3 (range of 0 to 53.9) was observed.

Pfizer said it will continue to monitor the long-term durability and safety of the treatment over 15 years.

With Beqvez now approved for use, Pfizer is launching a warranty program based on the durability of patient response to treatment.

The warranty aims to provide greater certainty to payers, maximize access for eligible patients who receive Beqvez, and offer financial protection by insuring against the risk of efficacy failure.

Beqvez is currently under review with the European Medicines Agency, and the treatment recently received regulatory approval in Canada.

Reuters noted that Pfizer has set a list price for Beqvez at $3.5 million in the U.S., similar to Australian drugmaker CSL Ltd's (OTC:CSLLY) rival gene therapy Hemgenix.

Price Action: PFE shares are up 0.88% at $25.48 at the last check Friday.

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This article FDA Green Lights Pfizer's Gene Therapy For Rare Bleeding Disorder Hemophilia originally appeared on Benzinga.Com

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