Congenital thrombotic thrombocytopenic purpura (cTTP) results from a deficiency in  ADAMTS13 (A disintegrin and metalloproteinase with thrombospondin motifs 13), a von Willebrand factor (VWF) cleaving protease. This leads to an accumulation of ultra-large VWF multimers in the blood and uncontrolled platelet aggregation and adhesion. Adzynma is a purified recombinant form of the ADAMTS13 protein designed to replace the missing or deficient ADAMTS13 enzyme.

The approval was based on data from a randomized, crossover phase 3 study (ClinicalTrials.gov Identifier: NCT03393975) that evaluated the safety and efficacy of prophylactic ERT with Adzynma in patients with cTTP. Study participants in the prophylaxis cohort (N=46) were randomly assigned to receive 6 months of treatment with either Adzynma or plasma based therapy in the first part of the trial (Period 1), and then crossed over to the other treatment for 6 months in the second part of the trial (Period 2). Thirty-five patients entered the 6-month single arm continuation period (Period 3).

There were no acute TTP events throughout the study among patients who received Adzynma. One acute TTP event occurred in a patient who received plasma-based therapy. Additionally, no subacute TTP events were reported among those who received Adzynma during Periods 1 and 2. Two patients receiving Adzynma had 2 subacute events of which one was treated with 4 supplemental doses. Four patients receiving plasma-based therapy had 5 subacute TTP events in Periods 1 and 2. A total of 7 supplemental doses were given to 3 of these patients.

The study also investigated the efficacy of on-demand ERT based on the proportion of acute TTP events that responded to Adzynma throughout the duration of the study. Patients were randomly assigned to receive on-demand treatment with Adzynma (n=2) or plasma-based therapy (n=3). Findings showed that all 6 acute TTP events resolved after treatment with either Adzynma or plasma based therapy.

“Adzynma provides patients with a treatment option that replaces their deficient ADAMTS13 enzyme and offers a favorable efficacy and safety profile and reduced administration time and volume compared to current plasma-based therapies,” said Spero R. Cataland, MD, professor of internal medicine at the Wexner Medical Center at The Ohio State University, co-director at the US Thrombotic Microangiopathy Alliance and Adzynma clinical trial investigator.

The most common adverse events reported with Adzynma were headache, diarrhea, migraine, abdominal pain, nausea, upper respiratory tract infection, dizziness and vomiting. The prescribing information also includes warnings and precautions related to hypersensitivity and immunogenicity.

Adzynma is administered intravenously once every other week for prophylactic ERT and once daily for on-demand ERT. The product is supplied as a lyophilized powder in single-dose vials containing nominally 500 or 1500 international units and is expected to be available in December 2023.

Allopurinol and febuxostat are similarly effective in controlling flares in patients with gout, including those with stage 3 chronic kidney disease (CKD), according to trial results published in the New England Journal of Medicine.

In double-blind CSP594 Comparative Effectiveness in Gout: Allopurinol vs Febuxostat trial (ClinicalTrials.gov identifier: NCT02579096), investigators randomly assigned 940 patients with hyperuricemia to receive allopurinol or febuxostat at titrated doses to achieve a serum urate target of 6mg/dL or lower (or 5mg/dL or lower if tophi were present). Approximately a third of patients in both groups had stage 3 CKD (30-59 mL/min/1.73 m² using the Modification of Diet in Renal Disease study formula for estimated glomerular filtration rate). The allopurinol and febuxostat groups received daily doses of 100 and 40mg, respectively, to start, then therapies were titrated until attainment of target uric acid levels or maximal dose. Patients also received guideline-directed anti-inflammatory prophylaxis with colchicine, nonsteroidal anti-inflammatory drugs, or glucocorticoids. After the maintenance phase, no study drug dose adjustments were allowed, and all anti-inflammatory treatments were discontinued except in the event of gout flare.

Results showed that 36.5% of the allopurinol group and 43.5% of the febuxostat group experienced the primary outcome of 1 or more gout flares during the observation phase; a 7% difference that met a criterion for noninferiority, James R. O’Dell, MD, of Veterans Affairs (VA) Nebraska-Western Iowa Health Care System in Omaha, Nebraska, and colleagues reported. Among patients with stage 3 CKD, allopurinol also proved noninferior to febuxostat with 31.9% vs 45.3% experiencing a gout flare, respectively, the investigators reported.

In both the allopurinol and febuxostat groups, 80% of patients, including those with stage 3 CKD, achieved and maintained target serum urate levels at 1 year.

“Our randomized double-blind trial demonstrates that allopurinol, when dosed appropriately as part of a titrate-to-target strategy, is noninferior to febuxostat with respect to flares of gout,” Dr O’Dell’s team wrote.

In 2019, the FDA issued a boxed warning concerning the cardiovascular safety of febuxostat based on results of the CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout) trial. The 2020 FAST trial (Febuxostat versus Allopurinol Streamlined Trial), however, showed no increased risk for cardiovascular events. In the current study, the investigators found no evidence that febuxostat increases cardiovascular morbidity or overall mortality compared with allopurinol. Serious adverse events (26.7% vs 26.1%), including cardiovascular events (8.1% vs 6.8%) and death (8 patients in each group), occurred in comparable proportions of the allopurinol and febuxostat arms, respectively. Dr O’Dell and colleagues suggested that the nearly ubiquitous use of colchicine in the early phases of the trial might have mitigated cardiovascular risks.

Dr O’Dell’s team made other observations that also warrant additional research. Hospitalization for heart failure was numerically higher among patients treated with allopurinol (23 vs 10 hospitalizations). A post hoc analysis showed that acute kidney injury occurred in 15 allopurinol-treated patients compared with 4 febuxostat-treated patients who had stage 3 CKD. Most AKI events were related to volume depletion or congestive heart failure, the investigators noted. All but 3 AKI events were transient.

Reference

O’Dell JR, Brophy MT, Pillinger MH, et al. Comparative effectiveness of allopurinol and febuxostat in gout management. N Engl J Med. Published online February 3, 2022. doi:10.1056/EVIDoa2100028

Alpha blockers do not increase the risk for falls, fractures, or death in the hemodialysis population, a new observational study concludes.

In phases 4 to 6 of the Japan Dialysis Outcomes and Practice Patterns (J-DOPPS) Study, 5149 patients on hemodialysis (mean age 65 years, 68% men) received anti-hypertensive drugs, including 717 patients (14%) prescribed alpha blockers such as doxazosin, bunazosin, prazosin, or urapidil. During a mean 2 years of follow-up, 247 fractures, 525 falls, and 498 deaths occurred in the overall cohort.

Multivariable analysis of the intent-to-treat population showed that patients prescribed alpha blockers had no higher risks of falls or fractures than patients not prescribed these agents, Ken Iseri, MD, PhD, of Showa University School of Medicine in Tokyo, Japan, and colleagues reported in Kidney Medicine. This result included patients at greater risk for falls due to advanced age, systolic blood pressure less than 140 mmHg, anemia, low body mass index, or large fluid removal volume.

“The face-to-face meeting with nephrologists three times per week may permit avoidance of undesirable events through achievement of optimal blood pressure management,” Dr Iseri’s team suggested. Pre-dialysis blood pressure levels were significantly higher in alpha blocker users, indicating that these agents were commonly prescribed for resistant or refractory hypertension.

Alpha blockers also conferred no higher risk for all-cause mortality in the total hemodialysis population, the investigators reported. Alpha blockers were significantly associated with a decreased risk of death among older patients (by 29%), women (32%), patients with a cardiovascular disease history (33%), and those with a pre-dialysis systolic blood pressure of 140 mmHg or greater (31%).

“We could not fully explain why this favorable effect was found only in specific hemodialysis populations, but not in total populations,” Dr Iseri’s team wrote. “However, recent studies have shown that alpha blockers may prevent cardiac remodeling and the development and progression of heart failure and have protective benefits against hyperinflammation and cytokine storm syndrome.”

Since this was an observational study of a single ethnicity and lacked data on patient strength, frailty, history of hypotension, bone mineral density, medication adherence, and other factors, more research is needed.

The Food and Drug Administration (FDA) has approved Altuviiio (antihemophilic factor [recombinant], Fc-VWF-XTEN fusion protein-ehtl), a first-in-class, high-sustained factor VIII (FVIII) replacement therapy.

Altuviiio is indicated for adults and children with hemophilia A (congenital factor VIII deficiency) for: routine prophylaxis to reduce the frequency of bleeding episodes; on-demand treatment and control of bleeding episodes; and perioperative management of bleeding. The novel recombinant FVIII therapy is designed to extend protection from bleeds by breaking the von Willebrand factor ceiling, which imposes a half-life limitation on current FVIII treatments.

The approval was based on data from the multicenter, open-label, nonrandomized, interventional phase 3 XTEND-1 study (ClinicalTrials.gov Identifier: NCT04161495), which evaluated the efficacy and safety of Altuviiio in patients 12 years of age and older with severe hemophilia A previously treated with FVIII replacement therapy.

The study included 2 parallel treatment arms: the prophylaxis Arm A (n=128), where patients received a weekly prophylactic 50 IU/kg dose of Altuviiio intravenously (IV) for 52 weeks; and the on-demand Arm B (n=26), where patients received on-demand treatment at doses of 50 IU/kg for 26 weeks, followed by weekly prophylaxis for 26 weeks.

Findings showed that weekly prophylactic treatment with Altuviiio resulted in clinically meaningful prevention of bleeds over 52 weeks; the median annualized bleeding rate (ABR) was 0 with a mean ABR of 0.70. An intra-patient comparison demonstrated a significant 77% (95% CI, 58-87) reduction in ABR with Altuviiio vs prior prophylactic FVIII replacement therapy. Additionally, patients with target joints at baseline (defined as ≥3 spontaneous bleeding episodes in a major joint which occurred in a consecutive 6-month period) achieved 100% resolution with 12 months of prophylactic treatment with Altuviiio. 

In XTEND-1, there were a total of 362 bleeding episodes treated with Altuviiio. Bleeding was resolved with a single 50 IU/kg injection in 96.7% of bleeding episodes. Perioperative hemostasis was evaluated in 13 major and 22 minor surgeries. Treatment with Altuviiio was rated as “excellent” in all of these surgeries. As for safety, the most common adverse reactions reported were headache and arthralgia.

The efficacy of weekly Altuviiio as routine prophylaxis was also evaluated in pediatric patients less than 12 years of age (N=67; XTEND-Kids [ClinicalTrials.gov Identifier: NCT04759131]). Patients received Altuviiio 50 IU/kg IV once weekly for 52 weeks. An interim analysis showed that among patients who received routine prophylaxis for 26 weeks (n=23), the mean ABR was 0.5 and the median ABR was 0 for treated bleeds.

“This approval marks an important clinical advancement for the hemophilia community because we have an option that can achieve higher levels of factor activity with a single simplified weekly dose,” said Lynn Malec, MD, Medical Director of Comprehensive Center for Bleeding Disorders and Associate Investigator at The Versiti Blood Research Institute, and Associate Professor of Medicine and Pediatrics at The Medical College of Wisconsin. “By maintaining high levels of factor activity throughout the week, patients can be confident in the bleed protection Altuviiio offers.”

Altuviiio is supplied in kits with a single-dose vial containing 250, 500, 750, 1000, 2000, 3000 or 4000 IU of factor VIII potency, a prefilled syringe, and a sterile vial adapter. The product is expected to be available in April 2023.

References

1. Press release: FDA approves once-weekly Altuviiio, a new class of factor VIII therapy for hemophilia A that offers significant bleed protection. News release. Sanofi-Aventis Groupe. Accessed February 23, 2023. https://www.globenewswire.com/news-release/2023/02/23/2614759/0/en/Press-Release-FDA-approves-once-weekly-ALTUVIIIO-a-new-class-of-factor-VIII-therapy-for-hemophilia-A-that-offers-significant-bleed-protection.html.
2. Altuviiio. Package insert. Sanofi-Aventis Groupe; 2023. Accessed February 23, 2023. https://www.fda.gov/media/165594/download.

Alvaiz is indicated for the treatment of:

• Thrombocytopenia in adult and pediatric patients 6 years and older with persistent or chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. It should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.
• Thrombocytopenia in adult patients with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy. It should be used only in patients with chronic hepatitis C whose degree of thrombocytopenia prevents the initiation of interferon-based therapy or limits the ability to maintain interferon-based therapy.
• Severe aplastic anemia in adults who have had an insufficient response to immunosuppressive therapy.

The approval was based on efficacy and safety data from clinical studies in adults (ClinicalTrials.gov Identifier: NCT00370331, NCT00102739, NCT00351468) and pediatric patients (ClinicalTrials.gov identifier: NCT01520909, NCT00908037) with persistent and chronic ITP, adults with chronic hepatitis-C associated thrombocytopenia (ClinicalTrials.gov Identifier: NCT00516321), and adults with refractory severe aplastic anemia (ClinicalTrials.gov Identifier: NCT00922883).

Alvaiz is supplied as 9mg, 18mg, 36mg, and 54mg tablets. It is not substitutable with other eltrombopag products on a milligram per milligram basis due to the observed bioavailability in studies conducted on Alvaiz.

The storms “hampered our ability to boost critically low blood supply levels,” said Red Cross spokesman Daniel Parra. “Since the beginning of the year, blood drives have been cancelled in nearly every state where the Red Cross collects blood, causing thousands of units of blood and platelets to go uncollected.”

Parra explained that to bring blood supplies back up to normal levels, the agency needs to collect an extra 8000 donations each week during the next few weeks.

Already, the US has the lowest number of people giving blood observed over the past 20 years, according to the Red Cross. When supplies are stretched thin, events such as storms can “have a huge effect on the availability of blood products,” Parra noted.

“Donors in areas unaffected by severe weather are vital to ensuring those in need of transfusions have access to lifesaving care across the Red Cross network,” he said.

More Information

AstraZeneca is stopping its phase 4 trial of Andexxa (andexanet alfa) early because the study achieved the prespecified criteria of superior hemostatic efficacy.

Andexxa was granted accelerated approval by the Food and Drug Administration (FDA) in May 2018 for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation was needed due to life-threatening or uncontrolled bleeding. Andexxa exerts its procoagulant effect by binding and sequestering the factor Xa (FXa) inhibitors.

The randomized, open-label, multicenter ANNEXA-I trial (ClinicalTrials.gov Identifier: NCT03661528) included adults 18 years of age and older presenting with an intracranial hemorrhage within 6 hours of symptom onset to baseline scan and within 15 hours of taking an oral factor Xa inhibitor. Patients were randomly assigned to receive either Andexxa or usual care.

The primary endpoint was the rate of effective hemostasis (defined as the change from baseline in the National Institutes of Health Stroke Scale of +6 or less at the 12-hour timepoint and ≤35% increase in hematoma volume compared with baseline on a repeat CT or MRI scan at 12 hours and no rescue therapies administered between 3 hours and 12 hours after randomization).

Following a planned interim assessment of efficacy (n=450), an independent Data and Safety Monitoring Board concluded that Andexxa demonstrated superior hemostatic efficacy after 1 month follow-up compared with usual care. According to the Company, this result was observed earlier than what had originally been anticipated. These confirmatory findings will be submitted to the FDA as the basis for converting to full approval.

“We are pleased that the study has met its efficacy endpoint at the planned interim analysis, showing improved control of bleeding with targeted anticoagulation reversal, compared to usual care,” said Stuart J. Connolly, MD, FRCPC, Senior Scientist at Population Health Research Institute and professor emeritus at McMaster University in Hamilton, Ontario. “We look forward to sharing the full efficacy and safety results after further analysis, with the hope that the data will pave the way for further guidance on the treatment of potentially life-threatening bleeds.”