The Food and Drug Administration (FDA) has changed the therapeutic equivalence rating for Accord Healthcare’s generic tacrolimus oral capsules from AB to BX making it no longer recommended as automatically substitutable for the brand name drug, Prograf (tacrolimus) oral capsules.

Tacrolimus is indicated for the prevention of organ rejection in adults with allogeneic kidney, liver, heart, or lung transplants, in combination with other immunosuppressants. The FDA’s decision was based on new data from several FDA-funded studies that assessed concerns from the transplant community regarding the substitutability of FDA-approved generic tacrolimus oral capsules that were approved before 2012. 

According to study findings, Accord Healthcare’s tacrolimus oral capsules may deliver elevated peak blood concentrations compared with the brand name drug leading to an increased risk for toxicity. However, no significant differences were observed in the trough blood levels, indicating no increased risk for organ rejection. The FDA is not aware of any postmarketing issues regarding the product’s safety or efficacy.

While the therapeutic equivalence rating for Accord Healthcare’s tacrolimus oral capsules has been changed, the product is still approved and can be prescribed. The change means that the data are insufficient to show that the product provides the same therapeutic effect as Prograf. Patients currently being treated with Accord Healthcare’s tacrolimus oral capsules should not make changes to their treatment without consulting their health care provider. 

Generic tacrolimus oral capsules manufactured by other companies are not impacted by this issue. Other tacrolimus dosage forms are also not affected.

Adverse events or quality problems should be reported to the FDA’s MedWatch program.

Increased rates of APOs are associated with rheumatic diseases like SLE, rheumatoid arthritis (RA), and dermatomyositis, but little is known about pregnancy outcomes among patients with ASDs. Therefore, researchers conducted a case-control study to assess the frequency of APOs among women with ASDs.

Data were taken from the TriNetX United States Collaborative Network database and included patients aged between 15 to 44 years who were pregnant, from January 1, 2016, to December 31, 2021.

Patients with ASDs were propensity score matched 1:1 with members of two control groups for comparison: 1) healthy patients without ASDs, RA, or SLE and 2) individuals with RA or SLE who were considered members of the disease-control group.

The study included 3654 patients with ASDs and 3654 members of the control groups (2147 patients with SLE and 889 with RA).

Patients with ASDs were at greater risk of experiencing spontaneous abortion and preeclampsia/eclampsia compared with members of the healthy control group.

Specifically, the risk for spontaneous abortion was 1.5 times higher among patients with ASDs than in the healthy control group (P <.001), while the risk for preeclampsia/eclampsia was 1.2 times higher among patients with ASDs compared with the healthy control group (P =.04).

Compared against women with SLE, women with ASDs were less likely to experience preeclampsia/eclampsia, have a preterm birth, experience preterm premature rupture of membranes (PPROM), or have a fetus with intrauterine growth restriction (IUGR).

Specifically, the risk for preeclampsia/eclampsia was 0.7 times lower (P =.001), the risk of delivering preterm was 0.5 times lower (P <.001), the risk for PPROM was 0.6 times lower (P =.004), and the risk of having a fetus with IUGR was 0.6 times lower (P <.001) among women with ASDs vs women with SLE.

Women with ASDs were more 1.2 times more likely to experience a spontaneous abortion than women with SLE (P =.003). Patients with ASDs and RA were at similar risk for APOs.

The study authors concluded, “These results suggest that patients with ASDs have increased rates of adverse pregnancy outcomes compared to healthy controls and are similar in risk to RA. In contrast, those with SLE have a greater frequency of APOs indicating that all these groups may benefit from multidisciplinary care with maternal-fetal medicine specialists.”

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Manufactured from pooled human plasma from US donors, Alyglo supplies a broad spectrum of neutralizing IgG antibodies to bacterial and viral pathogens, and their toxins. The product is manufactured using cation exchange chromatography, which removes coagulation factor XIa and reduces procoagulant activity. 

The approval was based on data from an open-label, single-arm, phase 3 study (ClinicalTrials.gov Identifier: NCT02783482) that evaluated the efficacy and safety of Alyglo in patients 17 years of age and older with PI. Study participants (N=33) received Alyglo infusion every 21 or 28 days for 12 months. The primary endpoint was the annualized rate of acute serious bacterial infections (SBIs).

The acute SBI rate was reported to be 0.03 during the 12-month study period, which met the predefined success rate of less than 1 acute SBI per patient per year. One patient experienced an acute SBI (1 episode of bacterial pneumonia). 

As for safety, the proportion of infusions with temporally associated adverse events occurring during or within 72 hours after infusion was 0.22. This result met the FDA-required prespecified endpoint of less than 0.40.

The most common adverse reactions reported with treatment were headache, nausea/vomiting, fatigue, nasal/sinus congestion, rash, arthralgia, diarrhea, muscle pain/aches, infusion site pain/swelling, abdominal pain/discomfort, cough, and dizziness. As with other IGIV products, the prescribing information for Alyglo includes a Boxed Warning regarding the risk of thrombosis, renal dysfunction, and acute renal failure. 

Alyglo is supplied in a single-dose vial in the following presentations: 5g in 50mL; 10g in 100mL; 20g in 200mL. 

The Food and Drug Administration (FDA) has granted Fast Track designation to KYV-101 for the treatment of patients with refractory lupus nephritis (LN).

KYV-101 is a novel, fully human anti-CD19 chimeric antigen receptor T-cell (CAR T) therapy designed to deplete B cells, including autoreactive B cells, in patients with autoimmune diseases. According to preclinical findings, KYV-101 CAR T cells derived from patients with lupus showed strong CAR-mediated and CD19-dependent activity against autologous B cells. The Company is currently enrolling patients in an open-label, multicenter phase 1 trial to evaluate KYV-101.  

“The FDA granting us Fast Track designation for KYV-101 means we can move more quickly toward bringing this potentially transformative and life-saving medicine to patients with lupus,” said Peter Maag, PhD, CEO of Kyverna. “We believe KYV-101 has the potential to drive greater and more rapid reduction of disease activity in patients with LN, and we look forward to sharing clinical data on patients in the second half of 2023.”

The table below is a review of notable updates that occurred in August 2022 for investigational products in development (not an inclusive list). Click on the status link to view our full coverage.

The Food and Drug Administration (FDA) has accepted for Priority Review the supplemental New Drug Application (sNDA) for avapritinib for the treatment of indolent systemic mastocytosis in adults.

The sNDA is supported by data from the 3-part, randomized, double-blind, placebo-controlled phase 2 PIONEER trial (ClinicalTrials.gov Identifier: NCT03731260), which included patients with indolent systemic mastocytosis whose symptoms were not adequately controlled by best supportive care (BSC). Study participants were randomly assigned to receive either avapritinib (n=141) or placebo (n=71), both in addition to BSC.

Results from the registrational part of the trial (Part 2) showed that treatment with avapritinib met the primary endpoint demonstrating a reduction of 15.6 points in the mean total symptom score (TSS) at week 24 compared with a reduction of 9.2 points for placebo (P =.003). TSS was assessed by the Indolent SM Symptom Assessment Form. Patients who continued treatment with avapritinib in the open-label extension study (Part 3) had a reduction to 20.2 points in mean TSS at week 48.

Significant improvements in patient-reported symptoms and objective measures of disease burden were also observed with avapritinib. Moreover, 53.9% of avapritinib-treated patients achieved at least a 50% reduction in serum tryptase at week 24 compared with none of the patients in the placebo arm (P <.0001). 

Treatment-related adverse events reported in the avapritinib arm were headache, nausea, peripheral edema and periorbital edema.

“People with indolent systemic mastocytosis experience debilitating symptoms and poor quality of life, and we have the potential to transform clinical outcomes for these patients by targeting the genetic driver of disease with Ayvakit,” said Becker Hewes, MD, Chief Medical Officer at Blueprint Medicines. “Ayvakit achieved the primary and all key secondary endpoints in the PIONEER trial, with highly meaningful reductions in patient-reported symptoms and all measures of mast cell burden studied, and a well-tolerated safety profile supporting chronic treatment.” 

A Prescription Drug User Fee Act target date of May 22, 2023 has been set for the application.

Avapritinib, a tyrosine kinase inhibitor, is currently marketed under the brand name Ayvakit^® for the treatment of adults with advanced systemic mastocytosis, including those with aggressive systemic mastocytosis, systemic mastocytosis with an associated hematological neoplasm, and mast cell leukemia. The product is also approved for adults with unresectable or metastatic gastrointestinal stromal tumor harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon mutation, including PDGFRA D842 mutations. 

References

1. Blueprint Medicines announces FDA acceptance of supplemental New Drug Application for Ayvakit^® (avapritinib) for the treatment of indolent systemic mastocytosis. News release. Blueprint Medicines. Accessed January 23, 2023. https://www.prnewswire.com/news-releases/blueprint-medicines-announces-fda-acceptance-of-supplemental-new-drug-application-for-ayvakit-avapritinib-for-the-treatment-of-indolent-systemic-mastocytosis-301727726.html.
2. Blueprint Medicines announces positive top-line results from PIONEER trial of Ayvakit^® (avapritinib) in patients with non-advanced systemic mastocytosis achieving primary and all key secondary endpoints. News release. Blueprint Medicines. Accessed January 23, 2023. https://ir.blueprintmedicines.com/news-releases/news-release-details/blueprint-medicines-announces-positive-top-line-results-pioneer.

Axatilimab is an investigational monoclonal antibody that targets colony stimulating factor-1 receptor. The application is supported by data from the phase 2 AGAVE-201 study (ClinicalTrials.gov Identifier: NCT04710576), which evaluated the safety and efficacy of axatilimab in 241 adult and pediatric patients with recurrent or refractory active GVHD whose disease had progressed after 2 therapies. Prior treatments included ruxolitinib (74%), ibrutinib (31%) and belumosudil (23%).

Study participants were randomly assigned to 1 of 3 treatment groups: 0.3mg/kg every 2 weeks, 1mg/kg every 2 weeks, or 3mg/kg every 4 weeks. The primary endpoint was overall response rate (ORR) defined as the proportion of patients in each dose group who achieved an objective response based on 2014 NIH Consensus Criteria for chronic GVHD by cycle 7 day 1.

Findings showed patients receiving 0.3mg/kg every 2 weeks had the highest ORR, 74% (95% CI, 63-83), within the first 6 months of treatment. Median time to response in this cohort was 1.7 months (range, 0.9-8.1); 60% of these patients maintained a response at 12 months. 

In the 0.3mg/kg dose group, 55% of patients achieved at least a 7-point improvement in the modified Lee Symptom Scale score (secondary endpoint). Additionally, organ specific responses were observed across all organs involved at baseline, with notable responses in fibrosis-dominated organs: esophagus (78%), joints and fascia (76%), lungs (47%), and skin (27%).

The most common treatment-emergent adverse events reported were increases in aspartate aminotransferase, blood creatine phosphokinase, lipase, lactate dehydrogenase, and alanine aminotransferase.

“Despite recent advancements in the treatment of patients with chronic GVHD, there remains a significant unmet need for patients who progressed on earlier lines of therapy,” said Hervé Hoppenot, CEO , Incyte. “Axatilimab’s novel mechanism offers a differentiated treatment approach which may help patients suffering from this devastating disease. We look forward to working closely with the FDA and our partners at Syndax on the review of our application for axatilimab for this indication.”

A Prescription Drug User Fee Act date of August 28, 2024 has been set for the application.

The Food and Drug Administration (FDA) has approved Ayvakit^® (avapritinib) for the treatment of adults with indolent systemic mastocytosis (ISM).

The approval was based on data from the randomized, double-blind, placebo-controlled phase 2 PIONEER trial (ClinicalTrials.gov Identifier: NCT03731260), which included patients with ISM who had moderate to severe symptoms despite receiving at least 2 symptom directed therapies. Patients were randomly assigned to receive either avapritinib 25mg (n=141) orally once daily or placebo (n=71), both in addition to best supportive care.

The primary endpoint was based on the absolute mean change from baseline to week 24 in the Indolent Systemic Mastocytosis-Symptom Assessment Form (ISM-SAF) total symptom score (TSS).

Results showed that treatment with avapritinib met the primary endpoint demonstrating a reduction of 15.33 points (95% CI, -18.36, -12.31) in the mean TSS at week 24 compared with a reduction of 9.64 points (95% CI, -13.61, -5.68) for placebo (treatment difference, -5.69; 95% CI, -10.16, -1.23; P =.012). Twenty-five percent of avapritinib-treated patients achieved at least a 50% reduction from baseline through week 24 in ISM-SAF TSS compared with 10% of patients who received placebo.

Additionally, the study met all key secondary endpoints with avapritinib demonstrating significant improvements in the following measures related to mast cell burden at week 24 vs placebo, respectively:

• Percentage of patients with at least a 50% reduction in serum tryptase: 53.9% vs 0% (2-sided P <.0001);
• Percentage of patients with at least a 50% reduction in peripheral blood KIT D816V allele fraction or undetectable: 67.8% vs 6.3% (2-sided P <.0001);
• Percentage of patients with at least a 50% reduction in bone marrow mast cells or no aggregates: 52.8% vs 22.8% (2-sided P <.0001).

“Ayvakit delivered statistically significant and consistent clinical improvements in the PIONEER trial, and based on these practice-changing data, I feel a tremendous sense of hope for the future for all those affected by the disease,” said Cem Akin, MD, PhD, Professor of Medicine at the University of Michigan, and an investigator on the PIONEER trial.

The most common adverse reactions reported with Ayvakit were eye edema, dizziness, peripheral edema, and flushing. Treatment with Ayvakit is associated with a risk of intracranial hemorrhage, cognitive effects, and embryo-fetal toxicity. Ayvakit is not recommended for the treatment of ISM patients with platelet counts of less than 50 x 10⁹/L.

Ayvakit, a tyrosine kinase inhibitor, is also indicated for the treatment of adults with advanced systemic mastocytosis and for adults with unresectable or metastatic gastrointestinal stromal tumor harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.

The product is supplied as 25mg, 50mg, 100mg, 200mg, and 300mg tablets in 30-count bottles.

The Food and Drug Administration (FDA) has granted Orphan Drug designation to belimumab for the treatment of systemic sclerosis.

Systemic sclerosis is a rare, chronic autoimmune disorder characterized by degenerative changes and thickening of the skin and other organs from excessive collagen deposition. Elevated B-lymphocyte stimulator (BLyS) levels and autoreactive B cells have been reported to play a role in the pathogenesis of systemic sclerosis.

By binding to soluble BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. A phase 2/3 trial evaluating belimumab for systemic sclerosis associated interstitial lung disease is expected to begin in the first half of 2023.

Belimumab is currently marketed under the brand name Benlysta for the treatment of active systemic lupus erythematosus or active lupus nephritis in patients 5 years of age and older who are receiving standard therapy.

Reference

Benlysta granted Orphan Drug designation by US FDA for the potential treatment of systemic sclerosis. News release. GSK. Accessed February 1, 2023. https://www.gsk.com/en-gb/media/press-releases/benlysta-granted-orphan-drug-designation-by-us-fda-for-the-potential-treatment-of-systemic-sclerosis/.

The Food and Drug Administration (FDA) has expanded the approval of Benlysta (belimumab) to include pediatric patients 5 to 17 years of age with active lupus nephritis who are receiving standard therapy. Benlysta, a B-lymphocyte stimulator (BLyS)-specific inhibitor, is also indicated for the treatment of patients 5 years of age and older with active systemic lupus erythematosus (SLE) who are receiving standard therapy.

The approval of Benlysta in pediatric patients with lupus nephritis was based on the extrapolation of efficacy from the intravenous (IV) study in adults with active lupus nephritis, and supported by pharmacokinetic data from IV studies in adults with active lupus nephritis and from pediatric patients with SLE. The estimated Benlysta exposures for pediatric patients were comparable to adults with active lupus nephritis.

The most common adverse reactions associated with Benlysta include nausea, diarrhea, pyrexia, nasopharyngitis, bronchitis, insomnia, pain in extremity, depression, migraine, and pharyngitis.

Benlysta is supplied as 120mg and 400mg of belimumab in 5mL and 20mL single-dose vials, respectively, for intravenous use. The product is also available in a single-dose prefilled autoinjector or syringe containing 200mg/mL of belimumab for subcutaneous use.

Benlysta may be administered as an IV infusion in patients aged 5 years and older or as a subcutaneous injection in patients aged 18 years and older.

References

1. GSK announces US FDA approval of Benlysta (belimumab) for pediatric patients with active lupus nephritis. News release. GlaxoSmithKline plc. Accessed July 27, 2022. https://us.gsk.com/en-us/media/press-releases/gsk-announces-us-fda-approval-of-benlysta-belimumab-for-pediatric-patients-with-active-lupus-nephritis/
2. Benlysta. Package insert. GlaxoSmithKline; 2022. Accessed July 27, 2022. https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Benlysta/pdf/BENLYSTA-PI-MG-IFU.PDF

Comparable remission rates were observed in a head-to-head study comparing benralizumab to mepolizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA) who were receiving oral corticosteroids (OCS) with or without stable immunosuppressive therapy.

The phase 3 MANDARA study (ClinicalTrials.gov Identifier: NCT04157348) included 140 patients with relapsing or refractory EGPA. Study participants were randomly assigned to receive a single subcutaneous (SC) injection of benralizumab 30mg or 3 separate 100mg SC injections of mepolizumab once every 4 weeks. 

The primary endpoint of the trial was the proportion of patients who were in remission (defined as a Birmingham Vasculitis Activity Score equal to 0 and OCS dose ≤4mg/day) at both weeks 36 and 48. Findings showed that benralizumab met the primary endpoint demonstrating noninferior rates of remission compared with mepolizumab.

“The positive MANDARA trial results are exciting because patients with eosinophilic granulomatosis with polyangiitis today have limited treatment options but face crippling symptoms, which can even be fatal if not treated,” said Dr Michael Wechsler, Principal Investigator. “This trial demonstrates that a biologic medicine given in a single monthly injection could help patients achieve remission rates comparable to the current standard of care, adding to the importance of benralizumab as a potential treatment option for eosinophilic granulomatosis with polyangiitis.”

According to AstraZeneca, full results from MANDARA will be shared at a future medical meeting.

Benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, is currently approved under the brand name Fasenra for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype.

HealthDay News — Biosimilar drugs could drive down prices for biologic drugs and generate savings of about $38.4 billion between 2021 and 2025, according to a study published online January 3 in the American Journal of Managed Care.

Andrew Mulcahy, PhD, from RAND Corporation in Arlington, Virginia, and colleagues projected US spending on biologics during a 5-year period under 3 scenarios: (1) a baseline scenario holding quarter 4 (Q4) of 2020 market conditions constant; (2) under main assumptions allowing for biosimilar market growth and entry; and (3) an upper-bound scenario assuming greater biosimilar uptake, more robust price competition, and quicker biosimilar entry.

The researchers found that estimated biosimilar savings from 2021 to 2025 under their main approach were $38.4 billion, or 5.9% of projected spending on biologics during the same period. An estimated $26.1 billion of savings was accounted for by biologics first facing biosimilar competition from 2021 to 2025, with $12.2 billion from evolving market conditions for already-marketed biosimilars. Under the main approach, $24.6 billion of savings were from downward pressure on reference biologic prices rather than lower biosimilar prices. Under the upper-bound scenario, savings were substantially higher ($124.5 billion).

“Biosimilars have the potential to lower spending on biologic drugs that account for a rapidly increasing share of overall US prescription drug spending,” Mulcahy said in a statement.

Abstract/Full Text

The Food and Drug Administration (FDA) has granted Fast Track designation to IMPT-514, a bispecific CD19/CD20-targeting chimeric antigen receptor (CAR) T-cell therapy for the treatment of active refractory lupus nephritis (LN) and systemic lupus erythematosus (SLE).

Manufactured from patients with LN and SLE, IMPT-514 is intended to “reset the immune system” in patients with autoimmune diseases through B cell depletion. SLE is characterized by abnormal B cell function and autoantibody production.

The investigational therapy will be evaluated in an open-label phase 1b/2 dose escalation trial in patients with active, refractory SLE who have received treatment with at least 2 prior therapies and have a SLE Disease Activity Index score of at least 8. The trial is expected to start in early 2024.

“Receiving [Fast Track designation] from the FDA reinforces the therapeutic promise that IMPT-514 holds as the first CD19/CD20 dual targeting CAR T-cell therapy with potential to improve disease activity and renal outcomes for patients with lupus.” said Sumant Ramachandra, MD, PhD, president, and chief executive officer of ImmPACT Bio. 

The FDA’s Fast Track designation helps to accelerate the development and review of products for serious and life-threatening conditions where no treatment exists or where the investigational therapy is likely to provide an advantage over currently available treatments.