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Monthly News Roundup - December 2023

Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on Dec 30, 2023.

Landmark FDA Approval for Casgevy, a CRISPR-Based Therapy for Sickle Cell Disease

This past month the U.S. Food and Drug Administration (FDA) cleared Casgevy (exagamglogene autotemcel), the first approved CRISPR/Cas9 genome-edited cell therapy for the treatment of sickle cell disease (SCD) in patients 12 years and older with frequent vaso-occlusive crises (VOCs). Casgevy, developed by Vertex Pharmaceuticals and CRISPR Therapeutics, has been shown to reduce or eliminate vaso-occlusive crises for patients with SCD.

• Sickle cell disease is a rare, inherited red blood cell disorder affecting hemoglobin, the protein that carries oxygen through the body. Pain crises, also called vaso-occlusive crises (VOCs), occur due to a build-up of abnormal sickle shaped blood cells in blood vessels. These blockages reduce blood and oxygen flow and lead to VOCs. Organ damage and shortened life span also occur with SCD. In the U.S, SCD is most common in African Americans.
• CRISPR / Cas9 can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. Casgevy is made specifically for each patient by editing the BCL11A gene and no donor is needed.
• Prior to receiving the treatment, blood stem cells are collected and sent for editing via CRISPR / Cas9 to help make hemoglobin F (fetal hemoglobin or HbF), which can increase overall hemoglobin levels and eliminate VOCs. In patients with SCD, increased levels of HbF prevent the sickling of red blood cells.
• It can take up to 6 months to manufacture and test Casgevy before it is sent back to the healthcare provider for a one-time intravenous (IV) infusion into the patient. Prior to treatment, patients undergo hematopoietic stem cell (HSC) mobilization to move stem cells from the bone marrow to the bloodstream, followed by apheresis (when a machine separates different blood cells). Full myeloablative conditioning with busulfan (a chemotherapy drug) is given between 48 hours and 7 days before the infusion of Casgevy. Conditioning helps to make space in the bone marrow for the new stem cells.
• In single-arm studies with 44 (31 evaluable) adult and adolescent patients, the primary outcome was freedom from severe VOCs episodes for at least 12 consecutive months during the 24-month follow-up period. Overall, 29 patients (93.5%) achieved this outcome with all treated patients achieving successful engraftment and no patients with graft failure or rejection.
• The most common side effects include low levels of platelets, low white blood cells, febrile neutropenia (fever and low white blood cells), headache, itching, mouth sores, nausea / vomiting, muscle pain, stomach-area pain. Symptoms may include fever, chills, infections, headache, bruising, and bleeding.

Lyfgenia Approved to Treat Patients with Sickle Cell Disease and a History of Vaso-Occlusive Events

The FDA has approved Bluebird Bio’s Lyfgenia (lovotibeglogene autotemcel), an autologous hematopoietic stem cell-based gene therapy for the treatment of patients 12 years of age or older with sickle cell disease (SCD) and a history of vaso-occlusive crises (VOCs). Lyfgenia is produced individually for each patient using their own blood stem cells. It’s infused back into the patient as part of an autologous hematopoietic stem cell transplant (HSCT) after myeloablative busulfan conditioning.

• Stem cells normally produce healthy red blood cells (RBC) that carry oxygen throughout the body, but sickle-shaped RBCs in SCD can clog vessels, deprive tissues of oxygen and lead to pain crises.
• Lyfgenia is a one-time gene therapy to treat SCD. It uses a lentiviral vector (gene delivery vehicle) for genetic modification. Lyfgenia is designed to add functional copies of the beta-globin gene into the patient’s own stem cells. It leads to production of anti-sickling hemoglobin that may decrease the proportion of sickle hemoglobin and help stop painful vaso-occlusive events.
• In 24-month single arm studies, effectiveness was evaluated based on complete resolution of vaso-occlusive events between 6- and 18-months after infusion. Overall, 28 (88%) of 32 patients achieved complete resolution during this time period.
• Lyfgenia carries a Boxed Warning for development of certain blood cancers. Other warnings and precautions include delayed platelet engraftment, neutrophil engraftment failure, insertional oncogenesis, and hypersensitivity (allergic) reactions.
• Common side effects (≥ 20%) include stomatitis (mouth, lips, throat sores), thrombocytopenia (low platelet counts), low red or white blood cells counts, and febrile neutropenia.

FDA Grants Approval to Avzivi (bevacizumab-tnjn), the Fifth Biosimilar to Avastin

This past month the FDA approved Avzivi (bevacizumab-tnjn), a vascular endothelial growth factor inhibitor biosimilar to Avastin used for the treatment of colorectal cancer, non-small cell lung cancer, glioblastoma, renal cell carcinoma, cervical cancer, and epithelial ovarian, fallopian tube, or primary peritoneal cancer. Avzivi is from Bio-Thera Solutions, Ltd.

• A biosimilar is an approved biological product with data showing that it is highly similar to the reference product, in this case Avastin (bevacizumab), and that there are no clinically meaningful differences.
• Bevacizumab works by locating and binding to VEGF molecules, preventing their interaction with VEGF receptors on the surface of endothelial cells. This prevents the rapid increase of endothelial cells and reduces new blood vessel formation, reducing cancer growth and progression.
• Avzivi is given as an intravenous (IV) infusion into a vein over 90 minutes for the first infusion, over 60 minutes for the second infusion (if first infusion tolerated), and then over 30 minutes for the following infusions (if the second infusion is well-tolerated).
• Warnings and precautions associated with Avzivi include gastrointestinal (digestive tract) perforations and fistula (abnormal connection between 2 organs or body parts); surgery and wound healing complications; bleeding (hemorrhage); blood clots; and high blood pressure, among others.
• Common side effects include epistaxis (nose bleed), headache, high blood pressure, runny nose / congestion, protein in the urine, taste changes, dry skin, bleeding, lacrimation (eye tears) disorder, back pain, and exfoliative dermatitis (severe skin inflammation).

Novartis’ Fabhalta OK’d for Adults with Paroxysmal Nocturnal Hemoglobinuria (PNH)

In December, Fabhalta (iptacopan) received FDA approval as the first oral monotherapy for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH). Fabhalta is a first-in-class, complement factor B inhibitor and works by binding to Factor B of the alternative complement pathway. This prevents destruction of red blood cells (RBCs) within and outside the blood vessels.

• PNH is an acquired (not inherited) disorder that makes red blood cells (RBCs) more likely to be destroyed early by the complement system (part of the immune system). RBC destruction causes anemia, fatigue, formation of blood clots (thrombosis) and other symptoms. The classic symptom of PNH is dark red/brown urine caused by the breakdown of the RBCs.
• ​FDA approval was based on the results of the APPLY-PNH trial in adults with PNH and anemia despite prior anti-C5 treatment, and supported by the APPOINT-PNH study in complement inhibitor-naïve patients. In the APPLY-PNH trial, patients who switched to Fabhalta experienced superior increases of hemoglobin levels ≥ 2 g/dL (82% vs. 0%) and hemoglobin level ≥ 12 g/dL (68% vs. 0%), both in the absence of RBC transfusions, compared to patients who continued on anti-C5 treatment.
• Fabhalta capsules are taken twice daily with or without food.
• The product label carries a boxed warning for an increased risk of serious and life-threatening infections. Warnings and precautions include hemolysis after discontinuation and elevated lipid levels.
• The most common side effects (in at least 10% of patients) include headache, diarrhea, stomach-area pain, bacterial or viral infection, cold-like symptoms, nausea, and rash.

Wainua Autoinjector Cleared to Treat Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

In December the FDA cleared Wainua (eplontersen) from Ionis Pharmaceuticals and AstraZeneca. Wainua is a transthyretin-directed antisense oligonucleotide indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) in adults. It is the only approved medication for ATTRv-PN that can be self-administered using an auto-injector.

• ATTRv-PN is a rare disease caused by the mutation of the TTR gene. This leads to the accumulation of misfolded mutated transthyretin (TTR) protein in the peripheral nerves. This causes severe nerve damage throughout the body and progressive loss of motor functions, such as walking. Without treatment, ATTRv-PN is generally fatal within a decade.
• Wainua contains eplontersen which is a ligand-conjugated antisense (LICA) medicine that works to treat ATTRv-PN by reducing the production of TTR protein.
• Approval was based on the 35-week interim analysis from the Phase 3 NEURO-TTRansform study. Patients treated with Wainua demonstrated consistent and sustained benefit on the co-primary endpoints of serum transthyretin (TTR) concentration and neuropathy impairment (mNIS+7). Published studies have shown beneficial effects up to 85 weeks.
• Wainua is self-administered by subcutaneous (under the skin) injection once monthly into the abdomen or upper thigh; when given by a caregiver or healthcare provider it can be given into the back of the upper arm.
• Warnings include reduced serum vitamin A levels. More common side effects include a reduction in vitamin A levels (15%), vomiting (9%) and protein in the urine (8%). Daily vitamin A supplementation is recommended.
• Wainua will be available in the U.S. in January 2024.

FDA Approves Iwilfin as Oral Maintenance Therapy for High-Risk Neuroblastoma

Iwilfin (eflornithine) from US WorldMeds has been FDA-approved to reduce the risk of relapse in adults and children with high-risk neuroblastoma (HRNB). It is indicated in patients who have demonstrated at least a partial response to prior therapies, including anti-GD2 immunotherapy.

• High-risk neuroblastoma is an aggressive solid tumor cancer that develops from nerve tissue. About 700 to 800 cases are diagnosed each year in the U.S., with 90% of diagnoses coming before age five with about one-half classified as high-risk. A high mortality rate is driven primarily by the risk of relapse after achieving remission.
• Eflornithine, the active ingredient in Iwilfin, works by irreversibly inhibiting the ornithine decarboxylase enzyme that facilitates polyamine synthesis and a transcriptional target of MYCN (an oncogene). Inhibiting this process helps to block tumor growth.
• In clinical studies, Iwilfin led to a 52% reduction in the risk of relapse and a 68% reduction in the risk of death. Approval was based on the results of a multi-site, single-arm, externally controlled study of children with high-risk neuroblastoma who received Iwilfin as maintenance therapy following standard of care treatment, including immunotherapy. Four years after immunotherapy, event-free survival (EFS) was 84% compared to 73% of patients in the external control group, and 96% of patients treated with Iwilfin were alive compared to 84% of control patients.
• Iwilfin tablets are administered by mouth twice daily with or without food until disease progression, unacceptable toxicity, or for a maximum of two years.
• Warnings and precautions include reduced production of blood cells (myelosuppression), liver toxicity, hearing loss, and risks to an unborn baby. Common side effects include hearing loss, middle ear infection, fever, lung infection (pneumonia), diarrhea, and laboratory abnormalities.

FDA Approves Long-Duration iDose TR Implant to Treat Glaucoma

iDose TR (travoprost intracameral implant), from Glaukos Corporation is now approved for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. iDose TR continuously delivers therapeutic levels of a proprietary formulation of travoprost inside the eye for extended periods of time.

• iDose TR is a preservative-free prostaglandin analog given as a single implanted dose per eye. An intracameral injection delivers medicine into the anterior chamber of the eye (the front part of the eye between the cornea and the iris). Efficacy with a single dose has been shown for up to 36 months in published studies.
• Approval is based on two Phase 3 pivotal studies (GC-010 and GC-012) with 1,150 subjects that compared single-dose iDose TR to topical timolol ophthalmic solution 0.5%, instilled twice a day. IOP reductions over the first 3 months were non-inferior to timolol (6.6-8.4 mmHg in the iDose TR arm versus 6.5-7.7 mmHg in the timolol control arm), meaning the clinical benefits iDose TR provided were not worse than those provided by timolol. iDose TR did not demonstrate non-inferiority over the next 9 months. At 12 months, 81% of iDose TR subjects were completely free of IOP-lowering topical medications across both trials.
• iDose TR should not be used in patients with eye infections, corneal endothelial dystrophy, prior corneal transplantation, or hypersensitivity. Warnings include use in patients with narrow angles or other angle abnormalities (iridocorneal angles), device dislocation, macular edema and possible permanent brown iris pigmentation.
• Common (2% to 6%) side effects include increases in intraocular pressure, iritis, dry eye, visual field defects, eye pain, ocular hyperemia, and reduced visual acuity.
• Commercialization of iDose TR is expected by the end of the first quarter of 2024. Glaukos has published a wholesale acquisition cost for iDose TR of $13,950 per implant.

Posted December 2023

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