Written and Reviewed by Team Pharmacally
The US FDA has granted approval for the Alhemo (concizumab-mtci) injection to be administered subcutaneously, once a day, as a prophylactic to prevent or reduce the number of bleeding events in adults and children 12 years and older with Haemophilia A or B with inhibitors. It is the first treatment for the subcutaneous injection in the patient population.
The FDA granted approval following data from the pivotal Phase 3 explorer7 trial evaluating the safety and effectiveness of Alhemo in reducing bleeds for adults and pediatric patients on a daily basis. In this study, subjects who received Alhemo prophylaxis had an 86% reduction in spontaneous and traumatic bleeding episodes when compared to those who received no form of prophylaxis.
Haemophilia A and B with inhibitors
Haemophilia A and B with inhibitors is a highly complex complication in the management of a patient with Haemophilia. The condition is an overview as follows:
Haemophilia A This is due to the deficiency of clotting factor VIII.
Haemophilia B: Caused by deficiency of clotting factor IX.
What are inhibitors?
Inhibitors are antibodies formed by the body’s immune response against replacement or infused clotting factors through injections, including factor VIII or IX. This means that the body renders them ineffective because it identifies the replacing factor as a foreign entity.
Incidence: Approximately 25-30% of patients with severe haemophilia A develop inhibitors. The risk is higher in patients who have not been previously exposed to clotting factor products or who have a family history of inhibitors.
Mechanism: The inhibitors are IgG antibodies that bind to Factor VIII, neutralizing its activity and preventing it from working in the coagulation cascade.
Inhibitors are much rarer in haemophilia B and occur in around 1-5% of patients. The factor IX replacement therapy may provoke severe allergic reactions, also called anaphylaxis, in patients with inhibitors.
Prevalence: Inhibitors are found in 3-5% of all patients with severe haemophilia B. It occurs less than in haemophilia A but still creates a serious challenge.
Mechanism: In the case of haemophilia B, it is IgG antibodies against Factor IX, neutralizing the factor’s function to prevent clotting.
Explorer7 trial
The explorer7 trial was a key phase 3, multicenter, open-label study focused on the efficacy and safety of Alhemo (concizumab-mtci) in patients aged 12 years or older with Haemophilia A or B with inhibitors. The enrolled participants included 133 male patients who had been treated with, or who required treatment with, bypassing agents.
Participants were assigned to one of four groups:
Arm 1: 19 participants received no prophylaxis (on-demand treatment).
Arm 2: Alhemo prophylaxis was administered to 33 patients.
Arms 3 and 4: Non-random allocation was used in 81 patients for the administration of Alhemo prophylaxis.
The dosing regimen with Alhemo was a loading dose of 1 mg/kg of body weight, with maintenance dose being given at a daily rate of 0.2 mg/kg of body weight. This dosing could be escalated based on the plasma concentration, measured at week 4.
The main objective was the annualized bleeding rate (ABR) of treated spontaneous and traumatic bleeding episodes: no prophylaxis group compared to Alhemo prophylaxis group. Results have shown a remarkable decrease in bleeding episodes for Alhemo prophylaxis recipients:
Mean ABR 11.8 episodes (95% CI, 7.0 to 19.9) for the no prophylaxis group, Arm 1.
Mean ABR 1.7 episodes (95% CI, 1.0 to 2.9) for the Alhemo prophylaxis group, Arm 2.
This entails a reduction of 86% in the number of treated bleeds for the Alhemo group relative to that of the no prophylaxis group. Safety assessments revealed that about 5% of the patients experienced injection-site reactions and hives. Importantly, no thromboembolic events were reported after resumption of treatment.
Based on these results, Alhemo received approval from the U.S. Food and Drug Administration in December 2024 for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and paediatric patients aged 12 years and older with Haemophilia A or B with inhibitors.
About Alhemo
Alhemo is a monoclonal, subcutaneously administered antibody whose mechanism of action is to produce haemostasis in all the types of Haemophilia, by inhibiting tissue factor pathway inhibitor, to enhance thrombin generation and further improve clotting.
In normal coagulation, tissue factor pathway inhibitor regulates the coagulation of blood by acting as an inhibitor to factor Xa, the key clotting enzyme. Concizumab acts by binding to TFPI, thus inhibiting its effect of inhibition on factor Xa. Consequently, this leads to enhanced thrombin generation and compensatory formation of clot in patients with Haemophilia.
By inhibiting TFPI, concizumab enhances the activity of factor Xa thereby promoting effective blood clotting even in the presence of inhibitors against factor VIII or IX. Such mechanism provides new therapy strategy of management of Haemophilia A and B with inhibitors.
Common Adverse Reactions
Injection Site Reactions: It is the most common adverse effect and occurs in more than 1 in 10 users. It may be characterized by redness, bruising, bleeding, or itching at the injection site.
Hives (Urticaria): Some patients may develop hives, which are raised, itchy welts on the skin.
Serious Adverse Reactions
Thromboembolic Events: Even though this side effect is very rare (approximately occurring in 0.9 percent of the treated patients), deep vein thrombosis and other pulmonary embolism might form due to massive blood clot inside the vessels, which needs appropriate medical care because of pain caused by deep swelling or chest constriction, with sudden breathing.
Hypersensitivity (Allergic) Reactions: Severe allergic reactions have been reported in approximately 0.3% of patients. Dizziness and loss of consciousness may occur along with symptoms such as widespread urticaria, rash, dyspnea, swelling of face, lips, or throat. Seek medical assistance immediately if any of these symptoms occur.
Conclusion and Future Prospects
The approval by FDA of Alhemo (concizumab-mtci) represents a groundbreaking step in the treatment of Haemophilia A and B with inhibitors. The subcutaneous, once-daily prophylactic therapy proves significantly effective in reducing bleeding episodes; for instance, the results from the explorer7 Phase 3 trial were breathtakingly good. For patients who have had very few treatment options up to now, Alhemo brings a new dimension of convenience and improved quality of life. It addresses the roots of challenges of clot formation in patients with Haemophilia, being inhibitor-independent, by targeting tissue factor pathway inhibitor (TFPI).
The future prospects of Alhemo look bright. Its novel mechanism of action creates the possibility for further research to establish its potential in younger paediatric populations or even other bleeding disorders. Post-marketing surveillance and further studies will allow for further exploration of long-term safety and efficacy. Additionally, advancements in monoclonal antibody treatments with the possibility of personalized medicine might allow for further refinement in treatments for Haemophilia patients in without inhibitors also. With Alhemo expected to launch commercially in early 2025, it will likely play a pivotal role in reshaping the Haemophilia treatment landscape, setting a benchmark for future advancements in this critical area of medicine.
References:
1. FDA approves drug to prevent or reduce the frequency of bleeding episodes for patients with haemophilia A with inhibitors or haemophilia B with inhibitors, Food and Drug Administration, 20 December 2024
2. FDA approves Alhemo® injection as once-daily prophylactic treatment to prevent or reduce the frequency of bleeding episodes for adults and children 12 years of age and older with haemophilia A or B with inhibitors, press release, Novo Nordisk, 21 December 2024
3. Meeks SL, Batsuli G. Haemophilia and inhibitors: current treatment options and potential new therapeutic approaches. Haematology Am Soc Hematol Educ Program. 2016 Dec 2; 2016(1):657-662. Doi: 10.1182/asheducation-2016.1.657. PMID: 27913543; PMCID: PMC6142469.
4. Ljung R, Auerswald G, Benson G, et al, Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients. Eur J Haematol. 2019 Feb; 102(2):111-122. Doi: 10.1111/ejh.13193. Epub 2018 Dec 6. PMID: 30411401; PMCID: PMC6936224.
5. Matsushita T, Shapiro A, Abraham A, explorer7 Investigators. Phase 3 Trial of Concizumab in Haemophilia with Inhibitors. N Engl J Med. 2023 Aug 31; 389(9):783-794. Doi: 10.1056/NEJMoa2216455. PMID: 37646676.
6. Alhemo™ (concizumab injection) Product Monograph, Novo Nordisk Canada Inc, https://www.novonordisk.ca/content/dam/nncorp/ca/en/products/alhemo-en-product-monograph.pdf
7. Chowdary, Pratima et al, Concizumab prophylaxis in people with haemophilia A or haemophilia B without inhibitors (explorer8): a prospective, multicentre, open-label, randomised, phase 3a trial, The Lancet Haematology, Volume 11, Issue 12, e891 – e904
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