Emerging Treatments in Blood Diseases: Health Canada approval in 2024

Brigitte Leonard, Ph.D

According to the Health Canada database, the agency has evaluated and decided on the faith of 53 products in 2024. Of these 53, only 44 were authorized for commercialization in Canada (83%). Of these 44, only 26 were new active substances and seven touch blood diseases.

In this article, you will find a summary of 5 products approved in 2024 and how they can make a difference in the patient's life. Among them, there is a real breakthrough innovation and 1st in-class approval.

Thank you to Vertex Pharmaceutical, GSK, Servier, CSL Behring and KYE Pharmaceutical for developing these new treatments. Your support for Canadians afflicted with blood diseases to improve their life is appreciated.

New hope for people with sickle cell disease or beta-thalassemia

Health Canada approved Casgevry for commercialization in September 2024 to treat two genetic blood disorders: sickle cell disease and beta-thalassemia.

In these two inherited diseases, the production of hemoglobin is affected. Hemoglobin binds and carries oxygen from the lungs to other parts of the body (Figure 1) Each red blood cell circulating in blood vessels contains several hundred million hemoglobin molecules.

Hemoglobin always contains four units called chains, which all contain a heme linked with iron (Figure 2). Hemoglobin chain types are different before and after birth. The predominant form of hemoglobin (Hemoglobin F) in the fetus will contain four chains: two alpha and two gamma. The body will stop producing this variant around 12 weeks after birth At that time, the Hemoglobin A variant, which contains four chains (two alpha and two beta), will become the most predominant and stay during the rest of our lives (Figure 2). Both types of chains and their structure are essential for the function of hemoglobin.

In sickle-cell disease and beta-thalassemia, a mutation occurs in the gene that produces the beta chain on chromosome 11. This mutation causes the production of abnormal beta chains and disrupts red blood cell production and oxygen transport.

Casgevy (exa-cel: exagamglogene autotemcel) is a gene therapy developed by Vertex Pharmaceuticals and CRISPR Therapeutics. The FDA approved it in the United States for treating sickle cell disease in December 2023 and beta-thalassemia in January 2024. EMA approved it for the European market in February 2024.

Casgevy is the 1st gene therapy approved that does not use a viral vector. Casgevy uses CRISPR/Cas9 technology to edit the patient's DNA cells that produce red blood cells. Casgevy does not repair the mutated gene on chromosome 11. It stimulates the production of the fetal form of hemoglobin silenced after birth The fetal form (gamma chains) replaces the defective beta chains in the composition of hemoglobin to eliminate issues with the abnormal beta chain.

Casgevy

In Sickle Cell Disease

In the clinical study CLIMB SCD-121, patients who experienced more than three crises yearly became free from crises after Casgevy treatment For a year, 97% of patients with sickle cell disease were free from crises. Also, participants didn't need hospitalization due to crises during the year. The clinical benefits are due to participants' capability to have early and sustained increases in total and fetal hemoglobin levels, reaching near-normal to normal levels at 6 months. Patients were able to maintain better blood count over time.

How does it work?

1) In the hospital, patients' stem progenitor cells from bone marrow that produce mature blood cells are harvested.

2) Patient cells are sent to a central facility to be processed:

Enrichment of progenitor cells

Modification of progenitor cells with Casgevy (called editing)

Proliferation of modified progenitor cells

Cells will be tested, frozen, and shipped back to the hospital.

3) Upon confirmation of viable modified cells, patients will receive intensive chemotherapy (busulfan) to destroy all stem progenitor cells in their bone marrow.

4) After the chemotherapy, modified stem progenitor cells will be infused back into the patients. Patients will need a month to recuperate and get a normal - near normal blood cell production.

The most common side effects in the CLIMB SCD-121 study can primarily be attributable to Busulfan treatment. They include low platelets and white blood cell levels, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia (fever and low white blood cell count), headache, and itching

Casgevy in beta-thalassemia

In the CLIMB THAL-111 clinical study, patients with a heavy need for transfusion have been included. They received, on average, 34 blood units per year, representing one transfusion every week to every two weeks Despite the level of transfusion received, they had a hemoglobin level below normal. Also, these patients had a high excess of iron in their blood, liver and heart, putting them at risk for complications due to organ damage. Treatment with Casgevy resulted in transfusion independence in 91% of patients enrolled in the trial. The safety profile was generally consistent with intensive chemotherapy busulfan. No deaths or cancers occurred

In conclusion

The data from these two clinical trials show that a one-time infusion of Casgevy provides early and sustained increases in total and fetal hemoglobin levels, resulting in durable improvement of patients' conditions and quality of life.

Myelofibrosis is a rare cancer characterized by an overproduction of abnormal blood cells and inflammation markers called cytokines. Treatment of myelofibrosis has improved significantly since the 1st JAK inhibitor, Jakavi, was approved in 2011 JAK inhibitors are targeted therapies for cancer, like myelofibrosis, because the disease is caused by mutations that overactivate the JAK/STAT pathway.

Currently, the FDA has approved a total of four JAK inhibitors:

Jakafi/Jakavi (Ruxolitinib) 2011

Inrebic (Fedratinib) in 2019

Vonjo (Pacritinib) in 2022

Ojjaara (Momelotinib) in 2023

Until last month, Health Canada only approved two JAK inhibitors:

Jakafi/Jakavi (Ruxolitinib) 2012

Inrebic (Fedratinib) in 2023

In November 2024, Health Canada approved Ojjaara produced by GSK.

Why is Ojjaara's addition to the Canadian treatment options good news for patients?

Anemia is often present at diagnosis and eventually develops in nearly all patients due to cancer progression. Anemia and blood transfusion are risk factors linked with leukemic transformation and mortality. Most available treatments for myelofibrosis exacerbated disease-related anemia. To avoid complications related to anemia, physicians will prescribe a small dose of JAK inhibitor, which limits its efficacy.

Ojjaara is as efficient as other JAK inhibitors. However, unlike other therapies, it can improve anemia by facilitating the production of blood cells. SIMPLIFY trials have demonstrated that patients can reach healthier blood levels and become transfusionindependent. Some patients could even delay complex procedures such as transplantation due to this treatment

This unique benefit of Ojjaara (MMB) is due to its capacity to target a molecule called ACVR1. By inhibiting ACVR1, Ojjaara reduces hepcidin production. Hepcidin levels are often higher than usual in myelofibrosis patients. The reduction of hepcidin allows better iron management and stimulates red blood cell production in patients with myelofibrosis

Conclusion

Now, patients with myelofibrosis who are anemic will be able to have access to a JAK inhibitor that can improve their symptoms, reduce their enlarged spleen, and prolong their life while increasing their quality of life (QoL).