The expansion of our Ig portfolio continued over the past year with successful regulatory approvals in neurology. In September 2017, the FDA approved PRIVIGEN® (Immune Globulin Intravenous [Human], 10% liquid) for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP), a rare and progressing disease that may cause permanent nerve damage. The FDA approval represents a significant milestone for patients with this debilitating and progressive disease.
In March 2018, the FDA and the EMA also granted approval for HIZENTRA® (Immune Globulin Subcutaneous [Human], 20% liquid) to treat CIDP. In the largest ever clinical study to investigate the treatment of CIDP and the first to evaluate the subcutaneous administration of Ig for the treatment of CIDP (the Polyneuropathy and Treatment with Hizentra or PATH study), HIZENTRA® maintained stable disease and prevented relapse for up to 24 weeks. The subcutaneous formulation will allow patients the flexibility to self-administer their treatment at a time, place and schedule that’s convenient for them.
Collaboration with external partners continues to provide CSL with important new opportunities to develop novel therapies for patients and address areas of unmet medical need. In January 2018 CSL and Momenta Pharmaceuticals, Inc. initiated a Phase I study in healthy volunteers to evaluate the safety and tolerability of the potential first-in-class recombinant Fc multimer protein M230/CSL730 in development to control inflammation associated with autoimmune diseases. Preclinical studies in animal models of autoimmune disease have shown that M230 matched potency and efficacy of intravenous immunoglobulin at significantly lower doses. M230/CSL730 offers CSL the potential to further grow and expand our long-term global leadership in helping patients with autoimmune diseases that are treated with immunoglobulins.
Haemophilia and coagulation products
CSL remains focused on easing the burden of care and improving the lives of Haemophilia patients. In September 2017, Japan’s Ministry of Health, Labour and Welfare approved AFSTYLA®, the only recombinant factor VIII single chain indicated for the treatment of haemophilia A.
In May 2018 the FDA approved a new 3500 IU vial size for IDELVION®, our long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin for the treatment of haemophilia B. For patients requiring high doses of IDELVION, the larger vial size will reduce the reconstitution time need to prepare multiple smaller vials for a similar dose. IDELVION is currently licensed for treatment intervals of up to 14 days. An ongoing Phase III extension study (PROLONG-9FP) is currently evaluating the possibility of extending the dosing interval to every 21 days. Global regulatory submissions to gain approval of the extended dosing regimen are planned for 2019.
Strong progress has been made in the expansion of our specialty products portfolio over the past year. In July 2017, following FDA approval, CSL launched HAEGARDA® (plasma derived human C1-Esterase Inhibitor [C1-INH]), the first and only subcutaneous preventative treatment for patients with Hereditary Angioedema (HAE). HAEGARDA® represents a new standard of care for HAE patients, reducing HAE attacks by 95% and the need for rescue medication by 99%. In order to remain at the forefront of innovation in HAE treatment, in May 2018 CSL announced an exclusive license agreement with CEVEC Pharmaceuticals to develop highly differentiated recombinant C1-INH proteins. Building on our deep knowledge and expertise of HAE and plasma derived C1-INH, CSL aims to leverage CEVEC’s expertise in the production of recombinant C1-INH using their proprietary CAP®Go technology. The technology provides the opportunity to develop innovative proteins with improved half-life and more convenient administration, further improving the quality of life for patients suffering from HAE.
Our commitment to remain at the forefront of innovation is stronger than ever. In August 2017, CSL acquired Calimmune Inc., a biotechnology company focused on the development of gene and stem cell-based therapies. The acquisition introduced a new ex vivo hematopoietic stem cell gene therapy (CAL-H) for the treatment of sickle cell disease into our Breakthrough Medicines pipeline. Clinical trials using CAL-H are anticipated to start in 2019. In addition, Calimmune’s proprietary platform technologies have the potential to develop new treatments for a wide range of other rare diseases that complement CSL’s product portfolio and expertise.
Over the past year we have continued to make strong progress in our Breakthrough Medicine portfolio with the completion of two Phase I trials and the initiation of a third using three of CSL’s novel monoclonal antibodies. CSL312 is a fully human an anti-factor XIIa monoclonal antibody that is being studied for use in multiple indications including as a subcutaneous therapy for HAE with the potential for administration once every two to three weeks. A Phase I study in healthy volunteers was completed in November 2017 and confirmed that CSL312 is safe and well tolerated with good bioavailability. A Phase II trial designed to evaluate the efficacy, safety and pharmacokinetics of CSL312 in the prophylaxis of angioedema attacks in HAE patients is anticipated to start in 2018/19.
CSL324 neutralises G-CSF activity and may provide a new treatment for rare inflammatory diseases associated with overactive neutrophils (white blood cells). The completion of a Phase I trial in healthy volunteers in January 2018 demonstrated that CSL324 can block receptors and lower neutrophil counts. A subsequent Phase Ib trial in patients with neutrophil driven disease is anticipated to start in 2018/19 and aims to provide proof of mechanism.
CSL346 targets VEGF-B and could potentially be used to control glucose absorption in Type 2 diabetics by targeting fatty acid metabolism. CSL346 may also be beneficial in the treatment of diabetic nephropathy, one of the most common kidney complications associated with Type 2 diabetes, where VEGF-B levels have been shown to be elevated in patients. A Phase I trial in healthy volunteers commenced in November 2017 in order to demonstrate that CSL346 is safe and well tolerated.
The largest clinical trial ever to be undertaken by CSL was announced in December 2017. CSL112 is a novel plasma derived apolipoprotein A-1 infusion therapy that has been shown to have an immediate and significant impact on the removal of cholesterol from arteries. The ApoA-1 Event reducinG in Ischemic Syndromes II (AEGIS-II) Phase III trial will enrol over 17,000 patients from approximately 1,000 medical centres around the world. The trial will evaluate the efficacy and safety of CSL112 for the reduction of early recurrent cardiovascular events following an acute myocardial infarction.
Antibody-mediated rejection (AMR) is a major cause of kidney transplant failure and is often associated with the activation of complement, a set of proteins that work with antibodies and play a role in the development of inflammation and tissue damage. C1-esterase inhibitor (C1-INH) present in human plasma regulates the complement pathway. Administering additional C1-esterase inhibitor to patients after solid organ transplantation is expected to reduce the action of the complement system, therefore reducing the likelihood of the transplanted organ being rejected. CSL’s plasma-derived C1-INH, registered as BERINERT®, has been used clinically for over 30 years, and has an excellent safety record in both acute and chronic prophylactic therapies for HAE. In October 2017, we received orphan designation for the use of human C1-INH in solid organ transplantation to control rejection. In November 2017, CSL initiated a Phase III trial to evaluate the efficacy and safety of plasma derived C1-INH (CSL842) in the treatment of refractory AMR in renal allograft recipients.
In December 2017 CSL and Vitaeris announced a strategic partnership to expedite the development of clazakizumab (an anti-IL-6 mAb, formerly ALD518) as a therapeutic option for solid organ transplant rejection. Clazakizumab is a best-in-class IL-6 antagonist that has been studied in clinical trials involving over one thousand patients worldwide. IL-6-driven chronic inflammation has been implicated in the development of AMR and a clinical study to further evaluate the role of IL-6 blockade as a means to preserve renal function and prevent renal allograft loss from AMR was initiated in January 2018. Our expertise in immunology, our pipeline and strategic partnerships are full of promise to address unmet needs in the transplant community.
Vaccines and licensing
Our Seqirus R&D team continued to advance the pipeline over the past year, which is critical to future growth. Key clinical trials are underway to support the registration of FLUAD™ QUADRIVALENT in the older adult population and to expand the age indication of FLUCELVAX QUADRIVALENT® down to 6 months. We also have a number of research and development programs in place to further optimise our adjuvant and cell-based technologies. Seqirus also has early stage collaborations that are exploring other transformational approaches including universal projects, synthetic technology and new delivery devices.