Emerging Therapies - Spring 2023
By Dr. David Clark
Spring 2023 - There is a huge amount of new product development going on in hemophilia B. The potential new products can currently be separated into three categories, 1) improved factor products, 2) rebalancing agents and 3) gene therapy. These updates are divided into those three categories. Within each category, the entries are generally listed in order of the names of the organizations developing the product.
IMPROVED FACTOR PRODUCTS
These are improved versions of the factor products that most people with hemophilia B are currently using. The improvements include longer half-lives and delivery by subcutaneous injection. This section also contains news about some newer products that are already on the market.
FDA Accepts Medexus’ Application for a Pediatric Indication for Ixinity
6/15/23
Medexus Pharmaceuticals markets Ixinity, a recombinant factor IX product for treatment of hemophilia B. It is currently only licensed for patients 12 years and older. They recently completed a Phase IV study (a clinical study that takes place after a product has already been licensed) to extend that indication to children under twelve. They announced that the US. FDA has accepted their license application for the additional application. [Medexus press release, 6/15/23]
TiumBio Developing Extended Half-Life Product for Inhibitor Treatment
4/4/23
TiumBio, a South Korean company, is developing TU7710, an extended halflife recombinant factor VIIa product for treatment of hemophilia A or B patients with inhibitors. The two factor VIIa products currently on the market, Novo’s NovoSeven and HEMA Biologics SEVENFACT, both have relatively short half-lives and may need to be infused more than once-a-day for treatment of a serious bleed. TU7710 is a factor VIIa molecule fused to a transferrin molecule. Transferrin is a normal human protein that binds iron from the gut and transports it to other tissues in the body. It has a longer lifetime in circulation that is expected to give TU7710 a half-life up to seven times longer than the current products. TiumBio is currently beginning a Phase Ia clinical study of TU7710.
TiumBio is also working on extended half-life versions of factor VIII for hemophilia A and factor IX for hemophilia B, also using transferrin. The company isrelatively new, but the staff have extensive experience working for SK Pharma on the hemophilia A product Afstyla. [TiumBio press release, 4/4/23]
Zea Biosciences to Make Lettuce for FIX Inhibitors
3/28/23
Back in the Winter 2016 issue, we told you about groups from the Universities of Florida and Pennsylvania (now also including a group from the University of Indiana) who were developing a factor IX product produced in lettuce. The product showed promise in eliminating inhibitors from hemophilia B patients. Since then, they have done extensive development on the project and are working toward a clinical study. They recently signed a deal with Zea Biosciences to produce the product. Zea is a specialist in producing plant-based biological medicines that was founded by Jim Wilson, one of the pioneers of gene therapy.
The idea is that tolerance, preventing or eliminating an inhibitor, can be achieved by orally exposing the intestines (gut) to the antigen, in this case factor IX. (An antigen is anything that triggers the immune system to make antibodies.) The immune system in the gut tends to produce tolerance by suppressing the regular immune system’s response against the antigen. This helps us keep from developing allergies to all the foods we eat, although some people do still develop food allergies.
People have worked for decades trying to develop an oral factor IX, one that can be taken as a pill or capsule. The problem is getting factor IX into the intestines since it tends to get broken down in the stomach. So, instead of purifying the factor IX from the lettuce, they leave it in the plant’s cells. Then, the lettuce is freeze-dried and crushed into a powder that is filled into capsules. The strong cell walls of the lettuce tend to protect the factor IX as it’s going through the stomach, so it can make its way to the intestines intact. The researchers have shown in mice and dogs that feeding them the product can eliminate an inhibitor or prevent its formation. [Zea press release, 3/28/23 and Srinivasan A, et al., Plant Biotechnol. J., 19:1952 (2021)]
REBALANCING AGENTS
Rebalancing agents tweak the clotting system to restore the balance so the blood clots when it should and doesn’t clot when it shouldn’t. The clotting system is a complex system of clotting factors that promote clotting and anticoagulants that inhibit clotting. In a person without a bleeding disorder, the system is in balance, so it produces clots as needed. In hemophilia, with the loss of some clotting factor activity, the system is unbalanced; there is too much anticoagulant activity keeping the blood from clotting. Rebalancing agents mainly reduce or inhibit the activity of the anticoagulants in the system. Most of these agents work to help restore clotting in people with hemophilia A or B, with or without inhibitors.
Centessa Announces Phase II Studies of SerpinPC, Plus Fast Track Designation
3/31/23
Centessa Pharmaceuticals is developing SerpinPC, an inhibitor of the anticoagulant activated protein C (APC) to control bleeding in patients with hemophilia A and B, with or without inhibitors. SerpinPC is a subcutaneous injection, once every two weeks. After good results in their Phase I/IIa study, they are now planning a full Phase II study to begin later this year. [Hemophilia News Today article, 3/31/23]
5/22/23
Centessa announced that they have received Fast Track Designation for SerpinPC from FDA. Fast Track is designed to facilitate development and expedite review of products that treat serious conditions with unmet needs. It brings more frequent meetings with FDA and possible eligibility for faster license reviews. [Centessa press release, 5/22/23]
Novo’s Concizumab Approved in Canada; Delayed in U.S.
3/10/23
Novo Nordisk is developing concizumab, an inhibitor of the anticoagulant tissue factor pathway inhibitor (TFPI) to control bleeding in patients with hemophilia A and B, with or without inhibitors. Concizumab is a once-daily subcutaneous injection. On 3/10/23 concizumab, brand name Alhemo, was approved in Canada for hemophilia B patients with inhibitors over 12 years of age. Note that Canada only gave the product a limited indication. Ultimately, the product is intended for all people with hemophilia, A or B, with or without inhibitors. Canada only gave it a limited indication for treatment of B inhibitor patients, a huge unmet need. [Novo Nordisk Canada press release, 4/17/23]
4/24/23
The U.S. FDA sent Novo a Complete Response Letter (CRL) requesting more information on the product. FDA wants additional details on the manufacturing process and on Novo’s plans for “monitoring and dosing of patients to ensure that concizumab is administered as intended.” The FDA is presumably concerned about the risk of thrombosis, which occurred in three patients during the clinical studies, resulting in a temporary clinical hold and a revision of the dosing instructions. Since they restarted the studies, there have been no additional thrombotic events. [Fierce Biotech article, 5/4/23 and Biospace article, 5/5/23]
Pfizer Reiterates Commitment to Hemophilia
4/17/23
World Hemophilia Day In January, Pfizer announced that it is stepping back from early-stage R&D for rare diseases. We didn’t know what that would mean for hemophilia, but during a media event for World Hemophilia Day, Pfizer “reiterated its goal to make sure patients living with hemophilia are seen, heard, and never forgotten as it continues to work tirelessly to find break-through solutions and therapeutic options to change their lives.” [Pfizer press release 4/20/23]
Pfizer Announces Positive Results from Phase III Studies of Marstacimab
5/30/23
Pfizer is developing marstacimab, an inhibitor of the anticoagulant tissue factor pathway inhibitor (TFPI) to control bleeding in patients with hemophilia A and B, with or without inhibitors. Marstacimab is a once-weekly subcutaneous injection. On 5/30, they announced that their pivotal Phase III study has met its primary endpoints. In 116 patients, both As and Bs, but without inhibitors, they saw a 92% reduction in the annualized bleeding rate (ABR) compared to on-demand treatment and a 35% reduction compared to prophylaxis with factor concentrates. They have not released the actual ABR numbers yet. They also saw no new safety concerns and there were no incidents of thrombotic complications.
Pfizer is currently analyzing the complete Phase III results, which will be presented at upcoming conferences, and plans to meet with FDA in the near future. They also have ongoing studies of marstacimab in inhibitor patients and in children. [Pfizer press release 5/30/23]
Sanofi Publishes Results of Phase III Fitusiran Studies
3/29/23
Sanofi is developing fitusiran, an inhibitor of the anticoagulant antithrombin, to control bleeding in patients with hemophilia A and B, with or without inhibitors. Fitusiran is a oncemonthly subcutaneous injection. Fitusiran is a silent interfering RNA (siRNA) that inhibits the production of antithrombin. In the last issue, we summarized the results from their Phase III study that were presented at the American Society of Hematology (ASH) and the European Association for Haemophilia and Allied Disorders (EAHAD) recent annual meetings. Now those results have been published in The Lancet for the Phase III study on inhibitor patients and in Lancet Haematology for the non-inhibitor patient study. [Young G et al., Lancet, online ahead of print, 3/29/23 and Srivastava A et al., Lancet Haematol., online ahead of print, 3/29/23]
GENE THERAPY
Gene therapy is the process of inserting new, functional factor IX genes into the body to allow it to produce its own factor IX.
Belief BioMed Completes Dosing in Phase III Study
4/23/23
Belief BioMed, a Chinese company, is developing BBM-H901, a gene therapy for hemophilia B that is delivered by an adeno-associated virus (AAV) vector and uses the Padua high-activity factor IX gene. In their earlier studies of dose exploration/escalation, ten patients with pretreatment factor IX levels below 2% were able to stop treatment with factor IX and had annualized bleeding rates (ABRs) of zero. The product appeared safe with no serious adverse events. Now they have begun a Phase III study. [Belief BioMed press release, 4/23/23]
CSL Announces First Patient Treated with Hemgenix
6/20/23
CSL Behring announced that the first commercial patient has been treated with their Hemgenix gene therapy for hemophilia B. Also, discussions between CSL and the payer community have been generally positive with payers insuring about 60% of the U.S. population establishing clear medical policies covering Hemgenix. CSL is providing ongoing training to clinical centers, primarily HTCs, who will administer the product and encouraging long-term data collection through ATHN.
For patients who have decided, along with their physicians, to move forward with Hemgenix treatment, CSL has established the HEMGENIX ConnectSM program. They will be assigned a dedicated support team including a Patient Resource Navigator and a CSL case manager to help with questions, monitor their treatment process and help with obtaining insurance coverage. [CSL press release 6/20/23]
CSL’s Hemgenix Licensed in Additional Countries
3/27/23
CSL’s Hemgenix gene therapy for hemophilia B has now been approved in several other countries, including the EU, UK, Liechtenstein, Iceland and Norway. [Pharma Times article, 3/27/23]
Freeline Makes More Cuts
4/4/23
Freeline Therapeutics has been developing FLT180a, a gene therapy for hemophilia B that is delivered by an adeno-associated virus (AAV) vector and uses the Padua high-activity factor IX gene. The treatment appeared promising, being able to increase factor IX levels into the normal range. Unfortunately, they have run into money problems and in mid-2022 decided to stop their work on FLT180a until they can find a development partner. Now, they have cut another gene therapy project for Fabry Disease and made more layoffs.
Their one remaining project is a gene therapy for Gaucher Disease. They say they have enough cash to fund operations into the second quarter of 2024. Biotech funding has become very tight, so unless something happens, this might be the end of FLT180a. [Biopharma Dive article, 4/4/23]
Genascence Developing Gene Therapy for Osteoarthritis
3/6/23
Genascence is developing GNSC-001, a gene therapy for treatment of osteoarthritis in the knee. It is delivered via an AAV vector and carries the gene for interleukin-1 receptor antagonist (IL-1Ra), a potent inhibitor of interleukin-1 (IL-1). IL-1 is considered one of the key molecules involved in osteoarthritis, causing inflammation and cartilage destruction.
The treatment is injected directly into the knee joint where it transforms the cells inside the joint capsule. Production of IL-1Ra by those cells is expected to inhibit the destruction caused by IL-1. IL-1Ra production appears to be localized to the joint.
Many hemophilia patients develop a similar condition called hemarthrosis due to bleeding into the joints. It is suspected that IL-1 is also an actor in the long-term damage in hemarthrosis, so GNSC-001 could also be effective in dealing with the pain and degradation of hemarthrosis.
In a Phase I study, nine patients were treated with increasing doses of GNSC-001. The researchers found elevated levels of IL-1Ra that persisted for at least the twelve months of the study, with no serious adverse events. Although the Phase I study only looked at safety, not efficacy (effectiveness), pain and function scores did improve. [C&ENews article, p, 13, 3/6/23]
Pfizer’s Gene Therapy License Application Accepted by FDA and EMA
6/27/23
Pfizer is developing fidanacogene elaparvovec, a gene therapy for hemophilia B. It is an AAV vector containing the Padua high-activity factor IX gene. The product was originally licensed from Spark Therapeutics in 2014. Pfizer submitted both a Biologics License Application (BLA) to the U.S. FDA and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) based on 15 months of data from their Phase III clinical study. They announced that both applications have been accepted by the agencies. FDA has set a goal for a decision on the application in the second quarter of 2024. The Phase III study is ongoing, and the 45 participants will be monitored for a total of 15 years. [Pfizer press release, 6/27/23]
Takeda Trims EarlyStage Efforts in AAV Gene Therapy
4/6/23
Takeda has been involved in hemophilia gene therapy through mergers and spinoffs going back through Shire to Baxalta and Baxter. Their gene therapy plans have never been too clear, but since March 2020, they have invested in gene therapy deals with ten small biotech companies, including one with Poseida Therapeutics for hemophilia A. Most of those deals have been for projects that use other vectors than AAV.
Now, they have announced that they will no longer perform early-stage R&D on AAV gene therapies or on rare hematology projects. Early-stage R&D is work that is done in the beginning stages of development, before clinical studies. They say that the changes won’t affect any projects currently in development.
Reading between the lines, this suggests that Takeda still has a strong commitment toward gene therapy, just not with AAV. Although AAV has gotten us to a licensed product for hemophilia B gene therapy, as well as numerous other gene therapies, it is not the ideal vector. It interacts strongly with the immune system, which causes problems. It also preferentially infects liver cells, which are probably not the best cell type for all applications. For instance, hepatocytes (liver cells) may not be the best place to make factor VIII for hemophilia A gene therapy.
Factor VIII is normally made in sinusoidal endothelial cells, which line the blood vessels in the liver, but are not hepatocytes. Targeting the wrong cell may be the reason that we’ve seen factor VIII levels decline over time in several A gene therapies. In contrast, factor IX is made in hepatocytes, its normal source. Thus, Takeda is not abandoning gene therapy but instead taking a leap into the future for non-AAV gene therapy. [Fierce Biotech article, 4/6/23]
