Hemophilia Emerging Therapies - December 2023
by Dr. David Clark
There is a huge amount of new product development going on in hemophilia B. The potential new products can 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.
Many of the updates below are from the annual meeting of the American Society of Hematology (ASH) on December 9 – 12, 2023 in San Diego. Copies of the abstracts (summaries) can be obtained for free on the meeting website, https://www.hematology.org/meetings/annual-meeting.
IMPROVED FACTOR PRODUCTS
These are improved versions of the factor products that most people with hemophilia B are currently using, also including products for inhibitor treatment. The improvements include longer half-lives and delivery by subcutaneous injection. This section also includes updates on some of the current products on the market.
STANDARD HALF-LIFE (SHL) VS. EXTENDED HALF-LIFE (EHL) FACTOR PRODUCTS
8/11/23 Two recent studies have looked at treatment outcomes in patients on EHL factor products. A group from treatment centers in Australia examined the data for 174 hemophilia patients, 115 with hemophilia A (HA) and 59 with hemophilia B (HB), from the Australia Bleeding Disorders Registry. All patients had been on EHL products for the entire year of 2019. Adherence to treatment was 87.2% in the HB patients (85.7% for HA) and 64.4% of the HB patients had no spontaneous bleeds for the year.
About one-third of the patients had their doses adjusted during the year with the main reasons being their response to the products, body-weight changes and breakthrough bleeds. The data also showed a significant impact of non-adherence (not taking the product as prescribed). [George C et al., Haemophilia, 29(5) 1283, 2023]
12/10/23 Another study of EHL vs. SHL products was performed by researchers from Pfizer using the data in the Adelphi Hemophilia Disease-Specific Programme, a survey of HA and HB patients in parts of Europe and in the U.S. In the 81 HB patients, 33 (42%) were on SHL products and 47 (58%) were on EHL products. They represented a range of severities from mild to severe.
The average annualized bleeding rates (ABRs) were 1.4 for those on SHL products and 0.9 for EHL products, not a statistically significant difference.
The adherence rate for those on SHL products was only 12%, while that for those on EHL products was 51%. This demonstrates one of the theoretical advantages of EHL products, that fewer infusions should result in better adherence. However, note that even on EHL products, half of the patients weren’t adherent. The study also showed that non-adherence led to higher ABRs, especially on SHL products. The average ABR for non-adherent patients on SHL products was 1.5 compared to an ABR of 0.5 for those with 100% adherence. There was a much smaller difference for those on EHL products, 1.0 for the non-adherent patients and 0.9 for the 100% adherent patients. Factor levels tend to fall much more slowly with EHL products than with SHL products.
Thus, both studies show that there are advantages to being on an EHL product. Both also show the importance of adherence. One take-away may be that if you tend to be non-adherent, you might be better off with an EHL product. [Thakkar S et al., ASH abstract 2616]
Despite the studies, one of the most important principles in medicine is that every patient is different. One of the advantages of having a number of different products available is that most patients will be able to find a product that works well for them. These are not interchangeable, commodity products. Some patients even do best on SHL product which includes Plasma. The choice of product should be left to the patient and their physician to find the product that has the best clinical benefit for the patient.
EXTENDED HALF-LIFE FACTOR IX FUSED TO FACTOR XIII SUBUNIT
9/14/23 A group of U.S. and European researchers are developing an extended half-life factor IX, rFIX-LXa- FXIIIB, in which a factor IX molecule is attached to the B-subunit of factor XIII. Factor XIII forms crosslinks between fibrin fibers to strengthen a new clot. It is also the clotting factor with the longest natural half-life in circulation. The group has shown in rats and mice that rFIX-LXa-FXIIIB forms clots that are indistinguishable from those formed by normal factor IX. [Desage S et al., Haemophilia, online ahead of print 9/14/23]
NOVO’S REBINYN PERFORMS WELL IN SURGERY
9/21/23 Novo Nordisk markets Rebinyn, an extended half-life factor IX that uses polyethylene glycol to stabilize the molecule in circulation. There is limited real-world experience on its use during surgery, so the group identified 31 actual surgical cases in which the patients were covered with Rebinyn. In the majority of procedures (27/31; 87%) hemostasis was judged to be “very good” or “excellent.” There were no cases of thrombosis and no reported surgical complications related to the use of Rebinyn. [Phua CW et al., Res Pract Thromb Haemost, online ahead of print 9/21/23]
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 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 REPORTS NEW DATA FROM PHASE II STUDY OF SERPINPC
12/10/23 Centessa Pharmaceuticals is developing SerpinPC, a rebalancing agent that inhibits the anticoagulant activated protein C (APC) to restore clotting. SerpinPC is a once every two weeks subcutaneous treatment for hemophilia A and B patients, with or without inhibitors. At ASH, Centessa presented data from subjects in their Phase II clinical study who have been on the product for about three years. In 20 patients, the median ABR fell from 35.6 prior to treatment, down to 1.0 with SerpinPC. There were no adverse events or thromboembolic episodes. The researchers also measured levels of D-dimer, which is a sensitive indicator of thrombosis and found no issues. [Baglin T et al., ASH abstract 2619]
PFIZER’S BLA AND MAA FOR MARSTACIMAB ACCEPTED BY FDA AND EMA
12/11/23 Pfizer is developing marstacimab, a rebalancing agent that inhibits tissue factor pathway inhibitor to restore clotting. Marstacimab is a once-weekly subcutaneous treatment delivered via an auto-injector pen for treatment of hemophilia A and B patients, with or without inhibitors. On 12/11/23, Pfizer announced that FDA has accepted their Biologics License Application (BLA, the application for a product license) for review. Their European Marketing Authorization Application (MAA) was also accepted for review by the European Medicines Agency (EMA). Decisions on their applications are expected in the 4th quarter of 2024 in the U.S. and in the first quarter of 2025 in Europe. [Pfizer press release 12/11/23]
PFIZER PRESENTS PHASE III DATA FOR MARSTACIMAB
12/9/23 At ASH, Pfizer presented the Phase III data for marstacimab that is the basis for their BLA and MAA (see above). In 116 subjects, the six-month lead-in phase of the studies before treatment found average ABRs of 7.85 for prophylactic treatment and 38.0 for on-demand treatment with clotting factors. The twelve-month treatment phase with marstacimab showed a reduction of the average ABR to 5.08 for the group that had been on prophy and to 3.18 for the group that had been on on-demand treatment. Patients who completed the twelve-month treatment phase were able to continue treatment with marstacimab in an extension study. The ABRs for the extension study (87 subjects for 16 more months) were 2.27 for the group that had originally been on prophy and 3.88 for the group that had been on on-demand treatment. There were no significant safety issues and no deaths. However, the quality of life data showed no significant difference from the subject’s earlier prophylactic or on-demand treatments. [Matino D et al., ASH abstract 285]
SANOFI REPORTS ON THE PHARMACOKINETICS OF FITUSIRAN
12/10/23 Sanofi is developing fitusiran, an RNA interference drug that decreases the body’s production of antithrombin (AT), an anticoagulant. At ASH, they presented an updated pharmacokinetic (PK) model to correlate the fitusiran dose with AT levels in circulation. The data for the new PK model was obtained from subjects in the Phase I, Phase I/II and Phase III clinical studies, a total of 339 participants. At one point, the Phase III study was placed on hold because some subjects developed signs of thrombosis (too much clotting), so Sanofi has been working on lowering the dose and better understanding the PK for fitusiran. They found that a starting dose of 50 mg by subcutaneous injection every two months would keep the AT level at the desired 15 – 35% of normal level. (The original clinical dose was 80 mg once a month, which gave an AT level below 10%, apparently too low to prevent thrombosis.) They are currently confirming that finding in clinical studies using the new dosage model. [Madrasi K et al., ASH abstract 2614]
GENE AND CELL 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. Cell therapy is the transplantation of whole cells that have been modified to perform a specific function such as producing factor IX.
BE BIO REPORTS ON GENETICALLY-ENGINEERED B CELLS FOR FACTOR IX PRODUCTION
12/10/23 Be Biopharma is developing a cell therapy for hemophilia B in which B cells are genetically modified using CRISPR/Cas9 techniques to produce factor IX. B cells are a type of white blood cell that are produced in the bone marrow from stem cells that continuously produce all of the body’s blood cells. They are part of the immune system; they recognize antigens (foreign materials that cause an immune response) and produce antibodies against those antigens. B cells continuously divide to produce new B cells that have a “memory” so the new cells can produce the same antibodies as the original cells.
The technique harvests B cells from a patient and then genetically engineers them in the laboratory using the CRISPR/Cas9 method to insert good factor IX genes into the cells. The transformed cells are then expanded (grown into additional cells) and transplanted back into the patient’s blood stream where they will eventually find their way to the bone marrow. The cells re-engraft into the bone marrow where they will continuously produce factor IX.
At ASH, Be Bio presented pre-clinical data from experiments in mice and non-human primates that suggests that the method works and appears safe. [Liu H et al., ASH abstract 463]
CSL GIVES UPDATES ON HEMGENIX
12/9-11/23 CSL’s Hemgenix gene therapy for hemophilia B has been on the market for over a year, and CSL continues to provide updates from their clinical studies. One of the unique features of their clinical studies was that they included subjects infected with hepatitis B and C viruses (HBV and HCV) and with HIV, the AIDS virus. People with active HBV/HCV infections or with uncontrolled HIV infections were excluded, but those with historic infections or controlled HIV infections were admitted. At ASH, they reported on the results for the infectious diseases.
Of the 54 Phase III study subjects, 31 (57.4%) had a history of chronic HCV infection while seven of the 31 also had a history of chronic HBV infection. Two subjects were co-infected with HCV and HIV and two were HBV positive, but negative for HCV and HIV.
These subject’s conditions did not appear to impact the success of the treatment or their factor IX expression. Both the HBV/HCV group and the non-infected group had the same average factor IX level prior to treatment, <1%. Interestingly, the HBV/HCV group had a higher median factor level after three years, 40.5% (range 4.8 to 80.3%) than did the non-infected group at 32.8% (8.6 to 55.5%), but the difference is probably not significant given the wide ranges. The bottom line is that Hemgenix appears safe and effective in patients with chronic HBV or HCV infections. [von Drygalski A et al., ASH abstract 2258]
Similarly, the studies also admitted subjects with HIV infections as long as the infection was under control. Of the 57 participants in both the Phase IIb and Phase III studies, five were infected with HIV. Four of the five had a history of treated HCV infection as well. As with the HBV/HCV subjects reported above, the treatment appeared to be safe and effective with a median factor IX level of 32.3% (range 31.5 to 58%) three years after treatment. However, because of the small number of subjects with HIV, CSL recommends continued study of HIV patients receiving Hemgenix. [Pipe S et al., ASH abstract 2256]
CSL also presented an update from the Phase III clinical studies three years after treatment. They found an average ABR of 1.52 compared to the pre-treatment level of 4.17. The average factor IX levels in the study subjects were 41.5% (range 5.9 to 113%) after the first year, 36.7% (4.7 to 99.2%) after year 2 and 38.6% (4.8 to 80.3%) after year 3. After three years 51 subjects (94%) did not need prophylaxis. [Pipe S et al., ASH abstract 1055]
9/9/23 At the earlier BIC conference in Italy, CSL presented data on the success rate for Hemgenix from the clinical studies. One of the main principles of pharmaceutical development is that you want a product that has a predictable, reproducible effect. One of the main issues with the current hemophilia B gene therapy products is that their effect is neither predictable nor reproducible. Patients achieve various factor levels after treatment.
Of the 54 total subjects, two (3.7% of total) did not express factor IX. One of those had an extremely high anti-AAV level before treatment and one quit partway through the infusion because of infusion-related reactions. The remaining 52 subjects were all able to quit prophylaxis. Of those, one subject (2% of total) had a factor level <5% of normal; 62% of subjects had a level between 5 and 40%; and 36% had levels above 40% after two years. Nine of the subjects (11%) received oral corticosteroids because of liver inflammation. [Pipe SW et al., BIC abstract OC-10]
FREELINE BEING TAKEN PRIVATE BY SYNCONA
11/22/23 Freeline Therapeutics has been developing verbrinacogene setparvovec (FLT-180a), 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 appears promising, being able to increase factor IX levels into the normal range. Unfortunately, they ran into money problems and in mid-2022 decided to stop their work on FLT180a until they could find a development partner. Now Syncona, a British investment firm, is working on a deal to take Freeline private (off the stock markets). The deal is expected to close in the first quarter of 2024. The company’s plans for further development of FLT-180a have not been announced. [Biopharma Dive article, 11/22/23]
PFIZER GIVES UPDATES ON GENE THERAPY
12/9-10/23 Pfizer is developing fidanacogene elaparvovec, 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. They presented two updates at ASH on the results from their clinical studies.
The first paper looked at six (out of 45 total) Phase III clinical study subjects who had returned to factor IX prophylaxis (RTP) after initially good results from the treatment. The six RTP patients switched back to prophylaxis either because their factor IX (FIX) levels dropped below 2% or because they had bleeding episodes. All six had initially responded well with FIX levels ranging from 7 to 22% of normal. At the time they returned to prophylaxis, however, their levels had fallen to a range of 0.5 to 5.8%. Their time of switching ranged from 155 to 623 days after treatment. All of the subjects had been given corticosteroids to reduce liver inflammation and hopefully stabilize their FIX production. Pfizer is still looking at the cause of their RTP. [Frenzel L et al., ASH abstract 2257]
Pfizer’s other paper reported on health-related quality of life (HRQoL) for 14 subjects in their Phase I/IIa study using questionnaires. At week 156 after treatment, the subject’s results from the Haem-a-Qol questionnaire fell by an average of 15.2 points, which represents a significant improvement in HRQoL. EQ-VAS scores had risen by 7 – 8 points two years after treatment indicating an improvement in overall health. A greater proportion of the subjects also reported increasing their physical activity by week 156 compared to their baseline before treatment. [von Mackensen S et al., ASH abstract 3628]
ACTIVATED FACTOR X STORED IN PLATELETS TO PROMOTE CLOTTING
10/1/23 A group of Chinese investigators is developing a hemophilia B treatment method involving activated factor X (FXa) stored in platelets. Factor X is a pivotal molecule in the clotting cascade. It can be activated by either activated factor IX (FIXa) or activated factor VII (FVIIa). FXa then recruits other clotting factors and other molecules to form a complex that reacts with prothrombin (factor II) to form thrombin (factor IIa). Thrombin then turns fibrinogen (factor I) to fibrin, which is a “sticky” molecules that binds to other fibrin molecules to form the clot.
Platelets are small blood cells that are also part of the clotting system. They are activated when the clotting cascade starts producing activated clotting factors. Activated platelets are also “sticky” and bind to other activated platelets as well as to fibrin. The combination of the clumped platelets covered by a network of fibrin strands, as well as other blood cells that get caught up and tangled in it, forms the actual clot that seals up a hole in the blood vessel.
The Chinese researchers found that they can genetically engineer the hematopoietic stem cells in the bone marrow to produce platelets that contain FXa. When those platelets are activated to form a clot, they release the FXa, which increases the amount of clotting occurring. They showed that these modified platelets could produce significant clotting in hemophilic mice, even in mice with inhibitors. The group initially was looking at treatment of inhibitor patients with the FXa- platelets, but have now expanded their target to include hemophilia patients without inhibitors. Whether this will be a viable alternative to factor IX gene therapy remains to be seen. [Han W et al., Nature Sci. Rep., 13(1), 16488, 2023]
JAPANESE GROUP REPORTS ON GENE THERAPY
9/14/23 Interest in gene therapy seems to be booming. A group of researchers in Japan is developing an improved AAV vector and delivery technique for gene therapy of factor IX. They are attempting to solve the problems of the high vector doses needed because of inefficient transfer of genes to cells and the immune issues caused by the viral vector. They have developed a vector called AAV.GT5 that is about 100 times more efficient at getting genes into liver cells. They have also shown that injection of AAV.GT5 directly into the liver, rather than into the general circulation, enhances gene transfer. AAV.GT5 also appears to be less immunogenic than current AAV vectors. Their recent report on experiments in pigs and macaques shows promising results. [Kashiwakura Y et al., Mol. Ther. Methods Clin. Dev., 30, 502, 2023]
ST. JUDE/UCL REPORTS ON ORIGINAL GENE THERAPY AFTER TEN YEARS
12/9-11/23 Around ten years ago, a large group of researchers from St. Jude Children’s Research Hospital, University College London (UCL) and other institutions performed the first successful hemophilia gene therapy clinical trials. At ASH, the group gave an update on those early patients. As of the end of 2022, the median follow-up period was 10.7 years (range 4 to 12) for the ten subjects in the study. The subjects received various doses with six subjects in the high-dose cohort.
Four of the six high-dose subjects developed liver inflammation and were treated with oral corticosteroids, which resolved the issue without any recurrence. Two other serious adverse events occurred in two of the patients. One patient developed lung cancer five years after treatment, but this was shown not to be associated with the treatment. Another 72-year-old subject developed prostate cancer twelve years after treatment. That case is still being investigated. The subjects developed low but persistent factor IX levels of 1.7%, 2.3% and 4.9% in the low, medium and high dose cohorts, respectively. Their median ABR over the 10-year period was 1.6 compared to an ABR of 14 before treatment. In the high-dose cohort, the median ABR was 1.0. [Reiss UM et al., ASH abstract 1056]
The St. Jude/UCL group also reported on the persistence of anti-AAV antibodies after treatment. Antibodies against AAV vectors could complicate future treatments using AAV vectors. First, they found that the levels of anti-AAV antibodies in the study subjects were much higher than would normally be obtained from an actual AAV infection. They also found that the antibodies have some cross-reactivity to other AAV types. The antibody levels gradually fell over the ten-year period but still remained too high for the subjects to receive another dose of gene therapy. Interestingly, they found that AAV5, which is used in Hemgenix, causes the mildest antibody responses, which may allow repeat treatment. [McIntosh JH et al., ASH abstract 2255]
RED BLOOD CELLS LOADED WITH FACTOR IX
12/11/23 A group from the University of Pennsylvania and Temple University has been exploring the possibility of attaching factor IX (FIX) molecules to the surface of red blood cells (RBCs). RBCs have a lifetime in circulation of about 120 days, so this would give the FIX an extra-long half-life. The FIX is linked to a mouse glycophorin A (GPA) antibody and then incubated with RBCs. RBCs have glycophorin A molecules on their surfaces, so the GPA antibodies bind to those molecules bringing the factor IX along with them. The group also found that if they inject just the bare FIX- GPA molecule into mice it will find the mouse’s RBCs and bind to them. Therefore, the FIX-GPA molecule could be used by itself without first attaching it to RBCs. The researchers showed that the FIX-GPA-RBC complex retains the clotting ability of the FIX molecule. [Peshkova AD et al., ASH abstract 5006]
SEN. BILL CASSIDY WANTS TO IMPROVE ACCESS TO GENE THERAPIES
12/6/23 Senator Bill Cassidy (R-Louisiana) is looking for feedback from stakeholders (involved parties) with the idea of crafting legislation that would make cell and gene therapies more accessible for patients. Cassidy points out that the small number of current gene and cell therapy treatments can be handled adequately, but as the number of approvals skyrocket over the next few years, the market is not sustainable. This is a balancing act because prices need to be low enough to let all patients have access, but still need to be high enough to give incentives for future research and product improvement. [Biospace article 12/6/23]
FRENCH STUDY SHOWS PATIENTS’ PERSPECTIVES ON GENE THERAPY
12/6/23 A French study looked at patient perspectives on hemophilia gene therapy. They received 137 responses to a questionnaire (about 3.5% of French people over 16 years old with severe or moderate hemophilia) with 80.3% from hemophilia A patients and 19.7% from hemophilia B patients. About 64.2% of respondents were curious about gene therapy, with 33.6% of the total being ready as soon as possible and 38.7% wanting to wait until more patients have been treated. Only 3.6% of patients stated that they would never be interested in gene therapy. About 39.5% of patients said that they were not knowledgeable enough about the treatments, and more than 60% had not discussed gene therapy with their physician or treatment center. [Pietu G et al., Haemophilia, online ahead of print 12/6/23