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In today’s blog post, I will discuss three issues relevant to patients with Hemophilia. One is about Emicizumab, a Factor VIII mimetic that in November 2016 was approved for patients with Hemophilia A with Factor VIII inhibitors by the FDA. Two is about a successful trial of gene therapy for Hemophilia B, and three is about two successful trials of gene therapy for Hemophilia A.

Emicizumab, formerly known as ACE910, now marketed as Hemlibra by Roche, is a recombinant humanized bispecific antibody that binds to activated factor IX and X, thus continuing the coagulation reaction, even if factor VIII was absent or neutralized by factor VIII antibodies. In 64 healthy volunteers (Uchida et al, Blood 2016; 127(13):1633-1641) no serious adverse events were observed after a single subcutaneous dose. In a non-randomized trial on 18 patients with severe Hemophilia A with or without inhibitors, an initial dose of emicizumab 1mg/kg followed by a weekly dose of 0.3mg/kg resulted in a fall in the median annualised bleeding rate (ABR) from 32.5 to 4.4, while an initial dose of 3mg/kg followed by a weekly dose of 1mg/kg resulted in a fall in the median ABR from 18.3 to 0, and an initial dose of 3mg/kg followed by a weekly dose of 3mg/kg resulted in a fall in the median ABR from 15.2 to 0 (Shima et al. NEJM 2016;374:2044-53). This dose finding Phase 2 study led to HAVEN-1 and HAVEN-2, randomized clinical trials that enrolled large numbers of patients with hemophilia. In HAVEN-1, 53 patients 12 years of age or older with hemophilia A with inhibitors who were previously treated with episodic treatment were randomized 2:1 to emicizumab 3mg/kg weekly subcutaneously for four weeks followed by 1.5mg/kg weekly thereafter or no prophylaxis. The annualized bleeding rate was 2.9 (95% confidence interval 1.7-5.0) in the treatment group versus 23.3 (95% confidence interval 12.3-43.9) in the group without prophylaxis, resulting in an 87% reduction in ABR (p<0.0001). 24 patients who had previously received prophylactic treatment with bypassing agents were prophylactically treated with emicizumab and showed a reduction in ABR by 79% (p<0.001) compared to the rate with previous prophylaxis with bypassing agent. Thrombotic microangiopathy and thrombosis were reported in two participants, both of whom had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. (Oldenburg et al. NEJM 2017;377:809-818) In HAVEN-2, patients 12 years old or younger or 12-17 years old and weighing less than 40kg with hemophilia A and with inhibitors who were previously treated with bypassing agents were treated prophylactically with emicizumab. In the interim analysis, the annualized bleeding rate for treated bleeds in 23 patients was 0.2, and for 13 of these patients, this was a reduction of 99% versus prior treatment. 64.9% of patients had no bleeds and 94.7% of patients had zero treated bleeds. (Young et al, Oral abstract, ASH 2017) This led to approval by the FDA of this drug as prophylaxis for patients with hemophilia A with inhibitors. (FDA approval here; full prescribing information here) A Phase III study on patients with hemophilia A without inhibitors is underway. Emicizumab is priced at $482000 a year for the first year and $448000 a year for subsequent years. (source) Financial assistance is available according to the Hemlibra website.

Even more exciting though, has been the success of gene therapy in seven men with severe hemophilia A who were given a single intravenous dose of adeno-associated virus serotype 5 vector encoding a B-domain deleted human factor VIII. Two other patients who received the same therapy at lower doses had Factor VIII levels at 3IU/dL or less. In the seven patients who received a high dose, factor VIII activity levels exceeded 5IU/dL 2-9 weeks after gene transfer and in six patients, the level exceeded 50IU/dL and was maintained at 1 year. Annualised bleeding rate among participants who had received prophylactic therapy declined from 16 to 1 and by week 22 after gene transfer, factor VIII use for reported bleeding ceased in all participants. The primary adverse event was an elevation in liver enzymes to 1.5 times the upper limit of normal or less. (Rangarajan et al. NEJM;2017:377(26):2519-2530). Phase 3 trials are eagerly awaited.


A similar success was reported in the same month by another group for Hemophilia B (Miesbach et al. Blood 2017;epub-2017-09-804419). Using the same adeno-associated virus 5 (AAV5) vector, with a liver-specific promotor driving expression of a codon-optimized human factor IX gene, a single dose of 5 x 10∧12 and 2 x 10∧13 copies/kg were each administered to five adults with hemophilia B whose factor IX activity levels were 2% or less and had severe bleeding phenotype. Factor IX level rose to 4.4 IU/dL in the low dose cohort and 6.9IU/dL in the higher dose cohort. Annualized spontaneous bleeding rate decreased from 9.8 to 4.6 in the low dose cohort and from 3.0 to 0.9 in the higher dose cohort. There was no reduction in traumatic bleeds. Factor IX prophylaxis was stopped in eight of nine patients who were receiving prophylaxis at time of study entry. Alanine aminotransferase was elevated in three patients, which were asymptomatic, limited and transient and were treated with prednisolone. In another report, (George et al. NEJM 2017;377(23):2215-2227), a single dose of AAV vector with liver-specific promotor and factor IX-Padua transgene at a dose of 5 x 10∧11/kg body weight was infused into ten men with hemophilia B with factor IX activity levels less than or equal to 2%. They were followed for for 28 to 78 weeks. Mean steady-state factor IX activity was 33.7 +/- 18.5% and annualized bleeding rate was reduced from 11.1 before vector administration to 0.4 after vector administration. Factor IX use declined from 2908 iu/kg to 49.3 IU/kg (p< 0.004). 8 patients did not use factor and 9 did not have bleeds after vector administration. An asymptomatic liver-enzyme elevation was noted in two patients and resolved with short term prednisolone treatment. This study is notable for using the Factor IX Padua variant which is a gain-of-function mutation associated with thrombophilia, with individuals carrying the mutation demonstrating 5-10 times the normal factor IX activity.


Thus, in the last three months, significant steps forward have been recorded for patients with hemophilia A and B. For patients with severe hemophilia A with inhibitors who hitherto have had no other options apart from treatment or prophylaxis with expensive bypassing agents, they now have emicizumab, which is more effective and cheaper. For all patients with hemophilia A and B, gene therapy effecting a one-time cure is coming closer to reality.


Hemoglobinopathy today

Last post, I talked about using CAR-T cell therapy to treat relapsed, refractory Non-Hodgkin B cell lymphoma. Today, I move on to benign hematology, namely hemoglobinopathy.

I published my case report of a case of homozygous mutation in the poly-adenylation signal on the beta-globin chain resulting in a thalassemia intermedia phenotype in Hemoglobin last year (abstract here, contact me for full text) . Today, I see more novel mutations and compound heterozygous genotypes reported in the same journal, for example the Jiangsu deletion, a large deletion in the alpha-globin gene cluster deleting most of the alpha 1 and alpha 2 globin genes, with the heterozygote exhibiting the alpha-0 thalassemia trait phenotype, described in China (abstract here)

In July 2017, FDA approved the use of Endari, which is L-glutamine powder, in patients with sickle cell disease. In a randomized phase 3 placebo controlled clinical trial, (oral presentation here)patients with sickle cell anemia or sickle-beta-0 thalassemia who were treated with Endari had less sickle cell crises (3 vs 4 events in a 48 week period), less acute chest crises (12 vs 27%), hospitalisations (2 vs 3), hospitalisation days (6.5 vs 11) and longer median time to first sickle cell crisis (84 vs 57 days) than those who were not, even after adjustment for hydroxyurea therapy. Endari is administered as an oral powder mixed with fluid twice daily in a weight-based manner. No significant adverse effects over placebo were observed. (full prescribing information here) Priced at 21 – 29 USD a packet, a daily dose of 6 packets a day for a patient weighing more than 65 kg will cost tp to 5220 USD a month, and a daily dose of 2 packets a day for a patient weighing less than 30 kg will cost up to 1740 USD a month.

Of note, there has been a real-world study of hydroxyurea in sickle cell disease patients. (abstract here) 652 patients treated in multiple centers in Italy were studied, with mean age of 24 +/- 15 years, with approximately 1:1 male to female ratio (51.4% males). Significant improvements in clinical manifestations occurred, including reduction in acute chest syndrome (risk reduction -29.3%) and vaso-occlusive crises (risk reduction -34.1%). Puzzlingly, there was an increase in silent cerebral artery infarction in treated patients (+42.4%) although there was no increase in stroke (+0.5%, p-value not significant). Mortality or quality of life benefit was not reported in the abstract.  Treated patients demonstrated reduced HbS, increased HbF, and decreased white cell count, platelet count and LDH level.

Finally, mouse models of thalassemia intermedia and major showed reduction of splenomegaly with JAK2 inhibitors used in conjunction with blood transfusions. (full text here) A phase 2a clinical study of the same was published as a letter to Blood on Nov 2, but there is no abstract available online. (link here)


Snow in Fall

Let’s start this blog!

Yescarta, axicabtagene ciloleucel, by Kite Pharma Inc, was approved by the United States Food and Drug Administration (FDA) on October 18, 2017, for treatment of adults with Large B Cell Non-Hodgkin Lymphoma who have relapsed after or not responded to at least two other different therapies (see FDA announcement)

This is a personalized gene therapy utilising chimeric antigen receptors (CARs) incorporated unto the patient’s own T cells. The patient undergoes apheresis at the clinic or hospital, to harvest mononuclear cells, which are sent to the central manufacturing laboratory. There, T cells are separated out using a density gradient. Then, they are activated with monoclonal anti CD3 antibody and interleukin-2 for 48 hours. Next, they are transduced with the CAR gene via a gammaretroviral vector. The CAR gene codes for an extracellular anti-CD19 single chain domain, an intracellular T cell receptor CD3 zeta and an intracellular CD28 costimulatory signalling domains. The resulting T cells are expanded until the target dose (2 x 10^6 cells/kg body weight) is achieved, then washed and cryopreserved. The cell product thus ready to be shipped to the clinical center and infused into the patient. Manufacturing processes are closed and follow GMP guidelines. Turnaround time is 14 days. (see review article)

The first clinical trial including patients with diffuse large B cell lymphoma (DLBCL) was reported in February 2015 in Journal of Clinical Oncology (full text here) by Kochenderfer et al. 15 patients with advanced B cell malignancies including nine with diffuse large B cell lymphoma were treated. They received conditioning chemotherapy with cyclophosphamide and fludarabine followed by CAR-T cell infusion one day later. Eight achieved complete remission (CR), four partial remission (80% overall response rate)  and two had stable disease. One patient died 16 days after infusion and one was lost to follow up. Remission duration ranged from 9 – 22 months; eight patients’ responses were ongoing at time of publication. Acute, transient toxicities included fever, hypotension, delirium and other neurological toxicities. A later report shows continued remission of up to 56 months in four of the five DLBCL patients who achieved CR  (see abstract).

Another clinical trial reported by the same NIH investigator group in June 2017 of 22 patients with advanced B cell lymphoma using a lower dose conditioning chemotherapy similiarly showed a 73% overall response rate with 55% complete remission (CR), 18% partial remission and lower neurological toxicity. Of the 12 patients who achieved CR, 11 are ongoing at time of publication. (full text here)

The early results of the first multicenter study, ZUMA-1, was published in Molecular Therapy in January 2017 by Locke et al. (full text here) Seven patients with relapsed / refractory DLBCL were given axicabtogene ciloleucel, then known as KTE C19, after conditioning chemotherapy (fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 concurrently daily for three days). Cytokine release syndrome were seen in 86% of patients and was grade 4 in one patient (14%). All patients experienced neurological side effects, and was grade 3 in three patients and grade 4 (14%) in one. One patient experienced severe cytokine release syndrome and neurological impairment and died from overwhelming infection, cytopenias and intracranial hemorrhage. She had an ongoing HSV-1 infection that was being treated and high inflammatory markers at the time of T cell infusion. Four patients (57%) achieved complete remission and one achieved partial remission (PR), with a overall response rate of 71%. Three patients’ CR were ongoing at more than 12 months. The other three patients have died from progressive disease. Based on the experience in this study, patients with a high level of baseline inflammatory state were ineligible to proceed with conditioning chemotherapy and CAR-T cell infusion.

The primary analysis of the ZUMA-1 trial was reported in June 2017. (oral presentation here) 101 patients with relapsed/ refractory diffuse large B cell lymphoma, primary mediastinal B cell lymphoma and transformed follicular lymphoma received axicabtogene ciloleucel. Overall response rate was 82% (CR 54%, PR 28%). Median duration of response was 8.2 months and was not reached in patients with CR. Median overall survival was not reached. The commonest Grade 3 or greater toxicities were neutropenia, leukopenia, anemia, febrile neutropenia and encephalopathy.  Cytokine release syndrome and neurotoxicity that were grade 3 or greater occurred in 13 and 28% of patients respectively. 3 patients died from toxicity (3%). All other CRS and neurological events resolved except one grade 1 memory impairment.

Yescarta is available through a restricted program under a Risk Evaluation and Mitigation Strategy (Yescarta REMS). The listed unit price is 373000 US dollars. It is to be administered in a healthcare facility with two doses of tocilizumab available prior to administration. It is contraindicated in patients with active infection and inflammatory disorders. Patients are to be monitored at least daily for seven days after administration. Cytokine release syndrome is to be treated emergently with supportive therapy, corticosteroids and or tocilizumab. Neurotoxicity is to be treated with supportive therapy or corticosteroids. (full prescribing information)

Patients with refractory diffuse large B cell lymphoma, or those relapsing after autologous stem cell transplant, have had few options previously – further lines of chemotherapy with low likelihood of response, or a high-risk allogeneic stem cell transplant. Median overall survival was less than 10 months. Yescarta opens up exciting possibilities for these patients, with slightly higher than 50% of patients achieving complete remission and many of these durable, offering a tantalising chance of cure. The price tag is high but the technical aspects are promisingly reliable.

This concludes this first post. Good luck!