REPORT SUMMARY of a Health Technology Assessment under art. 17, paragraph 7 of Regulation 9 from Dec. 01, 2015 of the Ministry of Health of the Republic of Bulgaria For the medicinal product Venclyxto 10 mg, 50 mg and 100 mg film-coated tablets Adopted on 15.08.2017 at a meeting of the Health Technology Assessment Commission under art. 5 of Regulation 9 from Dec. 01, 2015 about the terms and conditions for performing health technology assessments.
CONTENTS Page I. Analysis of the health problem 3 1.1. Description of the health problem based on a review of scientific and 3 epidemiological data. 1.2. Description of the suggested health technology 8 1.3. Description of other health technologies which are being reimbursed in our 9 country and which could be used as a therapeutic alternative or as a recombinant therapy along with the suggested health technology 1. Selection of basic comparative therapeutic alternative 12 1.1.1. Reimbursed pharmacotherapeutic analogue used for the treatment of the same disease or first choice therapy 12 1.1.2. The most commonly prescribed reimbursed health technology with the same or equivalent therapeutic indication 12 1.1.3. Non-drug therapies and non-medication 13 1.1.4. Selection of the basic comparative therapeutic alternative 13 2. Perspective of the assessment 13 3. Number of potential patients 13 II. Comparative analysis of the therapeutic efficacy/effectiveness and safety 14 III. Analysis of pharmaco-economic indicators 25 IV. Budgetary impact analysis 29 4.1. Epidemiology and therapy of the disease, clinical impact, economic impact 29 4.2. Model for Budget Impact Analysis 30 4.3. Assessment of the annual target population number 31 4.4. Assessment of the annual number of patients for whom the new therapy will 31 be applied 4.5. Assessment of the actual annual expenditure of public budgets 32 4.6. Assessment of the expenditure of public funds after the introduction of 33 Venclyxto 4.7. Outcomes 34 4.8. Sensitivity analysis 34 V. Discussion 36 VI. Recommendation 37 VII. Literature 39 Report for the health technology assessment for the medicinal product Venclyxto Page 2 of 31
I. Analysis of the health problem 1.1. Description of the health problem based on a review of scientific and epidemiological data. What is chronic lymphocytic leukemia (CLL) CLL is a lymphoproliferative disease characterized by clonal proliferation and progressive accumulation of morphologically mature, functionally inactive lymphocytes in the blood, bone marrow, lymph nodes and spleen. About 95-98% of lymphocytes isolated from patients with CLL have B-cell origin, while the rest have T-cell origin. The accumulated pathological cells found in CLL patients are clonal B-lymphocytes whose development has stopped at a level between pre-b and mature B-lymphocytes, and which usually express B-cell surface antigens such as CD19, CD20 and CD23 together with low levels of surface immunoglobulin as well as CD5, which is most commonly found on the surface of T-lymphocytes. A characteristic feature of clonal B-lymphocytes is the lack of expression of CD10 [1]. Etiology and risk factors of CLL Currently, CLL etiology is unclear, but age, male gender, Caucasian background, environmental impact, family history of lymphoproliferative or other malignancies are considered to be major risk factors for CLL development [2]. Clinical picture and course of CLL Although CLL patients most often have no complaints, the clinical picture in symptomatic patients is very varied, for example non-painful lymph node swelling (in the cervix, axillary, inguinal and other areas of the body), easy tiredness, hepatomegaly, splenomegaly, etc. [3]. Approximately 5-10% of all CLL patients experience one or more of the so-called "Bsymptoms", which include a fever of more than 38 C with no inflammatory disease, profuse night sweats, and unintended body weight reduction over 10% within the last 6 months. The clinical course of CLL is very diverse. Patients with CLL can be conventionally divided into three groups: reasons; (1) the first group does not require any treatment, the patients die for non-disease-related Report for the health technology assessment for the medicinal product Venclyxto Page 3 of 31
(2) in the second group an indolent disease is observed, followed by a progression of the disease requiring the onset of therapy; (3) the third group requires rapid onset of treatment due to the presence of an aggressive disease [3,4]. CLL progression is characterized by a gradual accumulation of malignant cells in the blood, bone marrow and lymphatic tissues. This results in disturbance in the formation and function of blood cells, especially erythrocytes, platelets and leukocytes, with subsequent manifestations of anemia, thrombocytopenia and immunosuppression. CLL is currently considered to be incurable by modern therapeutic approaches (except for allogeneic stem cell transplantation), with the main causes of death being systemic infections (pneumonia and septicemia), hemorrhage and cachexia [1]. Epidemiology of CLL CLL is the most common type of leukemia in the Western world [1], representing 0.94% of all newly diagnosed cancer patients in the United States of America. According to the Bulgarian National Cancer Register, the actual morbidity in 2012 is 4.1/100,000 people, which represents 299 newly diagnosed patients per year [5]. CLL disease is estimated at 3/10,000 people [6], which represents 2,190 patients with this disease in Bulgaria in 2012. CLL is most commonly diagnosed in individuals over 65 years of age, the median age at diagnosis being 70 years [7]. According to the literature, the presence of del 17p or mutations in the TP53 gene was found in 5-8% and 8-12% of CLL patients, respectively, at the time of diagnosis [8,9]. In patients with resistant or relapsed disease (after administration of a combination of rituximab, fludarabine and cyclophosphamide), the frequency of del 17p or mutations in the TP53 gene reaches 50% of the cases [10]. In addition, over 80% of del 17p patients have mutations in the TP53 allele, suggesting that mutations in the TP53 gene can also be observed in the absence of del 17p [8,9]. In Bulgaria, men have 1.3 times higher morbidity and 1.7 times higher mortality compared to women [5]. The mean five-year survival rate for CLL patients in Bulgaria is 46.0%. Diagnosis and prognostic factors of CLL CLL is diagnosed by performing a full blood count with peripheral blood smear and peripheral blood immunofetitis to detect 5 x 10 9 /L clonal B-lymphocytes with the CLL Report for the health technology assessment for the medicinal product Venclyxto Page 4 of 31
phenotype [1,3]. Computer tomography can be performed in patients with enlarged mediastinal, abdominal or pelvic lymph nodes. The prognosis of CLL patients is determined by the Binet and Rai clinical staging systems, which are based on the patient's objective status and the peripheral blood results. Based on these two staging systems, CLL patients are divided into three prognostic groups depending on the aggressiveness of the disease, thus improving the ability of clinicians to identify patients who need immediate treatment initiation. The Binet staging system (Table 1) takes into account five potential areas of concern in the human body by CLL: cervical, axillary, inguinal lymph nodes, spleen and liver. Patient stratification is based on the number of affected areas and the presence of anemia and/or thrombocytopenia [11]. Table 1. Binet staging system Stage A Stage B Stage C No anemia or thrombocytopenia, < 3 enlarged lymphoid areas No anemia or thrombocytopenia, 3 enlarged lymphoid areas Anemia (hemoglobin < 100 g/l) and/or thrombocytopenia (thrombocytes < 100 x 10 9 /L) The Rai staging system (Table 2) is based on the fact that CLL leads to a gradual and progressive increase in tumor burden of leukemic lymphocytes in the human body, starting with lymphocytosis. Table 2. Rai staging system [12]: Low risk Stage 0 Lymphocytosis in peripheral blood (>5 х 10 9 /L) and the bone marrow (30%) Interim risk Stage 1 Lymphocytosis in peripheral blood and bone marrow, and presence of enlarged lymph nodes Stage 2 Lymphocytosis in peripheral blood and bone marrow, with increased spleen and/or liver size (with or without enlarged lymph nodes) High risk Stage 3 Lymphocytosis in peripheral blood and bone marrow with concomitant anemia Stage 4 Lymphocytosis in peripheral blood and bone marrow with concomitant thrombocytopenia Report for the health technology assessment for the medicinal product Venclyxto Page 5 of 31
Currently, chromosomal and/or molecular disorders are considered the most important prognostic factors in CLL. Chromosomal disorders can be detected by FISH analysis in over 80% of newly diagnosed CLL patients [13]. The most common cytogenetic abnormalities are: del 13q (over 50% of cases), trisomy 12 (10-20%), del11q (5-20%), del 17p (3-8%), etc. [13]. The presence of del 11q as the only cytogenetic aberration has a favorable prognosis and results in the longest median overall survival of 133 months [14]. The presence of del 13q leads to significant lymphadenomegaly, refractory to fludarabine-based therapy and a shorter median overall survival of 79 months. The addition of an alkylating agent to the fludarabine-based immunochemotherapy can overcome the unfavorable prognosis of del 13q in patients with newly diagnosed CLL [14]. The presence of del 17p, which reflects the loss of the TP53 gene, is often associated with the presence of mutations in the remaining TP53 allele, and results in a very short overall survival (median of 32 months). The presence of del 17p and/or mutations in the TP53 gene results in therapeutic resistance to the action of fludarabine- or alkylating-based regimens as the two cytostatic preparations require the presence of a p53-dependent signaling pathway to induce cell death [14]. The prognostic significance of del 17p is probably determined by the proportion of malignant cells carrying this cytogenetic aberration [15]. Disease prognosis is more favorable when the percentage of del 17p-bearing cells is low. According to CLL-4 clinical tial data, the presence of del 17p in 10% of malignant cells resulted in a therapeutic response in 29% of patients and a median overall survival of 6 months [16]. According to another clinical study in 294 patients with CLL, patients with del 17p in 25% of the cells require a significantly later onset of treatment and have a longer median overall survival rate than other patients [17]. Treatment of CLL Treatment initiation is indicated in patients with CLL who experience active disease that occurs through an advanced Binet or Rai stage, large tumor burden, B-symptoms or recurrent infections. The majority of patients with early-onset CLL are being actively monitored. Currently, allogeneic stem cell transplantation (ASCT) is the only potential way to cure the disease [1]. According to the National Comprehensive Cancer Network, before starting treatment, the general condition, age, and concomitant illness of CLL patients must be estimated [18]. As the first line of treatment in patients with CLL in good general condition, aged under 65 and with a low number of concomitant diseases, the most commonly administered Report for the health technology assessment for the medicinal product Venclyxto Page 6 of 31
combinations are those of rituximab with fludarabine and cyclophosphamide (FCR), rituximab with bendamustine (BR) or ibrutinib [18]. As first-line therapy in patients with CLL in an impaired general condition, aged 65 years and with an increased number of concomitant diseases, the following are administered: chlorambucil in combination with an anti-cd20 antibody (e.g., obinutuzumab, ofatumumab or rituximab), BR, ibrutinib or a dose-reduced regimen fludarabine-containing regimen in combination with an anti-cd20 antibody and the like is administered. [18]. There is currently no generally accepted treatment regimen in patients with recurrent or refractory CLL. In patients with recurrent or refractory CLL, the diagnosis should be confirmed by a full blood count and peripheral blood flow cytometry. It is mandatory to conduct a FISH test to identify specific chromosomal deletions. The healing capabilities in patients with CLL are determined by the quality and duration of the therapeutic response in the conduction of previous treatment. In patients with CLL in whom the duration of the initial therapeutic response is significantly shorter than the median for the respective treatment, in case of a recurrence of the disease, administration of another treatment regimen may be considered. Patients with early relapse (<6 months) and those with del 17p/mutations in the TP53 gene may be given monotherapy with ibrutinib, and in the event of a full therapeutic response, ASCT therapy should be performed in young patients without serious co-morbidities. In the case of intolerance or contraindications for the use of ibrutinib, a combination of rituximab and idelalisib may be used. In patients with late relapse (> 12 months), the previous regimen, as well as monotherapy with ibrutinib or a combination of rituximab and idelalisib may be used [1,18]. 1.2. Description of the suggested health technology. Venetoclax is an oral, selective B-cell-lymphoma-2 (BCL) -2 protein inhibitor that is an anti-apoptotic protein [19]. Overexpression of BCL-2 may induce increased resistance to apoptosis and increased malignant cell survival characteristic of CLL [20]. Venetoclax binds directly to the BCL-2 protein by displacing proapoptotic proteins such as BIM (BCL-2-like protein 11), initiating the permeability of the external mitochondrial membrane and activating the caspases. This restores the ability of malignant cells to undergo apoptosis [21]. The starting dose is 20 mg venetoclax once daily for 7 days. The dose should be increased gradually over a period of 5 weeks to the recommended daily dose of 400 mg. Thus, tumor burden is gradually reduced, as well as the risk of tumor lysis syndrome. Patients Report for the health technology assessment for the medicinal product Venclyxto Page 7 of 31
should be instructed to swallow the tablets whole with water at approximately the same time each day. Tablets should be taken during meals to avoid the risk of lack of efficacy. The administration of the medication continues until disease progression or unacceptable toxicity on the part of the patient. On April 11, 2016, the US Food and Drug Administration (FDA) approved Venclexta/Venclyxto (venetoclax) for use in patients with CLL and del 17p who had been treated with at least one prior therapy [22]. On 08.12.2016 the European Commission approved the use of Venclyxto (venetoclax) as monotherapy in the following cases: (1) in adult patients with CLL in the presence of 17p del or TP53 mutation who are unsutable for or have faild a B-cell receptor pathway inhibitor; (2) in adult CLL patients in the absence of 17p del or TP53 mutation who have faild both chemoimmunotherapy and a B-cell receptor pathway inhibitor [23]. 1.3. Description of other health technologies which are being reimbursed in our country and which could be used as a therapeutic alternative or as a recombinant therapy along with the suggested health technology. The available therapeutic alternatives for the treatment of CLL in Bulgaria are the following: Rituximab Rituximab in combination with chemotherapy is indicated for the treatment of patients with newly diagnosed or recurrent/refractory CLL. Rituximab specifically binds to transmembrane antigen, CD20-non-glycosylated phosphoprotein localized on pre-b and mature B lymphocytes. The antigen is expressed on >95% of all B-cells in non-hodgkin's lymphomas. CD20 is detected both on normal and malignant B-cells, but not on hematopoietic stem cells, pro-b cells, normal plasmocytes or other normal tissues. This antigen does not internalize when bound to antibodies and is not secreted from the cell surface. CD20 does not circulate in the plasma as a free antigen and therefore does not compete for antibody binding. The rituximab Fab domain binds to the CD20 antigen of B lymphocytes, and the Fc domain may include effector function of the immune system, mediating B-cell lysis. Possible mechanisms of effector-mediated cell lysis include complement dependent cytotoxicity (CDC) due to C1q binding and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the surface of granulocytes, macrophages and NK-cells. It has been shown that binding of rituximab to the CD20 antigen on B lymphocytes induces cell death by apoptosis. Report for the health technology assessment for the medicinal product Venclyxto Page 8 of 31
In patients with CLL, prophylaxis with adequate hydration and use of uricostatics starting 48 hours before the start of therapy is recommended in order to reduce the risk of tumor lysis syndrome. In CLL patients with a lymphocyte count of > 25 x 10 9 /l, it is recommended to administer prednisone/prednisolone 100 mg intravenously shortly before the Rituximab infusion to reduce the severity of acute response to the infusion and/or syndrome of cytokine release. The recommended dose of Rituximab in combination with chemotherapy in previously untreated patients and in patients with relapsed/refractory disease is 375 mg/m 2 body surface area administered on day 0 of the first treatment cycle followed by 500 mg/m 2 body surface area per day 1 of each subsequent cycle, for a total of 6 cycles. Chemotherapy should be administered after the infusion of Rituximab. Ofatumumab Ofatumumab is indicated for the treatment of chronic lymphocytic leukemia (CLL) in patients who are refractory to fludarabine. Ofatumumab is a human monoclonal antibody (IgG1) that binds specifically to a particular epitope, including both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is a transmembrane phosphoprotein that is expressed on the surface of B lymphocytes from pre-b to mature B-lymphocyte stage and on the surface of B-cell tumors. B-cell tumors include CLL (which generally binds to lower levels of CD20 expression) and non-hodgkin's lymphomas (in which> 90% of tumors have high levels of CD20 expression). The CD20 molecule is not secreted from the cell surface and is not internalized after binding of the antibody. The recommended dose is 300 mg ofatumumab for the first infusion and 2,000 mg ofatumumab for all subsequent infusions. The infusion schedule is once weekly for 8 consecutive weeks followed by a 4 to 5-week interval of 4 consecutive monthly (i.e. every 4 weeks) infusions. Ibrutinib Ibrutinib is indicated for the treatment of adult CLL patients who have received at least one prior therapy, or as first-line therapy in patients who are unsuitable for immunochemotherapy in the presence of 17p deletion or TP53 mutation. Ibrutinib is a potent, low molecular weight inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib forms a covalent bond with a cysteine residue (Cys-481) in the active site of BTK, resulting in a sustained inhibition of BTK enzyme activity. BTK, a member of the Tec kinase family, is an important signaling molecule of the B-cell antigen receptor (BCR) pathway and cytokine receptors. The BCR pathway is Report for the health technology assessment for the medicinal product Venclyxto Page 9 of 31
involved in the pathogenesis of several B-cell neoplasms, including MCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma and CLL. The key role of BTK in signaling via B- cell surface receptors results in activation of the pathways necessary for B-cell movement, chemotaxis and adhesion. Preclinical studies show that ibrutinib effectively inhibits malignant B-cell proliferation and in vivo survival, as well as cell migration and cell-substrate adhesion in vitro. The recommended dose for CLL is 420 mg (three capsules) once a day. Bendamustine Bendamustine is indicated for the first-line treatment of CLL (stage B or C by Binet) in patients for whom the combination chemotherapy with fludarabine is inappropriate. Bendamustine is an alkylating antitumor agent with a unique action. The antineoplastic and cytotoxic effect of bendamustine hydrochloride is based mainly on crosslinking of single and double strands of DNA by alkylation. As a result, matrix function as well as DNA synthesis and repair are impaired. The antitumor effect of bendamustine has been demonstrated in several in vitro studies conducted with various human tumor cell lines (breast cancer, nonsmall cell and small cell lung carcinoma, ovarian carcinoma and various leukemias) and in vivo in various experimental tumor models with mouse, rat tumors and of human origin (melanoma, breast carcinoma, sarcoma, lymphoma, leukemia and small cell lung carcinoma). Dosage of Bendamustine is 100 mg/m 2 body surface area on days 1 and 2; every 4 weeks. Report for the health technology assessment for the medicinal product Venclyxto Page 10 of 31
2. Selection of basic comparative therapeutic alternative: 2.1. A basic comparative alternative is one that is most likely to be replaced in existing medical practice. This includes, but is not limited to: 2.1.1. reimbursed pharmacotherapeutic analogue used for the treatment of the same disease or first-line therapy; There is no reimbursed pharmacotherapeutic analog (a highly selective bcl-2 anti-apoptotic protein inhibitor) used to treat the same disease. 2.1.2. the most commonly prescribed reimbursed health technology with the same or equivalent therapeutic indication; Table 3 presents the current recommendations for the treatment of patients with recurrent or refractory CLL with or without del 17p and/or TP53 mutations according to the Bulgarian Hematology Association (2015) and the National Cancer Network (2017). Table 3 Current recommendations for the treatment of patients with recurrent or refractory CLL according to the Bulgarian Hematology Association and the National Cancer Network Bulgarian Hematology Association (2015) Patients > 70 years without del 17p or del 11q Reduced FCR Chlorambucil ± prednisone Bendamustine ± Rituximab HDMP (high dose methylprednisolone) ± Rituximab Rituximab+ Chlorambucil Dose-dense Rituximab Ofatumumab Lenalidomide+/- Rituximab Ibrutinib Clinical trials Patient age <70 years or older without serious concomitant illness Immunochemotherapy FCR FCM ±rituximab Bendamustine ±Rituximab National Cancer Network (2017) Patients with serious concomitant illnesses ( 65 years of age or younger) without del 17p/TP 53 mutations Ibrutinib (category 1) Idelalisib + rituximab Idealisib Venetoclax ± rituximab Chemo-immunotherapy Bendamustine ± rituximab Reduced dose FCR Reduced dose PCR HDMP + rituximab Rituximab + chlorambucil Ibrutinib, bendamustine, rituximab (category 3) Idelalisib, bendamustine, rituximab (category 3) Ofatumumab Obinutuzumab Lenalidomide ± rituximab Alemtuzumab ± rituximab Dose-dense rituximab (category 2B) Patients without serious co-morbidities (<65 years or younger) without del 17p/TP 53 mutations Ibrutinib (category 1) Idelalisib + rituximab (category 1) Idealisib Report for the health technology assessment for the medicinal product Venclyxto Page 11 of 31
Fludarabine + Alemtuzumab CHOP+ rituximab Hyper CVAD + rituximab. Dose-adapted EPOCH + rituximab. OFAR Alemtuzumab+ rituximab HDMP + rituximab Ibrutinib Lenalidomide +/- Rituximab Ofatumumab High-dose chemotherapy with autologous or allogenic bone marrow transplantation in clinical trials. Patients with del 17p CHOP +rituximab CFAR Hyper CVAD + rituximab Alemtuzumab+ rituximab High doses of Dexamethasone OFAR Bendamustine Ofatumumab Ibrutinib Lenalidomide+/- Rituximab High-dose chemotherapy with autologous or allogenic bone marrow transplantation in clinical trials. Venetoclax ± rituximab Chemo-immunotherapy FCR FC+ofatumumab PCR Bendamustine ± rituximab RCHOP OFAR Ibrutinib, bendamustine, rituximab (category 2B) Idelalisib, bendamustine, rituximab (category 2B) Ofatumumab Obinutuzumab Lenalidomide ± rituximab Alemtuzumab ± rituximab HDMP +rituximab Patients with del 17p/TP 53 mutations Ibrutinib Venetoclax ± rituximab Idelalisib +rituximab Idealisib HDMP + rituximab Lenalidomide ± rituximab Alemtuzumab ± rituximab Ofatumumab OFAR 2.1.3. non-drug therapies and non-medication when it is most commonly used in therapeutic practice or when there are no other treatment alternatives; - not applicable, this is a malignant hematological disease. 2.1.4. selection of the main comparative therapeutic alternative is consistent with national clinical practice, national consensus and pharmacotherapy guidelines. 3. Perspective of the assessment - the perspective is for the paying institution. Analyzes from the public point of view are used as additional ones. 4. Number of potential patients who will be eligible for treatment with the new health technology - presented in table 15 and 16 of point IV of this report. II. Comparative analysis of the therapeutic efficacy/effectiveness and safety. The therapeutic efficacy and safety of Venclyxto have been evaluated through clinical trials M13-982 and M12-175. Report for the health technology assessment for the medicinal product Venclyxto Page 12 of 31
M13-982 is an open-label, single-arm phase II multicenter clinical study investigating the activity and safety of venetoclax monotherapy in patients with recurrent or refractory CLL with del 17p [24]. According to the results of a predefined interim analysis, 70 (65%) of 107 patients continued their treatment during the analysis (April 2015), with 37 (35%) of 107 discontinuing treatment (22 patients due to disease progression, 9 - due to undesirable side effects, 2 - due to withdrawal of informed consent, 1 - due to non-treatment, and 3 - due to the conduct of ASCT). A total of 107 patients were enrolled in the study, where patients received 400 mg/day of venetoclax until disease progression, unacceptable toxicity, or discontinuation of treatment for any other reason. A weekly dose increase of venetoclax from a starting dose of 20 mg/day to a final dose of 400 mg/day (20, 50, 100, 200, 400 mg) was performed over a 4-5 week period. The mean follow-up of patients during the interim analysis was 12.1 months (range 10.1 14.2 months). The median time from diagnosis of the disease until the first venetoclax administration was 81.7 months, and from the last therapy to the first venetoclax administration 5.4 months. In all patients included in the study with the exception of one, del 17p was detected by fluorescence in situ hybridization. The medial content of del 17p in malignant cells was 50.3% (range 23-83.5%). The patients included in the clinical trial were at least 18 years of age and their median age was 67 years (range 37-85 years). Recurrent/refractory CLL has been defined as a recurrent or refractory disease after administration of at least one preceding therapy line (patients had to receive at least two cycles of the treatment). The objective status of the patients enrolled in the study, assessed according to the ECOG criteria, should have been 2. A detailed description of patient characteristics as well as inclusion and exclusion criteria are shown in Table 4. Table 4. Patient characteristics, inclusion and exclusion criteria of clinical study M13-982 Title: Venetoclax in patients with recurrent or refractory chronic lymphocytic leukemia with presence of del 17p: a multicenter, open-label, phase 2 study Study identifier NCT01889186, EudraCT number 2012-004027-20, M13-982 Analysis of the Inclusion patient cohort criteria studied Age 18 years Diagnosed CLL according to published 2008 criteria of the international CLL working group Presence of indication for treatment according to published 2008 criteria of the international CLL working group Measurable disease lymphocytosis > 5 x 10 9 /L or presence of palpable and measurable lymph nodes and / or organomegaly detected by physical examination Presence of refractory / recurrent disease after administration of at least one previous therapy line or untreated CLL Presence of del 17p in > 7% of peripheral blood malignant cells (found in a local or central laboratory) Objective status according to ECOG criteria 2 Satisfactory function of the bone marrow Absolute neutrophil count 1,000/μl Report for the health technology assessment for the medicinal product Venclyxto Page 13 of 31
Analysis of the patient cohort studied Exclusion criteria Absolute neutrophil count <1,000 / μl of screening, and bone marrow severely infiltrated by CLL, growth factors may be administered during the screening period and before the first dose of venetoclax to achieve the absolute neutrophil count required according to the study inclusion criteria Thrombocytes 30,000/mm 3 Hemoglobin > 8 g/dl Satisfactory coagulation, renal and hepatic function, determined according to the reference values of the laboratory during the screening period Activated partial thromboplastine and prothrombin time should not be more than 1.5 times the upper reference limit Calculated creatinine clearance> 50 ml/min AST and ALT 3; bilirubin 1.5 In patients with a high risk of developing tumor lysis syndrome, prior approval is required from the AbbVie medical monitor prior to including the patient in the study Allogeneic stem-cell transplantation performed Confirmed CLL transformation in the Richter's syndrome. Prolymphocytic Leukemia Active and uncontrolled autoimmune cytopenia (2 weeks before the screening period), autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura not responding to low-dose corticosteroids Preceding treatment with venetoclax A biological preparation used as an antitumor agent within 30 days prior to the first dose of venetoclax The patient received one of the following within 14 days or 5 half-lives, where applicable, prior to the first dose of the study drug, or did not recover to less than CTC Grade 2 clinically relevant side effects/toxicity of previous therapy Any antitumor therapy including chemotherapy or radiotherapy Research therapy involving target low molecular weight preparations Proven allergy to xanthine oxidase inhibitors and rasburicase Media age (range), years 65 years, n (%) < 65 years, n (%) Characteristics Venetoclax 67 (37-85) 61 (57) 46 (43) Gender, n (%) 37 (35) 70 (65) Objective state according to ECOG, n (%) 0 1 2 Stage according to Rai when joining the study Stage III Stage IV Other stage Stage according to Rai when joining the study Stage A-B Stage C Preceding therapies, n (%) Median number of preceding therapies (range) Bendamustine Resistant to bendamustine Fludarabine Resistant to fludarabine Resistant to bendamustine or fludarabine Idelalisib Ibrutinib Other B-cell receptor inhibitors 42 (39) 56 (52) 9 (8) 19 (18) 32 (30) 56 (52) 65 (61) 42 (39) 2 (1-4) 54 (50) 38 (70) 78 (73) 34 (44) 62 (58) 1 (1) 3 (3) 1 (1) Report for the health technology assessment for the medicinal product Venclyxto Page 14 of 31
Bulky disease One or more lymph nodes 5 cm No lymph nodes 5 cm Presence of mutations in the TP53 genes Yes No Intermediate Missing information Presence of mutations in the IGVH genes Yes No Missing information Presence of del 11q Yes No Absolute lymphocyte count 25 х 10 9 /L < 25 х 10 9 /L Median (х 10 9 /L) Serum β2-microglobulin 3 mg/l < 3 mg/l Missing information Complications related to the disease Neutropenia Anemia Thrombocytopenia Risk of development of tumor lysis syndrome Low Intermediate High 57 (53) 50 (47) 60 (56) 17 (16) 6 (6) 24 (22) 7 (7) 30 (28) 70 (65) 30 (28) 77 (72) 54 (50) 53 (50) 25.8 (7.9-89) 4 (4) 13 (12) 90 (84) 24 (22) 22 (21) 16 (15) 19 (18) 43 (40) 45 (42) Report for the health technology assessment for the medicinal product Venclyxto Page 15 of 31
Clinical efficacy of venetoclax according to the M13-982 clinical study During the interim analysis, 17 deaths were observed, with the median overall survival (OS) not being reached. The calculated 12-month OS was 86.7% (95% CI 78.6-91.9) established by an independent review committee Table 5. During the interim analysis, median progression free survival (PFS) was not reached. The calculated 12-month PFS was 72% (95% CI 61.8-79.8) as established by an independent review committee. The median time to progression of CLL was 6.3 months. The estimated time to progression of CLL at 12 months was 77% (95% CI 67-84) Table 5. A common therapeutic response was achieved in 54 (77%) of the predetermined cohort of patients (70 subjects). A common therapeutic response identified by an independent review committee was achieved in 85 (79.4%) patients. The review commission found complete remission, or incomplete restoration of blood count, partial remission and nodular partial remission, respectively in 8 (8%), 74 (69%) and 3 (3%) Table 5. Table 5. Clinical efficacy of venetoclax according to the M13-982 clinical study Therapeutic group Venetoclax Number of patients 107 ORR ORR-ICR, n (%) 95% CI 79.4 70.5-86.6 CR-ICR, n (%) 8 PR-ICR, n (%) 69.2 NPR-ICR, n (%) 3 ORR-IGA, n (%) 74 PFS Median PFS, months 12- months PFS, % 95% CI No information 72 61.8-79.8 OS Median OS, months 12-month OS, % 95% CI No information 86.7 78.6-91.9 Legend: ORR overall response rate; IRC independent review committee; CI confidence interval; CR complete remission, PR partial remission; NPR nodular partial remission; IGA investigator s global assessment; PFS progression free survival, OS overall survival The data presented in the table are as of 10.06.2016. Safety of venetoclax according to the M13-982 clinical study Because M13-982 is a single-arm clinical study, no results are presented that compare venetoclax with another therapeutic agent. The most common side effects of grade 3 and 4 associated with venetoclax are neutropenia (40%), infection (20%), anemia (20%) and thrombocytopenia (15%). The most common serious infections are pneumonia (6%), upper (2%) and lower respiratory tract (2%) infections. During the clinical study, a fatal outcome was observed in 18 (17%) patients, 14 (13%) of whom died due to progression of the disease, Report for the health technology assessment for the medicinal product Venclyxto Page 16 of 31
while 4 (4%) - due to an adverse event. All adverse events associated with the venetoclax treatment are presented in Table 6. Table 6. Adverse events observed in the M13-982 clinical study Adverse event (according to version 4.0 of the common terminology criteria of the National Cancer Institute) Degree 1-2 n (%) Venetoclax (n = 107) Degree 3 Degree 4 n (%) n (%) Degree 5 n (%) Any treatment-related adverse event 22 (21) 37 (35) 32 (30) 12 (11) Blood and lymphatic disorders 8 (8) 26 (24) 31 (29) 0 (0) Anemia 10 (9) 19 (18) 0 (0) 0 (0) Autoimmune hemolytic anemia 1 (1) 4 (4) 3 (3) 0 (0) Febrile neutropenia 0 (0) 4 (4) 3 (3) 0 (0) Immune thrombocytopenic purpura 0 (0) 1 (1) 4 (4) 0 (0) Leucopenia 0 (0) 4 (4) 1 (1) 0 (0) Neutropenia 3 (3) 18 (17) 25 (23) 0 (0) Thrombocytopenia 4 (4) 4 (4) 12 (11) 0 (0) Cardiac disorders 7 (7) 4 (4) 0 (0) 1 (1) Atrial fibrillation 4 (4) 2 (2) 0 (0) 0 (0) Heart and respiratory failure 0 (0) 0 (0) 0 (0) 1 (1) Gastrointestinal disorders 60 (56) 7 (7) 0 (0) 0 (0) Constipation 11 (10) 0 (0) 0 (0) 0 (0) Diarrhea 31 (29) 0 (0) 0 (0) 0 (0) Nausea 30 (28) 1 (1) 0 (0) 0 (0) Vomiting 15 (14) 1 (1) 0 (0) 0 (0) General disorders 54 (51) 4 (4) 1 (1) 1 (1) Progression of the disease 0 (0) 0 (0) 0 (0) 1 (1) Fatigue 23 (22) 0 (0) 0 (0) 0 (0) Fever 20 (19) 1 (1) 0 (0) 0 (0) Hepato-biliary disorders 2 (2) 2 (2) 0 (0) 1 (1) Impaired liver function 0 (0) 0 (0) 0 (0) 1 (1) Hyperbilirubinemia 0 (0) 2 (2) 0 (0) 0 (0) Infections 56 (52) 14 (13) 6 (6) 1 (1) Infections of the lower respiratory tract 4 (4) 2 (2) 0 (0) 0 (0) Nasopharyngitis 15 (14) 0 (0) 0 (0) 0 (0) Pneumocystis jirovecii pneumonia 0 (0) 2 (2) 0 (0) 0 (0) Pneumonia 4 (4) 4 (4) 1 (1) 0 (0) Septic shock 0 (0) 0 (0) 0 (0) 1 (1) Infections of the upper respiratory tract 14 (13) 0 (0) 2 (2) 0 (0) Neoplasms - benign, malignant, unspecified 5 (5) 9 (8) 3 (3) 7 (7) Progression of malignant neoplasm 1 (1) 2 (2) 1 (1) 7 (7) Skin carcinoma 2 (2) 2 (2) 0 (0) 0 (0) Nervous system disorders 28 (26) 3 (3) 2 (2) 1 (1) Headache 12 (11) 0 (0) 0 (0) 0 (0) Hemorrhagic stroke 0 (0) 0 (0) 0 (0) 1 (1) Vascular disorders 9 (8) 7 (7) 0 (0) 0 (0) Hypertension 2 (2) 4 (4) 0 (0) 0 (0) Report for the health technology assessment for the medicinal product Venclyxto Page 17 of 31
M12-175 is a multicenter, non-randomized, open-label, phase 1 dose escalation study investigating the safety, pharmacokinetic profile and efficacy of venetoclax in patients with recurrent or refractory CLL or small cell lymphoma [25]. The dose-escalating phase of the study included 56 patients who received active treatment in one of eight doses of venetoclax ranging from 150 to 1,200 mg/day. Additionally, 60 patients, who were an expanded cohort, were enrolled in the clinical trial, and a gradual dose increase of venetoclax was achieved to 400 mg/day. The patient characteristics as well as the inclusion and exclusion criteria of the study are presented in Table 7. Table 7. Patient characteristics, inclusion and exclusion criteria of the M12-175 study Title: A Phase 1 study evaluating the safety and pharmacokinetics of ABT-199 in patients with recurrent and refractory chronic lymphocytic leukemia and non-hodgkin's lymphoma Study identifier NCT01328626, M12-175 Analysis of the patient cohort studied Inclusion criteria Exclusion Criteria Age 18 years Patients should have: (arm A) recurrent or refractory chronic lymphocytic leukemia / small cell lymphoma, which needs treatment according to the investigator's opinion. Patients should have a recurrent or resistant standard illness such as fludarabine- (F, FC, FR, FCR) or alkyl-based (chlorambucil, bendamustine) regimens. In addition, the patient should not have other healing abilities and the patient should have depleted the therapeutic options that are considered standard care, or (arm B) recurrent or refractory non-hodgkin's lymphoma (NHL), which needs treatment according to the investigator's opinion. The patient should have a histologically documented diagnosis of NHL, defined according to the criteria of the World Health Organization's classification scheme. Patients should have recurrent or resistant standard disease therapy such as R-CHOP, R-CVP or fludarabinebased regimens. In addition, the patient should not have other healing options and the patient should have depleted the therapeutic options that are considered standard care. Patients with other lymphoproliferative disorders may be included in the study after consultation with Abbott's medical monitor. Objective condition according to ECOG criteria 1 Satisfactory bone marrow function, according to the local laboratory reference values, independent of the application of growth factors during the screening period. Satisfactory coagulation, renal and hepatic function, determined according to the reference values of the laboratory during the screening period The patient with CLL who has undergone allogeneic or autologous stem cell transplantation or a patient with NHL who has undergone allogeneic stem cell transplantation or was diagnosed with post-transplant lymphoproliferative disease, Burkitt lymphoma or Burkitt-like lymphoma, or lymphoblastic lymphoma/leukemia. Patient has AIDS. Patient with impaired cardiovascular status class 2, defined according to the criteria of the New York Heart Association. Class 2 impaired cardiovascular status is defined as a cardiac disease in which patients feel comfortable at rest, but in daily physical activity they feel fatigue, palpitations, dyspnea and heart pain. A patient who has a history of renal, neurological, psychiatric, pulmonary, endocrine, metabolic, immunological, cardiovascular or liver disease, which, in the opinion of the investigator, may adversely affect his/her Report for the health technology assessment for the medicinal product Venclyxto Page 18 of 31
participation in the study. A patient who received monoclonal antibody therapy as antineoplastic therapy within 8 weeks prior to the first dose of the test drug. Analysis of the patient cohort studied Analysis of the patient cohort studied Analysis of the patient cohort studied Analysis of the patient cohort studied Analysis of the patient cohort studied Characteristics Age Median (range) 70 years n (%) Gender n (%) Men Women Diagnosis n (%) CLL SLL Dose-escalating cohort (n=56) 67 (36-86) 20 (36) 41 (73) 15 (27) Expanded cohort (n=60) 66 (42-84) 14 (23) 48 (80) 12 (20) All patients (n=116) 66 (36-86) 34 (29) 89 (77) 27 (23) 49 (88) 7 (12) 53 (88) 7 (12) 102 (88) 14 (12) Rai stage III-IV n (%) 28 (50) 39 (65) 67 (58) Median number of previous 4 (1-10) 3 (1-11) 3 (1-11) therapies (range) Resistance to most recent therapy n (%) 23 (41) 22 (37) 45 (39) General condition by ECOG n (%) Stage 0 29 (52) 27 (45) 56 (48) Stage 1 27 (48) 31 (52) 58 (50) Missing information 0 2 (3) 2 (2) Tumor lymph nodes n (%) > 5 cm > 10 cm FISH analysis n/ total n with CLL (%) Del 17p Del 11q No Del 17p and Del 11q Missing information Mutational status of IGVH - n/ total n with CLL (%) Unmutated Mutated Missing information 29 (52) 10 (18) 19/49 (39) 13/49 (27) 16/49 (33) 7/49 (14) 26/49 (53) 6/49 (12) 17/49 (35) 38 (63) 12 (20) 12/53 (23) 15/53 (28) 27/53 (51) 3/53 (6) 20/53 (38) 11/53 (21) 22/53 (42) 67 (58) 22 (19) 31/102 (30) 28/102 (27) 43/102 (42) 10/102 (10) 46/102 (45) 17/102 (17) 39/102 (38) Clinical efficacy of venetoclax according to the M12-175 clinical study No maximally tolerated dose of venetoclax was established in the course of the study. General therapeutic response was recorded in 79% (92/116), with complete remission observed in 20% of patients. The administration of 400 mg of venetoclax resulted in 69% 15- month progression-free survival. Clinical efficacy data for venetoclax are presented in Table 8. Report for the health technology assessment for the medicinal product Venclyxto Page 19 of 31
Table 8. Clinical efficacy of venetoclax according to the M12-175 clinical study Therapeutic group Venetoclax Number of patients 116 ORR ОО, n (%) 95% CI 79 71-86 CR-IRC, n (%) 20 PR-IRC, n (%) 59 PFS Median PFS, months 15-month PFS, % 95% CI 25 66 51-77 OS Median OS, months 24-month OS, % 95% CI No information 84 No information Safety of venetoclax according to the M12-175 clinical study In 5.4% (3/56) of the patients in the dose-escalating cohort, the occurrence of tumor lysis syndrome was observed, which resulted in death in one of the patients. After dose adjustment, no tumor lysis syndrome was observed in any of the 60 patients enrolled in the expanded cohort. Other observed toxic effects include mild diarrhea (52%), upper respiratory tract infection (48%), nausea (47%), and neutropenia grade 3-4 (41%). The adverse drug events observed in clinical study M12-175 are listed in Table 9. Table 9. Adverse events observed in the M12-175 clinical study Adverse event (according to version 4.0 of the common terminology criteria of the National Cancer Institute) Adverse event Any adverse event Diarrhea Upper respiratory tract infection Nausea Neutropenia Fatigue Cough Fever Anemia Headache Constipation Thrombocytopenia Arthralgia Vomiting Peripheral edema Hyperglycemia Serious Adverse Event Any serious adverse event Febrile neutropenia Pneumonia Upper respiratory tract infection Any stage n (%) 115 (99) 60 (52) 56 (48) 55 (47) 52 (45) 46 (40) 35 (30) 30 (26) 29 (25) 28 (24) 24 (21) 24 (21) 21 (18) 21 (18) 18 (16) 17 (15) 52 (45) 7 (6) 5 (4) 4 (3) Venetoclax (n = 116) Stage 3-4 n (%) 96 (83) 2 (2) 1 (1) 2 (2) 48 (41) 4 (3) 0 1 (1) 14 (12) 1 (1) 1 (1) 14 (12) 1 (1) 2 (2) 0 10 (9) Report for the health technology assessment for the medicinal product Venclyxto Page 20 of 31
Immune thrombocytopenia Tumor lysis syndrome Diarrhea Fluid retention Hyperglycemia Prostate carcinoma Fever 3 (3) 3 (3) 2 (2) 2 (2) 2 (2) 2 (2) 2 (2) In May 2017 a search was made in the databases www.clinicaltrials.gov and www.clinicaltrialsregister.eu. The efficacy of venetoclax in patients with CLL was being studied in the following 3 ongoing phase III clinical trials: (1) NCT02756611: An open-label phase 3b, multicenter, one-arm study to evaluate the efficacy of venetoclax (ABT-199) in relapsed/refractory participants with chronic lymphocytic leukemia (CLL) including those with 17p deletion or TP53 mutation or those who have received a prior B-cell receptor inhibitor. This study will include 250 patients. (2) NCT02980731: An open-label phase 3b, multicenter, one-arm study to evaluate the effect of venetoclax on the quality of life in relapsed/refractory participants with chronic lymphocytic leukemia, including those with del 17p or TP53 mutation or those who have received a prior B-cell receptor inhibitor. This study will include 200 patients. (3) NCT02005471: A multicenter, phase III, randomized trial in patients with recurrent, refractory chronic lymphocytic leukemia evaluating the benefit of the administration of GDC-0199 (ABT-199) plus Rituximab compared to Bendamustine plus Rituximab. This study will include 389 patients. Currently, in addition to the above-mentioned studies, multiple phase 1 and 2 clinical trials are being conducted in patients with recurrent/refractory chronic lymphocytic leukemia. (1) NCT02966756: A phase 2, open-label study evaluating the efficacy of venetoclax in patients with recurrent or refractory chronic lymphocytic leukemia with del 17p. This study will include 70 patients. (2) NCT03045328: An open-label, phase 1-2 study of venetoclax with ibrutinib in patients with recurrent or refractory chronic lymphocytic leukemia and small cell lymphoma. This study will include 20 patients. Report for the health technology assessment for the medicinal product Venclyxto Page 21 of 31
(3) NCT01685892: A phase Ib multicenter dose-finding and safety study of venetoclax and obinutuzumab in patients with relapsed or refractory or previously untreated chronic lymphocytic leukemia. This study will include 81 patients. (4) NCT01671904: A phase Ib open-label study evaluating the safety and pharmacokinetics of venetoclax (GDC-0199, ABT-199) in combination with Bendamustine+Rituximab (BR) or Bendamustine+Obinutuzumab (BG) in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia. This study will include 100 patients. (5) NCT01682616: A phase 1b study evaluating the safety and tolerability of ABT- 199 in combination with Rituximab in subjects with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma. This study will include 50 patients. (6) NCT02141282: phase 2 open-label study of the efficacy and safety of ABT-199 (GDC-0199) in chronic lymphocytic leukemia subjects with relapse or refractory to B-Cell receptor signaling pathway inhibitor therapy. This study will include 120 patients. In addition, venetoclax is currently also investigated for other malignant hematopathies such as multiple myeloma, acute myeloid leukemia, diffuse B-cell lymphoma, manhocellular and follicular lymphoma. III. Analysis of pharmaco-economic indicators. 1. In the presented pharmaco-economic analysis, 23 published data on alternative technologies for the treatment of CLL were selected. There are no published evaluations of venetoclax health technology. The analysis made by the Marketing Authorization Holder is a cost-effectiveness analysis. 2. The pharmaco-economic analysis takes into account the health perspective and the point of view of the payer - the National Health Insurance Fund (NHIF), therefore only direct health costs related to the therapeutic alternatives used are included. The additional health costs associated with patient hospitalization are identical for the comparator therapeutic alternatives and can be neglected. Report for the health technology assessment for the medicinal product Venclyxto Page 22 of 31
3. The selected time horizon is 20 years, which is consistent with the progression of the disease and is sufficient to generate the identification and measurement of all important health costs and benefits. 4. Primary therapeutic efficacy data from randomized clinical trials are available over a period of 12 months to 17 months. The results for therapeutic efficacy after the end of the clinical trial to the end of the selected time horizon were modeled via a Markov model in a cohort of 1,000 patients. The applied Markov model has three possible health states: disease without progression, progression of the disease, and absorption death. All possible health conditions reflecting the course of the R/R CLL ± del 17p/TP53mut disease are included in the model and all the probabilities for transition from one health condition to another health condition are foreseen. 5. The analysis is from the point of view of society, not the payer, and therefore only direct medical expenses are included. 6. Costs and health benefits are discounted at an annual discontinuous factor of 5%. 7. The patient's health benefits in the model are measured as Quality-Adjusted Life-Year (QALY). The preferred unit of measurement is tailored to the therapeutic cycle and time horizon. 8. The Marketing Authorization Holder provides a one-way sensitivity analysis using the Tornado diagram, with a variation in cost and benefit parameters within a confidence interval of ± 20% around the average of each parameter. The results for the ICER of venetoclax versus alternative therapies remain within the acceptable cost range. 9. The Health-Related Quality of Life (HRQoL) tools used in patients with CLL include not only EQ-5D, but also EORTC QLQ-C30, FACT-G, and others. All instruments used assess the degree of fatigue, which is a major factor determining the quality of life in patients with CLL. 10. All data are presented in tabular and graphical form. 11. The structure of the analysis includes the modeling of health benefits and costs by comparing venetoclax vs. BSC (best supportive care) in two patient groups of second-line Report for the health technology assessment for the medicinal product Venclyxto Page 23 of 31
therapy in patients with CLL del17p/tp53mut and second line therapy in patients with R/R CLL who have undergone failed treatment with a Btk-inhibitor/PI3Kδ-inhibitor. The input data in the model are the efficacy and safety results obtained from clinical trials M13-982 and M14-032. The model results for cost effectiveness of venetoclax vs. BSC are included in a network meta-analysis comparing the cost-effectiveness data of the therapeutic alternatives in the two groups of patients. Additional costs (Δ costs), additional health benefits (Δ QALY) and their incremental ratio (ICER) of venetoclax compared to comparators are presented in the tables. In the CLL del 17p/TP53mut group, venetoclax dominates IBR with better therapeutic efficacy and lower cost of drug therapy, and is cost-effective compared to venetoclax vs. IDE/RIT and vs. RIT/BEN. For the third treatment line in patients with CLL del 17p/TP53mut and those with CLL non-del17p / TP53mute, the incremental ratio of venetoclax was calculated against BSC. Venetoclax is the only alternative in these patients. In the group of patients with R/R CLL refractory to one previous therapy, venetoclax again dominates IBR with better therapeutic efficacy and lower cost of drug therapy and is cost-effective therapy with venetoclax vs. OFA/BEN, vs. RIT/BEN and vs. IDE/RIT. In the group of patients with R/R CLL who are refractory to two previous therapies (immuno-chemotherapy and BCRSP-i therapy), venetoclax is a non-alternative therapeutic option due to the lack of comparators. Report for the health technology assessment for the medicinal product Venclyxto Page 24 of 31
IV. Budget impact analysis. 4.1. Epidemiology and therapy of the disease, clinical impact, economic impact Venclyxto is a medicinal product that is used as monotherapy in patients with chronic lymphocytic leukemia (CLL). CLL is an incurable and life-threatening hematological B-cell malignancy, representing 1/3 of all types of leukemias [27,28]. CLL mainly affects elderly patients, with an average age of diagnosis of 72 years. For this reason, many of these patients (89%) have at least one co-morbidity in the diagnosis (the median of two concomitant diseases) and are considered physically unfit for immunochemotherapy [27,28]. Venclyxto is used in adult CLL patients: in the presence of 17p deletion or a TP53 mutation in patients who are unsutable for or have failed a B-cell receptor pathway inhibitor, in the absence of 17p deletion or a TP53 mutation in patients who have failed both immunochemotherapy and a B cell receptor pathway inhibitor. According to the Bulgarian National Cancer Register, the incidence of C91 Lymphocytic Leukemia in 2012 in Bulgaria is 4.1 per 100,000 (3.3/100,000 in 2013) [5,25]. Morbidity in men is 4.6 in 2012 and 3.8 in 2013 of 100,000, and in women 3.6 in 2012 and 2.8 in 2013 of 100,000. The registered morbidity by age groups in 2012 shows a significant increase above 65 years - 16.0/100,000, above 70 years - 14.1/100,000, above 75 years - 11.9/100,000, above 80 years - 12,5/100,000, above 85 years - 15.4/100,000 compared to age groups ranging from 40-65 years, where the morbidity varies between 1.5-9.5/100,000. In 2013, 239 new cases of lymphoid leukemia (135 men and 104 women) were reported. The total reported rate of mortality by CLL in Bulgaria by 2012 is 2.3/100,000, which represents 170 deaths per year. Both morbidity and mortality are higher in men, 2.7/100,000 compared to women, 1.6/100,000. The mean five-year survival rate for CLL patients in Bulgaria is 46.0%. The five-year relative survival rate in Europe is significantly higher - 68.6%. Report for the health technology assessment for the medicinal product Venclyxto Page 25 of 31
Table 12. Epidemiological data for Bulgaria Epidemiological parameter Incidence Prevalence Value 2.96 /10,000 population 4.1/100,000 population Mortality 2.3 /100,000 Average overall survival Five-year 46% For 2012, data by the NCR 4.2. For the budget impact analysis, a model based on the following data and assumptions is applied: The patient population was determined based on data from the National Cancer Registry for 2012 for morbidity, mortality and 5-year survival for CLL listed in the table above. The target population was determined on the basis of frequency data of del ± 17p/TP53mut (9%) and R/R CLL (13%) who had failed treatment with Btkinhibitor/PI3Kδ-inhibitor for whom patients VEN is administered as a second line of monotherapy and the incidence of refractory to two treatment lines (20%) for whom VEN is administered as a third line of monotherapy. The budget impact of VEN as the second line of monotherapy is calculated on the basis of a comparison with the cost of treatment of patients in the target group with alternative therapies in comparison to the two scenarios with and without reimbursement of VEN (Table 14 and 15). The budget impact of VEN as the third line of monotherapy is calculated based on the cost of treatment of patients in the VEN target group due to lack of an alternative for this patient group (Table 16). The analysis period is 5 years Only direct costs are included The costs of comparing drug therapies were calculated on the basis of registered dosing regimens and reference prices in the positive drug list (PDL) in Bulgaria by March 2017 of all medicinal products. The prices of the medicinal products not included in the PDL are presented by the Marketing Authorization Holders. Report for the health technology assessment for the medicinal product Venclyxto Page 26 of 31
The adopted perspective is that of the payer (National Health Insurance Fund, NHIF) Reimbursement level - 100% 4.3. Assessment of the annual target population number Figure 1. Number of patients with CLL 4.4. Assessment of the annual number of patients who will be using the new health technology The total number of CLL patients does not change when VEN is introduced. 4.5. Assessment of the actual annual cost of public budgeting to treat patients Data on the actual annual cost of public budgeting for treatment of patients is provided in the report and the calculations are made accordingly. For the purposes of the calculations, the available drug therapies for the treatment of CLL are included. 4.6. Assessment of the cost of public funds following the introduction of VEN The data for assessing the cost of public funds following the introduction of VEN are provided in the report and are calculated correctly. 4.7. Outcomes Because in patients with R/R CLL del ± 17p/TP53mut VEN is a non-alternative third therapeutic line, an increase in NHIF spending over the 5-year period is expected, which for the same period is offset by expected savings on the introduction of VEN as the second line of monotherapy. Report for the health technology assessment for the medicinal product Venclyxto Page 27 of 31