Products

Date: 2017-03-23

Type of information: Withdrawal of a market application in the EU

Product name: Unituxin®

Compound: dinutuximab

Therapeutic area: Cancer - Oncology - Rare diseases

Action mechanism: monoclonal antibody. Unituxin® (dinutuximab) is a disialoganglioside, GD2-binding chimeric monoclonal antibody (formerly called ch14.18) that induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytoxicity (ADCC) and complement-dependent cytoxicity (CDC).

Company: United Therapeutics (USA - MD)

Disease: first-line therapy for pediatric patients with high-risk neuroblastoma

Latest news:

• • On March 23, 2017, Unituxin™ (dinutuximab) marketing authorization has been withdrawn and the product is no longer authorised in the UE.
• • On August 17, 2015, United Therapeutics Corporation announced that the European Commission (EC) has granted Marketing Authorisation for Unituxin™ (dinutuximab) for the treatment of high-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation (ASCT). Unituxin® is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin. The European approval was based on demonstration of improved event-free survival (EFS) and overall survival (OS) in a multicenter, open-label, randomized trial (ANBL0032) sponsored by the US National Cancer Institute under a Cooperative Research and Development Agreement with United Therapeutics and conducted by the Children's Oncology Group (COG).
• Trial design and results: The trial randomized (1:1) 226 patients to either the Unituxin/13-cis-retinoic acid (RA) arm or the RA alone arm. Patients in each arm received six cycles of treatment. The Unituxin/RA arm consisted of Unituxin in combination with granulocyte macrophage-colony stimulating factor and RA (cycles 1, 3, and 5), Unituxin in combination with interleukin-2 and RA (cycles 2 and 4), and RA (cycle 6). Patients were 11 months to 15 years of age (median age 3.8 years). The major efficacy outcome measure was investigator-assessed EFS, defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy or death. The primary intent-to-treat analysis found an improvement in EFS associated with dinutuximab immunotherapy plus isotretinoin as compared to isotretinoin alone. The two-year estimates of EFS were 66% among subjects receiving dinutuximab immunotherapy plus isotretinoin as compared with 48% in subjects receiving isotretinoin alone (log-rank test p = 0.033) although this difference did not reach formal statistical significance according to the pre-specified plan for interim analyses. In addition, OS was evaluated with 3 years of follow-up after the EFS analysis as a secondary endpoint with a significant improvement observed among ITT subjects randomly allocated to receive dinutuximab immunotherapy plus isotretinoin as compared with isotretinoin alone. The three-year estimates of OS were 80% compared with 67% among subjects receiving dinutuximab immunotherapy plus isotretinoin and isotretinoin alone, respectively (log-rank test p = 0.0165). Long-term overall survival was evaluated with five years of follow up after the EFS analysis and continued to demonstrate a survival advantage for patients who received dinutuximab immunotherapy compared to those who received isotretinoin alone. The five-year estimates of OS were 74% for dinutuximab immunotherapy compared to 57% for isotretinoin alone (log-rank test p = 0.030). The most frequently occurring (more than 30% of patients) adverse reactions reported during the neuroblastoma studies were hypotension (67%), pain (66%), hypersensitivity (56%), pyrexia (53%), urticaria (49%), capillary leak syndrome (45%), anaemia (45%), hypokalaemia (41%), platelet count decreased (40%), hyponatraemia (37%), alanine aminotransferase increased (35%), decreased lymphocyte count (34%) and decreased neutrophil count (31%). Additional adverse reactions characteristic of an allergic response were also reported - including anaphylactic reaction (18%) and bronchospasm (4%). Posology and method of administration: Unituxin® is to be administered by intravenous infusion over five courses at a daily dose of 17.5 mg/m2. It is administered on days 4-7 during courses 1, 3 and 5 (each course lasting approximately 24 days) and on days 8-11 during courses 2 and 4 (each course lasting approximately 28 days). The treatment regimen consists of Unituxin, GM-CSF, IL-2, and isotretinoin, administered over six consecutive courses. • On May 21, 2015, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Unituxin® for the treatment of high-risk neuroblastoma in children. The benefits with Unituxin® are an improvement in the 2-year estimates of event free survival and the 3-year estimates of overall survival. The most common side effects are pain, allergic reactions and hypotension. The full indication is: "Unituxin is indicated for the treatment of high-risk neuroblastoma in patients aged 12 months to 17 years, who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and autologous stem cell transplantation (ASCT). It is administered in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and isotretinoin."
• • On March 10, 2015, the FDA approved Unituxin® (dinutuximab) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), as a first-line therapy for pediatric patients with high-risk neuroblastoma. The FDA granted Unituxin® priority review and orphan product designation. With this approval, the FDA also issued a rare pediatric disease priority review voucher to United Therapeutics, which confers priority review to a subsequent drug application that would not otherwise qualify for priority review. This is the second rare pediatric disease priority review voucher granted by the FDA since inception of the rare pediatric disease review voucher program, which is designed to encourage development of new therapies for prevention and treatment of certain rare pediatric diseases. The voucher can be sold (without limitation), and the holder of the voucher can redeem it with a subsequently filed New Drug Application or Biologics License Application, requiring FDA to meet the review goals for a priority review, as opposed to a standard review. To qualify to receive a PPRV, a sponsor must submit an application for a drug or biologic intended to prevent or treat a rare pediatric disease. The rare pediatric disease application also must be eligible for priority review and rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population.
• The safety and efficacy of Unituxin® were evaluated in a clinical trial (ANBL0032) of 226 pediatric participants with high-risk neuroblastoma whose tumors shrunk or disappeared after treatment with multiple-drug chemotherapy and surgery followed by additional intensive chemotherapy and who subsequently received bone marrow transplantation support and radiation therapy. Participants were randomly assigned to receive either an oral retinoid drug, isotretinoin (RA), or Unituxin® in combination with interleukin-2 and granulocyte-macrophage colony-stimulating factor, which are thought to enhance the activity of Unituxin® by stimulating the immune system, and RA. Three years after treatment assignment, 63 percent of participants receiving the Unituxin® combination were alive and free of tumor growth or recurrence, compared to 46 percent of participants treated with RA alone. In an updated analysis of survival, 73 percent of participants who received the Unituxin® combination were alive compared with 58 percent of those receiving RA alone.
• Unituxin® carries a Boxed Warning alerting patients and health care professionals that Unituxin® irritates nerve cells, causing severe pain that requires treatment with intravenous narcotics and can also cause nerve damage and life-threatening infusion reactions, including upper airway swelling, difficulty breathing, and low blood pressure, during or shortly following completion of the infusion. Unituxin® may also cause other serious side effects including infections, eye problems, electrolyte abnormalities and bone marrow suppression.
• The most common side effects of Unituxin® were severe pain, fever, low platelet counts, infusion reactions, low blood pressure, low levels of salt in the blood (hyponatremia), elevated liver enzymes, anemia, vomiting, diarrhea, low potassium levels in the blood, capillary leak syndrome (which is characterized by a massive leakage of plasma and other blood components from blood vessels into neighboring body cavities and muscles), low numbers of infection-fighting white blood cells (neutropenia and lymphopenia), hives, and low blood calcium levels.
• The recommended dose and schedule for Unituxin® is 17.5 mg/m2/day as a diluted intravenous infusion over 10 to 20 hours for 4 consecutive days for a maximum of 5 cycles. Patients require intravenous treatment with opioids prior to, during, and for 2 hours following the Unituxin® infusion to mitigate neuropathic pain. Prior to each Unituxin® dose, administer required intravenous hydration and premedication with antihistamines, analgesics, and antipyretics.
• In connection with the Unituxin® approval, United Therapeutics agreed to certain postmarketing requirements (PMRs) and certain postmarketing commitments (PMCs). PMRs and PMCs are studies that sponsors conduct after FDA approval to gather additional information about a product's safety, efficacy, or optimal use. PMRs are required studies, whereas a sponsor voluntarily commits to conduct PMCs.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE: 2017-03-23

US authorization: 2015-03-10

UE authorization: 2015-08-17

Favourable opinion UE: 2015-05-21

Favourable opinion USA:

Orphan status USA: 2010-12-20

Orphan status UE: 2011-06-21

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes