Novartis said its leukaemia drug Tasignaâ (nilotinib) has received European Union approval as a new anti-cancer therapy for patients with a life-threatening form of leukaemia who are resistant or intolerant to prior treatment including Glivecâ (imatinib).
The US Food and Drug Administration (FDA) approved Tasigna in October 2007 based on the same pivotal clinical trial that supported the EU filing, but using a different analysis (including shorter duration of follow-up) that produced slightly different response rates.
The EU approval was supported by data showing that Tasigna produced a positive response in 49 per cent of patients in the chronic phase of Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML). Most patients achieved this response within three months of starting Tasigna treatment.
The European Commission decision applies in all 27 EU member states plus Norway and Iceland, and follows recent approvals in the US and Switzerland. Tasigna is now approved in a total of 37 countries, and was also submitted for approval in Japan in June.
"The approval of Tasigna gives us the opportunity to help more CML patients and, with Glivec as our first line agent, provide comprehensive treatment options for prescribers," said David Epstein, president and CEO, Novartis Oncology. "Tasigna drives home our commitment to develop compounds to fulfil unmet medical needs by pursuing indications for patients with limited treatment options."
CML is one of the four most common types of leukaemia, responsible for about 15 per cent of all leukaemia cases worldwide. Without treatment, CML typically progresses over three to five years from the initial (chronic) phase through a transition (accelerated) phase to a rapidly fatal form called blast crisis. Tasigna is indicated in the EU for the treatment of adults who are in chronic or accelerated phase Ph+ CML and have resistance or intolerance to prior therapy including Glivec.
Taken twice daily, Tasigna works by inhibiting the proliferation of cells containing an abnormal chromosome in patients with CML. It does this by targeting the production of the Bcr-Abl protein, which is produced only by cells containing the abnormal Philadelphia chromosome. This protein is recognized as the key driver of the overproduction of cancer-causing white blood cells in patients with Ph+ CML.
Tasigna was designed to target the Bcr-Abl protein more preferentially than Glivec without adding new mechanisms of action.
Earlier this year, a phase III clinical trial program was launched to compare Tasigna with Glivec for the treatment of newly diagnosed patients with chronic phase Ph+ CML. A study is also underway comparing these two targeted therapies in chronic phase Ph+ CML patients who had sub-optimal responses to previous therapy. Separately, a phase III program has been launched involving the use of Tasigna in patients with gastrointestinal stromal tumours (GIST) who are resistant or intolerant to prior treatment.
The EU approval of Tasigna was based on a pivotal clinical trial evaluating the rates of cytogenetic response (i.e. reduction or elimination of the Philadelphia chromosome) and confirmed hematologic response (i.e. normalization of white blood cell counts) in Glivec-resistant or -intolerant patients with Ph+ CML in chronic and accelerated phase.
The major cytogenetic response rate with Tasigna was 49 per cent for chronic phase patients and 27 per cent for accelerated phase patients. The complete hematologic response rate was 70 per cent for chronic phase patients who were not already in complete hematologic response at the start of the trial, and the confirmed hematologic response rate was 42 per cent for accelerated phase patients.
The most frequent grade 3 or 4 adverse events for Tasigna were primarily haematological in nature and included neutropenia and thrombocytopenia. Elevations were seen in bilirubin, liver function tests, lipase enzymes and blood sugar, which were mostly transient and resolved over time. These cases were easily managed and rarely led to discontinuation. Pancreatitis was reported in less than 1 per cent of cases. The most frequent non-hematologic drug-related adverse events were rash, pruritus, nausea, fatigue, headache, constipation, and diarrhoea. Most of these adverse events were mild to moderate in severity, the company said.
Glivec is approved in more than 90 countries including the US, EU and Japan for the treatment of all phases of Ph+ CML. Glivec is also approved in the EU, US and other countries for the treatment of patients with Kit (CD117)-positive gastrointestinal tumors (GIST), which cannot be surgically removed and/or have already spread to other parts of the body (metastasized). In Japan, Glivec is approved for the treatment of patients with Kit (CD117)-positive GIST. In the EU, Glivec is also approved for the treatment of adult patients with newly diagnosed Ph+ acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy and as a single agent for patients with relapsed or refractory Ph+ ALL. Glivec is also approved for the treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) who are not eligible for surgery. Glivec is also approved for the treatment of patients with myelodysplastic/myeloproliferative diseases (MDS/MPD). Glivec is also approved for hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CEL).
The effectiveness of Glivec is based on overall hematologic and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, and on objective response rates in GIST and DFSP. There are no controlled trials demonstrating increased survival. Not all indications are available in every country.
The majority of patients treated with Glivec in clinical trials experienced adverse events at some time. Most events were of mild to moderate grade and treatment discontinuation was not necessary in the majority of cases.
The safety profile of Glivec was similar in all indications. The most common
Rare/serious adverse reactions include: sepsis, pneumonia, depression, convulsions, cardiac failure, thrombosis/embolism, ileus, pancreatitis, hepatic failure, exfoliative dermatitis, angioedema, Stevens-Johnson syndrome, renal failure, fluid retention, oedema (including brain, eye, pericardium, abdomen and lung), haemorrhage (including brain, eye, kidney and gastrointestinal tract), diverticulitis, gastrointestinal perforation, tumour haemorrhage/ necrosis, hip osteonecrosis/avascular necrosis.
Novartis AG is a world leader in offering medicines to protect health, cure disease and improve well-being. In 2006, the Group's businesses achieved net sales of USD 37.0 billion and net income of USD 7.2 billion. Approximately USD 5.4 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 associates and operate in over 140 countries around the world.