Decision to fund venetoclax (Venclexta) for chronic lymphocytic leukaemia

Medicines

Decision

We're pleased to announce a decision to approve funding for venetoclax (Venclexta) for the treatment of chronic lymphocytic leukaemia (CLL).

In summary, from 1 December 2019:

  • venetoclax will be funded, in combination with rituximab, for the treatment of CLL that has relapsed within 36 months of previous treatment, and
  • venetoclax will be funded as monotherapy for the treatment of previously untreated CLL with a specific genetic mutation (17p deletion or TP53 mutation).  

The funding criteria for rituximab will be amended to allow for its use in combination with venetoclax.

Any changes to the original proposal?

This decision was subject to a consultation letter dated 1 September 2019

The proposal was approved as consulted on (including the rituximab Special Authority criteria) except, as a result of consultation feedback, the Special Authority criteria and restrictions for venetoclax were amended to:

  • clarify that only patients previously treated with funded venetoclax will not be eligible.
  • include funded access for patients with B-cell prolymphocytic leukaemia.

We have also applied the wastage rule to venetoclax (Venclexta) tab 100 mg in Section B of the Pharmaceutical Schedule from 1 December 2019 and the starter packs will able to be claimed as Original Packs (OP).

Who we think will be most interested

  • People who have CLL (a type of blood cancer) and their whānau
  • Groups such as Leukaemia & Blood Cancer NZ and CLL Advocates NZ
  • Haematologists/oncologists
  • Community and hospital pharmacies
  • DHB infusion service providers
  • Other organisations with an interest in cancer treatment

Detail about this decision

Venetoclax will be listed in Section B and Part II of Section H of the Pharmaceutical Schedule from 1 December 2019 at the following prices (ex-manufacturer, excluding GST):

Chemical

Formulation

Brand

Pack size

Price and subsidy

Venetoclax

Tab 10 mg

Venclexta

14 OP

$95.78

Venetoclax

Tab 50 mg

Venclexta

7 OP

$239.44

Venetoclax

Tab 100 mg

Venclexta

120

$8,209.41

Venetoclax

Tab 14 x 10 mg, 7 x 50 mg, 21 x 100 mg

Venclexta

42 OP

$1,771.86

The wastage rule will apply to venetoclax tab 100 mg in Section B of the Pharmaceutical Schedule from 1 December 2019. Starter packs will able to be claimed as Original Packs (OP).

A confidential rebate will apply to Venclexta reducing the net price to the Funder.

Venclexta will have protection from delisting and subsidy reduction until 30 November 2022.

Venetoclax will be funded for patients with CLL who meet the following Special Authority criteria (differences from criteria consulted on shown by additions in bold and deletions in strikethrough):

Special Authority for Subsidy – Retail Pharmacy – Specialist

Initial application - (relapsed/refractory chronic lymphocytic leukaemia) only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 7 months for applications meeting the following criteria:

All of the following:

  1. Patient has chronic lymphocytic leukaemia requiring treatment; and
  2. Patient has received at least one prior therapy for chronic lymphocytic leukaemia; and
  3. Patient has not previously received funded venetoclax; and
  4. The patient’s disease has relapsed within 36 months of previous treatment; and
  5. Venetoclax to be used in combination with six 28-day cycles of rituximab commencing after the 5-week dose titration schedule with venetoclax; and
  6. Patient has an ECOG performance status of 0-2.

Renewal - (relapsed/refractory chronic lymphocytic leukaemia) only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 6 months for applications meeting the following criteria:

Both:

  1. Treatment remains clinically appropriate and the patient is benefitting from and tolerating treatment; and
  2. Venetoclax is to be discontinued after a maximum of 24 months of treatment following the titration schedule unless earlier discontinuation is required due to disease progression or unacceptable toxicity. 

Initial application - (previously untreated chronic lymphocytic leukaemia with 17p deletion or TP53 mutation*) only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 6 months for applications meeting the following criteria:

All of the following:

  1. Patient has previously untreated chronic lymphocytic leukaemia; and 
  2. There is documentation confirming that patient has 17p deletion by FISH testing or TP53 mutation by sequencing; and
  3. Patient has an ECOG performance status of 0-2.

Renewal - (previously untreated chronic lymphocytic leukaemia with 17p deletion or TP53 mutation*) only from a relevant specialist or medical practitioner on the recommendation of a relevant specialist. Approvals valid for 6 months where the treatment remains clinically appropriate and the patient is benefitting from and tolerating treatment.

Note: ‘Chronic lymphocytic leukaemia (CLL)’ includes small lymphocytic lymphoma (SLL)* and B-cell prolymphocytic leukaemia (B-PLL)*. Indications marked with * is an are Unapproved indications.

The same changes to the restrictions for Venetoclax (Venclexta) will apply in Part II of Section H of the Pharmaceutical Schedule (the Hospital Medicines List; HML).

Changes will be made to the rituximab Special Authority criteria for CLL in Section B of the Pharmaceutical Schedule as consulted on.

Our response to what you told us

We’re really grateful for the time people took to respond to this consultation. Most responses were supportive of the proposal to fund venetoclax, but a number were also supportive of funding of ibrutinib for CLL.

A summary of the main themes raised in feedback, our responses to the feedback received, and changes we have made after listening to you are set out below.

Theme PHARMAC response

Support for the proposal and noted that once funded this will go a long way to help meet an urgent unmet need.

Support specifically for the funding of venetoclax monotherapy for the treatment of previously untreated CLL with 17p deletion or TP53 mutations, despite this being an unregistered indication.

Noted.

A number of individual patient stories which emphasised the importance of quality of life were provided.

We appreciate the considered responses and value the input provided.

Requests for access criteria amendments  

Patients who had a limited course of venetoclax monotherapy on a clinical trial or who have self-funded venetoclax are excluded in the current criteria.

We have amended the criteria to clarify that only patients previously treated with funded venetoclax will not be eligible under this criterion.

The option of retreatment would allow patients to stop treatment prior to the 24 months maximum, however, if there is no option for retreatment patients will generally all be treated for the full length of treatment allowed.

The decision to stop treatment prior to the 24 months is for patients and clinicians. The criteria are consistent with clinical advice from the Cancer Treatments Subcommittee (CaTSoP), based on the currently available evidence. Should new evidence for venetoclax retreatment become available, we would welcome a funding application for the use of venetoclax in this setting.

Request that a rare condition called B-cell prolymphocytic leukaemia, which is distinct, but very closely related to CLL, be included within this funding proposal.

Clinical advice sought from members of CaTSoP recommended that it would be appropriate for patients with B-cell prolymphocytic leukaemia to be treated with venetoclax and would likely obtain the same benefit.

The criteria have been amended to reflect this.

Request for the population with 17p deletion or TP53 mutation who relapse beyond 3 years from last treatment with aggressive disease and those with ECOG 0-3 be included.

The criteria are consistent with clinical advice from CaTSoP, based on the currently available evidence. Should new evidence become available, we would welcome a funding application for the use of venetoclax in these settings.

Medsafe has not assessed evidence for venetoclax in a previously untreated CLL population. Recommend that the proposal is revised to only fund venetoclax monotherapy in relapsed or refractory CLL consistent with its approved indications.

Noted. This is a small patient group expected to be 7-10 patients per year. Clinical advice from CaTSoP and a letter of support from a number of haematologists indicate that funding venetoclax in this setting is clinically appropriate.

Venetoclax is likely to provide substantial benefit for these patients who have a very high health need and limited alternative treatment options. We consider withholding funding from this patient group due to a lack of Medsafe approval is unreasonable. We also received a significant amount of supportive consultation feedback in response to our direct question on this aspect of the proposal.

The criteria include a note to indicate use in of venetoclax in this setting would be an unapproved indication, as we have done with other indications on the Pharmaceutical Schedule which fall outside the Medsafe approved indications for that product. In these situations, it is the prescriber’s responsibility to meet the requirements of the Medicines Act.

Heath sector impacts 

Although 17p deletion testing is widely available, the TP53 mutation assay is only currently available in a molecular haematology laboratory in Auckland. There may be pressure on this service as a result of this proposal. 

We acknowledge that this decision may have an impact on testing services.

PHARMAC does assess and consider the availability and additional costs of testing to the health sector; however, we note that DHBs are responsible for the provision and funding of testing services.

The majority of eligible patients have been receiving a repeat of their initial chemotherapy (minus rituximab) or chlorambucil given limited treatment options. Venetoclax/rituximab represents a more efficacious option and would not have a significant impact on chair time in the short and intermediate term.

Noted.

Noting its high cost, venetoclax should be a ‘PCT-only’ medicine.

Request that the wastage rule is applied to all four pack sizes of venetoclax.

PCT-only would require dispensing via hospital pharmacies. Although given the high list price the distribution margin is significant, we consider making this treatment only available from hospital pharmacies would create undesirable barriers to accessing the treatment. 

Given possible dosage reductions and the high cost of treatment, an amendment has been made to the listing to allow for the claiming of wastage by community pharmacies for the 100 mg tablet pack. We have also applied the ‘Original Pack’ (OP) rule to the three starter packs.

To avoid unnecessary wastage, prescribers are encouraged to prescribe full packs.

Support for funding ibrutinib in addition to venetoclax  

Substantial support for the funding of ibrutinib in addition to venetoclax, noting its different mechanism of action and that therapy resistance and treatment-related toxicities of ibrutinib and venetoclax do not overlap.

We have not yet specifically sought advice on groups of patients with CLL that would benefit most from ibrutinib if venetoclax were to be funded. We will likely seek advice from CaTSoP on this at a future committee meeting

This decision does not prevent us further considering the funding of ibrutinib in addition to venetoclax in the future. 

There is a growing body of evidence to suggest there is synergy between ibrutinib and venetoclax and the best results are achieved when they are used in combination.

The bulk of publications to date have used the reverse sequence of ibrutinib followed by venetoclax as ibrutinib was the first agent available.

Venetoclax and ibrutinib are supplied by different pharmaceutical companies and are both high cost medicines.

We have not yet received an application for the combination use of ibrutinib and venetoclax for the treatment of CLL, but we would welcome a funding application with supporting evidence for the use of these agents in combination.

This decision does not prevent us considering wider access to venetoclax or funding of ibrutinib in addition to venetoclax in the future. 

Other BTK inhibitors (from the same class as ibrutinib), such as zanubrutinib are being developed an could be an alternative option to ibrutinib in the future. 

Noted.

Ibrutinib would improve equity of access particularly for patients in the rural communities and those from low socio-economic communities given that it does not require rituximab infusion services and has less risk of tumour lysis syndrome.

The majority of patients on venetoclax will require intravenous rituximab to be given in a hospital outpatient setting once monthly for the first six months of the treatment only. Based on the available evidence, rituximab appears to increase the survival benefit compared to venetoclax monotherapy.

Whilst there may be additional costs associated with travel to receive rituximab infusions, many of those patients would currently be receiving infusion-based chemotherapy treatment meaning these patients will currently be travelling for treatment. We received consultation feedback that suggests minimal additional infusions would be required with the use of venetoclax/rituximab as compared to current treatment options.

CaTSoP has advised that tumour lysis syndrome is effectively minimised by administration using dose ramp-up, but hospital admission may be required for patients at high risk.

This decision does not prevent us further considering the funding of ibrutinib in addition to venetoclax in the future. 

A subset of CLL (approximately 10%) have 11q deletion. These patients often have bulky nodal disease and venetoclax outcomes are better but may not be as good as with BTK inhibitors. This subtype of CLL should have access to a BTK inhibitor.

We would welcome a funding application with supporting evidence for use of a BTK inhibitor specifically for the treatment of CLL with 11q deletion.

Ibrutinib would be a valuable treatment option in a number of CLL patient groups and Mantle Cell Lymphoma (MCL).

We have not yet specifically sought advice on groups of patients with CLL that would benefit most from ibrutinib if venetoclax were to be funded for the majority. We will likely seek advice from CaTSoP on this at a future committee meeting

Ibrutinib for MCL is currently ranked on PHARMACs Options for Investment list. This decision does not prevent us considering funding ibrutinib in the future.

Suggest ibrutinib be funded instead of venetoclax

This decision seems to have been based purely on price (and a fixed, as yet unproven two-year treatment period), rather than efficacy based on durable clinical evidence.

The decision is in line with clinical advice from CaTSoP and based on the currently available evidence.

Venetoclax with rituximab represents an affordable and cost-effective treatment option that we consider will meet the majority of the heath need for patients with CLL and provide substantial benefits over the status quo within the funding available.

This decision does not prevent us considering wider access to venetoclax or funding of ibrutinib in addition to venetoclax in the future. 

Ibrutinib is registered for 1st line treatment of CLL with 17p deletion and TP53 mutation with much published evidence and is supported in the international guidelines.

We are aware that there is published evidence available for ibrutinib in this setting and it is Medsafe approved for this indication. As above, clinical advice from CaTSoP and a number of haematologists supports funding venetoclax in this setting.

We would welcome a commercial proposal from the supplier to fund ibrutinib as a treatment option for this patient group.

The patient population in the pivotal trial for venetoclax plus rituximab (named MURANO) had a median of only one prior line of treatment. This is not concordant with the New Zealand cohort of relapsed refractory patients.

A decision to list venetoclax only is in conflict with international CLL treatment guidelines that suggest treating with ibrutinib first. There is more international experience with use of ibrutinib as it has been available now for six or seven years which is longer than venetoclax.

CaTSoP has reviewed the relevant literature including the MURANO clinical trial and considered there was good quality evidence of benefit.

CaTSoP recommended funding of venetoclax and rituximab with a high priority. Given the limited funded treatment options available in New Zealand, there will likely be many patients who have only had only one prior line of treatment.

More information, including links to the PTAC and Subcommittee minutes, can be found in the Application Tracker records for venetoclax(external link)

If you have any questions about this decision, you can email us at enquiry@pharmac.govt.nz; or call our toll free number (9 am to 5 pm, Monday to Friday) on 0800 66 00 50.