Dasiprotimut-T

Published

dm+d

Unassigned

New Medicines

LymprevaNon-Hodgkin lymphoma (NHL)

Information

Lympreva
New molecular entity
Biovest International
Biovest International

Development and Regulatory status

None
None
None
Yes
Yes
01. Granted fast track status in US on basis of PII data. Now in PIII trials (1).
02. Oct 08: Compassionate use drug access programme agreement with IDIS in Europe. Sales expected to begin in Q1 2009 (3,4)
03. Orphan Drug status in EU (4)
04. Jun 09: The company hopes to seek accelerated approval in the US. If successful it will conduct further trials, including use post- rituximab-containing regimens and use as booster maintenance therapy. It also plans to make it available in the EU on a named-patient basis ahead of seeking formal EU approval (5).
05. Jan 10: Granted orphan drug status in the US (6).
06. Jun 10: Accentia Biopharmaceuticals (parent company of Biovest) files its proposed Plan of Reorganization with the US Bankruptcy Court & is now positioned to emerge from Chapter 11 protection this summer as a fully restructured company (7). Development of its pipeline products is expected to continue (6).
07. Jul 10: Granted orphan drug status in US for mantle cell lymphoma [8].
08. Oct 11: Granted orphan status in the US for Waldenstrom´s macroglobulinemia, a rare subtype of B-cell non-Hodgkins lymphoma [10].
09. May 12: Biovest plans to file a Marketing Authorization Application with the EMA for BiovaxID to treat follicular NHL via the centralised procedure. EU approval would establish BiovaxID as the first cancer vaccine available in Europe for lymphoma pts. Pre-filing meetings have taken place in the EU & Canada, & are planned in the US [11].
10. Aug 12: At the pre-filing meeting the FDA requested a second PIII trial to confirm the data generated in the PIII trial BV30. The FDA will work with Biovest on the trial design which is likely to explore the use of a specific subtype of the idiotype biomarker found in a retrospective analysis of the first PIII study. Biovest will continue to advance filings in the EU and Canada supported by evidence from the 3 human trials conducted to date in collaboration with the US National Cancer Institute [13].
11. Sep 12: Filing for EU marketing approval anticipated in ealry 2013 [14].
12. Jan 14: Marketing Authorisation Application accepted by EMA. [15]
13. Apr 15: EU negative opinion. The CHMP considered that the main study was inadequately designed and carried out to establish benefit of dasiprotimut-T. In addition, effectiveness following induction treatment with current standard of care (anti-CD20 therapies) has not been demonstrated. The CHMP also had concerns regarding some aspects of manufacture and quality control. The CHMP concluded that the benefits of Lympreva did notoutweigh its risks and recommend that it be refused marketing authorisation [17].
14. Dec 16: No development reported. Biovest website (www.biovest.com) not accessible [18].

Category

Vaccine - Induces a tumour-specific cytotoxic T lymphocyte response
The UK incidence of follicular NHL is 3-5 per 100,000 and most (90%) will present with stage III or IV disease. These patients are considered for chemotherapy and would be eligible for this vaccine if they have prolonged remission [16].
Non-Hodgkin lymphoma (NHL)
Subcutaneous

Trial or other data

01. Oct 08: P3 fast-tracked clinical trial closed to allow administration of the vaccine to control patients after an increase in cancer-free survival of 44% reported. The trial involved an ITT population of 117 patients with newly diagnosed follicular non-Hodgkin´s lymphoma who had achieved a complete clinical remission after chemotherapy. They were randomised 2:1 to a planned schedule of 5 vaccinations with BiovaxID or a control vaccine, given with GM-CSF. The median duration of complete remission was 44.2 vs. 30.6 months after a median follow-up period of 56.6 months. The difference in disease-free survival was greatest at 36 months (61% vs. 37% of patients cancer-free at this stage). The company suggest that this might be the optimal time for a booster (2).
02. Jun 09: Results of the pivotal Phase III BV-301 study in follicular lymphoma (FL) highlighted at the ASCO meeting. In the planned ITT analysis, which included patients in complete remission after chemotherapy who received either vaccine plus control or control alone, median disease-free survival improved from 30.6 months to 44.2 months. It is likely that further trials will be needed to determine its place in therapy, as the standard of care in has changed since 2000 when the trial started to include rituximab (5).
03. Dec 10: An analysis of data from the PIII trial for non-Hodgkin´s lymphoma suggests that improved disease-free survival depends on an integral tumour protein fragment (isotype) administered as part of each patient´s vaccine, according to a report at ASH. Among the 75 patients receiving BiovaxID, 35 received BiovaxID manufactured with an IgM isotype and 40, BiovaxID manufactured with an IgG isotype with each treatment vaccine produced to correspond with the patient´s tumour immunoglobulin isotype. Of 40 patients receiving control, 25 had tumours with IgM isotype and 15 had tumours with IgG isotype. Two of the patients in the vaccinated treatment/control population had a tumor with mixed IgM/IgG isotypes and were excluded from the analysis. Of the 35 patients with IgM tumour isotype receiving BiovaxID/ IgM isotype, median time to relapse was 52.9 months vs 28.7 months in the IgM tumour isotype control-treated patients (log-rank p=0.001; HR=0.34 (p=0.002); [95% CI: 0.17-0.68]. In contrast, among 40 patients with IgG tumour isotype receiving BiovaxiD/ IgG isotype, median time to relapse was 35.1 months, vs 32.4 months in control-treated patients with IgG tumour isotype (log-rank p=0.807; HR=1.1 (p=0.807): [95% CI: 0.50-2.44] [9].
05. Jun 12: Long-term (median 10-year follow-up) outcomes from a PII BiovaxID® lymphoma vaccine trial reported at ASCO. Vaccination following rituximab combination chemotherapy induced nearly universal T-cell immune responses, which strongly correlated with overall survival and time-to-next treatment benefits in 24 patients with mantle cell lymphoma (MCL). Patients with a high degree of T-cell response to vaccination experienced an estimated survival of approximately 75% at 10-years, vs 25% in the group of with a low degree of T-cell GM-CSF responses. Time-to-next-treatment benefit was improved10-fold for those patients with a high T-cell response (51.9 months vs 5.5 months from the time of first progression) [12]
06. Aug 12: In a review of unmet need in the US, Biovest estimates that 50% of follicular lymphoma patients achieving first remission do not receive any treatment even though they at near-universal risk of relapse. A primary contributing factor to this need for additional consolidation agents is the immunosuppressive nature of all approved consolidation agents, which target the same antigen, CD20, used as part of induction therapy. This includes rituximab which when used as a consolidation agent (rituximab maintenance) is generally administered on a bi-monthly dosing schedule over several years resulting in immunosuppression that is significantly prolonged as compared to the use of rituximab as an agent in first line induction therapy or following disease progression [13].
07. Jul 13: formerly B cell lymphoma vaccine

Evidence based evaluations

27 June 2014NHSC/NIHR