Sipuleucel-T

Published

dm+d

Unassigned

New Medicines

ProvengeProstate cancer, castration-resistant - first-line

Information

Provenge
New molecular entity
Dendreon
Dendreon

Development and Regulatory status

Licence withdrawn
Licence withdrawn
Launched
01. Fast track in US for asymptomatic, metastatic, androgen independent prostate cancer(1). Failed to meet primary endpoint in PIII trial (2). Company still planing to file in US in 06 (4). Submission of clinical and non-clinical sections of BLA in US, expecting to complete submission late 06 (7). US rolling submission complete Nov 06 (8). Assigned priority review in US (9). Positive recommendation from a US regulatory panel Mar 07 (10). FDA recommends approval but have issued an approvable letter requesting additional efficacy data May 07 (11). FDA has specified that Dendreon must provide either positive interim data or a final analysis of survival from an ongoing PIII IMPACT (D9902B) study to support BLA (12).
02. Apr 09: Because data from the IMPACT study met the criteria outlined in its Special Protocol Assessment (SPA) agreement with the FDA, the company intends to file an amendment to its existing BLA in Q4 2009 to gain a licence (15).
03. Apr 09: the Financial Times report that, according to some experts, the FDA may ask Dendreon for a confirmatory PIII study to support the results of the successful PIII IMPACT study announced earlier in the week. This is the first cancer vaccine submitted for FDA approval so it’s ‘unknown territory’. It is also speculated that the company will face challenges before its manufacturing process for the new vaccine is approved (16)
04. Sep 09: Company expects to file in US in mid-Nov 09 and hopes to get a regulatory decision mid-2010 [19].
05. Nov 09: The amended submission to the FDA has been completed. It includes data from the IMPACT trial, which was conducted under a Special Protocol Assessment agreement with the FDA [20].
06. Nov 09: FDA expected to make a decision on the application by 1 May 10 [21].
07. Apr 10: Approved in US for the treatment of asymptomatic or minimally symptomatic prostate cancer that has spread to other parts of the body and is resistant to standard hormone treatment [24].
08. Apr 10: The FDA has asked for a post marketing study to evaluate the risk of stroke in patients who receive sipuleucel-T [28].
09. May 10: Dendreon are planning to work on gaining approval in the EU [26].
10. Jan 11: Dendreon plans to file in EU late 2011 or early 2012, with approval expected in 2013. After meeting with the EMA, the company believes existing data is sufficient for the submission [33].
11. Jan 12: Filed in the EU [36].
12. Jun 13: EU positive opinion for sipuleucel-T (autologous peripheral blood mononuclear cells activated with PAP-GM-CSF; Provenge) for treatment of asymptomatic or minimally symptomatic metastatic (non-visceral) castrate resistant prostate cancer in male adults in whom chemotherapy is not yet clinically indicated. Provenge is the fourth advanced therapy to be approved in Europe [38].
13. Sep 13: Marketing authorisation granted in the EU [39].
14. Nov 14: Dendreon files for bankruptcy protection but continues to provide Provenge to patients in the US [42].
15. May 14: Dendreon is preparing for the first EU launches of sipuleucel-T, in the UK and Germany. It will initially be available through Centres of Excellence, beginning with fewer than 10 centres. Sipuleucel-T has been included in the new European Association of Urology(EAU) guidelines which recommend the product for patients with asymptomatic, minimally symptomatic mCRPC. Dendreon aims to have the it available in Q4 2014 [40].
16. Feb 15: Valeant buys Dendreon [45].
17. May 15: The European Commission withdraws the marketing authorisation for Provenge (sipuleucel-T) in the EU. The withdrawal was at the request of Dendreon UK Ltd which notified the EC of its decision to permanently discontinue marketing the product for commercial reasons [47].
18. Jan 17: The EU licence remains withdrawn [48].

Category

Vaccine. Autologous cellular immunotherapy consisting of peripheral blood mononuclear cells obtained by leukapheresis and activated in vitro with a recombinant fusion protein.
The age-standardised incidence of prostate cancer in the UK in 2008 was 97.9 per 100,000 population. [37]
Prostate cancer, castration-resistant - first-line
Intravenous

Further information

Yes

Trial or other data

01. Shown extended survival but did not reach significance with primary measure of efficacy (3). PII data showed that sipuleucel + bevacizumab extended PSADT of the 21 evaluable pts by >85% from 6.9 months before treatment to 12.7 months after treatment. Results also showed that 29% of pts had >200% increase in their PSADT after receiving combination therapy. Treatment led to PSA reductions in 43% of evaluable pts, including one with a PSA reduction of >50%, and 3 with PSA reductions of >25% (5). PIII trial (D9901) data demonstrated significant survival benefit (4.5 months longer than with placebo) and favourable safety profile of sipuleucel in men with advanced androgen-independent prostate cancer(6). Also associated with 41% overall reduction in risk of death, 34% of pts on sipuleucel alive 36 months after treatment vs. 11% of pts on placebo and had 31% delay in their time to disease progression vs. pts on placebo (6). Canadian Agency for drugs and technologies in health (CADTH) have issued a review (13).
02. Oct 08: Dendreon announced completion of the planned interim 2yr analysis of the P3, randomized, double-blind, placebo-controlled IMPACT (IMmunotherapy for Prostate AdenoCarcinoma Treatment, D9902B) trial in 512 men with metastatic androgen-independent prostate cancer. The independent data monitoring committee reported a 20% reduction in the risk of death in the sipuleucel-T arm vs. placebo (HR= 0.80; 95% CI 0.610-1.051). No safety concerns were raised and the panel recommended that the study continue to its final analysis, expected mid-2009. If the study demonstrates a 22% mortality, based on 304 events, it is likely to meet its primary endpoint of overall survival.
03. Apr 09: Company report that the pivotal PIII IMPACT study met its primary endpoint of improving overall survival vs. placebo. The magnitude of the survival difference in the ITT population met the pre-specified level of statistical significance. Details of study results are to be announced by the company 28/4/09 at the American Urological Association meeting. Because the data met the criteria outlined in its Special Protocol Assessment (SPA) agreement with the FDA, the company intends to file an amendment to its existing BLA in Q4 2009 to gain a licence. (15)
04. Apr 09: Data from the PROTECT (PROvenge Treatment and Early Cancer Treatment) (or P-11) PIII study in 176 patients with non-metastatic androgen-dependent prostate cancer with PSA recurrence following surgical removal of the prostate, suggests that sipuleucel-T induces a long-term memory immune response that is durable for at least a year and that can be maintained following boosting. Following 3 mo of hormone treatment, patients were given active treatment or placebo at weeks 0, 2 and 4. A treatment booster infusion was offered if PSA ≥3.0ng/mL which occurred at between 0.2 to 5.5 years (median 1.1 years). Patients continue to be followed for the clinical endpoints of time to distant failure, typically the appearance of a positive bone scan, and for overall survival. The study also found that CD54 upregulation on Antigen Presenting Cells (APCs), a measure of potency, is a correlate of immune activation (17)
05. Apr 09: Further data from the PIII IMPACT study were presented at the AUA Annual Meeting. The ITT analysis demonstrated that PROVENGE extended median survival by 4.1 months vs placebo (25.8 v 21.7 months), improved 3-year survival by 38% (31.7% vs 23.0%), and reduced the risk of death by 22.5% (HR=0.775). The study achieved a p-value of 0.032, exceeding the pre-specified level of statistical significance defined by the study´s design (p-value
06. Mar 10: Updated three-year survival results from the Impact study demonstrate a 40% increase in survival vs placebo. Patients treated with Provenge lived an average of 4.1 months longer than patients on placebo [22].
07. Analysts have projected a range of prices for Provenge from $40,000 to $75,000 per patient [23].
08. Launched in US where cost is $93,000 (£60,000) for the three doses given two weeks apart. Patients have immune system cells collected by leukapheresis about 3 days before each infusion. The cells are sent to the company lab where they are processed with a recombinant protein found in most prostate cancers. The company say this helps to activate the immune system and acts as a prostate cancer associated antigen and an immune cell activator. The activated cells are infused into the patient, with each infusion taking about 1 hour. the company say that as the therapy is individualised, it will only be bale to provide treatment to about 2000 patients during the next year, at centres that had participated in trials (25).
09. Jun 10: an integrated analysis of safety data from 4 PIII studies was presented at an American Urological Association meeting. The safety population included 904 patients randomized to receive 3 IV doses of sipuleucel-T or placebo at two-week intervals; 83.4% had an ECOG score of O, meaning that they were fully active and able to perform pre-disease activities without restrictions. Sipuleucel-T was reported to produce only minor or moderate AEs, including chills, fever and headache. These reactions occurred
10. Jul 10: Results of the IMPACT study published in the N Engl J Med (2010;363:411-22). 512 men with prostatic cancer that had progressed on combined androgen blockade, were randomised in a 2:1 ratio to treatment with three doses of sipuleucel-T or matching placebo over a 4-week period. At the data cutoff in Jan 2009, there had been 331 deaths (64.6%) over the median 34.1 months follow-up (61.6% in the sipuleucel-T group vs 70.8% in the placebo group, adjusted hazard ratio 0.78 [95% CI 0.61 to 0.98]. Median survival was 4.1 months longer in the sipuleucel-T group (25.8 vs. 21.7 months). Sipuleucel-T had no effect on disease progression: time to objective progression was 14.6 weeks vs. 14.4 weeks (HR 0.95; [0.77 to 1.17]; P=0.63). AEs were mostly mild to moderate, and those appearing more often in the sipuleucel-T group were consistent with cytokine activation (fever, chills). In an accompanying editorial notes that (1) the control group was not ideal (2) the lack of an effect on tumour progression raises concern that there could have been an unmeasured prognostic variable that was not balanced between the groups and (3) the cost of the treatment is $93,000 in the US, or $23,000 per month of survival advantage [28].
11. Sep 10: In the US, the Centers for Medicare and Medicaid Services will consider a nationwide policy for coverage of Provenge on the 17 Nov – this is an unusual step for a cancer treatment [29].
12. Sep 10: Dendreon has signed an agreement with GSK covering the commercial production and supply of the antigen used in the manufacture of Provenge. Dendreon has already placed an initial order for about $8.3 million of antigen, and delivery will start in Aug 2011. The agreement is to Dec. 2015, unless earlier terminated, and provides an option to Dendreon to request one or more two-year extensions to the term [30].
13. Nov 10: Provenge shows only "moderate" evidence for its use according to an internal analysis by the Centers for Medicare and Medicaid Services. An advisory panel will convene next week to review the analysis and discuss whether to support Medicare coverage. The CMS report stated that, based on data from three clinical trials, Provenge did offer a significant survival benefit. However, it didn´t show a significant difference in progression of the disease vs placebo and Quality of life wasn´t measured [31].
14. Nov 10: The Centers for Medicare and Medicaid Services panel approved use of Provenge by the organisation but only for licensed indications. The panel affirmed that Provenge offers a survival benefit and awarded the treatment 3.6 on a 5-point scale. But the panel gave low ratings to the drug´s ability to handle pain and other symptoms. The agency will consider the panel´s advice--and its own internal review, which found ‘moderate’ evidence for Provenge reimbursement--in making its final determination [32].
15. Jan 11: Dendreon considers that the European market for Provenge is about the size of the US market. In the US, Dendreon achieved revenues of $48 million for Provenge in 2010 and predicts 2011 sales of $350 million to $400 million. The company are planning to hire a contract manufacturer to supply the European market initially while it builds a plant in Germany [33].
16. Aug 11: According to an integrated safety analysis of four RCTs (total n=904), sipuleucel-T is mainly associated with mild to moderate, short-term, reversible adverse events, & is therefore suitable for administration in the outpatient setting. The most common Aes (>15%) were chills, fatigue, pyrexia, back pain, nausea, arthralgia & headache. Those reported at least twice as often in the sipuleucel-T group by 5% or more of pts were chills, pyrexia, headache, myalgia, influenza-like illness & hyperhidrosis. These events generally occurred within 1 day of infusion, were grade 1 or 2 in severity and resolved in 2 days or less. The incidence of serious AEs was 24.0% in sipuleucel-T cases & 25.1% in controls. Those reported in 2 or more pts on sipuleucel-T within 1 day of infusion included pyrexia, chills, atrial fibrillation, catheter sepsis, haematuria, hypertension, hypoxia, infusion related reaction & nausea. Grade 3 or greater AEs were reported within 1 day of infusion in 6.7% sipuleucel-T cases & 2.3% controls. The incidence rate of reported cerebrovascular events was 3.5% for sipuleucel-T cases & 2.6% in controls. Accounting for the time from randomisation, the number of events per 100 person-years of follow-up was 2.01 (95% CI 1.25–3.08) for sipuleucel-T cases vs. 1.50 (95% CI 0.65–2.96) for controls. A total of 19 secondary malignancies were identified, including 14 (2.3%) in the sipuleucel-T gp & 5 (1.7%) in the control gp. There was no evidence of a specific type of secondary malignancy in either gp [34].
17. Sep 11: Dendreon has cancelled its supply contract with GSK [35].
18. Oct 14: NICE issues preliminary draft guidance recommending againts use of Provenge. NICE states that Provenge was shown to prolong overall survival compared with placebo , but there were uncertainties in the evidence about how well sipuleucel-T works compared with some other existing treatments. Also it was not proven to delay progression of the disease unlike current treatments. The Committee noted that, for the subgroup of patients who had not had prior chemotherapy, the cost per QALY was at least £512,000 (company’s analyses) or at least £244,000 (Evidence Review Group’s analyses) for Provenge compared with Johnson & Johnson’s (discounted) abiraterone. When abiraterone was not included in the ERG’s analysis, the cost per QALY for the drug compared with best supportive care was - at £112,000 or £61,400 for a subgroup of patients with certain levels of prostate-specific antigen levels - still well above normal cost-effectiveness thresholds [41].
19. Jan 15: NICE draft guidance maintains that the available evidence shows that the price the NHS is being asked to pay for the drug is too high for the benefit it may provide to patients [43].
20. Jan 15. NICE issues final appraisal determination recommending against the use of sipuleucel-T for the first-line treatment of prostate cancer. [44]
21. Feb 15: NICE issues TA332 recommending against use of Provenge. NICE stated that Dendreon has been unable to show that sipuleucel-T works better than other treatments currently available. It was also not proven to delay the progression of the disease, unlike current treatments. The NHS cost is around £50,000 per patient, with a cost per QALY versus best supportive care (as calculated by Evidence Review Group) of more than £60,000 [46].

Evidence based evaluations