The Pixantrone “Ghost Post”…Plus Today’s Safety Data (Our Take)
May 19, 2009 at 10:35 pm EST | Tags: ASCO, Clinical Trials, Conferences, Filings & Approvals, Gossip & Rumors
Cell Therapeutics made some news today at BIO. The company followed up with more safety data from its EXTEND trial, stating that at a cumulative total doxorubicin equivalent exposure of > 600mg/m2, the frequency of CHF among Pixantrone (Pix) recipients was 7% vs. 48% reported for doxorubicin (Dox).
To translate, the statement essentially says that Pix has a better cardiac safety profile (i.e. low incidence of CHF) than Dox does in patients who have already been treated with Dox.
Patients with less than 300 prior dox have their CHF incidence drop from 5.6% (if on Dox again) to 2.9% (if they go on Pix). If patients have had >600 prior dox, the CHF incidence for going on Dox again is 48%. If they take Pix, their incidence will be drastically lower — 4%!
Here’s the data:
The numbers look good on the surface, but we have two issues:
It’s against historical data (it’s OK, but we’d rather see a comparator arm)
The sample sizes are drastically different (620 for Dox and 70 for Pix). This allows for an uneven comparison (again, apples vs. oranges).
In our opinion, this still doesn’t answer the question of cardiac safety in heavily pretreated patients, especially since there were no CRs in patients with >350 mg/m2 of prior anthra exposure.
Misleading to us, but I guess we can wait for ASCO. In the end, it’s about PFS, which looks good to us.
We’ve also received dozens of emails regarding our Pixantrone “Ghost Post.” CTIC has advised us it would prefer we not post the slides for the upcoming presentation at ASCO, yet. So, we’ve decided to post our notes, in true analyst form, from the slides. These notes are a follow up to our Pixantrone: Hype or Truth article, which also received rave reviews.
So, by popular demand, here’s our updated Pixantrone notes (we are leaving out redundancies or info we’ve already covered):
Pixantrone – Novel Aza-anthracenedione
designed to reduce harmful oxygen radical species
no extravasation concerns thus far in clinical trials
Historic: low incidence (<2%) of cardiac side effects despite heavy prior anthracycline (anthra) Rx
Phase 3 Trial Design
comparator drugs: oxal, VP-16, Rituxan, gemcitabine, mito, fludar
Completed protocol directed treatment (6 cycles) — Pix 20 (27%), Control 16 (23%)
Dc’ed treatment — 49 (70%), 53 (76%)
Prior stem cell transplant — 11 (16%), 10 (14%)
Number of prior chemotherapy regimens: median (range) — 3 (2-9), 3 (2-8)
Exposure to Study Drug Treatment (safety population)
Pix arm N=68, Control arm N=67
1-3 cycles — 32 (47%), 40(60%)
4-6 cycles — 36 (53%), 27(40%)
Intent to Treat: Primary endpoint achieved
results released
Intent to Treat: Increased progression free survival > 80%
Change in median cardiac function
Pix (Baseline Echo/Cycle 2/Cycle 4/End of Treatment): 61 (N=40), 64 (N=23), 61 (N=20), 60 (N=22)
Control (same time points): 62 (N=37), 61 (N=32), 61 (N=20), 61 (N=20)
Pix (Baseline MUGA/End treatment/6-month): 58 (N=64), 59 (N=28), 56 (N=10)
Control (same time points): 59 (N=64), 58 (N=23), 58 (N=6)
1 case of CHF due to Pix reported
Responses in Heavily Pretreated Patients (>350mg/m2 prior anthras)
PR w/ 371 mg/m2 prior Dox exposure (PDE)
CRu w/ 384 PDE
CRu w/ 386 PDE
2 PRs w/ 413 and 452 PDE
CRu w/ 439 PDE
2 CRu’s 588 and 778 PDE (dropped 2nd to AEs)
No CRs in heavily pre-treated
Commercial Assumptions
Price at $24/mg to $1,200 vial
Assume approval in US Dec ‘09 and EU Sep ‘10
15/20/25% peak penetration for 1st/2nd/3rd line aggressive NHL
Opaxio Update
potential CHMP opinion in late July
interim PFS results late Q4 for GOG212
good cure rates in espohageal/gastric
CRs in GBM
And that’s it…stay tuned!
Image from clker
No positions or disclosures in CTIC, partners or competitors
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very good insight; and thanks
Ah the Ghost Post returns!!! Great notes!!!
i noticed that in the first paragraph it was fixed from 4% to 7%, however in the last it still states 4%
“Patients with less than 300 prior dox have their CHF incidence drop from 5.6% (if on Dox again) to 2.9% (if they go on Pix). If patients have had >600 prior dox, the CHF incidence for going on Dox again is 48%. If they take Pix, their incidence will be drastically lower — 4%!”
Yeah I saw that. I couldn’t find out where the 7% came from. 1/25 = 4%, to me at least. Perhaps it was past my bedtime.
There were 2 CR’s in the heavily pretreated group plus 6CRu and 4PR’s
We read your notes and have received a few calls asking for a better explanation of the information we released at the BIO conference this week in Atlanta regarding a historical comparison of cardiac congestive events on the PIX301 study compared to the expected dose dependant incidence with standard doxorubicin dosing.
It is important to note that the comparator arm did not contain treatment with a class of drugs known for cardiac side effects (with the exception of 4/68 patients who received mitoxantrone). Thus the only way to put the safety data with pixantrone in perspective is to provide, solely for illustrative purposes, the numerical events of CHF (irrespective of relationship to drug) by total doxorubicin equivalent exposure, and see how it would stack up based on literature review.
Here’s some background relevant literature:
JCO 1995, 13:2530-2539, Sonnenveld et al. Study of CNOP Vs CHOP in 148 elderly patients >=60 years of age with aggressive NHL. Only 31% (23 patients) of CNOP and 45% (33 patients) of CHOP patients received all 6 cycles of therapy (for CHOP that would be 300mg/m2 of doxorubicin). LVEF declines of >=15% occurred in 10/22 CHOP patients treated with 300mg/m2 who had LVEF’s measured, and who got 6 cycles (300mg/m2 of dox). 4/33 patients who received 6 cycles of CHOP developed CHF (12%). On intent to treat 4/74 = 5.5%. Thus at standard CHOP exposure of 300mg/m2 – 5.5% develop CHF on an intent to treat basis.
NEJM 1998, 319:745-752 Speyer et al. Study of FDC (flurouracil, doxorubicin, cyclophosphamide) with or without ICRF-187 (an investigational cardio-protectant agent) in 92 women with metastatic breast cancer. LVEF declines of 7% from baseline were observed in the 250mg/m2 to 399mg/m2 group, with 16% declines in the group receiving between 400mg/m2 and 499mg/m2. CHF developed in 11/46 patients (24%). Their median doxorubicin exposure was 397mg/m2.
Cancer 2003, 97:2869-2879, Swain et al. CHF in patients with doxorubicin treatment- retrospective meta-analysis of 3 trials. In this publication women with metastatic breast cancer treated with FDC in 3 separate trials were reviewed and combined to examine the dose-dependent increase in CHF at various levels of total doxorubicin exposure. Overall 178,500mg/m2 was administered to 630 patients (283mg/m2 dox exposure), 32/630 patients developed CHF (5.1%). These data are consistent with the other studies reporting approximately 5% rates of CHF in the standard CHOP dose of 300mg/m2. As noted in Swain, the majority of CHF events occurred at or above a total of 500mg/m2. Using a Kaplan Maier estimation, Swain developed a table estimating 5% incidence at 400mg/m2, 16% at 500mg/m2, 26% at 550mg/m2 and 48% at 700mg/m2.
Importantly in each of these reviews (and well documented in all the literature as well as the doxorubicin drug label), cardiac toxicity is a linear cumulative life-time dose dependant side effect of this class of agents.
Since PIX301 was not a randomized trial against standard doxorubicin, and given that patients had a median of ~300mg/m2 of prior doxorubicin exposure before starting on pixantrone, these patients, based on the literature cited, would be expected to have a significant frequency of CHF events given the median cumulative doxorubicin equivalent exposure of 535mg/m2 (>26% CHF and >50% declines in LVEF >20% from baseline according to historical literature) if this were standard doxorubicin.
The table presented at BIO (and noted in our press release) was an illustrative representation of the number of reported CHF events at various total cumulative doxorubicin equivalent exposure for standard 300mg/m2 levels upward to in excess of 650mg/m2. We do not present this as definitive clinical evidence of lower cardio toxicity, and we agree with your notes that a randomized comparison to doxorubicin would be the gold standard for demonstrating a lower incidence of cardiac damage. Such a trial has completed its 2 year follow up period (CHOP-R Vs CPOP-R, n=124 patients). This study extensively measured (every 2 cycles x 6 cycles, then every 3 months for 2 years) cardiac function which is evaluated by an independent cardiologist blinded to treatment assignment. These data will be included in the NDA safety update, and we hope to have it presented at this year’s ASH meetings.
We hope this information, and the new efficacy and safety information being presented at ASCO will further clarify the unique risk-benefit profile pixantrone has over standard anthracyclines and the impressive efficacy in patients with relapsed/refractory aggressive NHL.
Cell Therapeutics
Pixantrone – real progress? However, research never stops and – with continuing support from the Foundation – a new molecule, similar to mitoxantrone, has been developed. The new drug, called pixantrone, has the same immunosuppressive properties as mitoxantrone but with a much lower level of cardiac toxicity. Immunosuppressors are in fact anticarcinogenic substances whose toxic properties are used to control the blood cells responsible for immune responses in order to “reduce” immunity in certain autoimmune disorders, including MS.
Thus the Charcot Foundation Charcot decided to conduct a phase I/II clinical study on 20 patients. Named PIXAMS, this project will be implemented – starting early in 2008 – in four specialised centres: The National Centre for MS (in Melsbroek), the Neurology Department of the Catholic University of Louvain (UCL) and the Neurology Department of the University of Rennes.
What hope for the future? The results of the PIXAMS project – which should enable researchers to confirm the lower cardiac toxicity and equal (or even higher) therapeutic efficacy of pixantrone in comparison with mitoxantrone – are eagerly awaited by the scientific community and patients alike. If the results are positive, pixantrone could be prescribed to a larger proportion of MS patients, repeatedly, if necessary. It would then be possible to delay the onset of handicaps by five to ten years in younger patients and to block the progression of the disease for longer periods in patients who already have some degree of disability. If the efficacy and good tolerance of pixantrone are confirmed, this will constitute a major step forward in the treatment of MS and pixantrone will eventually replace mitoxantrone.
It is hoped that the PIXAMS study and the use of pixantrone will make it possible to improve the quality of life of MS patients very significantly