Replies to post #900 on Biotech Values

[isolution]

Therapeutic window


Dew, I am nto comparing squalamine to anything when I say narrow (but sufficient) therapeutic window, I simply say that drug potency level is close to maximum tolerated dose.

An example of wide window could be Paracetamol, a moderate could be Fentanyl (precise dosage is required by anesthesiologist)

I have no further comment on QT, I also know it is classically required by FDA and I have also read in the abstract:
"It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent"

Remember that people suffering for ARMD are old (>75)...

That could be why Driscoll keep talking about local means to deliver their drug...;-)

[DewDiligence]

I sold OXGN this morning because the article in Clinical Cancer Research (see abstract below) looks bad for OXGN’s CA4P. Moreover, my confidence in OXGN’s management has been shaken.

I now think this study on CA4P’s cardiac toxicity may be the reason OXGN recently grabbed the opportunity to raise capital from their shelf registration (even though there was no immediate need for cash) and the reason OXGN was one of the very few biotech companies which did not attend the JPMorgan conference last week.

QTc-prolongation has been the death knell of other drug candidates I have followed; when independent clinicians recommend that future CA4P trials restrict patient enrollment on account of cardiac toxicity, it is not something to be taken lightly. Even if CA4P is ultimately approved by the FDA, one has to question the impact of labeling restrictions on the drug’s commercial success.

The good news in all this is that I think GENR’s Squalamine is now in better shape than ever.

--
[I think this abstract speaks for itself. Emphasis added by Dew]

http://clincancerres.aacrjournals.org/cgi/content/abstract/10/1/96?etoc

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Cardiovascular Safety Profile of Combretastatin A4 Phosphate in a Single-Dose Phase I Study in Patients with Advanced Cancer

Matthew M. Cooney12, Tomas Radivoyevitch3, Afshin Dowlati12, Beth Overmoyer12, Nathan Levitan12, Kelly Robertson2, Sandra L. Levine4, Kathleen DeCaro4, Carol Buchter5, Anne Taylor6, Bruce S. Stambler7 and Scot C. Remick12

1Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University (CWRU), School of Medicine, Cleveland, Ohio;2 Developmental Therapeutics Program, Comprehensive Cancer Center at University Hospitals of Cleveland and CWRU, Cleveland, Ohio;3 Department of Epidemiology and Biostatistics, CWRU, School of Medicine, Cleveland, Ohio;4 General Clinical Research Center, University Hospitals of Cleveland and CWRU School of Medicine, Cleveland, Ohio;5 Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington;6 Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota; and7 Division of Cardiology, Department of Medicine, University Hospitals of Cleveland, Cleveland Veterans Affairs Medical Center, CWRU, Cleveland, Ohio

Purpose: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors.

Experimental Design: CA4P was administered in a dose-escalating fashion starting at 18 mg/m2 i.v. every 21 days, and the maximal dosage was 90 mg/m2. Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett’s formula QTc = QT/(R-R interval)1/2, and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and Cmax versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed.

Results: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion.

Conclusions: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.
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