Avid Bioservices Inc (CDMO)

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A total take on Bavituximab side-effects

As a backgrounder for those that want to understand the side effect grading and cause coding here is the related COMMON TOXICITY CRITERIA MANUAL from the National Cancer Institute. I think that is an unsuspected source.

As the source for the safety information, and to use the SAME data as the past discussion here on the board here is the report of Dr. Gerber based on the PII COMBINED CONTROAL ARM Doce+Placebo + Doce+1mg Bavi versus Doce+Bavituximab 3mg.

Both links form the basis for what follows.

Introduction
Erroneously many people think that if a drug under investigation shows side effects it is by definition due to that drug. That is not how it is. The SOC, the drug to compare with, is also administered with the drug under investigation and therefore that arm also shows the related side effects. One must therefore look to some DIFFERENCE between control arm and the arm with the drug under investigation.

Another thing most people do not know is that the side-effect grading (say the severity of the side effect) is not saying ANYTHING about which of the drugs in a combination are the cause of the side-effect.

The only side-effects that one can be sure off are those seen by the SOC alone, in ALL other cases one must look at the side-effect CODING.

Code Descriptor Definition 
 5: Definite The adverse event is clearly related to the investigational 
 agent(s) 
  
 4: Probable The adverse event is likely related to the investigational agent(s) 
  
 3: Possible The adverse event may be related to the investigational agent(s) 
  
 2: Unlikely The adverse event is doubtfully related to the investigational agent(s) 
  
 1: Unrelated The adverse event is clearly not related to the investigational agent(s)

So combined with the grades below an impression can be formed.

 
 Grades (General Definitions) 
 0 = No adverse event or within normal limits 
 1 = Mild adverse event 
 2 = Moderate adverse event 
 3 = Severe and undesirable adverse event 
 4 = Life-threatening or disabling adverse event 
 5 = Death related to adverse event 
 

Due to the combined control arm, a consequence of the dose switching by our CRO, CSM in Fargo, we do not have isolated Docetaxel alone data. So I guess, unless I overlooked them, that is why there are no CAUSE CODES in the document either. What we do however have to go on is the multiple times repeated statement of either PPHM, the Ex-Thorpe Lab, the current combined Brekken+ex-Thorpe lab and individual investigators running ISPs, that : Bavituximab has no significant side effects of its own.

In my book that would mean that the CAUSE CODE would range between 1 and 3 included. I am sure that some of the minor side effects, and I am thinking specifically about the well know effects from SYSTEMIC IMMUNE ACTIVATION (Fever, Headache, etc) are emphasised by Bavituximab because it does exactly that: ACTIVATE THE IMMUNE SYSTEM.

I think it is therefor reasonable to say that such side effects are welcome as they are actually a form of measurable feed-back that confirms bavituximab is working and has the intended effect, namely the activation of the immune system. As you will see most side effects that might be increased by bavituximab fall in that category.

Grades in %  
 Arm                     Docetaxel+Placebo   Docetaxel  
                         +Bavi 1 mg	    +Bavi 3 mg 
  
 Preferred Term          G-all   G3-4        G-all        G3-4 
 -------------------------------------------------------------------- 
 Fatigue                 29.1	10.1	    35.0	 7.5 
 Nausea	                27.8	 0.0	    37.5	 0.0 
 Neutropenia	        24.1	20.3	    32.5	22.5 
 Cough	                21.5	 0.0	    25.0	 0.0 
 Periph. Edema	        20.3	 0.0	    15.0	 0.0 
 Diarrhea	        20.3	 0.0	    17.5	 2.5 
 Anemia	                17.7	 1.3	    25.0	12.5 
 Alopecia	        17.7	 0.0	    20.0	 0.0 
 Pyrexia                 16.5	 0.0	    20.0	 0.0 
 Asthenia	        16.5	 1.3	    30.0	 7.5 
 Leukopenia	        15.2	11.4	    10.0	 7.5 
 Anorexia	        15.2	 1.3	    27.5	 0.0 
 Constipation	        15.2	 0.0	    17.5	 2.5 
 Dyspnea                 13.9	 2.5	    12.5	 2.5 
 Vomiting	        11.4	 0.0	    15.0	 0.0 
 Arthralgia	        10.1	 0.0	    20.0	 2.5 
 Extremity Pain	        10.1	 0.0	    12.5	 0.0 
 Chest Pain	        10.1	 1.3	    20.0	 0.0 
 Headache	        10.1	 1.3	     7.5	 2.5 
 Back Pain	        10.1	 0.0	    20.0	 0.0 
 P.S. Neuropathy          8.9	 1.3	    10.0	 0.0 
 Product. Cough	         8.9	 0.0	    17.5	 0.0 
 Dizziness	         7.6	 1.3	    10.0	 0.0 
 Dyspnea, Exertional	 6.3	 0.0	    10.0	 0.0 
 Weight Decreased	 6.3	 0.0	    10.0	 0.0 
 Hypotension	         5.1	 1.3	    15.0	 0.0 
 Dehydration 	         5.1	 1.3	    10.0	 2.5 
 Stomatitis	         5.1	 0.0	    10.0	 2.5 
 Abdominal Pain	         3.8	 0.0	    12.5	 0.0 
 Mucosal Inflammation	 2.5	 0.0	    12.5	 0.0 
 

We will look at grade 3-4 only because that is what matters given the grades description above. As of those grades the side effects are qualified as : Severe and undesirable adverse event

Out of the 30 side effects listed the Bavituximab arm has a higher (less good) percentage then the control arm. Without the CODING we don't know if Bavituximab CAUSED them but just lets assume worst case that it did. In 2 cases it MILDED the side effects and in 4 cases it totally took them away. So let's look what side effects are assumed to be increased by Bavituximab in grade 3-4:

Neutropenia and Anemia
No problem, SUSEPTABILITY to infection doesn't do anything it is based on white blood-cell count. White blood cells are ALSO destroyed by Chemo. Yet Bavituximab diminishes infections, as another part of the document shows, hence it has the cure in case it would be the cause of these infection. Pallor and weariness due to deficiency of red cells or of haemoglobin in the blood, Anemia, is CERTAINLY not cause by Bavituximab but is know to be a side effect of all Chemo.

Diarrhea, Constipation, Headache, Arthralgia (Joint pain), Asthenia (Weakness), Dehydration
Unpleasant, treatable and not harmful when treated.

Stomatitis
Infected lips/Sour mouth. We could call this a possible side effect of bavituximab if Bavi would prove to be the cause of Neutropenia. Possibly the exteriorisation of the infection and the lower part of exposed PS of it on the vacular side might make it impossible for Bavi to deal with this infection or MILD it.

Conclusion

If we consider the PII data as valid although from where I stand the lack of a Bavituximab less arm to compare with make it less, then we can say that the statement: NO SIGNIFICANT side effects is correct.

Such statement is always weighted in relation to what other drugs do (if something breaks down your wall then something that causes a few bricks more to fall is sometimes insignificant as those bricks ALONE wouldn't have been a problem if that something else wouldn't have made the wall fall to begin with). And very possibly the few bricks extra wouldn't have fallen at all if the wall didn't came down to begin with.

And as we do not have the NCI CAUSE CODINGS we kind of even don't know if the above side-effects of which, in a worse case assumption, I assumed that all increases where cause by Bavi, are caused by Bavi.

What we know for sure is that there are certainly no NEW side effects that didn't exist AT ALL in Chemo alone that were added to the list.

Last but not least remember that you need to subtract the % of each other. Neutropenia 22.5% in Bavi arm vs 20% in Control arm means a potential increase cause by Bavi of 2.5% and not 22.5%.

Add to that:

In this trial, there was a lower incidence of vascular events in the docetaxel with bavituximab 3 mg/kg arm (n ¼ 1; DVT) than in the combined docetaxel with placebo/bavituximab 1 mg/kg arm (n ¼ 5; DVT, PE, CVA).

and I think we are good in the safety and side-effects area.

It would have been better if we compared with historical Docetaxel alone arms or possibly SUNRISE 178 look-in 1 side effect data but we don't have it.