Comments (continue).
BIOD (short) 04.21.12 updated to AVOID or SELL
September 22th, 2010 by BiotechInvest
Well, as I promised before I will write comments about all companies that have binary events in October. Since first post was extremely positive (ALXA), next will be negative. So, it will be about Biodel.
Usually I try to analyze company science basis before investment. Here (with Biodel) is nothing to analyze. Biodel’s VIAject (now Linjeta) is just a simple mixture of conventional insulin, EDTA and citric acid.
Now Biodel called VIAject enough modestly "more-rapid-acting injectable regular human insulin". Modestly because couple years ago they called it "ultra rapid-acting insulin".
"More-rapid" than what?
Insulin lispro (marketed by Eli Lilly as "Humalog") is a fast acting insulin analogue. The subcutaneous doses of Humalog ranging from 0.1 to 0.4 U/kg, peak serum levels were seen 30 to 90 minutes after dosing. VIAject T max is around 30-40 minutes (company website) i.e. VIAject is really 20 minutes faster than Humalog. Humalog was engineered through recombinant DNA technology, the penultimate lysine and proline residues on the C-terminal end of the B-chain are reversed. This modification does not alter receptor binding, but blocks the formation of insulin dimers and hexamers. This allowed larger amounts of active monomeric insulin to be immediately available for postprandial injections.
Biodel scientists just added citric acid to destroy hexamers first and EDTA to remove zinc (that actually stabilizes insulin hexamer). From the first point of view VIAject is genius invention ("Everything of genius is simple.").
Question is why big pharma scientists invented Humalog when they wanted to have a fast acting insulin. May be scientists in big pharma are so stupid that even never tried to dissolve insulin at low pH and add EDTA to remove zinc. But sure that they knew that "insulin is produced and stored in the body as a hexamer (a unit of six insulin molecules), while the active form is the monomer. The hexamer is an inactive form with long-term stability, which serves as a way to keep the highly reactive insulin protected, yet readily available. The hexamer is far more stable than the monomer, which is desirable for practical reasons; however the monomer is a much faster reacting drug because diffusion rate is inversely related to particle size. A fast reacting drug means that insulin injections do not have to precede mealtimes by hours, which in turn gives diabetics more flexibility in their daily schedule. Monomeric insulin can aggregate and form fibrillar interdigitated beta-sheets. This can cause injection amyloidosis, and prevents the storage of monomeric insulin for long periods." In simple word monomeric insulin is very unstable. http://en.wikipedia.org/wiki/Insulin_zinc_susp_purified_pork
However, first generation of VIAject was very painful because injected solution was very acid (pH 4). Now adjusted to pH 7 it seems like OK for patients.
So, VIAject was provided as an aqueous solution which is stored frozen, or in a two part kit consisting of dry powder insulin and diluent, at least one of which contains citric acid and EDTA. The pH of both reconstituted mixture and frozen solution was approximately pH 4. Everything should be mixed shortly before or at the time of administration. Well, conversion of hexamer to monomeric insulin happens right before injection and there is no problem with stability. However, at time of human trial it was suddenly discovered that acid solution (pH 4) is very painful if injected subcutaneously in human.
So, Biodel proposed to use U-100 pH-neutral commercial formulation of VIAject® is associated with less injection site discomfort than the U-25 pH 4. In a regulatory filing, Biodel said it would launch VIAject only after a disposable pen version of the human insulin product is approved and plans to submit the pen to the FDA for review in early 2011.
Well, it seemed like that the problem was completely resolved. Of course, I understand that pH 4 can be easy adjusted to pH 7 with sodium hydroxide. But what the form of insulin will be in this adjusted solution?
Again, at pH 4 (citric acid) and EDTA insulin is monomeric, but you must immediately inject it because of stability problem. If you adjust this solution to pH 7 (to reduce injection site discomfort i.e. pain) insulin must aggregate in hexamer or stay monomeric because EDTA cheated all zinc. Here is the problem. What will be inside this proposed "disposable pen version" of VIAject?
This question is like logistic trap. If the answer is: solution of monomeric insulin. Everybody knows that solution of monomeric insulin is very unstable. If the answer is: solution of hexamer insulin i.e. after adjusting pH to 7 insulin converted back to hexamer form. This is the stable form but it will be just conventional insulin.
The main idea of VIAject invention was to keep separately conventional hexamer insulin (dry powder) and diluent solution with citric acid and EDTA. Patients should mix it together before injection and use it immediately. I don't see here any problem with stability of insulin. May be this is not very comfortable as insulin pens but it's OK because it's "ultra rapid-acting insulin".
Now Biodel is seeking approval to market VIAject® in the United States as a 100 IU/cc, pH7 (neutral) injectable liquid, in 10 ml vials and 3 ml pen cartridges.
So, FDA may ask questions what is inside of these pens. Monomeric insulin solution? It's very unstable. Hexamer insulin solution? What is the advantage?
"India clinical trial" problem…
"Biodel believes that including the data from India is not valid for determining non-inferiority. If HbA1c data from India are included in the analysis, the adjusted treatment group difference increases slightly to -0.3 which is generally considered to be not clinically meaningful.
Biodel Submits VIAject® New Drug Application to FDA for Treatment of Diabetes based on more than 884 patients who participated in Phase 1, 2 and 3 clinical trials of the drug in the United States, Germany and India. I'm sure that FDA officers will never separate United States trial data from India data. In this case conclusion is clear: VIAject is working worse than Humalog.
Conclusion:
It's very high probability that Biodel will get FDA "complete response letter" with recommendations to perform new efficacy trials and questions about formulation stability.
Disclosure: no BIOD positions now, may be short positions will be opened close to PDUFA.
BIOD (short) continue
October 3th, 2010 by BiotechInvest
“The Biodel data does suggest that the India subgroup is different, and perhaps analyzing the data without this subgroup is appropriate, Specifically, HbA1C variability is more than double (0.99 versus 0.4 and 0.38) and the mean HbA1c measurements are larger by about 0.2-0.3 in the India subgroup. The increased variability and means in the India group will result in larger confidence interval which could account for the switch from concluding non-inferiority to inferior.”
Management at Biodel has offered a few explanations including mishandling of the blood samples used in the analysis and a poorly controlled patient population in terms of starting HbA1C concentration.
Recently I read very interesting discussion about Biodel India anomalous HbA1 results.
Author stated “that Biodel should stick to the heat exposure explanation and not suggest other explanations that call efficacy into doubt.” http://seekingalpha.com/article/227766-biodel-upside-from-potential-linjeta-approval
I understand that main aim of this discussion is the attempt to convince the BIOD investors (long and potential) that FDA will buy any explanation of India samples anomaly and will exclude them from analysis. After this exclusion trial data will demonstrate non-inferiority (the goal of the study) over Humulin® in both type I and type 2 diabetics and VIAject will be approved.
I am not sure that FDA commissioners will do it.
All FDA commissioners are have a Doctoral level degree (M.D., D.O., D.V.M., D.D.S., D.P.M., Pharm.D., or Ph.D.). So, they will be very critical to any explanations.
OK. What kind of questions I will ask if I am FDA commissioner?
First one: Is it really that short time (day or less) blood samples incubation at India room temperature (30°C) will sharply increase HbA1c level?
All published scientific papers suggest that better keep samples at 4°C before analysis. But may be India is so poor country that lab technicians don’t have ice to keep blood samples in transit to a central laboratory. So, how many hours this transit took? To compromise samples it must took at least 24 hours at 30°C.
The measurements of HbA1 were conducting during last 2 decades, so temperature effect on sample instability was intensively studied. Early work abstract said: “At 30 degrees C, whole blood or erythrocytes from some donors are stable for one day, but after two days and seven days, results are frequently higher.” (PDF file of paper is here).
So, you can keep blood samples at 30°C but no more that 24 hours.
Well, FDA commissioner will ask: should I believe that blood samples were transported between labs more that 24 hours? Answer: I can’t buy it.
Another explanation of anomalous results “poorly controlled patient population in terms of starting HbA1C concentration. Biodel stated that the Indian population had HbA1C levels in the “in the nines” whereas the other patient populations were “in the sevens”. He was referring to the percent hemoglobin glycation.”
This explanation is more scientific. At 9 % of HbA1c estimated average glucose level is very high i.e. 212 (170–249) mg/dL. At 7 % of HbA1c glucose level is 154 (123–185) mg/dL. HbA1c ≥ 6.5% is level for the diagnosis of diabetes (glucose is > 140 mg/dL).
A high HbA1c represents poor glucose control. So, Europe groups were more healthy in term of diabetes (had more stable glycemic control before trial). And it’s really difficultly to decrease very high HbA1c level
Sure those diabetes patients in Europe before trial were continuously monitored with HbA1c values and these data were used in assessing glycemic control and their insulin regimens changed more often. May be in India diabetics were not aware of the hemoglobin A1c levels and relied on blood or urine glucose measurements to monitor treatment. Finally India patients had more advanced diabetes stages when it’s difficultly to control blood glucose level.
In principle FDA commissioners can buy this explanation.
Will it help Biodel to get an approval without additional efficacy trial? I don’t think so.
04.21.12 by BiotechInvest
just want to update BIOD, because again BIOD wants to fool biotech investors
new team - old bluff...
actually old one invented by Sol that the monomeric insulin is fast acting and stable together. Well, they said that acid solution (pH 5) is painful (indeed). So we will adjust pH to 7 and inject patients. But at pH 7 monomeric insulin is unstable and it will form a terrible mess like the fibrillar and filamentous insulin amyloids and etc.
BTW where is Sol? Bought a bungalow on Seychell's when sold BIOD at $15?
GL to new BIOD believers. Your money are needed here:
Dr. Errol B. De Souza Ph.D., 59 Chief Exec. Officer, Pres and Director 634.00K;
Mr. Erik Steiner (Sol's sun still wants a bungalow) , 46 Co-Founder and VP of Operations 265.00K;
Mr. Gerard J. Michel MS, MBA, 49 Chief Financial Officer, Chief Accounting Officer, VP of Corp. Devel. and Treasurer 413.00K ;
Dr. Alan Krasner M.D., 49 Chief Medical Officer 401.00K
Altogether around $2M + bonuses when BIOD Market Cap: 22.45M