Replies to post #51720 on Biotech Values

[masterlongevity]

"Plus, I think Gotleib was fear mongering and overstating the value of lucentis over avastin (does he consult for dna?).

I don't know what design flaws he was referencing but I'm looking forward to the outcome to see whether there is any relevant clinical difference avastin vs lucentis (I predict not). "


There have been some evidence show that lucentis may be mroe effective. Two DME studies published by DRCRN ahve shown Avastin not to be very effective and Lucnetis to be effective.

These are clearly phase II non comparative trials, but you can't help but compare..


Lucantis and Avastin are clearly very different products, with a much diffent molecuilar design. PFroma preclinical perspective there is evey reasont o beleive that Lucnetis will be superior and less toxic; However, as we know, preclinical results do not always translate. DNA clearly made the right decision in developing Lucentis and IMHO deserve to reap the rewards for their innovative work. Lucentis is still very cost effective in QALY terms, (more so than macugen or Visudyne) and well with ithe threshhold of 50,000 per QALY, but it is impossible to compete with aliquotted avastin in term of cost-effectiveness.


IF the NIH trial ever starts and finishes ( was orignally supposed to start in Q3 06), i don't think the results will eb conclusive. DNA has argued that the trial is not large enough to detect statistical differences in safety. Not sure what will happen here. Lucentis is currently the market share leader, but how that will change is anyone's guess

see DME abstracts below...

: Ophthalmology. 2007 Aug 13; [Epub ahead of print] Links
A Phase II Randomized Clinical Trial of Intravitreal Bevacizumab for Diabetic Macular Edema.Diabetic Retinopathy Clinical Research Network.
OBJECTIVE: To provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME). DESIGN: Randomized phase II clinical trial. PARTICIPANTS: One hundred twenty-one eyes of 121 subjects (109 eligible for analysis) with DME and Snellen acuity equivalent ranging from 20/32 to 20/320. INTERVENTIONS: Random assignment to 1 of 5 groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22), or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n = 22). MAIN OUTCOME MEASURES: Central subfield thickness (CST) on optical coherence tomography and best-corrected visual acuity (VA) were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks. RESULTS: At baseline, median CST was 411 mum and median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction > 11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and 5 of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and 9 of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. Endophthalmitis developed in 1 eye. The following events occurred during the first 24 weeks in subjects treated with bevacizumab without attributing cause to the drug: myocardial infarction (n = 2), congestive heart failure (n = 1), elevated blood pressure (n = 3), and worsened renal function (n = 3). CONCLUSION: These results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial. A phase III trial would be needed for that purpose.


Am J Ophthalmol. 2006 Dec;142(6):961-9. Epub 2006 Aug 2. Links
Vascular endothelial growth factor is a critical stimulus for diabetic macular edema.Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, Campochiaro PA.
The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.

PURPOSE: The role of vascular endothelial growth factor (VEGF) in diabetic macular edema (DME) was tested with ranibizumab, a specific antagonist of VEGF. DESIGN: A nonrandomized clinical trial. METHODS: Ten patients with chronic DME received intraocular injections of 0.5 mg of ranibizumab at baseline and at one, two, four, and six months. The primary outcome was change in foveal thickness between baseline and seven months, and the secondary outcome measures were changes from baseline in visual acuity and macular volume. RESULTS: Mean values at baseline were 503 microm for foveal thickness, 9.22 mm3 for macular volume, and 28.1 letters (20/80) read on an Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart. At seven months (one month after the fifth injection), the mean foveal thickness was 257 microm, which was a reduction of 246 microm (85% of the excess foveal thickness present at baseline; P = .005 by Wilcoxon signed-rank test for likelihood that this change is due to ranibizumab rather than chance). The macular volume was 7.47 mm3, which was a reduction of 1.75 mm3 (77% of the excess macular volume at baseline; P = .009). Mean visual acuity was 40.4 letters (20/40), which was an improvement of 12.3 letters (P = .005). The injections were well-tolerated with no ocular or systemic adverse events. CONCLUSION: Intraocular injections of ranibizumab significantly reduced foveal thickness and improved visual acuity in 10 patients with DME, which demonstrated that VEGF is an important therapeutic target for DME. A randomized, controlled, double-masked trial is needed to test whether intraocular injections of ranibizumab provide long-term benefit to patients with DME.

[Biowatch]

>Companies could theoretically get sued or have liability esp if they're actively promoting off label. But this is a rare case where the drug company has a large disincentive to encourage an off label use.<

Yes, the company has ZERO financial incentive to promote Avastin for off-label use in AMD. Correct me if I am wrong, but doctors rarely get sued for off label use of a drug, as an individual doctor doesn't have the deep pockets of a company.

A particular doctor might be subject to liability for eye infections if they didn't store the Avastin properly, as one vial is suitable for use in multiple patients for a two week period after it is used initially. One infection that might occur even if a vial was only used once might be blamed on improper storage or mishandling.

Then again, given that this was an eye disease that led to legal blindness a few years ago, it is nice to have several treatments available to slow or even reverse the problem.

The claim that:
Since a single cancer infusion of Avastin contains a large volume of the drug, breaking that same dose down into the small aliquots needed for the eye injections is literally pennies on the dollar, making the government's study of it -- when it was clearly not designed for eye treatments -- a matter of cost containment. Surely if Avastin ends up harming those eyes -- a plausible consequence of this off-label, if not illegally "compounded" use -- it won't be Uncle Sam on the hook with product liability lawyers, but Genentech.

raises the question of why Avastin is so much cheaper to produce on the scale needed to treat AMD, and why it couldn't be packaged in smaller single use vials for AMD thus eliminating the "compounding" issues.

Yes, Avastin is a smaller protein, thus potentially slightly more capable of crossing the retinal-blood barrier, but the chance of it getting into the bloodstream in sufficient quantity to do harm elsewhere is almost nil, in my humble opinion.

[DewDiligence]

DNA has finally taken preemptive action against
off-label Avastin use for AMD, which has garnered
a ~50% share of the US AMD market by prescription
volume, but a tiny share of the market by dollar sales
due to the minuscule price per AMD dose. Will DNA’s
crude approach really work… or will it end up costing
DNA even more in public goodwill?

http://online.wsj.com/article/SB119213222981256309.html

>>
Genentech to Curb Avastin's Use
In Treating Eye Degeneration

By JACOB GOLDSTEIN
October 11, 2007 4:25 p.m.

Genentech Inc. said it will no longer make its cancer drug Avastin available to so-called compounding pharmacies in a bid to curb its widespread use in treating a degenerative eye disease -- which has cut into sales of the company's high-priced eye drug.

Although regulators haven't authorized Avastin's use against eye disease, it is chemically very similar to Genentech's Lucentis, which was approved last year to treat wet macular degeneration, a condition caused by an overgrowth of vessels in the retina that leak and damage vision. Compounding pharmacies re-package vials of Avastin into syringes that contain a once-monthly dose of the drug for use in the eye and cost about $40. A once-monthly dose of Lucentis costs about $2,000.

In the first six months of this year, U.S. sales of Avastin [for all indications] were $1.1 billion, and Lucentis sales were $420 million.

In a letter explaining the decision, Genentech pointed out that Lucentis was developed expressly for use in the eyes, and said the Food and Drug Administration has expressed safety concerns about the repackaging of Avastin for that use.

Avastin, which is sold through wholesalers, will continue to be available to hospital pharmacies and directly to doctors. But it won't be available to compounding pharmacies as of Nov. 30.

Anne Fung, a San Francisco ophthalmologist, said she worries that some doctors may try to do the repackaging work themselves without the proper safety equipment. "This move is taking it out of a regulated environment into an unregulated environment," she said. That could increase the risk of contamination and serious eye infections.

Dr. Fung, who said Avastin and Lucentis are split roughly 50-50 among macular-degeneration patients, said she would likely try to get Avastin from a hospital pharmacy for her patients. That could increase the cost of treating her patients.

Genentech spokeswoman Dawn Kalmar said most macular-degeneration patients are covered by Medicare, and said the company helps connect patients who can't cover their copayment -- which can be $400 a month for Lucentis -- with charities that help with payment.
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