Replies to post #43561 on Biotech Values

[DewDiligence]

Re: ISIS ALT elevations

>I am surprised you didn't comment about this. I don't believe the drug could get approved or a partnership deal signed with the alt elevations observed.<

The only reason I didn’t comment on the ALT elevations is that it’s old news. See, for instance, message #37415 from November (#msg-14794270):

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In Isis' press release, it stated the drug demonstrated a strong safety profile and was well tolerated. But one area investors should keep a close eye on is liver toxicity. The threshold of liver function that is usually cited during the testing of drugs is three times the upper limit of normal (ULN) of the enzyme ALT. Drug companies don't want to see their test subjects go above three times ULN. Of the 40 patients who received the drug, two experienced greater than three times ULN, while eight fell into the two-to-three-times ULN category.

Isis CEO Dr. Stanley Crooke stresses that readings were taken on a weekly basis (vs. monthly in other studies) and that it's more important to look at the figures compared with the numbers of readings (roughly 1,100) vs. the number of patients. He adds, "If you take the average person off the street and run liver enzymes on them weekly, over a period of three months, you will find multiple times when their liver enzymes might be up."

The Street seems to buy into this line of reasoning. However, not everyone is taking the numbers at face value. One hedge fund manager who is short Isis and requested anonymity counters the CEO's argument, stating, "The incidence of ULN readings increases significantly at higher doses, which is evidence that suggests a drug effect."

He says it's important to note that liver toxicity is a cumulative effect, and that is why he's particularly interested in the two-to-three-times ULN numbers, considering that the trials were short -- five weeks and three months of dosing.

Comparatively, phase III trials for cholesterol fighters such as Bristol-Myers Squibb's (BMY) Pravachol, Merck's (MRK) Zocor and Pfizer's (PFE) Lipitor involved thousands of patients over a longer time period. Since high cholesterol is a chronic condition, the money manager is concerned that with readings already in the two-to-three-times ULN category after such a short time, more patients may cross the threshold with continuous use of ISIS 301012.
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I don’t have a strong opinion about whether this is enough to stop a partnership deal from being consummated. What we do know is that ISIS is anxious to get one signed before starting phase-3.

The CC Tuesday morning may provide a better feel for how this will shake out.

[osprey]

ISIS drugs have hepatic toxicity as a general dose limiting property. It's been seen many times with AS agents not targeting cholesterol lowering pathways. The ALT elevations at 400 mg most likely have nothing to do with lowering lipid levels since high dose statins don't show it at anywhere this level.

The ALT elevations occur at 10 weeks. Cholesterol lowering drugs are to be taken for years and decades. They need year timescales data to critically evaluate a drug for chronic administration and that data would be interesting. The effects on LDL are impressive but the chronic toxicity might yet sink this drug. At any rate, as an injectable, the market will always be limited compared to the oral drugs.

ISIS is the surrealist of the biotech world. They have been making surreal claims for 15 years.

Toxicol Appl Pharmacol. 2004 Nov 15;201(1):66-83. Links
Toxicology of antisense therapeutics.Jason TL, Koropatnick J, Berg RW.
Cancer Research Laboratories, London Regional Cancer Centre, London, Ontario, Canada N6A 4L6.

Targeting unique mRNA molecules using antisense approaches, based on sequence specificity of double-stranded nucleic acid interactions should, in theory, allow for design of drugs with high specificity for intended targets. Antisense-induced degradation or inhibition of translation of a target mRNA is potentially capable of inhibiting the expression of any target protein. In fact, a large number of proteins of widely varied character have been successfully downregulated using an assortment of antisense-based approaches. The most prevalent approach has been to use antisense oligonucleotides (ASOs), which have progressed through the preclinical development stages including pharmacokinetics and toxicological studies. A small number of ASOs are currently in human clinical trials. These trials have highlighted several toxicities that are attributable to the chemical structure of the ASOs, and not to the particular ASO or target mRNA sequence. These include mild thrombocytopenia and hyperglycemia, activation of the complement and coagulation cascades, and hypotension.

Dose-limiting toxicities have been related to hepatocellular degeneration leading to decreased levels of albumin and cholesterol.

Despite these toxicities, which are generally mild and readily treatable with available standard medications, the clinical trials have clearly shown that ASOs can be safely administered to patients. Alternative chemistries of ASOs are also being pursued by many investigators to improve specificity and antisense efficacy and to reduce toxicity. In the design of ASOs for anticancer therapeutics in particular, the goal is often to enhance the cytotoxicity of traditional drugs toward cancer cells or to reduce the toxicity to normal cells to improve the therapeutic index of existing clinically relevant cancer chemotherapy drugs. We predict that use of antisense ASOs in combination with small molecule therapeutics against the target protein encoded by the antisense-targeted mRNA, or an alternate target in the same or a connected biological pathway, will likely be the most beneficial application of this emerging class of therapeutic agent.