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Biotech / Medical : Regeneron Pharmaceuticals -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (333)	12/11/1999 5:54:00 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 3559

Rick, I will tried. In several steps. With best of my capacity (which is limited, but so far did give good results). MZ-winner doesn't come overnight. If at all. Example are TTP, NBIX, CELG,..it took more than two years for each. Maybe will never come here. So far REGN is at three years dormant stage. However, I believe that message will go through and I hope wake-up call will materialize. For the beginning few thought on “Yancopoulos Institute for Basic Research” and FDA licensed bio-manufacturing facility. I believe that real break through new drug will not come without deep and complete understanding of the basic science and life secret. Several new bio-drug (Enbrel, Herceptin, Rituxan,..) actually were ahead of underlain science at some point, but science did quickly ketch-up and explained why are this drug so effective. Going forward (and as discussed at MLNM and elsewhere at SI and now recognized among pharmas and bts) not only target validation but also identifying and selecting the best point/target in complex cascade of the disease pathology is the only way and blind without help from basic research. Otherwise we will return to trial and error approach. So, Yancopoulos/REGN work on basic science is a right choice, imo. Yes, long one and without (for now) real results (Axokine still have a chance to be first one). However, Yan was the only one who openly criticize Folkman & Com (read ENMD) work on anti-angiogenesis as (in the most part) a crap-shot. I believe that he will be able to prove this. Otherwise he would not put his scientific reputation on stake. Counting manuscripts in top scientific journals REGN is on top of list. Knowledge is priceless, and there is no substitution. Luck can help intermediary, but long term....???? Short comment on recent news about bio-manufacturing FDA compliance. So far among bt only big shot (CHIR, AMGN, BGEN, CNTO, IMNX, GNE..) were able to build independently manufacturing facility for bio-products. For all other bt this is the last step, and usually results in delay, incompetence, unresolved FDA issue and ultimately delay/failure, or.... Results are known. REGN is now ahead of his own drug-development cycle. Having this facility on place and operational they did: 1. separate themselves from any future contract manufacturing dependence and uncertainty, 2. build franchise business unit which can generate (with minimal investment in expansion) ~$50-100 MM annually and with very good margin, 3. leverage business plan and reduced forward risk, 4. will keep significant portion of the drug revenue (if and when they reach market) in house, 5. significantly reduce BLA preparation and review time by FDA (when it come to that point), .... People who directly deal with this FDA issue can describe much better than I did importance of having their own facility ready for bio-drug production and marketing. Not to mentioned that BGEN, NDA, AMGN are investing >$100 MM each in their own new manufacturing facility. One have to ask why? Also, I have to mention that REGN did build and upgrade this business unit with significant finical help from MRK. One point for successful business approach where own knowledge and experience are combine with others money. More on REGN drugs pipeline and pharma business plan in following posts. Miljenko PS: It isn't succinctly description. :( I may sound like preach, but few lurks may got interested and trigger their own DD.

To: scaram(o)uche who wrote (333)	12/11/1999 6:33:00 PM
From: Miljenko Zuanic	Respond to of 3559

Drugs pipeline. Current drug in trials are BDNF, NT3 and AXOKINE (Ax). Ax is the most promising and REGN main focus going forward. I mentioned in one my early post that my hard was broken when REGN reported on drug side effects which may limit significantly therapeutic/marketing potential. I truly did see Ax as break through new drug. First drug which may threat successful obesity at its basic level. But, before I review Ax in length (and with help from others, I hope), BDNF will probably be the first drug to reach market. Why am I so positive that BDNF will work (at least) for some ALS pts? When it didn't so far? There is nothing which work for ALS. And I do not see anything for next 10 years which it may. If I am wrong I would like to hear other SI freaks info. So, if BDNF do work it will have market monopoly for some time. I will not go in details over BDNF history (discussed so many time here before). AMGN/REGN rushed through PII clinical trials (with significant push from AMGN because they needed any good results to bust investor confidence at that time) without fully exploiting drug doses and regimens (formulations). There is two way in conducting clinical trial. Good and bad (short) one. Chose short approach and you put your fate in luck. Normally, REGN failed in PIII. They learned lesson. Also, there was some good things. At the higher drug dose arm certain pts did have significant medical benefit from drug. To explore this, REGN run confirmatory prospective small BDNF trials where they tested progressive increase in drug dose up to individual pt tolerance. ncbi.nlm.nih.gov Neurology 1999 Apr 22;52(7):1427-33 A controlled trial of recombinant methionyl human BDNF in ALS: The BDNF Study Group (Phase III). OBJECTIVE: To replicate the beneficial effect of brain-derived neurotrophic factor (BDNF) in 1,135 ALS patients in a multicenter trial. BACKGROUND: In a phase I through II study, BDNF appeared to increase survival and retard loss of pulmonary function in ALS patients. METHODS: Patients were randomized to placebo, or 25 or 100 microg/kg BDNF for 9 months. RESULTS: The study failed to show benefit of BDNF treatment for the primary end points. Survival in patients treated with 25 microg/kg BDNF was identical to placebo, but there was a trend toward increased survival in the 100-microg/kg group. As a whole, survival was better than anticipated when planning the study. The 9-month probability of survival was approximately 85% across all groups. This diminished the power of the study. Among the 60% of patients with baseline forced vital capacity of < or = 91%, survival was significantly greater for 100 microg/kg BDNF versus placebo. For the 20% of patients treated with 100 microg/kg BDNF reporting altered bowel function as an adverse effect of BDNF in the first 2 weeks of dosing, defined as BDNF "responders," 9-month survival was significantly better than for placebo (97.5% versus 85%). CONCLUSIONS: Although the primary end point analysis failed to demonstrate a statistically significant survival effect of BDNF in ALS, post hoc analyses showed that those ALS patients with early respiratory impairment and those developing altered bowel function showed statistically significant benefit. Further clinical trials of BDNF using either intrathecal delivery or high-dose subcutaneous administration are in progress. I do not know results from this small trials (they tested high drug dose tolerability), but based on them REGN are currently running large (300 pts) open label trial where physician will explore max tolerated drug dose for each patient individually. Exceptional drug tolerability (except altered bowel function side effects) allowed this approach (very rare in PIII clinical trial practice) and FDA agreed upon. I believe that this is registration trial and predetermined protocol end-points are set for drug marketing acceptance. So, based on excessive studies on BDNF rule in LT motorneuron survival and regeneration, as well other neuro-functions, (here REGN basic research, knowledge and gained experience count) and recent Somitomo interest to continue drug development, I am projecting (with high level probability) that BDNF will succeed in ALS and reach market by 3Q 01. Counting only REGN plant revenue and niche ALS market, company MC will rise significantly from current level. Very low risk opportunity for investment. Because, all other program I didn't included, upper potential is far higher. Miljenko

To: scaram(o)uche who wrote (333)	12/11/1999 6:43:00 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 3559

Business plan So far REGN is developing new dug alone or with equal partnership base (50:50). They have deal with AMGN (with additional financial support) and with P&G (with exceptional R&D support). Normally, AMGN collaboration didn't generate anything yet (so, who care), while P&G pharma business expertise can't be counted too seriously. We know that AMGN have high failure rate in picking up other bt projects and that P&G have very limited experience. This all can be seen as nothing more than neutral, if not negative for bt company. But, my question is: “is this real true”? Only time can tell for sure. Also, REGN have additional project, cytokine trap technology, which they develop independently. This is now ready for partnership. CEO indicate that REGN will continue to strike deal on equal level, 50:50. If this time partner is from big fat pharma (and I believe that it is), than WS will start to think differently. Or, I am lost case here and I will give-up. Anyway, REGN business plan sound as very good one. If they progress in any of this 50:50 deal than return is there. So, why chose REGN when there is so many better sound stories in Universe. Here come Yan & Com. approach. No hype, no big stories. Do your job right, do it completely. Results will come when you expect them least. This I learned from my chemistry. When I lost all my hope that I will make certain reaction/synthesis work, suddenly there is something good and new! And, most important REGN current stock price is very attractive and chip. Cheers, Miljenko