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Some notes from the InterMune Wachovia call today
I'll try to update the ReadMe First after the February 8th Q4 Call. I also caught the Vertex call and on first listen heard a couple things encouraging (for InterMune longs). One in particular was the mention about combining with possibility of combining with other PI in earlier stage of development [read into it what you will].
• Pirfenidone trial “currently enrolling and enrolling well”
• 191 in Phase 1 studies as we speak, proof of concept data in 2007, February 8th give more in terms of timing
• Number of research projects in pulmonary and hepatology and we look forward to advancing other products from that effort in the future.
• We were very encouraged by that [Shionogi] news.
• Actimmune today is actually a little higher now but about 60K per year.
• Composition of matter for Actimmune expires 2022 in US. Orphan drug in US and Europe. US and Canadian rights.
• Pirfenidone world-wide rights (excluding Japan, Korea and Taiwan). Method of use patent expires 2011 and have Orphan drug. Relying on it for exclusivity in US and Europe.
• Recently announced top-line results in PR of Phase 3, very encouraging for us. About 250 patients. Primary end-point was VC. Did disclose a significant effect vs. placebo. Did not disclose P value, InterMune knows but not allowed to disclose.
• Number of patients roughly same (we are running 2 trials), dosing different but on mg/kg are very similar (our 800 similar to their 600 on Japanese population), change in percent predicted vs. vital capacity (modest differences; measure lung capacity).
• Phase 1A initiated in December and Mfg milestone in January. Significant since complex molecule and showed able to produce relevant quantities for study.
• Next 8-9 months should get another 25 million.
• Are working with Roche to develop follow on compounds and similar financial terms.
• 170 million in cash + 60 million Roche up-front + 10 million January – Q4 burn.
• Note due 2011, in money (21.63) low coupon rate. Well position there.
• 33 million outstanding, 41 fully diluted. Shelf of 175 million filed.
• February 8th financial results and 2007 guidance and discuss milestones for R&D programs (191 and other programs). Pirfenidone capacity enrollment expected to be completed in 2nd half of year.
• [Question] What we said is there are 2 interim looks (for efficacy). Very specific about not saying when/if they occurred just saying they have very specific efficacy stopping boundaries.
• [Question] Shionogi planning to file end of march (what said publicly). Not disclosed when they plan to present or further disclose data from trial. We have data sharing so do or will have access to data but unable to comment. Will use it to inform our own trial.
• [Question] Haven’t talked much to manufacturing aspect. Are encouraged by progress as is Roche. Key issue since complexity of molecule. Confident we can solve issues and made great progress. Certainly for trials/needs ahead of us can support that.
• [Question] Material for Phase 1 produced much earlier. Material looking ahead to completing Phase 1 and beyond. Material for Phase 1 produced well before December.
• [Question] There are additional deliveries scheduled. Achieved certain scale with production that was important achievement with the milestone.
• [Question] Phase 1A/Phase 1B Study. Proof of concept data this year. More information on February 8th.
That is an interesting study in the prior message (#msg-7959424).
Do you think the observation can be generalized outside of cancer-chemo and the end point? I would think a mortality end point may have better correlation between P2 and P3 (but this is just speculation on my part).
Edit: Link to Journal Article added
http://www.jco.org/cgi/content/full/23/28/6982
Maybe rfj is playing the balance sheet?
A quick look shows about 95 million and 60 million shares, so they will be near cash in the 1.50 range (this is very rough estimate).
I think they have a couple other products too. My concern would be what you think management would do. A few years back TKT could have been had below cash and shareholders would have had a 10 bagger.... But I'm sure others can name companies that have just drained the cash away.
Rather then buyout rumors could it be people are starting to get excited about potential for BH4 in Uncontrolled Hypertension? Results of the 2A study will come within a month.
I think we get success in at least one of the cardio vascular indications the company is pursuing. I really like the way they are doing things with multiple Phase 2's and things such as dividing the diabetic vs. non-diabetics. The company is really giving shareholders many shots on goal at relatively low risk.
I really like the company pursuing BH4 in sickle cell disease too! Being an Orphan indication the 7/10 year exclusivity and similar population size as PKU make it a valuable niche.
BH4 could really be a gold mine for the company! FYI here is a link for more info.
http://www.bh4.org/BH4_Start.asp
I say forget about selling the company for a while! We still have a way to go!!
ViRexx:
The PR is out just Yahoo doesn't have it (I am guessing that is where you are looking). I can see it in a few places.
For what its worth, I think if someone is to speculate on OvaRex United is a better way to go. They'll likely get the majority of the profits (should it have positive results and reach the market) and the deal REX did for X-US a couple months ago was TERRIBLE! It was basically a financing not a deal. And it will be some time before ViRexx gets some serious revenue from OvaRex now that they gave away the rest of their territories. So this (HUGE) dilution likely isn't the last. From their perspective hopefully it lasts them till the Summer when IMPACT trial results are out and if positive they get a pop in price to dilute more...
I still think OvaRex has a chance (from Review of data and some of the literature on Ovarian Cancer trials) but a few things bother me about it.
That XOMA gets some royalty from DNA on Lucentis has been disclosed; I was looking for a quantitative assessment of the royalty
Don't quote me on this but I thought I heard on one of the calls an analyst talking as if 1% was the royalty and not being disputed. This is going from memory. Here is a quote from a PR would seem to be consistent too. Sorry don't know the x-US portion of your question.
"Royalty percentages on BCE licenses range from 0.5% to 3% of net sales, and the royalty on LUCENTIS(tm) is toward the lower end of this range."
Webcast Calendar
[Please see updating procedure at the end of this post. Events listed here are regular quarterly conference calls unless indicated otherwise. All times are U.S. ET. unless indicated otherwise.]
NOTE: ANYONE MAY UPDATE THIS FILE
Edits: Wachovia Securities 2007 Healthcare Conference
ABT 1/24 9am
AMGN 1/25 5pm
AZN 2/1 8am
BIIB 2/15 8:30am
IMCL 1/25 11am
JNJ 1/23 8:30 am
LLY 1/31 8am
MEDI 2/7 8am
MEDX 2/7 4:30 PM
MRK 1/30 9am
MYGN 2/6 10am
PFE 1/22
SNY 2/13 3am (?)
SGP 1/29 8am
VRTX 2/1 5pm
WYE 1/30 8am
Wachovia Securities 2007 Healthcare Conference Boston, MA
January 29-31, 2007
http://www.wsw.com/webcast/wa38/
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Procedure For Updating Calendar
When adding or modifying entries, please follow these steps:
1. Copy the complete text from the old list. You can find a pointer to this list in the iBox at the top of the main message-board screen.
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phrm / sppi - satraplatin
I will admit that I am an optimist (in general) on potential. I was actually think 3-4 years out post approval. I discount a year or so from that for SPPI because of Milestone's they'd receive for EU/US approval (I believe it is in the 50 million range if my memory is accurate).
I liked that fact that Satraplatin had limited toxicity and that the efficacy was good and yet I don't believe the MTD was reached. GPC had quite a number of Phase 1's and 2's in the works/planned. I think some of the combo trials in lung/solid tumors could offer good potential. I thought of the possibility of using an Oral Platinum in maintainence in other hard to cure cancers (like Ovarian) may be interesting targets too.
BTW, Was looking through some old posts and noticed your comment on ENCY/Thelin approval not likely pending another trial. You seemed to have been right on about it, curious as to why you thought that. Did you see something in their package that seemed weak or is more because when the FDA says jump you better?
I like Pharmion (a lot actually) I just have given up hope of getting it under 20 any time soon (and if that were to happen now it would likely be because of something so unfavorable I would lower my target). I actually think Thalidomide (European sales) will at least remain solid (if not grow for some time), I buy Mahaffys arguments on it anyway. I also like the potential for the Methylgene compound they licensed a while back. What is waying against my liking them more is:
1-The nearly double in price since I was close to purchasing (granted they have had good news since so I should pay more)
2-Their two main revenue sources have pretty significant competion (Revlmid-2 fronts, Velcade, etc.)
3-While I think Vidaza and Thalidomide could hold up I think the market will get nervous pretty easily on either dropping (I thought that might give me a buying Opportunity).
I am not a big Mahaffy fan but will admit he (sounds) a lot better then Dr. Raj anyway. I think he paid a lot for both the Methylgene compound and Satraplatin but he may look good in the end.
My reasoning for SPPI (at current levels) over PHRM (at current levels) is:
10% royalty could possibly generate $50 million in a couple years (I think easily and wouldn't be suprised to see a lot more uses for an Oral Platinum drug pushing sales much higher). With their current burn that could give them .50 - .75 EPS.
In the meantime you get the milestones from GPC and should they get lucky in a settlement with GPC that could be very significant for SPPI.
Then longer term they have a couple of shots on goal with their Bladder cancer compound and the drug for prostate cancer/benign prostatic hypertrophy. The fact that Dr. Raj does small deals makes me less nervous too (but I don't like all the Options/Warrants sitting out there).
I think Pharmion will be putting a lot of money into R&D for the next couple years anyway so people may go through a period where they don't know whether to value it on revenue or pipeline potential. But I still keep watching it for an opportunity.
I appreciate your insights poorgradstudent and would be interested in any of your thoughts on Pharmion/Satraplatin
SPPI Question
I've been looking at Spectrum (again) after failing to buy Pharmion when I had the chance (in the 15 range) and think GPC is too risky in case anything should go wrong with Satraplatin (they do have an early stage compound but I don't think much else).
Anyway my question is about all the options and warrants outstanding. Rather then dig threw some filings I was hoping someone may have a good understanding of the 15 million or so options (I believe about 6 million) and warrants (I believe about 9 million) and could give me a brief overview of the price/dates of expiration. TIA
I still am not thrilled with management (from listening to calls) but as a way to play Satraplatin they seem to offer the safest risk/reward ratio.
Don't know who put together the board info but provides a nice summary. I've owned a few shares for about a year now.
I was glad to see the company didn't do a big financing to dramatically increase the sales force (one of the good things with Mr. Sandgaard owning most of the equity) and the stock price being pretty depressed.
The (relatively) recent sales force additions should continue to drive the revenue growth but I've noticed the 4th quarters have tended to drop off. I am ready to add should that happen again (though mid 20's is pretty cheap for the few thousand shares that have traded there). I think we are now selling at a pretty cheap level (on a multiple of sales). It would be nice to obviously become more profitable but to me can't see a big drop off in sales coming (based on history) and it doesn't look like Mr. Sandgaard is going to dilute at these levels so the risk should be minimal at current prices.
Unless the sales force is taking a while to become more productive it seems the profitability will not grow dramatically (based on past quarter). Wonder if the company would consider doing something to partner (particularly overseas). If you get a bigger device company pushing the neuro-move perhaps a nice royalty would be a quicker way to some nice profitability? Just a thought.
Curious if anyone has talked to Mr. Sandgaard directly. If so any opinions? TIA
How do you feel about these:
- Lowering the mound
- Smaller ballparks
- (Allegedly) More lively baseballs
- Corked bats
Unfortunately Steroids are but one of many things that makes records and comparisons difficult
Thanks, I don't own any Royalty Trusts.
I should clarify at the time I owned it Drug Royalty was NOT operated as a Royalty Trust.
If so, are you current with the Canadian government's " Halloween Surprise" to unit holders of these companies?
No Idea what you are referring to.
Yes, Drug Royalty is Canadian. I don't own it any longer they went private (low premium - Still feel taken). Haven't checked lately but last I did they still were.
Fear
Good to see the board here. Like that you have the milestones another you may want to add is "late 2007" goal to file IND for Phenylase. Also while I believe these will be investigator studies they are planned for 1H '07 for BH4 in PAH and erectile function.
I got the impression the Phenoptin Diet study would be early February (if not late January) but I could be wrong on that.
This may be slightly off topic as it does not pertain to a specific company and is a little long (and may not paste well) but I found it interesting. I would have expected considerably more targets (this may have made a good quiz :)
http://www.nature.com/nrd/journal/v5/n12/full/nrd2199.html
How many drug targets are there?
John P. Overington1, Bissan Al-Lazikani1 and Andrew L. Hopkins2 About the authors
Top of pageAbstractFor the past decade, the number of molecular targets for approved drugs has been debated. Here, we reconcile apparently contradictory previous reports into a comprehensive survey, and propose a consensus number of current drug targets for all classes of approved therapeutic drugs. One striking feature is the relatively constant historical rate of target innovation (the rate at which drugs against new targets are launched); however, the rate of developing drugs against new families is significantly lower. The recent approval of drugs that target protein kinases highlights two additional trends: an emerging realization of the importance of polypharmacology, and also the power of a gene-family-led approach in generating novel and important therapies.
Surprisingly, for an industry that spends in excess of US$50 billion on research and development each year, there is a lack of knowledge of the set of molecular targets that the modern pharmacopoeia acts on. If we are to develop predictive methods to identify potential new drug targets, it is essential that we establish with confidence the number, characteristics and biological diversity of targets of approved drugs.
Drews and Reiser were the first to systematically pose and answer this question, identifying 483 drug targets1, 2. Later, an analysis by Hopkins and Groom challenged this figure and suggested that 'rule-of-five'-compliant3 drugs acted primarily through only 120 underlying molecular targets4. Subsequently, in 2003, Golden proposed that all then-approved drugs acted through 273 proteins5, 6. By contrast, Wishart et al.7 reported 14,000 targets for all approved and experimental drugs, although they revise this number to 6,000 targets on the DrugBank database website. In 2006, Imming et al. catalogued 218 molecular targets for approved drug substances8, whereas Zheng et al. disclose 268 'successful' targets in the current version of the Therapeutic Targets Database9, 10. Here, we propose a consensus number of 324 drug targets for all classes of approved therapeutic drugs (Table 1), reconciling earlier reports into a current and comprehensive survey. The details of this target list, including the names of the targets, target class, cellular location and United States Adopted Names (USAN) or launch dates, are illustrated in the accompanying poster on the molecular pharmacopoeia (see Further information online).
Table 1 | Molecular targets of FDA-approved drugs
Full table
Figures and tables index
Download Power Point slide (230 KB)
In order to produce this consensus on the number of molecular targets, a comprehensive analysis of the US FDA's Orange Book (for primarily small-molecule drugs) and the Center for Biologics Evaluation and Research (CBER) website (for biological drugs) was performed. This analysis identifies in excess of 21,000 drug products; however, when duplicate active ingredients, salt forms, supplements, vitamins, imaging agents, and so on are removed, this number is reduced to only 1,357 unique drugs, of which 1,204 are 'small-molecule drugs' and 166 are 'biological' drugs.
Of the 1,204 small-molecule drugs, 803 can be administered orally, 421 can be dosed parenterally and 275 can be used as topical agents (for this analysis, buccal, rectal, inhalational and other such routes of administration are considered as topical agents). A further complicating factor in these analyses is that some drugs are dosed as prodrugs. Interestingly, a significant number — at least 192 (16%) — of the small-molecule drugs are prodrugs. The rule-of-five3 is routinely used to assess the likelihood of oral absorption for drugs. In our analysis, 885 of all small-molecule drugs pass the rule-of-five test; of these, 619 (70%) are actually dosed orally, whereas 159 (20%) of orally dosed drugs fail at least one of the rule-of-five parameters.
Assignment of efficacy targets
In order to identify the efficacy targets — the molecular targets through which the drug mediates its approved therapeutic activities — we conducted a comprehensive analysis of the literature for each drug. The criteria for assignment was strict in that strong evidence of cell-based and/or in vivo evidence linking the target (and specific target sub-type) to the effect of the drug must exist alongside binding data. We were able to assign protein molecular targets believed to be responsible for the efficacy of a drug to 1,065 of the unique drugs. Where possible, we also recorded the particular domain in the protein that binds the drug, as well as the known binding sites/residues.
The literature is often complex in terms of the information provided about efficacy targets. For cases in which a specific target protein is believed to be the sole or major route through which a drug achieves its efficacy, we assign the drug against this single target; for example, the histamine H1 receptor is believed to be the major mechanistic target for cetirizine and hydroxyzine, and acebutolol acts through the 1 adrenoceptor, although all these drugs show binding to other G-protein-coupled receptors (GPCRs) in in vitro assays. In other cases, the drug acts through a number of target subtypes: for example, carvedilol acts through blocking a number of - and -adrenoceptors. Finally, a drug can act through multiple distinct mechanisms, and therefore unrelated targets. For example, ritonavir is an HIV protease inhibitor; however, it is usually given in combination with other HIV protease inhibitors because it inhibits the cytochrome P450 3A4 (CYP3A4)-mediated metabolism of other HIV protease inhibitors such as lopinavir. In such cases, both HIV1 protease and human CYP3A4 are regarded as the molecular targets.
There is a relatively small, but clinically significant, class of drugs that bind to either ribosomes or DNA, or that have no distinct or an unknown mode of action. The literature changes frequently in terms of the knowledge available about drug indications and mechanisms of action, and so this information needs to be reviewed regularly.
Efficacy targets of current drugs
On the basis of existing knowledge, we were able to determine that all current drugs with a known mode-of-action act through 324 distinct molecular drug targets. Of these, 266 are human-genome-derived proteins, and the remainder are bacterial, viral, fungal or other pathogenic organism targets. Small-molecule drugs modulate 248 proteins, of which 207 are targets encoded by the human genome (Table 1). Oral small-molecule drugs target 227 molecular targets, of which 186 are human targets.
A complicating feature of any such analysis is that many drugs have complex and relatively poorly understood pharmacology, and often limited selectivity against related proteins, and some targets are actually complex multimeric proteins with variable subunit compositions and so on. If one makes the assumption that proteins related down to 50% identity show related pharmacology, then this list of 324 targets expands to 604 genes for the human genome (comparison carried out against ENSEMBL genome June 2006 release containing 29,679 genes). Extending the analysis to include all close homologues (35% identity or closer) increases the number to 1,048 genes (3.5% of the genome). This line of reasoning lead to the initial estimate of the size of the druggable genome4. Understanding the real pharmacological footprint of current drugs offers many opportunities for both developing new, optimized agents with different selectivity profiles, and also more efficient lead discovery and optimization strategies.
Current biological drugs target 76 proteins, with currently marketed monoclonal antibody therapeutics acting on 15 distinct human targets. So far, only nine targets are modulated by both small-molecule and biological drugs, with the differing agent types usually targeting different domains or binding sites. This relatively small number of jointly modulated targets is driven by both technical and commercial considerations. For example, the biological drugs cetuximab and panitumumab target the extracellular domain of the receptor tyrosine kinase EGFR (ERBB1), whereas the small-molecule drugs gefitinib and erlotinib target the adenine portion of the ATP-binding site of the cytosolic catalytic kinase domain within the same receptor.
Drug polypharmacology
It was clear from both our curation of drug targets from the literature and also data-mining of known affinity values of drugs for targets (as abstracted in a large database of medicinal chemistry literature17) that many drugs show clinically relevant polypharmacology (that is, they are 'dirty drugs18). Quite expectedly, closely related members of the gene family will show significant drug promiscuity, and, as a result of the generally similar function of these proteins, give rise to complex composite clinical pharmacology. The point of genuine multitarget effects of drugs is well illustrated by several recently launched protein kinase inhibitors. Imatinib, originally developed as a highly selective inhibitor of c-ABL11 (and which target association led to its first approval for chronic myeloid leukaemia), has subsequently been discovered to be have significant activity against several other clinically relevant kinases, such as c-KIT12, 13, 14, leading to expansion of the clinical utility of this important therapeutic. Sorafenib has been recently launched as an explicit multikinase inhibitor, affecting both tumour proliferation and tumour angiogenesis pathways, and acting through at least RAF-kinase, vascular endothelial growth factor 2 (VEGFR2), VEGFR3, platelet-derived growth factor receptor- (PDGFR ), KIT and FLT315. Finally, sunitinib is a further recently approved protein kinase inhibitor with a similar target footprint to sorafenib12.
At a reductionist level, this polypharmacology can be rationalized by similarities of key pharmacophores in the binding sites of proteins from different families16, and, when comparing proteins from within the same protein family, polypharmacology can be rationalized by similarities or differences in the physicochemistry of the equivalent residues lining the binding site. The recent work on large-scale mapping of polypharmacology interactions reveals the extent of promiscuity of drugs and leads across the proteome17. Placing such aspects of polypharmacology on a firm practical and theoretical footing is a major challenge for the development of future safe and clinically differentiated therapies17, 18.
Patterns in drug targets
In order to identify the familial relationships between all drug targets, we analysed the presence of domains, using the SCOP19 and PFAM20 databases. Approximately 130 'privileged druggable domains' cover all current drug targets. This number is in stark contrast to the projected number of protein families and folds (10,000 folds21 and more than 16,000 families22).
Analysis of the gene-family distribution of targets by drug substance for both small-molecule and biological drugs (Fig. 1) reveals that more than 50% of drugs target only four key gene families: class I GPCRs, nuclear receptors, ligand-gated ion channels and voltage-gated ion channels. The targets with the most number of drugs approved are the glucocorticoid receptor and the histamine H1 receptor (see accompanying poster; also available online). Protein kinases are relatively over-represented considering the small number of launched drugs against these targets: there are currently five approved drugs against the protein catalytic domain, acting on 18 protein kinases.
Figure 1 | Gene-family distribution of current drugs per drug substance.
The family share as a percentage of all FDA-approved drugs is displayed for the top ten families. Beyond the ten most commonly drugged families, there are a further 120 domain families or singletons for which only a few drugs have been successfully launched. Data based on 1,357 dosed components from >20,000 approved products, FDA, December 2005. GPCR, G-protein-coupled receptor.
High resolution image and legend (24 KB)
Figures and tables index
Download Power Point slide (233 KB)
A common property of most current drug targets is their cell-surface location: 60% of drug targets are located at the cell surface, compared with only 22% of all proteins in the human genome. Despite this strong pattern of membrane association, there is a high degree of structural characterization of drug targets, with 105 drug targets themselves and over 92% (300) of drug targets being similar to known proteins in the Protein Data Bank (PDB)23. Although it is still highly debatable whether useful design and docking can be performed in all cases, this high structural coverage clearly illustrates the progress structural biology has been making in its application to drug discovery.
The Online Mendelian Inheritance of Man (OMIM) database24 provides associations between genetic loci and diseases. A smaller number of disease associations are linked directly to a specific gene. In an analysis of these data, 1,620 distinct human protein sequences are linked directly to a genetic disease. Of these, 105 are drug targets, corresponding to 47% of human drug targets that are directly associated with a disease. In an analysis against an earlier version of the human genome, only 7% (1,620 out of 22,218) genes have explicit disease associations.
The availability of this carefully curated database allowed us to perform further analyses that address other features of the properties of marketed small-molecule drugs of broad relevance. One example is of the potency distribution of marketed drugs. We identified binding-affinity-related endpoints for all drug–efficacy target pairs identified in the above analyses. The extracted data included all IC50, EC50, ED50, Ki, Kd and pA2 data; data were transformed as appropriate onto a log affinity scale and are detailed in Fig. 2. As can be seen, the median affinity for current small-molecule drugs is around 20 nM.
Figure 2 | Frequency distribution for small-molecule drug potencies.
High resolution image and legend (19 KB)
Figures and tables index
Download Power Point slide (228 KB)
One striking feature of the analysis is how infrequent it is for new protein domains to join the exclusive drugged domain set. Using the same dataset analysed by a recent National Institute for Health Care Management Research and Educational Foundation (NIHCM Foundation) study examining drug innovation25, of 361 new molecular entities (NMEs) approved by the FDA between 1989 and 2000, 76% targeted a precedented drugged domain and only 6% targeted a previously undrugged domain; the remainder have either unknown targets (4%) or are believed not to have distinct molecular targets underlying their action (17%). Analysis of the rate of target innovation is shown in Fig. 3. As can be seen, the rate is surprisingly constant over the past 20 years, with an average rate of first-against-target drugs of 5.3 new 'drugged' targets per year, although over individual years the rate is quite variable. The recent set of multikinase-targeted drugs are clearly a significant modern pattern, following the 2001 launch of imatinib. The first approved indications for drugs acting on the new drug targets are commonly orphan diseases, suggesting that innovation primarily occurs at the edges of the market (as is typical behaviour of innovation in other industries26), whereas innovations in the major disease indications can occur as rarely as once a decade, owing to the challenge of showing superior safety and efficacy profiles over existing therapies with very large and costly outcome-based clinical trials.
Figure 3 | Rate of target innovation.
The y-axis represents the year of first drug launch against each target, and the x-axis is the year of each subsequent drug release, with the plot ordered so that more recently 'drugged' targets are shown at a higher y ordinate. Region a reflects periods of high target innovation (after 1982) while region b is predominantly the re-use of established mechanisms. The rate of new protein families per year is 1.9.
High resolution image and legend (46 KB)
Figures and tables index
Download Power Point slide (255 KB)
Concluding thoughts
It is clear from this work, and the recent work of others, that despite the huge efforts and resources aligned to drug discovery as a commercial process, there is relatively little publicly accessible data addressing the fundamental question of how current drugs work. We hope this perspective helps address some of the issues surrounding our current knowledge of the complexities of drug action, and also provides a useful assembly of data that could only have been achieved through careful consolidation of literature, and other disparate data sources. Given this collection of historical drug targets, it is now possible to start to address the development of computer-based approaches to rationally score and assess the likely success of future drug targets. It is tempting to see advances in technology as transforming the rate of innovation in discovery, but there has been little evidence of technological developments to date improving our ability to tackle new target classes with increasing speed and success, and it would seem that small, incremental changes and hard-won gains in fundamental biology and chemistry, and clinical science, is still state of the art. As James Black is famously quoted as saying: "the most fruitful basis for the discovery of a new drug is to start with an old drug"27.
Links
FURTHER INFORMATION
Poster on the molecular pharmacopoeia
Top of pageAcknowledgements
We thank I. Carruthers, R. Cox, S. Rehman and J. Stevenson for assistance with data curation and analysis.
Competing interests statement
The authors declare competing financial interests.
Top of pageReferences
Drews, J. Genomic sciences and the medicine of tomorrow. Nature Biotechnol. 14, 1516–1518 (1996).
ArticleDrews, J. & Ryser, S. Classic drug targets. Nature Biotechnol. 15, 1318–1319 (1997).
ArticleLipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Del. Rev. 23, 3–25 (1997).
ArticleISIChemPortHopkins, A. L. & Groom, C. R. The druggable genome. Nature Rev. Drug Discov. 1, 727–730 (2002).
ArticleGolden, J. B. Prioritizing the human genome: knowledge management for drug discovery. Curr. Opin. Drug Discov. Dev. 6, 310–316 (2003).
ChemPortGolden, J. Towards a tractable genome: knowledge management in drug discovery. Curr. Drug Discov. 17–20 (2003).
Wishart, D. S. et al. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 43, D668–D672 (2006).
Imming, P., Sinning, C. & Meyer, A. Drugs, their targets and the nature and number of drug targets. Nature Rev. Drug Discov. 5, 821–834 (2006).
ArticleZheng, C., Han, L., Yap, C. W., Xie, B. & Chen, Y. Progress and problems in the exploration of therapeutic targets. Drug Discov. Today 11, 412–420 (2006).
ArticlePubMedChemPortZheng, C. J. et al. Therapeutic targets: progress of their explorations and investigation of their characteristics. Pharma. Rev. 58, 259–279 (2006).
ChemPortDruker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Med. 2, 561–566 (1996).
ArticleFabian, M. A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nature Biotechnol. 23, 329–336 (2005).
ArticleAtwell, S. et al. A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase. J. Biol. Chem. 279, 55827–55832 (2004).
ArticlePubMedISIChemPortHeinrich, M. C. et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 96, 925–932 (2000).
PubMedISIChemPortAhmad, T. & Eisen, T. Kinase inhibition with BAY 43–9006 in renal cell carcinoma. Clin. Cancer Res. 10, 6388S–6392S (2004).
ArticlePubMedISIChemPortWeber, A. et al. Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: New pharmacological opportunities due to related binding site recognition. J. Med. Chem. 47, 550–557 (2004).
ArticlePubMedChemPortPaolini, G. V., Shapland, R. H. B., van Hoorn, W. P., Mason, J. S. & Hopkins, A. L. Global mapping of pharmacological space. Nature Biotechnol. 24, 805–815 (2006).
ArticleHopkins, A. L., Mason, J. S. & Overington, J. P. Can we rationally design promiscuous drugs?. Curr. Opin. Struct. Biol. 16, 127–136 (2006).
ArticlePubMedChemPortMurzin, A. G., Brenner, S. E., Hubbard, T. & Chothia, C. SCOP: a structural classification of proteins database for the investigation of sequences and structures. J. Mol. Biol. 274, 536–540 (1995).
Bateman, A. et al. The Pfam Protein Families Database. Nucleic Acids Res. 32, D138–D141 (2004).
ArticlePubMedISIChemPortKoonin, E. V., Wolf, Y. I. & Karev, G. P. The structure of the protein universe and genome evolution. Nature 420, 218–223 (2002).
ArticlePubMedISIChemPortVitkup, D., Melamud, E., Moult, J. & Sander, C. Completeness in structural genomics. Nature Struct. Biol. 8, 559–566 (2001).
Berman, H. M. et al. The Protein Data Bank. Nucleic Acid Res. 28, 235–242 (2000).
PubMedISIChemPortMcKusick, V. A. in Mendelian Inheritance in Man 12th Edn (John Hopkins University Press, Baltimore, 1998).
NIHCM 24 pp (National Institute for Health Care Management Research and Educational Foundation, 2002).
Christensen, C. M. The Innovator's Dilemma: When New Technologies Cause Great Firms to Fail (Harvard Business School Press, Cambridge, 1997).
Raju, T. N. The Nobel chronicles. Lancet 355, 1022 (2000).
ArticlePubMedChemPortTop of pageAuthor affiliations
John P. Overington and Bissan Al-Lazikani are at Inpharmatica Ltd., 1 New Oxford Street, London, WC1A 1NU, UK.
Andrew Hopkins is at Pfizer Global Research and Development, Sandwich, Kent, CT13 9NJ, UK.
Correspondence to: John P. Overington1 Email: j.overington@inpharmatica.co.uk
I used to own a Drug Royalty company (Drug Royalty) till it was sold out at a tiny premium and their is another in Europe Royalty Pharma that I believe is currently private (talked of going public) they have some big royalties (including Rituxan). I don't know why people look down on Royalty companies it is VERY high margin and in an industry of high risk it has lower risk and can often have very high upside.
He also mentioned polymerase inhibitors in short "the street" interview at the JP Morgan conference. If you didn't catch it here is the link
http://www.thestreet.com/_yahoo/video/executiveinterviews/10331778.html?cm_ven=YAHOO&cm_cat=...
It was interesting how he referred to "other" protease inhibitors (besides SGP). I think the comments of exploring BID dosing speaks more then his comments of other PI's.
What about Dale Murphy?
I had a similar thought. My feeling is if they are on the ballet though should be considered so either remove them or don't judge them but the current situation leaves it in the hands of the voters to decide. If that is the case then why not be able to remove people already in who for one reason or another would not meet todays standard? If for example a recent inductee would admit to having used amphetamines (which I believe were common in the 70's) shouldn't the same voter who elected not to vote for McGwire not vote for this candidate?
Anyone know about the usefulness of this technology and any hints on what it could mean re InterMune. TIA
http://biz.yahoo.com/prnews/070109/cltu054.html?.v=73&printer=1
InterMune Licenses Qualyst's B-CLEAR(R) Technology for Drug Discovery
Tuesday January 9, 9:00 am ET
RALEIGH, N.C., Jan. 9 /PRNewswire/ -- Qualyst today announced that InterMune, Inc., a biotechnology company with a pipeline portfolio addressing idiopathic pulmonary fibrosis and hepatitis C infections, has signed a multi- year license to use Qualyst's proprietary, patented B-CLEAR® system for its drug discovery programs. Terms were not disclosed.
B-CLEAR® is a sandwich-cultured hepatocyte system for the in vitro assessment and in vivo prediction of critical pharmacokinetic properties, including hepatobiliary disposition, hepatic uptake, hepatic accumulation, biliary clearance and drug transport. B-CLEAR® offers research organizations the ability to generate physiologically-relevant data and enable decision making in critical areas related to hepatic transport and adverse drug interactions, helping to avoid costly drug development challenges, and enabling better prediction of bioavailability, pharmacokinetics, species- specific drug dosing and candidate selection.
"As knowledge of the critical nature of drug transporters increases, companies that use B-CLEAR® are able gain a competitive advantage by acting on observed transport-related properties of their therapeutic leads," stated Scott Neuville, Qualyst president and CEO."
About Qualyst, Inc.
Qualyst commercializes novel and proprietary ADMET products for drug discovery and development. Qualyst's products allow pharmaceutical and biotechnology researchers to make faster, better decisions regarding drug candidate compounds, saving valuable time and research dollars in the process. Qualyst, Inc. was founded on discoveries from breakthrough research at the University of North Carolina at Chapel Hill in 2001. For additional information, please refer to the company's web site at www.Qualyst.com or call 919-313-6500.
Thanks for the link.
Actually had come across Pipex a little while ago. Before I could do some DD on them stock went from the 1's to now in the 6's which puts the market cap in the 300-400 million range. I wish I had done some DD faster on it as I may have bought but now I see it as pretty pricey considering they'll need more cash to go through Phase 3 and the other use of tetrathiomolybdate (WIlson's Disease) seems to not offer much of a market opportunity (considering price of other drugs in class). If it drops back down and their future funding/partnering clears up I'll look at them more closely.
I've pretty much come to the conclusion that Pulmonary Fibrosis in general is really more akin to treatments for Cancer rather then other diseases (even PAH). I think combination therapy will be used and some will respond to some treatments/combinations better then others. I also think slight improvements (slowing progression of the disease) will be considered major advances at this stage (which is the big difference with PAH). And of course I think pricing of therapies will be along the lines of some of the newer higher priced oncology drugs (and PAH drugs).
Protease inhibitor clinical trial question.
Can anyone tell me how VX-950 went through Phase 1 in terms of time line/trials (when they began/finished/etc). Any articles/links would be greatly appreciated as well.
I am curious because InterMune is doing a 1A trial (Health Volunteers) before proceeding to 1B (infected patients).
Don't know how much board interest there is in InterMune outside of 191 (HCV) but here are a few thoughts on whats happened in the past few weeks and from reviewing some things...
1) After reviewing past calls I would venture to guess the "mystery" HCV preclinical candidate in development is either a Polymerase or a Helix inhibitor. Further more I would venture they start to discuss it perhaps as early as later this year and perhaps in the 2008/2009 time frame it enters the clinic. I don't follow this side of InterMune as well as many posters here so not sure what would make the most sense to pursue. In some of the past calls (InterMune not Array) they seem to be very enthusiastic about it and Array gets a larger royalty so I am sure they are more incentivized.
2) If any took advantage of the market not picking up on the Pirfenidone Shionogi news could have made $6-7 before the afternoon 8K filing on the 22nd. I posted the Shionogi PR before trading and was beginning to question myself but I took advantage and added even more. It is good to know that the "smaller" investor can still get ahead of the market in some instances.
3) Along the lines of #2. In my opinion several of the analysts coming out with comments are either off base or don't fully understand. I think some have their models and don't have any vision at all (I wouldn't mind negative reports if they were well reasoned; always appreciate things I may have missed). There are some good ones who have been touting the promise of their PI program but few seem to have a good grasp of the IPF side.
4) The "financing" was actually something I was wondering about (before they filed). If I understand things correctly they can repurchase the convertible (at 21 and change) if the holders try to redeem. So with the price considerably above the convert value InterMune would need the cash if all the note holders would convert (I think Dan likes to have in the $150 million range on the balance sheet). If I am right in my interpretation the beauty of this would be reducing the dilution by a couple million shares if say they can replace the current convertible with one priced in the $40/share range then you cut the dilution of the past note in half!
5) Also I believe there could be some near-term event drivers that (if favorable) could potentially further drive up the share price giving the company an opportunity to build some additional cash:
a) 191 Phase 1A completion/safety OK
b) Pirfenidone CAPACITY trial enrollment completing early
c) INSPIRE interim efficacy reached (just a guess but I say we have one one of the two interim looks in INSPIRE this quarter)
d) Release info on Preclincal HCV target
e) Pirfenidone partner or plan to develop alone in EU
f) Shionogi filing in Japan. Setting price (would guess US/EU price would be along same lines). Getting decision on it and then finally how quickly the up-take is.
I am not big on companies that issue, but I was thinking of a few things I'd like the company to do with some "extra" cash that could really build some value (one is to go at marketing Pirfenidone alone in EU).
OK I have rambled enough. Since there doesn't seem to be a whole lot of interest in the company outside of HCV, I'll probably wait till after the Q4 call to update the InterMune ReadMeFirst.
Shionogi Top Line Results of Pirfenidone Trial -- Relevance to InterMune
Don't know if anyone posted this yet (am traveling and have a slow dial-up connection when have access). Happy holidays to everyone (I am much happier with this news), really a great board and best wishes for a better 2007 (2006 was so-so for me) UTHR offset BMRN and ITMN gains!
This is bigger news then any 191 progress (to date anyway). Lets see what InterMune does (not just stock price but as far as plans for Pirfenidone).
http://www.shionogi.co.jp/ir_en/news/detail/e_061222.pdf
December 22, 2006
Shionogi & Co., Ltd.
Results of Phase III Clinical Trials of the Idiopathic Pulmonary Fibrosis
Treatment S-7701
Osaka, December 22, 2006 — Shionogi & Co., Ltd. (Head Office: Osaka; President:
Motozo Shiono) today announced that it has achieved the primary objectives of Phase
III clinical trials for the idiopathic pulmonary fibrosis treatment S-7701 (generic name:
pirfenidone), which the Company is developing in Japan under a license from
U.S.-based Marnac, Inc. and KDL, Inc., Tokyo.
Idiopathic pulmonary fibrosis (IPF) is a medical condition of unknown etiology with
poor prognosis in which progressive fibrosis of the alveolar walls produces irreversible
“honeycomb lung”*. In general, restrictive impairment (reduction of vital capacity (VC)
and total lung capacity (TLC)) is evident. As the symptom (fibrosis of the alveolar
walls) progresses, gas exchange in the lungs (exchange of oxygen and carbon dioxide)
becomes difficult. In some cases, oxygen therapy becomes necessary. Because of its
severity, IPF is designated as a “specified disease” (in other words, an intractable
disorder).
Under development as a treatment for IPF, S-7701 has been designated as an orphan
drug (a drug used to treat a rare disease) by the Pharmaceuticals and Medical Devices
Agency.
*Honeycomb lung: A high-resolution CT scan of the lung yields a honeycomb pattern.
In the Phase III clinical trials for this drug with VC change (from before commencement
of treatment to 52 weeks after commencing treatment) as the primary endpoint, both
high and low doses of the drug (600mgl per day, three times a day and 400mgl per day,
three times a day, respectively), significantly inhibited worsening of the condition
compared with a placebo.
While continuing to conduct further analysis and study, Shionogi plans to expedite the
application process based on these clinical results, with the intention of submitting a
new drug application (NDA) within the current fiscal year.
OT (partially): NIH VideoCasts
Thought some may be interested in some of these
http://videocast.nih.gov/PastEvents.asp?c=998
For the lucky ones with Fiber connections it may come in handy, I don't think I'll get the full 1.4 gigabyte of the PAH Conference before my flight :)
would be tough to blind an injectable drug with an oral drug
As an aside, Actimmune is a 3x week injectable and it is being blinded. Its a terrible enough disease and then to receive a Placebo injection! One way this could be interpreted is the lack of options speak to what patients/docs will try (though it is available off-label). Also, this is one reason why I speculate that Pirfenidone should complete enrollment much earlier then company forecast (prior posts). One could speculate the hurdle for approval is lower as well.
** Edit **
sorry misread the part about blind injectable with Oral, thought injectable period. You can delete this post
**
Thanks for looking that up.
This is certainly far from scientific but if one would want to speculate (like me) and Vertex doesn't come up with a way to reduce dropouts would the following be reasonable guesses:
1) If 950 goes to 12+24 of PEG-ribavirin -> Dropouts 12% (9% + 3%) If 80% of those SVR's come out to 70.4%.
2) If 950 goes to 12+48 of PEG-ribavirin -> Dropouts 18% (9% + another 9% for 36 remaining weeks of PEG). If 85% of those get SVR's that comes out to 69.7% of all treated.
3) If 950 goes to 24+24 of PEG-ribavirin -> Dropouts 30% (18% + 12%) speculate on 90% of those SVR's come out to 63%
4) 950 goes to 24+48 of PEG-ribavirin -> Dropouts 40% (18% + 12%) say 95% SVR that would be 57%.
I would guess 2 the most likely of these which would still leave a lot of room for improvement. Just speculating curious what anyone else would think.
Interesting Avalon Pharmaceuticals call if you get a chance to here even just the very end of the call. I don't follow the company and just happened to be listening out of curiosity. A caller called in to say the drug works for his father and thanked the company. The company while appreciative did state that they did not know this person or know he'd call. A guess that is one of the thing with allowing anyone to ask questions it could put management in a bit of a predicament. Still even if accurate I doubt anyone can draw significance from 1 case.
Thought maybe Roche or someone said something I missed or you had some French connection :).
Dew,
24 week of total VX-950? Dr. Pappas on the call today (thanks again Dr. Bio) seemed to think that going beyond 12 weeks would be problematic.
FYI, What the Susquehanna analyst was saying the first few minutes sounded a lot like whats been posted here 950 is a good drug but the valuation of the company is a bit ahead of itself (paraphrasing).
Just out curiosity where did you see the 191 data in 1H '07 not that I disagree because it sounds very reasonable, just InterMune won't gave a date till their CTA is accepted and I haven't seen anything from the French yet.
Think 3x day dosing outside of a clinical setting may impact dropouts more.
Notes from call thus far (but I have an app. at 10:30) Please execuse spelling/typos/grammar/etc.
Like VX-950 think market cap of over 5 billion ahead of itself. Market reacting to drop outs
RVR (Negative at week 4) – Very strong positive predictive value for SVR
Week 4 not just increasing pool of potential relapse but those who will go on to get positive value. Disappointed didn’t see week 4 data, presumable have it for more patients then week 12 data.
Skin reactions and discontinuations of some concern. 9% after 12 weeks little higher. Perhaps more serious rash of concern. Raise the concern that > 12 week prohibitive.
Ribavirin with VX-950 and relation to anemia? Majority effimacis on rash and GI upset. Nothing suggests interaction between 950 and ribavirin directly regarding anemia.
Polymerase GI tox vs. Protease GI tox. Think there will be dose related GI tox with these compounds. Both Idenix and Roche PM’s GI side-effects occurring and dose related and some case may occur prior to significant inhibition of viral replication. Think similar situation will occur with PI’s but serious not reported (severe nausea vomiting, pancreatisis). Ribavirin known to aggravate these side effects so concern when this is added.
Risk of skin rash? Discontinuation due to skin worrisome because with PEG/Ribavirin don’t generally lead to this. Maybe 950 aggregate PEG/Ribavirin and not directly causing it.
Probability on filing based on PROOVE this data increase or decreases probability? Doesn’t change it having expected very low to begin with.
Thanks for being Nice.
Thanks for the info. Just trying to gage the tolerability.
A quick search and found between 6 and 11% (for full course of therapy not at the 12 week level) for PEGs.
I think if they end up with 12 weeks its not too bad but if ultimately its 24 weeks+ and the discontinuations double (or more), its not looking too good.
ITMN - One would hope less drug and higher concentration of it in the liver would potentially lead to less AE's.
No conference call?
Do you know if the dropout rate for the PEG arm is consistent with historical avg.? Or what is expected at 48 weeks for PEG/Ribavirin? TIA
I'm not a subscriber so this is just the abstract and link from Nature Biotechnology. Therapies in PAH have always had premium pricing in what was thought to be a (relatively) small market (I've seen 50K US and similar in EU reported in articles/company filings going back about as few as 2-3 years or so). The prices range from about 10-20K a year for Revatio/Viagra to as high as 100-250K for Remodulin (depending on dose). The number of patients on therapy now is probably around 30K, the prevalence is probably double what was thought just 2-3 years ago AND now combination therapy is being thought as the best way to treat the disease in most patients. Companies in Field now/soon include: Actelion (Tracleer and soon Ilhprost via CoTherix acquisition), GSK/Gilead (Flolan/Ambrisentan), United Therapeutics (Remodulin), Pfizer (Viagra/Revatio), Isis/Lilly (Cialis), Encysive (Thelin). There are some earlier stage compounds too from many companies including Biogen, United Therapeutics, BioMarin, Epix among others.
http://www.nature.com/nbt/journal/v24/n12/abs/nbt1206-1457.html
Nature Biotechnology - 24, 1457 (2006)
Published online: 6 December 2006; | doi:10.1038/nbt1206-1457
Niche indications could drive higher valuations
John Ransom
Lone Tree, Colorado
Foster City, California–based Gilead surprised Wall Street with a proposal to purchase Westminster, Colorado–based Myogen on 2 October 2006 in a tender offer of $2.5 billion in cash. The acquisition could demonstrate that companies with niche applications are becoming more attractive to better-established biopharmaceutical companies.
You beat me to my edit :).
Maybe I am missing something in how baseball setup this bidding system but what is to stop a team from bidding a really high figure (say 50 million) much higher then any other team would even consider and not really having an intention of signing the player (except if they'll accept a dirt cheap price)? If they "lose" it really doesn't cost them anything does it? And it would prevent another team from getting that player (for at least 1 year).
gfp
I had been following Pharmion for a while and decided of the three companies that would be how I'd play Satraplatin. GPC is obviously a better pure play and I too kept thinking Spectrum is cheap but after listening to management and (as importantly) some of GPC's calls it seems to me Spectrum management at best may not be stating things in as clear a manner as possible.
With Pharmion you get foreign rights, 200 million in annual revenue (today) and a few other compounds too. If Pharmion drops back below 20 (for no bad reason) I will seriously consider it again (may not happen though). I hope Revlimid does real well one quarter and people start getting too excited about it and totally discount Thalidomide. I think it (Thalidomide) may do well in Europe if they get first line approval for multiple myeloma.
Thanks for the reply. I was just thinking of some of the various possible ways things could play out. Don't see a "winner" take all approach and especially not the first-to-market cannibalizing it. Think it is probably too early to know with any degree of certainty just curious on the feasibility and if an "easier" regiment could potentially lead to patients seeking treatment sooner.
About the PROVE-1 results, I know there are a lot of knoweldgeable posters in this area I am not one! I would just be guessing with little to back it up. If you want a guess I would say 95%, 85% and 75%. I actually would like to see the compound do quite well I think it would be good for all PI's.... Wouldn't mind seeing some management miscue's to delay things though :)
HCV treatment question
Was just making notes for the InterMune BMO call and looking at some of the Vertex data from an article or two and had a thought (perhaps others are way ahead of me and have ruled it out completely or considered it). Anyway 191 so far as shown to have strong potency for the resistant variants of 950. Granted it is not proven in humans yet and there are lot of things that could show up but I was wondering if things progress along these lines would a treatment regimen without a PEG (and possibly Ribavirin as well) be possible (i.e. using combo PI's and perhaps Polymerase Inhibitors)? Or are there other reasons you'd want to keep using an Interferon? TIA
Since a couple people mentioned ENCY lately thought I would post on the PH market.
There seems to have been an interesting NIH meeting a couple days ago that didn't receive much press (that I saw anyway)
http://www.strategicresults.com/ph/index.html
It had a number of the big names in PH and what seemed like (I wasn't there and am just judging based on comments from the website) some interesting presentations.
On was by Dr. Nazzareno Galiè http://www.strategicresults.com/ph/galie.html
on "What have we learned and what do we need to know about the treatment of pulmonary hypertension"
In the summary it mentions one of the things lacking is head-to-head studies between the three types of therapies (Prostacyclins, ET Antagonists and PD5's) as well as combination studies. While we are starting to get combo studies as it'll probably be nearly impossible to recruit Placebo controlled studies with several treatment options approved it would be interesting if a company would do a head-to-head study. I don't have access to hard data but it appears there are at least as many patients on Revatio/Viagra as on Tracleer and so I'd image a fair amount are just taking it (Revatio) as a single agent. I would think a head-to-head study against it, especially at the recommend dose 20mg tid would stand a good chance of showing better efficacy (especially in 6 minute walk) based on what Tracleer and Remodulin have done in other studies. OK, I guess the trial would have to be quite large to show statistical significance but I wonder if it would have a dramatic increase on acceptance on one over the other?
I am a United shareholder and was thinking along the lines of a head-to-head with their Oral Prostacyclin (down the road). Perhaps small investigator studies are the best way to go?