I had the time this evening to proofread and correct my previously posted summary of today's meeting. The emended version is set forth below.
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A sizable audience was present and the Q&A at the end was lively. There was lots of concern (understandable) about the very low stock price and low market capitalization (barely $60M at the moment).
I came away very enthusiastic (OK, I’ve been there before). First, I’ll give you what for me were the two most important “new” pieces of information. Then I’ll post my notes from the meeting (I brought my laptop again and was typing furiously most of the time).
First, here’s something new that I learned about Xerecept. Before the meeting, I had heard that the results from the Xerecept trial weren’t looking that impressive. I came away from today’s presentations with just the opposite impression (see below for more detail). From Paul’s perspective, the problem with public perception is that the recent press release about the Open Label trial was much more conservative in what it stated that it needed to be. But there is a reason for that. Celtic, not NTII, controls press releases for Xerecept (Xerecept owns the drug), and Celtic doesn’t give a damn about NTII’s stock price. Celtic does, however, care about its credibility among practitioners in the field and so they Celtic deems it better to avoid any hype. Any with the results of just 20 participants in the Open Label study being available as of the date of the press release, Celtic decided to be conservative in describing the trends. As explained in more detail below, there is lots of reason to be hopeful about some excellent data on Xerecept from the Phase III trial.
Second, here’s something new that I learned about Viprinex. We were told (in response to my question) that the author of the recent report (published in the Lancet) concerning the failed German trial of Ancrod (i.e., Viprinex) was, for lack of a more polite word, a crackpot. The author did not look at all of the available data from that trial. His conclusion, that Ancrod’s window of opportunity is the same as Tpa’s – just 3 hours and not 6 hours – is contradicted by a large amount of data that he ignored. Both Paul and an investigator from that failed German trial have submitted scathing letters to the Lancet, pointing this out. Hopefully the Lancet will publish them or a response to them. According to Paul it usually takes about 6 weeks before letters are published. Paul stated categorically that the clinical evidence of Ancrod’s 6-hour efficacy window was “overwhelming” and that NTII’s new stroke advisory panel of experts uniformly debunked the crackpot’s report in the Lancet.
What follows are my meeting notes, presented generally in the order that the information was presented at the meeting.
Paul gave the opening presentation, then let Lisa Carr give us the overview on the Xerecept trials, then she let Dr. Brushnev, MD, give us a report on one patient that he monitored for a year in the Open Label trial of Xerecept. Then Paul gave the updates on Viprinex and Memantine (Namenda).
Paul began his remarks by expressing his deep disappointment at the current price of the stock. He affirmed that from an operational standpoint, the company continues to make progress and that those efforts will lead, if the company is successful, to a very hefty increase in the stock price.
Xerecept
· Because the clinical trials are double-blinded, we don’t know what is happening with the two pending clinical trials.
· When a trial participant completes his/her course of therapy, he/she almost always needs to continue treatment for the peritumoral brain edema. Before the Open Label trial received FDA approval, those patients were all forced to go back onto Dexamethasone. With the Open Label trial, any trial participant can elect to go onto Xerecept once he/she completes the double-blinded trial’s protocol. Bear in mind that a patient who elects to enroll in the Open Label trial does not know whether or not he/she received Xerecept or Dexamethasone in the Phase III trial protocol that he/she just completed.
· Paul expressed his great excitement at the data being mined from the Open Label trial. As described below, in the anecdotal report of one patient’s experience, some patients enrolling in the Open Label trial experience tremendous improvements in their symptoms, leading one to infer that during the double-blinded trial they probably had been receiving Dexamethasone and first received Xerecept upon starting the Open Label trial.
· Lisa Carr stepped in to give the details on the Xerecept trials:
o A couple months ago, NTII presented a poster on the Open Label study at the Society of Neuro-Oncology meeting. That same poster was on display in the room where the stockholders meeting was being held, but I sheepishly admit that I neglected to examine it closely.
o Most of the patients in the Open Label study came from the chronic edema protocol.
o The poster looked at first 20 patients to complete at least one month of treatment. The treatment range was 4 to 48 weeks.
o The findings from these first 20 patients was that 2/3ds of the patients could reduce or eliminate their use of Dexamethasone (this result applies to patients at high risk and to older patients too).
o Steroid side effects were reduced in the patients participating in the Open Label study. These Dexamethasone side effects include cushingoid appearance or “squirrel face” or “buffalo hump,” myopathy (muscle wasting), insomnia and weight gain. Again, it is tempting to infer that those who showed the most improvement over the course of the Open Label trial had been receiving Dexamethasone and not Xerecept during the Phase III protocol.
o Long-term treatment with Xerecept appears safe and well tolerated.
o The press release announcing these results did not give much of an indication that this was particularly good news. A member of the audience interrupted Lisa to ask a question was asked about this: i.e., why wasn’t the press release more encouraging? Paul replied. This product belongs to Celtic so all press releases come from Celtic. In the scientific community, 20 patients don’t count for much. But, there are now 50 patients in the Open Label trial, so there will be more information to release soon.
· Dr. Brushnev, MD, from Florida Hospital, presented a case study on one patient who participated in the Open Label study. His remarks follow.
o There are 20,000 new primary brain cancers per year in the USA. “Primary” meaning that the cancer originates in the brain.
o There are probably more than 200,000 new cases of metastatic brain cancer per year in the US. No one is keeping track of these numbers in the US.
o Up to 40% of patients with systemic cancers will have a brain involvement.
o Over 9 million people in USA are living with brain cancer.
o He estimated the market for peritumoral brain edema at 2,000,000 people.
o Brain tumors excrete chemicals that make tissues leaky and this leads to edema. If left untreated, patients with peritumoral edema will die from the edema. So the edema must be treated. Up to now, the only drug you can use has been Dexamethasone. There is a mixed love-hate relationship between oncologists and this drug. It works but it causes so many nasty side effects. Some studies are asking whether the side effects are worse than the edema.
o Florida Hospital has enrolled several patients in the chronic protocol. Recruitment was difficult. But lately, accrual is picking up and he is excited to be able to track the efficacy and effects of the drug in the Open Label study.
o The case study he presented involved a 42-year-old male with anaplastic astrocytoma. The patient’s cancer has been in remission, but the edema remains a problem requiring treatment.
o Dr. Brushnev appears to have assumed that the patient had received Dexamethasone during the Phase III trial. Dr. Brushnev stated that the patient had not tolerated the Dexamethasone well. The patient started gaining weight, developed “moon face,” muscle weakness (he couldn’t walk), frequent urination, insomnia, tremor, skin breakdown (he suffered from skin lesions and bruised easily), abnormal blood tests, and foot edema (could not put his shoes on).
o The patient had been very self-sufficient before the disease – an outdoorsman. He was suicidal from the Dex side effects. Each time they tried to decrease the Dex, he failed. When he got suicidal, the hospital offered participation in the Xerecept trial. He was reluctant because he couldn’t be promised that he would be receiving the Xerecept and not the placebo. But with the assurance that he could enroll in the Open Label trial after competing the Phase III protocol, he agreed to enroll.
o In November 2005, Dr. Brushnev started him on the Open Label trial. Today, the patient still has tremors and striae (skin breakdown) but all the other side effects that presumably Dexamethasone had been causing have resolved. That is remarkable. Even the striae have/has improved.
o Dr. Brushnev showed us a chart showing, month by month, how the various Dexamethasone side effects had resolved during the Open Label period. Curiously, the patient’s weight actually went up during the first two months of treatment with Xerecept, but then his weight began dropping dramatically. Dr. Brushnev speculated that the initial weight gain had to do with Xerecept stimulating development of muscle tissue.
o The symptom and quality of life improvements of this one patient were very very exciting. His weight reduced from 260 to about 212 over the course of 12 months of treatment from November 2005 to November 2006.
o The photographic comparison of the patient between Nov. 2005 and Nov. 2006 was remarkable. He looks pretty normal today.
o Side effects from Xerecept include eyelid swelling, local skin reaction at the injection site, nausea, and systemic flush. This is very mild stuff.
o The patient is on a chemo break at the moment. Xerecept is the only drug he is taking. He self-injects.
o This patient is completely off Dexamethasone. He has improved dramatically neurologically. His quality of life has improved dramatically. He is enjoying hunting again.
o The enthusiasm of Dr. Brushnev for Xerecept was palpable.
o As medicine continues to make more and more progress in extending the life of brain cancer patients (an actual cure for brain cancer continues to be elusive), the need for a drug like Xerecept will increase.
o New forms of radiation therapy make brain edema worse and that creates more need for a drug like Xerecept.
· At this point Paul resumed giving the presentation
Viprinex
· Stroke has been like the elephants graveyard for drug therapy, but the need for better stroke therapies keeps increasing.
· Tpa is the only approved drug for treatment of stroke.
· Tpa only has a 3-hour time window. Paul believes that Viprinex will have a 6-hour time window for treatment.
· Another potential advantage of Viprinex over Tpa concerns brain bleeds. Tpa increases the incidence of brain bleeds from 2-3% (the placebo rate) to 6-7%. Paul hopes that Viprinex will have a bleed rate as low as placebo’s.
· AZN and Renovis had a stroke drug that recently failed in the clinic. That drug was a neuroprotectant, not an anti-fibrinogen (like Xerecept).
· An unnamed Japanese company just suspended a trial of a neuroprotectant.
· NUVO also had a stroke drug fail very recently. It was a recombinant form of bat venom.
· Virtually all of the failures were with neuroprotectant agents.
· Three drugs have had successful Phase III trial results for stroke: Tpa, proeurokinase (spelling?) and Ancrod (in the US trial, but not in the European trail). Proeurokinase succeeded in a clinical trial, but it needed to be given intra-arterial, so the sponsor abandoned it.
· All snakes have different venom. A failure of one snake’s venom has no implications for another snake’s venom. (I believe Paul was alluding here to NUVO’s failed trial with the recombinant bat venom drug).
· Thrombin tends to cleave off both the alpha chains and beta chains of a fibrin molecule, transforming the fibrin molecule into fibrinogen. Once the repelling effects of the alpha and beta chains have been removed from the molecule, the resulting fibrinogen molecules then tend to attach to each other in sideways conglomerations and form clots.
· Viprinex cleaves off only the alpha and not the beta chains. The persisting repelling effect of the remaining beta chains prevents side-by-side deposition of the fibrin molecules.
· Viprinex has a second mechanism of action in the Plasminogen pathway. Viprinex stimulates breaking up clots when plasminogen converts into plasmin. We don’t yet know (but hope to find out during the coming year) how Viprinex stimulates the conversion of plasminogen into plasmin, which dissolves fibrinogen clots. Plasmin produces a gentler lysing of the clots.
· Viprinex’s third mechanism of action involves thinning of the blood. The blood tends to thicken during a stroke. By thinning the blood, Viprinex improves peripheral circulation of blood in the brain of the stroke patient.
· The drug safety monitoring board has access to the unblinded data from the Viprinex trial. Monthly the board reviews the data and lets NTII know if there are any untoward side effects. So far so good.
· NTII has formed an advisory board of 8 of the top stroke specialists in the USA. Paul was most proud of this group of experts. They have all volunteered to stay on to be advisors to NTII for the development of Viprinex.
· The bugaboo for NTII has been slow patient recruitment. Paul admitted that NTII could have done a better job to get more trial sites initially. But the company has turned the corner and now there is a lot of activity going on and a lot of excitement. But until data can be shown, the market will show skepticism.
· Paul hopes to have an interim analysis sometime in 2007. He declined to predict in which quarter of 2007. That data will be a binary event for NTII.
· In response to a question about the failed German Phase III trial, Paul pointed out at least three factors that may have contributed to the failure (factors that should not apply to the current trials). First, the German trail used a higher dose of Viprinex and administered it over a longer period of time. The current trials use a single dose that is much lower than what was used in the German trial. Second, the failed German trial allowed patients with high blood pressure to enroll. Patients with high blood pressure area at heightened risk for brain bleeds. Third, the failed German trial was, due to a fluke, not truly random as between (a) the age of patients in the Viprinex arm and (b) the age of patients in the placebo or Tpa trial. The patients in the Viprinex arm tended to be older and therefore at heightened risk of a poor outcome.
· The interim analysis will cover 325 patients.
· Contrary to the recently published (in the Lancet) report on the German trial, claiming that Ancrod does not work beyond the 3-hour time window, there is overwhelming evidence from the German trial that Ancrod works within a 6-hour time window. For whatever reason, the scientist who published the report chose not to review data from that study that contradicted his conclusions. Another researcher has sent a very critical letter to the Lancet, as has Paul. The 8 stroke experts on NTII’s scientific advisory board all agree that the 6-hour time window is supported by the past data from the German trial.
· Paul continues to pursue outlicensing the drug for Europe. He is in active discussions with three companies, but so far no hits. The big barriers are the lack of data on the new dosing regimen and skepticism about the failed German trial. (After the meeting I overheard Paul saying that the failure of the AZN-Renovis trial brought a quick end to a promising negotiation he had been developing. That Pharma company’s representative told Paul, at that time, that they’d rather pay a lot more money later, once the results of the Phase III trial are in, than take a chance on the Phase III trial failing.)
· NTII will have enough money to get through June of next near.
· It may be possible to monetize the Memantine cash flow. They continue to try to get a partner for Europe and they may need to do a PIPE.
· The market opportunity for Viprinex is $500M worldwide. Tpa generates $80M per year, but that lower amount is due to Tpa’s problems with a short treatment window for and increased incidence of bleeding in the brain.
· There are $15M in progress payments left for Xerecept. These progress payments will all be based on approvals for US, Europe, and Japan.
Memantine
· Namenda is doing well in the market place.
· For diabetic neuropathy, the drug seems to be no more effective than Neurontin. For that reason, Forrest passed on developing the product. For the diabetic neuropathy indication, the product has reverted back to Merz. NTII, Merz, and the hospital that owns the patent for diabetic neuropathy are now all in negotiations to decide how to go forward.
In one of the closing comments, the Chairman of the Board praised Paul or the great deal he struck with Celtic upon the sale of Xerecept. The royalty NTII would receive upon sales of Xerecept is very high for a deal of this type. |
